BACKGROUND ART Since 1983 when Helicobacter pylori (hereinafter sometimes abbreviated as H. Pylori or HP) was first isolated [Lancet, L. 1273 (1983)], its relation to gastritis and gastrointestinal ulcer has gathered attention. This is because whereas HP is not usually found in the gastric mucus and on the gastric epithelium of healthy humans [APMIS, 96, 84 (1983)], it is detected at a high rate among patients with chronic gastritis or gastric ulcer. [Am. J.

Gastroenterol., 32, 2283 (1987)].

The cure rate of gastroduodenal ulcers rose phenomenally with the development of H2 blockers and proton pump inhibitors (briefly, PPI). However there still are refractory cases not even responding to judicious treatments with those drugs, thus posing a serious problem.

According to a report reviewing such refractory gastric ulcer cases [Japanese Journal of Gastroenterology, 89, 571 (1992)], depressions were found in the amount of gastric mucus, apparently owing to the ammonia produced by HP. It

has also been reported that a sustained HP infection retards healing of the ulcer or is involved in relapses of the ulcer [Lancet, 335, 1233 (1990): N. Engl. J. Med., 328, 308 (1993)]. Thus, the well-documented findings, inclusive of the above, suggest that clearance of HP contributes to an early cure or prevention of relapse of ulcers.

It is reported that microorganisms of the genus Helicobacter, particularly Helicobacter pylori, have high urease activity and that they are able to survive, even in the stomach, by synthesizing ammonia from urea and thereby neutralizing the strongly acidic environment.

In the treatment of various diseases caused by HP, chemotherapy comprising a two-drug combination therapy using a bismuth drug and an antibiotic or a three-drug combination therapy using a bismuth drug, metronidazole (USP 2,944,061) and either tetracycline (e.g. USP 2,712,517) or amoxicillin (USP 3,192,198) is practiced today. Metronidazole, mentioned above, is an imidazole derivative having anti-HP activity and has been used in combination with antibiotics. The bismuth drug, antibiotic, metronidazole, etc. are generally administered by the oral route.

However, in order to insure a sustained and effective <BR> <BR> <BR> local concentration for inhibiting the growth of HP in their habitat, said bismuth drugs, antibiotics, metronidazole, etc. must be administered in massive doses, daily. However this therapy entails many problems, for example side effects such as vomiting and diarrhea.

Meanwhile, many phosphoric amide derivatives having urease inhibitory activity are known (USP 3,317,637, USP 4,517,003, USP 4,528,020, EP 210703, USP 4,182,881, USP 4,221,730, Japanese Patent Unexamined Publication No.

99490/1983, Japanese Patent Publication No.7379/1967, USP 4,629,491, J. Pharm. Sci., 189, 57(1968), etc.). However, whether those phosphoric amide derivatives ever show antimicrobial activity, particularly anti-HP activity, in

vivo, is not known.

Under the circumstances, various drugs having anti-HP activity are currently administered to patients with gastroduodenal ulcers. Some proton pump inhibitors (PPIs) having anti-HP activity have also been developed but their anti-HP effects are not high enough and monotherapies using them have not been fully rewarding. On the other hand, combination therapies using an antiulcerative agent, such as an H2 blocker, and a PPI in combination with an antimicrobial preparation have also been attempted with a fair success [e.g. Medical Journal of Australia, 151, 431 (1988), George L.L. et. al.; Medical Journal of Australia, 153, 145 (1990), Peterson W.L. metal.; New England Journal of Medicine, 324, 1043 (1991); and New England Journal of Medicine, 328, 308 (1993)].

Heretofore, as anti-HP agents, amoxicillin (hereinafter sometimes abbreviated as AMOX), metronidazole (briefly, MZ), bismuth acetate, and tetracycline have been used either independently or in combination but because they must be administered in massive doses (e.g. AMOX 750 mg or MZ 500mg, to be administered 3 times daily), those therapies entail side effects such as diarrhea, vomiting, and nausea with a fairly high frequency. There also is an apprehension about emergence of resistant bacteria.

On the other hand, combination therapies using a plurality of drugs having dissimilar mechanisms of action, such as administration of a pharmaceutical composition containing an anti-HP antibiotic substance (such as AMOX) and pantoprazole (WO 92/03135), or a combination therapy using amoxicillin and omeprazole [Scandinavian Journal of Gastroenterology, 24, 49 (1989)] are known, but their <BR> <BR> <BR> antiulcerative effects are not satisfactory enough and they involve side effects such as those mentioned above.

Meanwhile, a gastrointestinal mucosa-adherent matrix has been developed for ensuring a prolonged residence of the active ingredient and the consequent

improvement in availability of the ingredient. As the preferred active ingredient of such a preparation, an antiulcerative agent or a therapeutic drug for gastritis has been mentioned (Japanese Patent Unexamined Publication No.132416/1993), and actually the preparation has been applied to a combination therapy using an antiulcerative agent and an antimicrobial agent (Japanese Patent Unexamined Publication No. 126189/1995). However, preparations including a urease inhibitor are not known.

DISCLOSURE OF INVENTION In view of the above state of the art, the inventors of the present invention did many investigations with the objective of developing a pharmaceutical composition ensuring the stability and increased anti-HP efficacy of a urease inhibitor. As a result, they have discovered that a urease inhibitor, which is inherently acid-labile, can be stabilized in a composition, (particularly a matrix) comprising an oleaginous base, particularly a polyglycerol fatty acid ester and/or a lipid. The inventors have further discovered that the efficacy of the urease inhibitor can be augmented either by incorporating a a viscogenic agent capable of being viscous with water (hereinafter sometimes referred to as a viscogenic agent), in the matrix, or coating the matrix with a coating composition containing the viscogenic agent. The present invention has been developed on the basis of the above findings.

The present invention, therefore, is directed to: (1) A pharmaceutical composition comprising a urease inhibitor and an oleaginous base, (2) A pharmaceutical composition according to (1), which is a matrix, (3) A pharmaceutical composition according to (1), which is a gastrointestinal mucosa-adherent composition, (4) A pharmaceutical composition according to (1), which is a gastrointestinal mucosa-adherent matrix,

(5) A pharmaceutical composition according to (1), wherein the oleaginous base is a polyglycerol fatty acid ester and/or a lipid, (6) A pharmaceutical composition according to (5), wherein the polyglycerol fatty acid ester is an ester of a polyglycerol having a degree of polymerization ranging from about 2 to about 20 with a fatty acid containing about 8 to about 40 carbon atoms, (7) A pharmaceutical composition according to (5), wherein the HLB number of the polyglycerol fatty acid ester is about 1 to about 9, (8) A pharmaceutical composition according to (5), wherein the amount of the polyglycerol fatty acid ester and/or the lipid used is about 20 to about 95 weight% to the total weight of the composition, (9) A pharmaceutical composition according to (1), wherein the amount of the urease inhibitor used is about 10 to about 50 weight% to the total weight of the composition, (10) A pharmaceutical composition according to (1), wherein the urease inhibitor is a phosphoric amide derivative or a salt thereof, (11) A pharmaceutical composition according to (10), wherein the phosphoric amide derivative is a compound of the formula (I): wherein R represents an amino group which may be substituted, or a salt thereof, (12) Apharmaceutical composition according to (11), wherein R is a group represented by the formula: -NHCOR1 wherein R1 represents hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted,

(13) A pharmaceutical composition according to (10), wherein the phosphoric amide derivative is a compound of the formula (Ia): wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a salt thereof, (14) A pharmaceutical composition according to (13), wherein Rla represents an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted, (15) A pharmaceutical composition according to (13), wherein Rla represents a 5-membered aromatic heterocyclic group which may be substituted, (16) A pharmaceutical composition according to (13), wherein Rla represents a thienyl group or a furyl group, each of which may be substituted by 1 to 3 substituents selected from the group consisting of a C13 alkyl group which may be substituted by 1 to 3 halogens, a C13 alkoxy group, halogen, nitro, cyano, a (C16 alkyl)carbonyl and (C16 alkyl)sulphonyl, (17) A pharmaceutical composition according to (13), wherein Rla represents a thienyl group or a furyl group, each of which is substituted by one or two C1-3 alkyl groups, (18) A pharmaceutical composition according to (1), wherein the urease inhibitor is N-(diaminophosphinyl)- 5-methyl-2-thiophenecarboxamide or a salt thereof, (19) A pharmaceutical composition according to (1), wherein the urease inhibitor is N-(diaminophosphinyl)- 2-methyl-3-furancarboxamide or a salt thereof, (20) A pharmaceutical composition according to (1), wherein the urease inhibitor is N-(diaminophosphinyl)- 5-methyl-3-furancarboxamide or a salt thereof, (21) A pharmaceutical composition according to (1),

wherein the urease inhibitor is N-(diaminophosphinyl)- 3,5-dimethyl-2-furancarboxamide or a salt thereof, (22) A pharmaceutical composition according to (1), wherein the urease inhibitor is N-(diaminophosphinyl)- 3,5-dimethyl-2-thiophenecarboxamide or a salt thereof, (23) A pharmaceutical composition according to (4), wherein the matrix comprises a viscogenic agent, capable of being viscous with water, (24) A pharmaceutical composition according to (4), which is a matrix coated by a coating material containing a viscogenic agent, (25) A pharmaceutical composition according to (23) . wherein the amount of the viscogenic agent used is about 0.5 to about 30 weight% to the total weight of the composition, (26) A pharmaceutical composition according to (23) or (24), wherein the viscogenic agent is an acrylic polymer or a salt thereof, (27) A pharmaceutical composition according to (9), <BR> <BR> <BR> <BR> wherein the urease inhibitor is an anti-Helicobacter Dvlori substance, (28) A pharmaceutical composition according to (27), which is a preparation for the prophylaxis, treatment, or prevention of relapse of a Helicobacter pylori related gastrointestinal disease, (29) A pharmaceutical composition according to (23) , which comprises (i)a urease inhibitor, (ii)a polyglycerol <BR> <BR> <BR> <BR> fatty acid ester and/or a lipid, and (iii)a acrylic polymer, or a salt thereof, (30) A pharmaceutical composition according to (29), <BR> <BR> <BR> wherein (i)the urease inhibitor is a compound of the formula (I), wherein R represents an amino group which may be substituted, or a salt thereof, (ii)the polyglycerol fatty acid ester and/or a lipid is behenic acid <BR> <BR> <BR> <BR> hexa(tetra) glyceride and/or tetraglycerol polyricinolate, and (iii)the molecular weight of the acrylic polymer is

about 20x104 to about 600x104, (31) A pharmaceutical composition according to (29), wherein (i)the urease inhibitor is a compound of the formula (Ia), wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a salt thereof, (ii)the polyglycerol fatty acid ester and/or a lipid is behenic acid hexa(tetra)glyceride and/or tetraglycerol polyricinolate, and (iii)the molecular weight of the acrylic polymer is about 20x104 to about 600x104, (32) A pharmaceutical composition according to (30), wherein Rla represents a thienyl group or a furyl group, each of which may be substituted by 1 to 3 substituents selected from the group consisting of a C13 alkyl group which may be substituted by 1 to 3 halogens, a C13 alkoxy group, halogen, nitro, cyano, a (C1-6 alkyl)carbonyl and (C1-6 alkyl)sulphonyl, (33) A pharmaceutical composition according to (30), wherein R1a represents a thienyl group or a furyl group, each of which is substituted by one or two C13 alkyl groups, (34) A pharmaceutical composition according to (1), which is used in combination with an antibiotic and/or an antacid and/or an acid secretion inhibitor (35) An anti-Helicobacter pylori composition which comprises the pharmaceutical composition according to (1), (36) A pharmaceutical composition for the prophylaxis, treatment, and prevention of relapse of a Helicobacter pylori related gastrointestinal disease, comprising the pharmaceutical composition according to (1).

The present invention is further directed to a method of producing the composition and preparation and to the use of the composition and preparation.

The present invention provides solid pharmaceutical compositions and preparations containing the composition, preferably as fine granules.

In the contex of the present invention, the gastrointestinal mucosa-adherent matrix which is solid at room temperature includes the form in which each matrix particle comprising a polyglycerol fatty acid ester and/or a lipid and a active ingredient may be coated with a coating composition containing the viscogenic agent.

The invention further provides a technology for stabilizing acid-labile urease inhibitors.

The urease inhibitor for use in the present invention includes but is not limited to flurofamide (Micro. Ecol.

Health Dis. 4 (suppl.) S145, 1991), the phosphoric amide derivatives described in the literature (USP 3,317,637 etc.), hydroxamic acid derivatives (the 15th Medicinal Chemistry Symposium, Synopsis of Lectures at the 4th Annual Meeting of Medical Chemistry Group, page 167, P-41), etc., and plant extracts such as cassia extract (Synopsis of Lectures at the 117th Congress of the Pharmaceutical Society of Japan, 27 [H1] 9-5, p.81, 1997). Among them, phosphoric amide derivatives are particularly suitable for the purposes of the invention.

The phosphoric amide derivative can include compounds of the formula (I): wherein R represents an amino group which may be substituted, inclusive of their parmaceutical acceptable salts, and preferably compounds of the formula (Ia): wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, inclusive of their parmaceutical acceptable salts.

With respect to the above formulas, the substituents in the "amino group which may be substituted" represented by R are exemplified by (1) acyl groups, (2) carboxyl groups which may be esterified, and (3) hydrocarbon groups which may be substituted. The amino group may be substituted by 1 or 2, preferably 1 of these substituents, whether identical or not. The substituents are preferably an acyl group or a carboxyl group which may be esterified, more preferably an acyl group.

(1) The acyl group as a substituent in the "amino group which may be substituted" represented by R, is exemplified by acyl groups derived from carboxylic acids, thiocarboxylic acids, sulfonic acids, sulfinic acids, carbamic acids, thiocarbamic acids etc., specifically those represented by the respective formulas: -COR1, -CSR2, -So2R3, -SOR4, -CONHR5 or -CSNHR6, wherein R1, R2, R3, R4, R5 and R6 independently represent a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, etc.

Preferable acyl groups include those derived from carboxylic acids (-COR1) and those derived from sulfonic acids (-So2R3), and those derived from carboxylic acids are more preferable.

The "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6, is exemplified by saturated or unsaturated aliphatic chain hydrocarbon groups, saturated or unsaturated alicyclic hydrocarbon groups and aryl groups.

Such saturated aliphatic hydrocarbon groups include straight-chain or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (e.g., Cll0alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl), and straight-chain or branched saturated aliphatic hydrocarbon

groups having 1 to 6 carbon atoms are preferable.

Such unsaturated aliphatic hydrocarbon groups include straight-chain or branched unsaturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms (e.g., C210 alkenyl groups such as ethenyl, l-propenyl, 2-propenyl, l-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, l-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3- methyl-2-butenyl, l-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, l-heptenyl and l-octenyl; C210 alkynyl groups such as ethynyl, l-propynyl, 2-propynyl, l-butynyl, 2- butynyl, 3-butynyl, l-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-hexynyl, 3-hexynyl, 2.4-hexadiynyl, 5- hexynyl, l-heptynyl and l-octynyl), and straight-chain or branched unsaturated aliphatic hydrocarbon groups having 2 to 6 carbon atoms are preferable.

Such saturated alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms (e.g., monocyclic or bicyclic C3-12 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl), and saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms are preferable.

Such unsaturated alicyclic hydrocarbon groups include unsaturated alicyclic hydrocarbon groups having 5 to 12 carbon atoms (e.g., C5-12 cycloalkenyl groups such as l-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2- cyclopenten-l-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl: C5-12 cycloalkadienyl groups such as 2 ,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and 2, 5-cyclohexadien-1-yl and 2,4-cycloheptadienyl).

The hydrocarbon group in the "hydrocarbon group which

may be substituted" may be a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms substituted by the above saturated or unsaturated alicyclic hydrocarbon group (e.g., C3 @ cycloalkyl-Cl8 alkyl groups and C5 cycloalkenyl-Cl8alkyl groups, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3- cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl), or the like.

Such aryl groups include monocyclic or fused polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms. Such aromatic hydrocarbon ring groups include phenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4- or 9-phenanthryl, 1-, 2-, 4-, 5- or 6-azulenyl and acenaphthylenyl, and C610 aryl groups such as phenyl, l-naphthyl and 2-naphthyl are preferable.

The "hydrocarbon group which may be substituted" may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents include (1) lower alkyl groups which may be substituted, (2) lower alkoxy groups which may be substituted, (3) aryl groups which may be substituted, (4) lower cycloalkyl or lower cycloalkenyl groups which may be substituted, (5) heterocyclic groups which may be substituted, (6) carboxyl groups which may be esterified, (7) carbamoyl groups which may be substituted, (8) amino groups which may be substituted, (9) hydroxyl groups which may be substituted, (10) thiol (mercapto) groups which may be substituted, (11) acyl groups, (12) halogens (e.g., fluorine, chlorine, bromine), (13) nitro, and (14) cyano.

The lower alkyl group in the lower alkyl group (1) which may be substituted, is exemplified by C1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl

and isohexyl.

The lower alkoxy group in the lower alkoxy group (2) which may be substituted, is exemplified by C16 alkoxy <BR> <BR> <BR> groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy and isohexyloxy.

Said lower alkyl group (1) and lower alkoxy group (2) may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents include halogens (e.g., fluorine, chlorine, bromine) and lower (C13) alkoxy groups (e.g., methoxy, ethoxy, propoxy).

The aryl group in the aryl group (3) which may be substituted, is exemplified by C614 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, and phenyl, l-naphthyl and 2-naphthyl are preferable among others.

The cycloalkyl group in the lower cycloalkyl group (4) which may be substituted, is exemplified by C3 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The cycloalkenyl group in the lower cycloalkenyl group (4) which may be substituted, is exemplified by C36 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

Said aryl group (3), said lower cycloalkyl group (4) or said lower cycloalkenyl group (4) may have 1 to 5, preferably 1 to 3, optionally chosen substituents at any possible positions, and these substituents include alkoxy groups (e.g., C1-3 alkoxy groups such as methoxy, ethoxy and <BR> <BR> <BR> propoxy), halogen atoms (e.g.,fluorine, chlorine, bromine, <BR> <BR> <BR> iodine) , alkyl groups (e.g.. C1-3 alkyl groups such as methyl, ethyl and propyl), amino, nitro and cyano.

The heterocyclic group in the heterocyclic group (5) which may be substituted, is exemplified by aromatic heterocyclic groups and saturated or unsaturated non-

aromatic heterocyclic groups (aliphatic heterocyclic groups) having at least 1 hetero atom selected from oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and aromatic heterocyclic groups are preferable. Such aromatic heterocyclic groups include 5- to 7-membered aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic groups containing 2 to 4 nitrogen atoms, and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom.

These aromatic heterocyclic groups may be fused with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom.

Such aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and aromatic fused heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, 1 , 2 -benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, a-carbolinyl, - carbolinyl, r-carbolinyl, acridinyl, phenoxazinyl, <BR> <BR> phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazol[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3- b]pyridazinyl), and preferable are furyl, fused furyl,

thienyl, fused thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl and fused azolyl groups thereof. The azolyl groups include 5-membered aromatic heterocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl) and 5-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl), and the fused azolyl groups include groups formed by fusion of a benzene ring with a 5-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms (e.g., benzimidazolyl) and groups formed by fusion of a benzene ring with a 5-membered aromatic heterocyclic ring containing 1 nitrogen atom and 1 sulfur atom or oxygen atom (e.g., benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl).

Particular preferred are furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, 1, 2 -benzisoxazolyl, benzothiazolyl, benzo[b]thienyl, oxazolyl and isoxazolyl, and furyl and thienyl are more preferred.

Such non-aromatic heterocyclic groups include 5- to 7-membered non-aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, and 3- to 7- membered non-aromatic heterocyclic groups containing 1 nitrogen atom and 3 or fewer hetero atoms (e.g., nitrogen, oxygen and sulfur atoms), such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl and imidazolidinyl. These non-aromatic heterocyclic groups may be fused with a benzene ring, a 6-membered ring containing 2 or fewer nitrogen atoms, a 5-membered ring containing 1 sulfur atom, or the like. Such fused non- aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl.

The heterocyclic groups may have 1 to 3 optionally chosen substituents at any possible positions. Such <BR> <BR> <BR> substituents include alkoxy groups (e.g., C1-4 alkoxy groups such as methoxy, ethoxy and propoxy) which may be <BR> <BR> <BR> substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g., fluorine, chlorine, bromine, iodine), alkyl groups (e.g., Cl4alkyl groups such as methyl, ethyl and propyl) which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), aryl groups (e.g., C6-10 aryl groups such as phenyl, l-naphthyl and 2-naphthyl), and nitro.

The carboxyl group (6) which may be esterified include carboxyl groups, (lower (C16) alkoxy)carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec- butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl), (C6-10 aryl)oxycarbonyl groups (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl) and (C710 aralkyl)oxycarbonyl group (e.g., (phenyl-Cl4 alkyl)oxycarbonyl groups such as benzyloxycarbonyl etc.), and the carboxyl group, methoxycarbonyl and ethoxycarbonyl are preferred.

The substituents in said carbamoyl group (7) which may be substituted, or in the amino group (8) which may be substituted, are exemplified by lower (C16) alkyl groups which may be substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C36 cycloalkyl groups which may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C610 aryl groups which may be substituted (e.g., phenyl, l-naphthyl, 2- naphthyl), C712 aralkyl groups which may be substituted <BR> <BR> (e.g., phenyl-C1-4 alkyl groups such as benzyl and phenethyl.

and naphthyl-Cl2 alkyl groups), and C610 arylsulfonyl groups which may be substituted (e.g., benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl), and 1 or 2 of these substituents, whether identical or not, may be present. The substituents in such lower (C1-6) alkyl groups which may be substituted, C36 cycloalkyl groups which may be substituted, C610 aryl groups which may be substituted, C712 aralkyl groups which may be substituted, and C610 arylsulfonyl groups which may be substituted, include halogens (e.g., fluorine, chlorine, bromine), alkoxy groups (e.g., Cl4alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogens, alkyl groups (e.g., C14 alkyl groups such as methyl, ethyl and propyl) which may be substituted by 1 to 3 halogens, and nitro, and 1 to 5 of these substituents maybe present. Also, the amino group which may be substituted, may form a cyclic amino group resulting from binding of two substituents on the nitrogen atom with the nitrogen atom, and such cyclic amino groups include l-azetidinyl, l-pyrrolidinyl, piperidino, morpholino and l-piperazinyl.

The substituents in said hydroxyl group (9) which may be substituted, and the thiol group (10) which may be substituted, are exemplified by hydrocarbon groups which may be substituted, and heterocyclic groups which may be substituted. The "hydrocarbon group which may be substituted" is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted," represented by R1, R2 , R3, R4, R5 or R6 above, and preferable are lower (C16) alkyl groups which may be <BR> <BR> <BR> <BR> substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C3-6 cycloalkyl groups which may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C610 aryl groups which may be substituted (e.g., phenyl, l-naphthyl, 2-naphthyl), and

C712 aralkyl groups which may be substituted (e.g., phenyl-Cl4 alkyl groups such as benzyl and phenethyl, and naphthyl-C12 alkyl groups). These lower (C16) alkyl groups, C36 cycloalkyl groups, C6-10 aryl groups and C712 aralkyl groups may have 1 to 5 optionally chosen substituents at any possible positions, and these substituents include halogens (e.g., fluorine, chlorine, bromine), alkoxy groups (e.g., C1-4 alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogens, alkyl groups (e.g., C1-4 alkyl groups such as methyl, ethyl and propyl) which may be substituted by 1 to 3 halogens, nitro, amino and cyano. The "heterocyclic group which may be substituted" is exemplified by the same groups as those mentioned below in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6.

The acyl group (11) is exemplified by formyl groups, carbonyl groups substituted by a hydrocarbon group which may be substituted, sulfinyl groups substituted by a hydrocarbon group which may be substituted, and sulfonyl groups substituted by a hydrocarbon group which may be substituted. The hydrocarbon group which may be substituted is exemplified by the same groups as those mentioned in the " hydrocarbon group which may be substituted represented by R1, R2, R3, R4, R5 or R6 above, and preferable are lower (C16) alkyl groups which may be substituted, C3-6 cycloalkyl groups which may be substituted, C6-10 aryl groups (e.g., phenyl, naphthyl) which may be substituted, and C7-12 aralkyl groups (e.g., phenyl-Cl4 alkyl groups, naphthyl-Cl2 alkyl groups) which may be substituted. Preferable acyl groups include formyl groups, (C16 alkyl)carbonyl groups, (C3-6 cycloalkyl)carbonyl groups, (C6-10 aryl)carbonyl groups, (C7-12 aralkyl)carbonyl groups, (C16 alkyl)sulfinyl groups (C3-6 cycloalkyl)sulfinyl groups, (C610 aryl)sulfinyl groups, (C7-12 aralkyl)sulfinyl groups, (C1-6 alkyl) sulfonyl groups,

(C3-6 cycloalkyl)sulfonyl groups, (C610 aryl)sulfonyl groups and (C712 aralkyl)sulfonyl groups. These acyl groups may have 1 to 5 optionally chosen substituents at any possible positions, and such substituents include halogens, alkoxy group (e.g., Cl4alkoxy groups) and alkyl groups (e.g., C14 alkyl groups).

The heterocyclic group in the "heterocyclic group which may be substituted" represented by R , R², R , R4, R5 or R6, is exemplified by aromatic heterocyclic groups and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups) having at least 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and aromatic heterocyclic groups are preferred.

Such aromatic heterocyclic groups include 5- to 7-membered aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic groups containing 2 to 4 nitrogen atoms, and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom. These aromatic heterocyclic groups may be fused with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom.

Such aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and aromatic fused heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl,

quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, -carbolinyl, - carbolinyl, Y-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[l,2-lpyridazinyl, imidazo[ 1, 2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3- b]pyridazinyl), and furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl and fused ring groups thereof are preferred. Particularly furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, benzo[b]thienyl, oxazolyl and isoxazolyl are preferred, and furyl and thienyl are more preferred.

Such non-aromatic heterocyclic groups include 5- to 7-membered non-aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, and 3- to 7- membered non-aromatic heterocyclic groups containing 1 nitrogen atom and 3 or fewer hetero atoms (e.g., nitrogen, oxygen and sulfur atoms), such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl and imidazolidinyl. These non-aromatic heterocyclic groups may be fused with a benzene ring, a 6-membered ring containing 2 or fewer nitrogen atoms, a 5-membered ring containing 1 sulfur atom, or the like. Such fused non- aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl.

The heterocyclic group in the "heterocyclic group

which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, may have 1 to 4, preferably 1 to 3, optionally chosen substituents at any possible positions. Such substituents include (i) lower alkyl groups which may be substituted, (ii) lower alkoxy groups which may be substituted, (iii) aryl groups which may be substituted, (iv) lower cycloalkyl or lower cycloalkenyl groups which may be substituted, (v) heterocyclic groups which may be substituted, (vi) carboxyl groups which may be esterified, (vii) carbamoyl groups which may be substituted, (viii) amino groups which may be substituted, (ix) hydroxyl groups which may be substituted, (x) thiol groups which may be substituted, (xi) acyl groups, (xii) halogens (e.g., fluorine, chlorine, bromine), (xiii) nitro, and (xiv) cyano.

The lower alkyl group (i) which may be substituted, the lower alkoxy group (ii) which may be substituted, the aryl group (iii) which may be substituted, the lower cycloalkyl group or lower cycloalkenyl group (iv) which may be substituted, the heterocyclic group (v) which may be substituted, the carboxyl group (vi) which may be esterified, the carbamoyl group (vii) which may be substituted, the amino group (viii) which may be substituted, the hydroxyl group (ix) which may be substituted, the thiol group (x) which may be substituted, and the acyl group (xi), are exemplified by the same substituents as those mentioned in the substituents in the "heterocyclic group which may be substituted" represented by R , R², R , R4, R5 or R6 above.

Particularly preferable for R , R², R , R4, R5 and R6 are alkyl groups which may be substituted (preferably C14 alkyl groups), alkenyl groups which may be substituted (preferably C24 alkenyl groups), aryl groups which may be substituted (preferably C610 aryl groups such as phenyl, l-naphthyl and 2-naphthyl), and aromatic heterocyclic

groups which may be substituted (preferably furyl, benzofuranyl, thienyl, benzothienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl, or fused azolyl).

These alkyl groups, alkenyl groups and aryl groups may have 1 to 3 (preferably 1 to 2) optionally chosen substituents at any possible positions. Preferable substituents include (1) lower (C13) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), (2) lower (C13) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), (3) C610 aryl groups (e.g., phenyl) which may be substituted by 1 to 3, preferably 1 to 2, substituents selected from halogens (e.g. fluorine, <BR> <BR> <BR> chlorine, bromine, iodine) , amino, nitro and cyano, (4) C6-10 aryloxy groups (e.g., phenoxy) which may be substituted by 1 to 3, preferably 1 to 2, substituents selected from lower (C13) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), halogens (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano and amino, (5) heterocyclic groups (e.g., thienyl, benzimidazolyl, benzoxazolyl) which may be substituted by 1 to 3, preferably 1 to 2, halogens (e.g., fluorine, chlorine, bromine, iodine), (6) amino groups which may be substituted by a p-toluenesulfonyl group etc., (7) hydroxyl groups, (8) thiol groups which may be substituted by a C610 aryl groups (e.g. phenyl) which may have 1 to 3 (preferably 1 to 2) substituents selected from halogens and lower (C13) alkoxy groups, or thiol groups which may be substituted by a heterocyclic group (e.g., benzoxazolyl, benzothiazolyl) which may have 1 to 3 (preferably 1 to 2) substituents selected from halogens and lower (C13) alkoxy groups, (9) halogens (e.g., fluorine, chlorine, bromine), (10) nitro, and (11) cyano.

These aromatic heterocyclic groups may have 1 to 3 (preferably 1 to 2) optionally chosen substituents at any possible positions. Preferable substituents include (1) lower (C13) alkyl groups which may be substituted by 1 to

3 halogens (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl, chloromethyl), (2) C610 aryl groups (e.g., phenyl), (3) lower (C13) alkoxy groups which may be substituted by 1 to 3 halogens (e.g., methoxy, ethoxy, propoxy, iso-propoxy, fluoromethoxy, chloromethoxy), (4) halogens (e.g., fluorine, chlorine, bromine), (5) nitro, (6) cyano, (7) (lower (Cl6)alkyl)carbonyl groups and (8) (C16 alkyl)sulfonyl groups.

(2) The "carboxyl group which may be esterified" as a substituent in the "amino group which may be substituted" represented by R, is exemplified by groups represented by the formula: -COOR7, wherein R7 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.

Said hydrocarbon group is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above. Said hydrocarbon group may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine, bromine), nitro, and cyano.

Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may

be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4 R5 or R6 above.

Said heterocyclic group is exemplified by the same groups as those mentioned in the heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above. Said heterocyclic group may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine, bromine), nitro, and cyano.

Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1. R2, R3, R4 R5 or R6 above.

Preferably groups for R7 include lower (C16) alkyl groups which may be substituted, lower (C36) cycloalkyl groups, C6-10 aryl groups, and C7-12 aralkyl groups, and lower (C13) alkyl groups are more preferable.

Such lower (C16) alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl.

Such lower (C36) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Such C6-10 aryl groups include phenyl, l-naphthyl and 2-naphthyl.

Such C712 aralkyl groups include phenyl-Cl4 alkyl groups such as benzyl and phenethyl, andnaphthyl-Cl2alkyl groups.

These lower (C16) alkyl groups, lower (C36) cycloalkyl groups, C6-10 aryl groups and C7-12 aralkyl groups may have 1 to 3 optionally chosen substituents at any possible positions, and these substituents include halogens (e.g., fluorine, chlorine, bromine).

(3) The "hydrocarbon group which may be substituted" as a substituent for the "amino group which may be substituted" represented by R, is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above. Said hydrocarbon group may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups,

halogens (e.g., fluorine, chlorine, bromine), nitro, and cyano.

Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.

With respect to the formula (I) above, R is preferably an amino group which may be substituted by 1 or 2, preferably 1 substituent selected from the group consisting of (1) an acyl group selected from -COR1, -CSR2, -SO2R3, -SOR4, -CONHR5 and -CSNHR6 wherein each of R1, R2, R3, R4, R5 and R6 is (1-1) a hydrogen atom; (1-2) a hydrocarbon group selected from the group consisting of: (a) an alkyl group having 1 to 10 carbon atom, (b) an alkenyl group having 2 to 10 carbon atoms, (c) an alkynyl group having 2 to 10 carbon atoms, (d) a cycloalkyl group having 3 to 12 carbon atoms, (e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms, (g) a C37 cycloalkyl-Cl8 alkyl group, (h) a C57 cycloalkenyl-Cl8 alkyl group, and (i) an aryl group having 6 to 10 carbon atoms, each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of: (i) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of

halogen and a C13 alkoxy group, (ii) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (iv) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C13 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of

halogen, a C14 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C16 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (ix-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710

aralkyl)oxycarbonyl group, (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of aCl6alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of aCl4alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents

selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-2) a C1-6 alkoxy group which may be substituted by

1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C13 alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen,

and nitro, or a cyclic amino gorup, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen. a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group,

(x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C1-6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C1-4 alkyl group, (xii) halogen, (xiii) nitro, and (xiv) cyano, or (1-3) a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of (i) a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (ii) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (iv) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by

1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C712 aralkyl group and a C610 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C712 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of

(ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (ix-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each

of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-lO) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C6-10 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C1-6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a ( C7 12 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C6-10 aryl)sulfonyl, and a (C712

aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C14 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C16 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (x-2) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen,

halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalky, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstitruted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a

C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C6-10 aryl)sulfonyl, and a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group,

(xii) halogen, (xiii) nitro, and (xiv) cyano, (2) an optionally esterified carboxyl group represented by the formula: -COOR7 wherein R7 is (2-1) a hydrogen atom; (2-2) a hydrocarbon group selected from the group consisting of: (a) an alkyl group having 1 to 10 carbon atoms, (b) an alkenyl group having 2 to 10 carbon atoms, (c) an alkynyl group having 2 to 10 carbon atoms, (d) a cycloalkyl group having 3 to 12 carbon atoms, (e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms, (g) a C37 cycloalkyl-C1-8 alkyl group, (h) a C57 cycloalkenyl-C1-8 alkyl group, and (i) an aryl group having 6 to 10 carbon atoms, each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of: (i) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ii) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of aC13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (iv) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by

1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C16 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of

(ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (ix-6) a carboxyl group. a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C7-10 aralkyl)oxycarbonyl group, (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each

of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-lO) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a ( C7 12 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C7-12

aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C14 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C16 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (x-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen,

halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a

C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C7-12 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C1-4 alkyl group, (x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the consisting of formyl, a (C1-6 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C6-10 aryl)sulfonyl, and a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (xii) halogen,

(xiii) nitro, and (xiv) cyano, or (2-3) a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of (i) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ii) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (iv) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C6-10 aryl)oxycarbonyl group or a (C7-10 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro,

(viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C16 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C16 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstitued or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted

by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (ix-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group

and a C6-10 aryl group, (ix-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C1-6 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or

substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (x-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, aC13 alkyl group, amino, nitro and cyano, (x-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group. a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a

C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a Cl4alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalky, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-ll) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712

aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (xii) halogen, (xiii) nitro, and (xiv) cyano, and (3) a hydrocarbon group selected from the group consisting of (a) an alkyl group having 1 to 10 carbon atoms, (b) an alkenyl group having 2 to 10 carbon atoms, (c) an alkynyl group having 2 to 10 carbon atoms, (d) a cycloalkyl group having 3 to 12 carbon atoms, (e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms, (g) a C3-7 cycloalkyl-C1-8 alkyl group, (h) a C5-7 cycloalkenyl-C1-8 alkyl group, and (i) an aryl group having 6 to 10 carbon atoms, each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:

(i) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ii) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of aCl3alkoxy group, halogen, aC13 alkyl group, amino, nitro and cyano, (iv) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each

of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro,

(ix-6) a carboxyl group. a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (ix-7) a carbaomoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C16 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, a C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cl4alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-lO) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said

C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C6-10 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C1-6 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of

halogen and a C13 alkoxy group, (x-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of

halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C1-6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the

group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C1-6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C1-4 alkyl group, (xii) halogen, (xiii) nitro, and (xiv) cyano.

With respect to the formula (I) above, R is preferably a group represented by the formula: R -CO-NH- or R3-So2-NH- wherein R1 and R3 have the same meanings as defined above, and the former (R1-CO-NH-) is more preferable.

Particularly preferred among the compound represented by the formula (I)is a compound represented by the formula (Ia): wherein R1a represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a compound represented by the formula (Ib):

wherein Rlb represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted.

Namely, R1 is preferably Rla or Rlb. R1 is more preferably Rla.

With respect to the formula (Ia), the cyclic hydrocarbon group in the "cyclic hydrocarbon group which may be substituted" represented by Rla, is exemplified by the saturated or unsaturated alicyclic hydocarbon groups and aryl groups (aromatic hydrocarbon groups) mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferable are C610 aryl groups such as phenyl, l-naphthyl and 2-naphthyl.

With respect to the formula (Ia), the heterocyclic group in the "heterocyclic group which may be substituted" represented by Rla, is exemplified by the same groups as those mentioned in the heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5orR6above, and preferable are aromatic <BR> <BR> <BR> <BR> heterocyclic groups such as thienyl (e.g., 2- or 3-thienyl), <BR> <BR> <BR> <BR> <BR> <BR> furyl (2- or3-furyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), azolyl [e.g., oxazolyl (e.g., 2-, 4- or 5- oxazolyl), isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl)],

fused ring groups of thienyl or azolyl [e.g., benzothienyl (e.g., 2- or 3-benzo[b]thienyl), benzoxazolyl (e.g., 2-, 5- or 6-benz[d]oxazolyl), benzothiazolyl (e.g., 2- benzo[d]thiazolyl)] and fused furanyl groups [e.g., benzofuranyl (e.g., 2- or 3-benzo[b]furanyl)], and 5- membered aromatic heterocyclic groups such as thienyl and furyl are more preferred.

The heterocyclic group in the "heterocyclic group which may be substituted" and the cyclic hydrocarbon group in the "cyclic hydrocarbon group which may be substituted" represented by R1a, may have 1 to 3, preferably 1 to 2, optionally chosen substituents at any possible positions.

These substituents are exemplified by the same groups as those mentioned in the substituent to the "heterocyclic group which may be substituted" represented by R , R², R , R4, R5 or R6 above, and preferable are lower (C1-3) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl, chloromethyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), C6-10 aryl groups (e.g., phenyl), lower (C13) alkoxy groups <BR> <BR> <BR> (e.g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine, bromine), nitro, cyano, (C1-6 alkyl)carbonyl groups and (Cl6 alkyl)sulfonyl groups.

The heterocyclic group which may be substituted for Rla, is exemplified by a heterocyclic group which may have 1 to 4 substituents selected from the group consisting of: (i) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ii) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group,

(iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (iv) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C6-10 aryl)oxycarbonyl group or a (C7-10 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a

C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C13 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (ix-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C7-10 aralkyl)oxycarbonyl group, (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group,

a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C3-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C16 alkyl, a C36 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a Cl4alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-lO) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or

substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting of formyl, a (C16 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C14 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C16 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-2) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of

aCl3alkoxy group, halogen, aC13 alkyl group, amino, nitro and cyano, (x-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C13 alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group, a (C1-6 alkoxy)carbonyl group. a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said

C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-ll) an acyl group selected from the group consisting of formyl, a (Cl6 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C6-10 aryl)carbonyl, a (C7-12 aralkyl)carbonyl, a (Cl6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (Cl6 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C6-10 aryl)sulfonyl, a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C14 alkyl group, (x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting

of formyl, a (C1-6 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C610 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C610 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C1-6 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, and a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C14 alkyl group, (xii) halogen, (xiii) nitro, and (xiv) cyano.

The cyclic hydrocarbon group which may be substituted for Rla, is exemplified by (a) a cycloalkyl group having 3 to 12 carbon atoms, (b) a cycloalkenyl group having 5 to 12 carbon atoms, (c) a cycloalkadienyl group having 5 to 12 carbon atoms, or (d) an aryl group having 6 to 10 carbon atoms, each of which may have 1 to 3 substituents selected from the group consisting of: (i) a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (ii) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (iii) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, aC13 alkyl group, amino, nitro and cyano, (iv) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3

alkoxy group, halogen, a C13 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (vi) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano,

and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-l) a C16 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-2) a C16 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C13 alkoxy group, (ix-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-4) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (ix-6) a carboxyl group, a (C1-6 alkoxy)carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1

or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C16 alkyl, a C36 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cl4alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a 6-10 aryl group, (ix-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (ix-ll) an acyl group selected from the group consisting of formyl, a (Cl6 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C6-10 aryl)carbonyl, a (C712 aralkyl)carbonyl, a (C16 alkyl)sulfinyl, a (C3-6

cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C712 aralkyl)sulfinyl, a (C16 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C610 aryl)sulfonyl, a (C712 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a C14 alkyl group, (ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C16 alkyl group, a C36 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C1-6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-2) a C1-6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group, (x-3) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of aC13alkoxygroup, halogen, aCl3alkyl group, amino, nitro and cyano, (x-4) a C3-7 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano,

(x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C14 alkoxy group which may be substituted by halogen, halogen, a C14 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (x-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C610 aryl)oxycarbonyl group or a (C710 aralkyl)oxycarbonyl group, (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group and a C6-10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group which may be substituted by halogen, a C14 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cl4alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group

consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-10) a thiol group which may be substituted by a C1-6 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and C7-12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, nitro, amino and cyano, and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C1-4 alkyl group and a C6-10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a (Cl6 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C6-10 aryl)carbonyl, a (C7-12 aralkyl)carbonyl, a (Cl6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (Cl6 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C6-10 aryl)sulfonyl, a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C14 alkyl group, (x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting of formyl, a (Cl6 alkyl)carbonyl, a (C3-6 cycloalkyl)carbonyl, a (C6-10 aryl)carbonyl, a (C7-12 aralkyl)carbonyl, a (Cl6 alkyl)sulfinyl, a (C3-6 cycloalkyl)sulfinyl, a (C6-10 aryl)sulfinyl, a (C7-12 aralkyl)sulfinyl, a (Cl6 alkyl)sulfonyl, a (C3-6 cycloalkyl)sulfonyl, a (C6-10 aryl)sulfonyl, and a (C7-12 aralkyl)sulfonyl, each of said groups being unsubstituted

or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C14 alkoxy group and a C14 alkyl group, (xii) halogen, (xiii) nitro, and (xiv) cyano.

With respect to the formula (Ia), Rla is preferably an aromaic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted", more preferably "a 5-membered aromatic heterocyclic group which may be substituted". Examples of such groups include a thienyl group or a furyl group, each of which may be substituted by 1 to 3, preferably 1 or 2, substituents selected from the group consisting of a C13 alkyl group which may be substituted by 1 to 3 halogen, a C1-3 alkoxy group, halogen, nitro, cyano, a (C16 alkyl)carbonyl, and (C16 alkyl)sulfonyl, preferably a thienyl group which may be substituted by 1 or 2 C1-3 alkyl groups or a furyl group which may be substituted by 1 or 2 C13 alkyl groups.

Rla is particularly preferably a thienyl group or a furyl group each of which is substituted by 1 or 2 C1-3 alkyl groups.

The non-cyclic hydrocarbon group in the "non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted" represented by Rlb above, is exemplified by the sturated or unsaturated aliphatic chain hydrocarbon groups mentioned to exemplify the hydrocarbon group in the

"hydrocarbon group which may be substituted" represented byR1, R2, R3, R4, R5 orR6above. Saidnon-cyclichydrocarbon group has, at any possible positions, at least 1, preferably 1 or 2, of (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, and/or (vi) thiol group substituted by a heterocyclic group which may be substituted.

Said "cyclic hydrocarbon group which may be substituted" (i) is exemplified by the "aryl groups which may be substituted" and the "lower cycloalkyl or lower cycloalkenyl groups which may be substituted" mentioned to exemplify the substituents of the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2. R3, R4 R5 or R6 above.

Said "heterocyclic group which may be substituted" (ii) is exemplified by the same groups as the "heterocyclic group which may be substituted" mentioned to exemplify the substituents in the "hydrocarbon group which may be substituted" represented by R , R², R , R4, R5 or R6 above.

The cyclic hydrocarbon group in said "hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted" (iii) and "thiol group substituted by a cyclic hydrocarbon group which may be substituted" (v) is exemplified by the saturated or unsaturated alicyclic hydrocarbon groups and aryl groups (aromatic hydrocarbon groups) mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2. R3, R4 R5 or R6 above.

The heterocyclic group in said "hydroxyl group substituted by a heterocyclic group which may be substituted" (iv) and "thiol group substituted by a

heterocyclic group which may be substituted" (vi) is exemplified by the same groups as the heterocyclic group mentioned to exemplify the "heterocyclic group which may be substituted" represented by Rl, R2, R3, R4, R5 or R6 above.

Said "alicyclic hydrocarbon group" may have 1 to 5, preferably 1 to 3, optionally chosen substituents at any possible positions. Such substituents are exemplified by the same groups as those mentioned to exemplify the substituents of the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferably exemplified by lower (C1-3) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl, chloromethyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C13) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine, bromine), nitro, amino and cyano.

Said "heterocyclic group" may have 1 to 4, preferably 1 to 3, optionally chosen substituents at any possible positions. Such substituents are exemplified by the same groups as those mentioned to exemplify the substituents of the heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferably exemplified by lower (C14) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), lower (C14) <BR> <BR> <BR> <BR> alkoxygroups (e.g., methoxy, ethoxy, propoxy, isopropoxy), halogens (e.g., fluorine, chlorine, bromine) and C6-10 aryl groups (e.g., phenyl).

Said non-cyclic hydrocarbon group may have optionally chosen substituents at any possible positions, in addition to the above "cyclic hydrocarbon group which may be substituted", "heterocyclic group which may be substituted", and the like, but the total number of substituents in said non-cyclic hydrocarbon group is

preferably 1 to 3, more preferably 1 to 2. Such substituents are exemplified by the same groups as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R , R², R , R4, R5 or R6 above.

The cyclic hydrocarbon group in the "non-cyclic hydrocarbon group substituted by a cyclic hydrocarbon group which may be substituted" for Rib, is preferably exemplified by aryl groups (C1-4 aryl groups such as phenyl, l-naphthyl and 2-naphthyl), cycloalkyl groups having 3 to 7 carbon atoms, or cycloalkenyl groups having 3 to 6 carbon atoms.

The cyclic hydrocarbon group may have 1 to 5, preferably 1 to 3, substituents. Such substituents are preferably exemplified by C13 alkoxy groups, halogens, C13 alkyl groups, amino, nitro and cyano.

Rb is preferably a non-cyclic hydrocarbon group substituted by a heterocyclic group [e.g., an aromatic heterocyclic group such as thienyl (e.g., 2- or 3-thienyl), furyl (e.g., 2- or 3-furyl), azolyl [e.g., oxazolyl (e.g., 2-, 4- or 5-oxazolyl), isoxazolyl (e.g., 3-, 4- or 5- isoxazolyl)], fused ring groups of thienyl, furyl or azolyl [benzothienyl (e.g., 2- or 3-benzo[b]thienyl), <BR> <BR> <BR> benzofuranyl (e.g., 2-or 3-benzo[b]furanyl), benzoxazolyl (e.g., 2-, 5-or6-benz[d]oxazolyl), benzisoxazolyl (e.g., 3-, 4- or 5-benz[d]isoxazolyl), benzothiazolyl (e.g., 2-benzo[d]thiazolyl), benzimidazolyl (e.g., 1- benz[d]imidazolyl)]] which may be substituted, more preferably a non-cyclic hydrocarbon group substituted by a thienyl or furyl group which may be substituted. Said non-cyclic hydrocarbon group is preferably exemplified by C1-10 alkyl groups (preferably C13 alkyl groups such as methyl, ethyl and propyl), C2-10 alkenyl groups (preferably C2-4 alkenyl groups such as ethenyl) and C2-10 alkynyl groups (preferably C24 alkynyl groups such as ethynyl). Said aromatic heterocyclic group may have 1 to 3 optionally

chosen substituents at any possible positions. Such substituents are preferably exemplified by lower (C13) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl, chloromethyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), C6-10 aryl groups (e.g., phenyl), lower (C13) alkoxy groups (e. g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine, bromine, iodine), and nitro.

The non-cyclic hydrocarbon group may have a substituent such as a cyano group in addition to the "cyclic hydrocarbon group which may be substituted", "heterocyclic group which may be substituted", and the like.

Rb iS preferably exemplified by (a) C1-10 alkyl groups.

(b) C2-10 alkenyl groups and (c) C2-10 alkynyl groups, each of which may have 1 to 3 substituents selected from the group consisting of: (i) a C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C13 alkyl group, amino, nitro and cyano, (ii) a C37 cycloalkyl group or a C36 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkoxy group, halogen, a C1-3 alkyl group, amino, nitro and cyano, (iii) an aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-3 alkoxy group which may be substituted by halogen, halogen, a C13 alkyl group which may be substituted by halogen, a C6-10 aryl group, and nitro, (iv) a hydroxyl group or a thiol group, each of which are substituted by a C36 cycloalkyl group which may be substituted by 1 to 5 substituents selected from the group

consisting of a C13 alkyl group which may be substituted by halogen, a C13 alkoxy group which may be substituted by halogen, halogen, nitro, amino and cyano, (v) a hydroxyl group or a thiol group, each of which <BR> <BR> <BR> are substituted by a C6-10 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C13 alkyl group which may be substituted by halogen, a C13 alkoxy group which may be substituted by halogen, halogen, nitro, amino and cyano, and (vi) a hydroxyl group or a thiol group, each of which are substituted by a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of a C1-4 alkyl group, a C1-4 alkoxy group, halogen, and a C6-10 aryl group. Said Cll0alkyl groups, C2-10 alkenyl groups and C2-10 alkynyl groups may be substituted by further 1 cyano group.

In the present invention, the compound represented by the formula (I) or (Ia) is preferably exemplified by <BR> <BR> <BR> N- (diaminophosphinyl) -5-methyl-2-thiophenecarboxamide, N-(diaminophosphinyl)-2-methyl-3-furancarboxamide, N-(diaminophosphinyl)-5-methyl-3-furancarboxamide, N-(diaminophosphinyl)-3,5-dimethyl-2-furancarboxamide, and N-(diaminophosphinyl)-3,5-dimethyl-2- thiophenecarboxamide.

In the present invention, the salt of the compound represented by the formula (I), (Ia) or (Ib) is preferably a pharmaceutically acceptable salt, exemplified by salts formed with inorganic bases, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids and salts formed with basic or acidic amino acids. Preferable salts formed with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and

magnesium salt; and aluminum salt. Preferable salts formed with organic bases include ammonium salts and salts formed with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.

Preferable salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. Preferable salts formed with organic acids include salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

Preferable salts formed with basic amino acids include salts formed with arginine, lysine and ornithine.

Preferable salts formed with acidic amino acids include salts formed with aspartic acid and glutamic acid. These salts can be obtained by conventional methods.

Hydrates and non-hydrates of the compound represented by the formula (I), (Ia) or (Ib) are included in the scope of the present invention.

The salt of the compound represented by the formula <BR> <BR> <BR> (II) or (III) below is exemplified by the same kinds of salts as those mentioned as the salt of the compound represented by the formula (I) above.

Production method for the compound represented by the formula (I) is hereinafter described. Both the compound represented by the formula (Ia) and the compound represented by the formula (Ib) are within the scope of the formula (I).

The compound represented by the formula (I) can be produced by reacting a compound represented by the formula (Il) R-H (Il)

wherein the symbol has the same meanings as defined above, or a salt thereof, with phosphorus pentachloride, then reacting the resulting compound or a salt thereof with formic acid to yield a compound represented by the formula (III): wherein the symbol has the same meanings as defined above, or a salt thereof, and then reacting it with ammonia.

The desired compound can also be produced by reacting the compound represented by the formula (II) or a salt thereof with phosphorus oxychloride to yield the compound represented by the formula (III) or a salt thereof, and reacting it with ammonia.

In the reaction of the compound represented by the formula (II) or a salt thereof with phosphorus pentachloride or phosphorus oxychloride, any solvent can be used, as long as it does not interfere with the reaction, and such a solvent includes halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane, ether solvents such as dioxane, tetrahydrofuran and diethyl ether, and hydrocarbon solvents such as benzene and toluene, and the reaction temperature is about -50 to 100 C, preferably about -20 to 80 C. The amount of phosphorus pentachloride or phosphorus oxychloride used is 0.5 to 10 mole equivalents, preferably 1 to 2 mole equivalents, per mole of the compound represented by the formula (II) or salt thereof. In the reaction with formic acid of the compound or its salt obtained by reacting the compound represented by the formula (II) or its salt with phosphorus pentachloride, halogenated solvents, ether solvents and hydrocarbon solvents as those mentioned above can be used. The reaction temperature is about -50 to 50 C, preferably about 0 to 30 C. The amount of formic acid used is 0.5 to 10 mole

equivalents, preferably 1 to 3 mole equivalents, per mole of the compound obtained by reacting the compound represented by the formula (II) or its salt with phosphorus pentachloride. In the reaction of the compound represented by the formula (III) or its salt with ammonia, halogenated solvents, ether solvents and hydrocarbon solvents as those mentioned above can be used. The reaction temperature is about -50 to 50 C, preferably about -20 to 10 °C .

The compound (I) or its salt may be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, distillation, fractional distillation, solvent extraction, chromatography, crystallization and recrystallization.

In the compounds or salts thereof to be used for the above reactions, a protecting group may be used for an amino group, carboxyl group or hydroxyl group not involved in the reaction. The addition and removal of the protecting group can be achieved by known means.

Useful amino group-protecting groups include formyl, and C16 alkylcarbonyl (e.g., acetyl, propionyl), phenylcarbonyl, C16 alkyl-oxycarbonyl (e.g., <BR> <BR> <BR> methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl, C710 aralkyloxy-carbonyl (e.g., phenyl-Cl4 alkyloxy-carbonyl such as benzyloxycarbonyl), trityl, phthaloyl and N,N- dimethylaminomethylene, each of which may have substituents. These substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, C16 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl) and nitro groups, and the number of substituents is about 1 to 3.

Useful carboxyl group-protecting groups include C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl and silyl, each of which may have substituents. These substituents include halogen

atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, C16 alkyl-carbonyls (e.g., acetyl, propionyl, valeryl) and nitro groups, and the number of substituents is about 1 to 3.

Useful hydroxyl group-protecting groups include C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, C710 aralkyl (e.g., phenyl-Cl 4 alkyl such as benzyl), formyl, C16 alkyl-carbonyl (e.g., acetyl, propionyl), phenyloxycarbonyl, benzoyl, (C7-10 aralkyloxy)carbonyl (e.g., phenyl-Cl 4 alkyloxy-carbonyl such as benzyloxycarbonyl), pyranyl, furanyl and silyl, each of which may have substituents. These substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C16 alkyl (e.g., methyl, ethyl, propyl), phenyl, C7-10 aralkyl (e.g., phenyl-C1-4 alkyl such as benzyl) and nitro groups, and the number of substituents is about 1 to 4.

Protecting groups can be removed by per se known methods or similar methods thereto, such as treatment with acid, base, reducing agent, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate etc.

The pharmaceutical composition of the present invention is a composition in which a acid-labile urease inhibitor has been stabilized, particularly a pharmaceutical composition in which the urease inhibitor has been stabilized in an oleaginous matrix. The present invention further provides a urease inhibitor-containing gastrointestinal mucosa-adherent pharmaceutical composition including a viscogenic agent in its formulation to insure adhesion to the gastrointestinal mucosa.

Referring to oleaginous bases other than the polyglycerol fatty acid ester, any oleaginous substance having a melting point not below about 40°C, specifically within the range of about 40 to about 120 C, is generally

referred to by the term "lipid" in this specification. The term "stabilized in an oleaginous base" as used herein means the state in which the particular urease inhibitor has been dissolved or dispersed in an oleaginous base as well as the state in which the urease inhibitor has been covered or coated with an oleaginous base.

When the composition is a gastrointestinal mucosa-adherent composition, it is adequate that the composition contains a viscogenic agent therein or is coated with the coating material containing a viscogenic agent. That is to say that the present invention includes a pharmaceutical composition containing both an oleaginous base and a urease inhibitor, and which contains a viscogenic agent dispersed at least around the surface layer of the composition.

It is also to be understood that inasmuch as the adhesion to the gastrointestinal mucosa is ensured by containing a viscogenic agent, the composition is referred to as being "gastrointestinal mucosa-adherent" even when it is provided with a coating layer not containing a viscogenic agent, e.g. an enteric coating layer or a gastric coating layer. The term "around the surface layer" is used to mean not only the very surface of the matrix but also the surface region inclusive of the coating layer. The term "coating" is used herein to mean not only the process in which the entire surface of the particulate matrix is uniformly covered with a coating agent but also the process in which the surface of the matrix is partially covered.

Furthermore, when the oleaginous base or the coating agent is a mixture, it may not exhibit a definite melting point but merely soften at a given temperature. In this specification, the term "melting point" is used to cover the softening point of such a mixture as well.

Referring to the oleaginous base for use in the present invention, any oily substance that can be used as

a pharmaceutical oleaginous base can be employed. As such, the oleaginous base includes but is not limited to higher saturated fatty acids, fatty acid esters of alcohols (glycerol, polyglycerol, oils, hydrogenated oils, waxes, etc.), higher alcohols, phospholipids, sterols, sterol esters, and hydrocarbons. Particularly, fatty acid esters of alcohols are preferred.

Referring to said "fatty acid esters of alcohols", the "fatty acid" may for example be a monocarboxylic acid or a dicarboxylic acid. The dicarboxylic acid includes but is not limited to oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, phthalic acid, isophthalic acid, terephthalic acid, and sebacic acid. The monocarboxylic acid includes straight-chain saturated fatty acids such as acetic acid (C2), propionic acid (C3), butyric acid (C4), valeric acid (C5), caproic acid (C6), heptanoic acid (C7), caprylic acid (C8), nonanoic acid (Cg), capric acid (Cl0), undecanoic acid (C11), lauric acid (C12), tridecanoic acid (C13), myristic acid (C14), pentadecanoic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (C18), nonadecanoic acid (C19), arachic acid (C20), heneicosanoic acid (C21), behenic acid (C22), tricosanoic acid (C23), lignoceric acid (C24), etc.; straight-chain unsaturated fatty acids such as 10-undecenoic acid, ll-dodecenoic acid, 12-tridecenoic acid, trans-2-tetradecenoic acid, myristoleic acid, trans-9-tetradecenoic acid, 10-pentadecenoic acid, trans-2-hexadecenoic acid, palmitoleic acid, palmitoelaidic acid, 10-heptadecenoic acid, trans-lO- heptadecenoic acid, trans-2-octadecenoic acid, petroselinic acid, petroelaidic acid, oleic acid, elaidic acid, cis-vaccenic acid, trans-vaccenic acid, linoleic acid, linoelaidic acid, y-linolenic acid, a-linolenic acid, 7-nonadecenoic acid, 10-nonadecenoic acid, trans-10- nonadecenoic acid, 10,13-nonadecadienoic acid, trans- 10 ,trans-13-nonadecadienoic acid, 5-eicosenoic acid, 8-

eicosenoic acid, ll-eicosenoic acid, trans-ll-eicosenoic acid, 11,14-eicosadienoic acid, 8,11-eicosadienoic acid, mead acid, homo-g-linolenic acid, 11,14,17-eicosatrienoic acid, 5,8,11-eicosatrienoic acid, arachidonic acid, eicosatetraenoic acid, 5,8,11,14,17-eicosapentenoic acid (EPA), 12-heneicosenoic acid, erucic acid, brassidic acid, 13,16-docosadienoic acid, 13,16,19-docosatrienoic acid, 7,10,13,16-docosatetraenoic acid, 7,10,13,16,19- docosapentenoic acid, 7,10,13,16,19-docosahexenoic acid (DHA), 14-tricosenoic acid, trans-14-tricosenoic acid, 15-tetracosenoic acid, etc.; branched fatty acids such as <BR> <BR> <BR> isolauric acid, ll-methyldodecanoic acid, isomyristic acid, 13-methyltetradecanoic acid, isopalmitic acid, 15- methlyhexadecanoic acid, isostearic acid, 17- methyloctadecanoic acid, isoarachic acid, 19- methyleicosanoic acid, 9-methylundecanoic acid, 10- methyldodecanoic acid, ll-methyltridecanoic acid, 12- methyltetradecanoic acid, 13-methylpentadecanoic acid, 14-methylhexadecanoic acid, 15-methylheptadecanoic acid, 16-methyloctadecanoic acid, etc.; and hydroxy-fatty acids such as b-hydroxybutanoic acid, y-hydroxybutanoic acid, 3-hydroxynonanoic acid, 2-hydroxydecanoic acid, 2- hydroxylauric acid, 2-hydroxytetradecanoic acid, 3- hydroxymyristic acid, 2-hydroxyhexadecanoic acid, 2- hydroxyoctadecanoic acid, 12-hydroxystearic acid, 2- hydroxyeicosanoic acid, 2-hydroxydocosanoic acid, ricinoleic acid, ricinoelaidic acid, and so forth. Thus, fatty acids from C6 to C40 can be mentioned.

Preferred, among them, are straight-chain saturated or unsaturated fatty acids, with C8-C22 fatty acids being particularly suited for routine use.

The alcohol for use in said "fatty acid esters of alcohols" includes straight-chain or branched monohydric alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, n-butyl alcohol, n-pentyl alcohol, n-hexyl alcohol, n-heptyl alcohol, n-octyl alcohol, n-decyl

alcohol, n-lauryl alcohol, n-myristyl alcohol, n-cetyl alcohol, n-octadecyl alcohol, isopropyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isopentyl alcohol, tert-pentyl alcohol, etc., dihydric alcohols such as ethylene glycol, propylene glycol, 1,3-propanediol, etc., and trihydric alcohols such as glycerol.

While the fatty acid alcohol ester is the ester of any of said fatty acids with an alcohol such as those mentioned above, saturated or unsaturated waxes and fatty <BR> <BR> <BR> acidglycerides (e.g. mono-, di-, andtriacylglycerols) are particularly preferred. Those substances may be synthetic compounds or naturally-occurring substances. As to natural oils, waxes, etc., those composed of more than one fatty acid esters with or without other minor components such as free fatty acids and hydrocarbons can also be employed. Glycerol or polyglycerol fatty acid esters are particularly useful.

Referring to the "glycerol or polyglycerol fatty acid ester", the degree of polymerization of the polyglycerol is preferably about 2 to about 16 and more preferably about 2 to about 10.

The glycerol or polyglycerol fatty acid ester can be used alone or as a mixture of two or more species.

The preferred glycerol fatty acid ester is a fatty acid triglyceride (triacylglycerol) composed of 1 molecule of glycerol and 3 molecules of fatty acid. The fatty acid forming a di- or triacylglycerol may be of the same kind or different kinds. Here, preferred fatty acids are saturated fatty acids each containing about 4 to about 22 carbon atoms. Particularly preferred are saturated fatty acids of about 6 to about 18 carbon atoms.

The above-mentioned "glycerol fatty acid ester" may be any of commercial products such as Miglyol 810 (caprylic/capric acid triglyceride, fatty acid composition = caprylic acid 65 to 75%, capric acid 25 to 35%), Miglyol 812 (caprylic/capric acid triglyceride, fatty acid

composition = caprylic acid 50 to 65%, capric acid 30 to 45%), Miglyol 829 (glycerol di(caprylate/caprate) <BR> <BR> <BR> succinate, fatty acid composition = caprylic acid 35 to 45%, capric acid 20 to 30%, succinic acid 12 to 16%), Miglyol 840 (propylene glycol dicaprylate, fatty acid composition = caprylic acid 65 to 80%, capric acid 15 to 30%), Dynasan 110 (capric acid triglyceride), Dynasan 112 (lauric acid triglyceride), Dynasan 114 (myristic acid triglyceride), Dynasan 116 (palmitic acid triglyceride), Dynasan 118 (stearic acid triglyceride) (all available from Huls Aktiengesellschaft, Germany), Panacete 800, Panacete 810, and Panacete 875 (all available from NOF Corporation), and Triester F-810 (caprylic/capric acid triglyceride) (available from Nikko Chemicals (Tokyo)). Those glycerides can also be used in combination. Aside from the above-mentioned glycerides, the mono-, di-, and triglycerides of C14-C22 saturated fatty acids (e.g. myristic acid, palmitic acid, stearic acid, behenic acid, etc.), for example l-monostearin, 1-monopalmitin, etc., can also be employed.

The polyglycerol fatty acid ester may be any of a monoester, a diester, and a polyester. Polyglycerol fatty acid esters are not polymorphic crystallographically and do not substantially interact with the active ingredient so that even when they coexist with such active ingredient, the latter substances are substantially not deactivated but remain stable for an extended period of time.

Polyglycerol by definition is "a polyhydric alcohol containing n (cyclic) - (n+2) (straight-chain or branched) hydroxyl groups and (n-l) (straight-chain or branched) - n (cyclic) ether bonds per molecule" [Polyglycerin Esters, (ed.) Sakamoto Yakuhin Kogyo Co., Ltd., published May 2, 1986, p12], and whichever of a straight-chain ester and a branched-chain ester can be used in the present invention.

For example, compounds of the following formula can be employed.

wherein n represents a degree of polymerization which is an integer of not less than 2. The value of n is generally about 2 to about 50, preferably about 2 to about 16, and for still better results, about 2 to about 10. The polyglycerol includes but is not limited to diglycerol, triglycerol, tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol, nonaglycerol, decaglycerol, pentadecaglycerol, eicosaglycerol, and triacontaglycerol.

Among those polyglycerols, tetraglycerol, hexaglycerol or decaglycerol is used in many cases.

The fatty acid includes saturated or unsaturated fatty acids each containing about 8 to about 40, preferably about 12 to about 25, and more preferably about 15 to about 22 carbon atoms. The fatty acid thus includes but is not limited to palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, ricinoleic acid, caprylic acid, capric acid, and behenic acid. Among those fatty acids, stearic acid, oleic acid, lauric acid, linoleic acid, ricinoleic acid, and behenic acid are preferred.

The polyglycerol fatty acid ester includes but is not limited to behenic acid hexa(tetra)glyceride, caprylic acid mono(deca) glyceride, caprylic acid di(tri)glyceride, capric acid di(tri)glyceride, lauric acid mono(tetra)glyceride, lauric acid mono(hexa)glyceride, lauric acid mono(deca)glyceride, oleic acid mono(tetra)glyceride, oleic acid mono(hexa)glyceride, oleic acid mono(deca)glyceride, oleic acid di(tri)glyceride, oleic acid di(tetra)glyceride, oleic acid sesqui(deca)glyceride, oleic acid penta(tetra)glyceride, oleic acid penta(hexa)glyceride,

oleic acid deca(deca)glyceride, linoleic acid mono(hepta)glyceride, linoleic acid di(tri)glyceride, linoleic acid di(tetra)glyceride, linoleic acid di(hexa)glyceride, stearic acid mono(di)glyceride, stearic acid mono(tetra)glyceride, stearic acid mono(hexa)glyceride, stearic acid mono(deca)glyceride, stearic acid tri(tetra)glyceride, stearic acid tri(hexa)glyceride, stearic acid sesqui(hexa)glyceride, stearic acid penta(tetra)glyceride, stearic acid penta(hexa)glyceride, stearic acid deca(deca)glyceride, palmitic acid mono(tetra)glyceride, palmitic acid mono(hexa)glyceride, palmitic acid mono (deca) glyceride, palmitic acid tri(tetra)glyceride, palmitic acid tri(hexa)glyceride, palmitic acid sesqui(hexa) glyceride, palmitic acid penta(tetra)glyceride, palmitic acid penta(hexa)glyceride, palmitic acid deca(deca)glyceride and polyglycerol polyricinolate (e.g. tetraglycerol polyricinolate).

The preferred polyglycerol fatty acid ester includes behenic acid hexa(tetra)glyceride (e.g. Poem J-46BTM, Riken Vitamin Co.; HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid penta(tetra)glyceride (e.g. PS-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid mono(tetra)glyceride (e.g. MS3lOTM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid penta(hexa)glyceride (e.g.

PS-500TM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid sesqui(hexa)glyceride (e.g. SS-SOOTM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid deca(deca)glyceride (e.g.

DAS-750TM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid mono(hexa)glyceride (e.g. PO-500TM, Sakamoto Yakuhin Kogyo <BR> <BR> <BR> Co., Ltd.), oleicacidpenta(tetra)glyceride (e.g. p0310TM, Sakamoto Yakuhin Kogyo Co., Ltd.), oleic acid deca(deca)glyceride (e.g. DAO-750TM, Sakamoto Yakuhin Kogyo Co., Ltd.), stearic acid mono(deca)glyceride, polyglycerol polyricinolate (e.g. tetraglycerol polyricinolate (e.g. CRS-75TM, Sakamoto Yakuhin Kogyo Co.,

Ltd.), and mixtures of such glycerides.

Those polyglycerol fatty acid esters can be used each alone or as a mixture of two or more species.

The molecular weight of the polyglycerol fatty acid ester is generally about 200 to about 5,000, preferably about 300 to about 3,000, more preferably about 2,000 to about 3,000. The hydrophile-lipophile balance (HLB) value of the polyglycerol fatty acid ester is generally about 1 to about 22, preferably about 1 to about 15, more preferably about 1 to about 9 and for still better results, about 1 to about 4. Two or more polyglycerol fatty acid esters differing in HLB value from each other may be used in combination to provide for the necessary HLB value. By <BR> <BR> adjusting the HLB value of the polyglycerol fatty acid ester judiciously, the dissolution and release kinetics of the active substance can be controlled.

A suitable polyglycerol fatty acid ester is selected according to the species of active ingredient used and the intended dosage form. Generally, polyglycerols with degrees of polymerization in the range of about 2 to about 16 are preferred. The particularly preferred range is about 2 to about 10. Preferred are esters such that the fatty acid has formed an ester bond with at least one of the (degree of polymerization +2) hydroxyl groups, preferably such that the fatty acid or acids have formed ester bonds with not less than 60%, more preferably not less than about 80%, of the total number of hydroxyl groups in the polyglycerol. The fatty acid or acids are preferably saturated acids each containing about 6 to about 22, preferably about 8 to about 18 carbon atoms. The fatty acid involved in the formation of the ester bonds may be of the same kind or different kinds.

When the composition is designed to be adherent to the gastrointestinal mucosa, the polyglycerol fatty acid ester should also be selected with reference to the type of viscogenic agent to be employed. Preferably, those

esters which are solid at atmospheric temperature (ca 15C) are employed. The melting point of the polyglycerol fatty acid ester may for example be about about 15 to about 800C, preferably about 30 to about 75°C, and for still better results, about 45 to about 75°C. A gastrointestinal mucosa-adherent composition according to the present invention may be produced by using a mixture of two or more different polyglycerol fatty acid esters and in such a case a liquid polyglycerin fatty acid ester may be included in the mixture if the final matrix is solid at atmospheric temperature.

The "polyglycerol fatty acid ester" which can be used with advantage in the above application can also be procured from commercial sources. For example, PS-310, MS-310, HB-310, PO-310, PO-500, DAO-750, DAS-750, etc. are available from Sakamoto Yakuhin Kogyo Co., Ltd. (Osaka), Poem J 46B from Riken Vitamin (Tokyo), and Tetraglyn 5- S (tetraglycerol pentastearate), Decaglyn 10-S (decaglycerol decastearate), etc. from Nikko Chemicals (Tokyo).

Those esters can be used each alone or as a mixture of two or more species. Moreover, they can be used in combination with glycerol fatty acid esters and/or other oleaginous bases.

The "oil" mentioned above includes but is not limited to soybean oil, olive oil, rapeseed oil, peppermint oil, sesame oil, castor oil, tsubaki oil, wheat germ oil, fennel oil, corn oil, sunflower oil, cottonseed oil, coconut oil, <BR> <BR> <BR> <BR> peanut oil, etc., the corresponding hydrogenated oils, beef tallow, and lard. Among those oils and fats, hydrogenated cottonseed oil, hydrogenated castor oil (e.g. LubriwaxTM, Freund Industrial), and hydrogenated soybean oil are preferred.

The "wax" mentioned above includes but is not limited to carnauba wax, sperm wax, beeswax, and white Japan wax.

The "higher saturated fatty acid" mentioned above

includes C822 fatty acids, inclusive of salts thereof, among the fatty acids mentioned hereinbefore, such as caprylic acid, capricacid, palmitic acid, stearic acid, andbehenic acid etc.

The "higher alcohol" mentioned above includes but is not limited to C1020 alcohols such as cetyl alcohol and stearyl alcohol.

The "phospholipid" mentioned above may for example be hydrogenated lecithin.

The "sterol or its ester" mentioned above includes but is not limited to cholesterol, a-cholestane, t3- cholestanol, epicoprostanol, demosterol, fucosterol, lanosterol, ergosterol, 0-sitosterol, esters of cholesterol with C2-24 saturated fatty acids, and esters of cholesterol with Cm424 unsaturated (the number of double bonds 1-6) fatty acids.

The "hydrocarbon" mentioned above includes but is not limited to paraffin and microcrystalline wax.

The above-mentioned oleaginous bases can be used each alone or in combination.

In consideration of the stability of the active ingredient and the absorption kinetics of oral preparation, the above-mentioned glycerol or polyglycerol fatty acid esters and waxes are most generally chosen as the oleaginous base in the practice of the invention.

The pharmaceutical composition according to the present invention is a composition for oral administration in which the active ingredient has been stabilized. This "pharmaceutical composition" may be liquid or solid, and can be produced by analogue to the per se known technology.

The following is a typical production process.

When an oleaginous base which is liquid at atmospheric temperature (about 5 to about 300C) is employed, the active ingredient is added and dispersed therein with agitation to provide the objective composition.

When an oleaginous base which is solid at atmospheric

temperature (about 5 to about 30) is employed, it is melted or otherwise liquefied and after the active ingredient is dispersed therein, the dispersion is solidified. For example, the oleaginous base is heated to a temperature close to or beyond its melting point and the active ingredient is dissolved or dispersed in the liquefied base in the per se known manner. This solution or dispersion is then solidified by cooling. In the course of solidification, the solution or dispersion may be molded into particles or pellets. The per se known molding techniques can be employed for this purpose. When powders are desired, spherical particles with a diameter of about 0.1 to about 1,000 Fm are manufactured. The molding technology includes the spray drying process which comprises spraying said solution or dispersion containing the active ingredient in a hot air current and the spray chilling process in which oil droplets are prepared and rapidly chilled.

The proportion of the oleaginous base relative to the total weight of the composition is generally about 5 to about 98 weight , preferably about 20 to about 95%, more preferably about 40 to about 95% and to the active ingredient in the composition may, for example, be about 0.01 to about 15,000 times by weight, preferably about 0.1 to about 1,000 times by weight, and for still better result, about 0.1 to about 100 times by weight. However, insofar as the active ingredient can be completely covered with the oleaginous base, the above range need not be strictly adhered to.

The concentration or content of the active ingredient in the composition can be judiciously selected according to the physicochemical properties of the composition.

When the composition is a liquid, the concentration of the active ingredient may be about 0.01 to about 200 (w/v), preferably about 0.1 to about 100% (w/v). When the composition is a solid preparation, the content of the

active ingredient may be about 0.01 to about 95% (w/w), preferably about 0.1 to about 50% (w/w), and more preferably about 5 to about 50% (w/w).

In addition, where necessary, preservatives (e.g. benzyl alcohol, ethyl alcohol, benzalkonium chloride, phenol, chlorobutanol, etc.), antioxidants (e.g. 2-t- butyl-4-hydroxyanisole, propyl gallate, ascorbyl palmitate, a-tocopherol, etc.), thickeners (e.g. lecithin, hydroxypropylcellulose, aluminum stearate, etc.), and other additives can be incorporated.

When the pharmaceutical composition of the invention is to be embodied as a urease inhibitor-containing gastrointestinal mucosa-adherent preparation, the composition may be processed into any preparation that will adhere to the mucosa in the target region of the gastrointestinal tract, stays long within the tract, and/or promotes absorption of the active ingredient in the absorption site. The preferred preparation includes a matrix. The matrix is preferably prepared using said polyglycerol fatty acid ester. For example, it may be a gastrointestinal mucosa-adherent matrix comprising said polyglycerol fatty acid ester and said vicogenic agent. It may also be a gastrointestinal mucosa-adherent matrix comprising said lipid, which is described in detail below, and said viscogenic agent. The still more preferred matrix is a matrix comprising said polyglycerol fatty acid ester, lipid, and viscogenic agent. The gastrointestinal mucosa-adherent matrix is preferably a matrix in which said viscogenic agent has been dispersed in said polyglycerol fatty acid ester and/or lipid or a matrix comprising said polyglycerol fatty acid ester and/or lipid as coated with said viscogenic agent. The melting point of such a gastrointestinal mucosa-adherent matrix may for example be about 30 to about 120 C, preferably about 40 to about 120°C.

The lipid, among said oleaginous bases, is one having a melting point of about 40 to about 120 C, preferably about

40 about to 95 C . The lipid includes but is not limited to saturated fatty acids of about 14 to about 22 carbon atoms (e.g. myristic acid, palmitic acid, stearic acid, behenic acid, etc.) or their salts (sodium salts, potassium salts, etc.); higher alcohols of about 16 to about 22 carbon atoms (e.g. cetyl alcohol, stearyl alcohol, etc.); fatty acid glycerol esters such as the monoglycerides, diglycerides, triglycerides, etc. of the above-mentioned fatty acids (e.g.

1-monostearin, l-monopalmitin, etc.); oils (e.g. castor oil, cottonseed oil, soybean oil, rapeseedoil, beef tallow, etc., inclusive of the corresponding hydrogenated oils); waxes (e.g. beeswax, carnauba wax, sperm wax, etc.); hydrocarbons (e.g. paraffin, microcrystalline wax, etc.); and phospholipids (e.g. hydrogenated lecithin etc.).

Preferred, among those lipids, are oils, waxes, C14 22 saturated fatty acids, higher(Cl6 22) alcohols, and hydrocarbons. The more preferred lipids are hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean oil, carnauba wax, stearic acid, stearyl alcohol, and microcrystalline wax.

A agent capable of being viscous with water, (viscogenic agent) is not particularly restricted in kind as log as it becomes sufficiently viscous with water to attach itself to the gastrointestinal mucosa and is pharmaceutically acceptable. Preferred, however, are those agents which are markedly swollen by water and develop high degrees of viscosity. The viscogenic agent, thus, includes synthetic polymers and naturally-occurring viscogenic materials. The preferred polymer is a polymer such that the viscosity of a 2% aqueous solution thereof at 200C is about 3 to about 50,000 cps., preferably about 10 to about 30,000 cps., and for still better results, about 15 to about 30,000 cps. However, when a polymer which gains in viscosity on neutralization is used, the preferred polymer is such that the viscosity of a 0.2% solution after neutralization at 20°C is about 100 to about 500,000 cps,

preferably about 100 to about 200,000 cps, and for still better results, about 1,500 to about 100,000 cps.

The value of the viscosity is measured with a Brookfield viscometer.

Preferably, the above-mentioned polymer is an acidic polymer which includes but is limited to carboxyl- or sulfo-containing polymers and the corresponding salt- containing polymers. Particularly preferred are carboxyl-containing polymers and carboxylate salt- containing polymers.

The carboxyl (inclusive of its salt)-containing polymer is preferably an acrylic homopolymer or copolymer containing acrylic acid as a monomer unit or a salt thereof.

The salt includes monovalent metal salts such as the sodium salt, potassium salt, etc. and divalent metal salts such as the magnesium salt, calcium salt, etc. and ammonium saltand so on. The acrylic polymer, inclusive of its salt, includes polymers containing carboxyl groups in a proportion of about 58 to about 63 weight % and having a molecular weight of about 20x104 to about 600x104, and preferably about 100x104 to about 500x104. The preferred acrylic polymer, inclusive of its salt, includes acrylic acid homopolymers and their salts (sodium, ammonium, calcium and so on). Such polymers are listed under the heading of carboxyvinyl polymer in Japanese Standards of Pharmaceutical Ingredients (October 1986).

As specific examples of said polymer, there can be mentioned carbomer [Carbopol, the trademark of The B. F.

Goodrich Company] 940, 934, 934P, 940, 941, 974P, 971P, 1342 (NF XVII), EX214 etc. (hereinafter referred to as carbopol), HIVISWAKOTM 103, 104, 105, 204 and (Wako Pure Chemical Industries), NOVEON AA1TM (The B. F. Goodrich Company), and calcium polycarbophil (USP XXII).

The naturally-occurring viscogenic agent includes but is not limited to mucin, agar, gelatin, pectin, carrageenin, sodium alginate, locust bean gum, xanthan gum,

tragacanth gum, gum arabic, chitosan, pullulan, curdlan, waxy starch, sucralfate, and cellulose and its derivatives (e.g. cellulose sulfate).

The most preferred viscogenic agent is an acrylic polymer or its salt in the present invention.

These viscogenic agents can be used alone or in combination.

Referring to the amount of the viscogenic agent, its amount in the gastrointestinal mucosa-adherent composition may for example be about 0.005 to about 99 weight %, preferably about 0.5 to about 45 weight %, more preferably about 1 to about 30 weight %, furthermore preferably about 1 to about 25 weight %, and for the still better result, about 1 to about 20 %. When, for example, the viscogenic agent is dispersed in a composition comprising the polyglycerol fatty acid ester or the lipid, the amount of the viscogenic agent is about 0.005 to about 95 weight %, preferably about 0.5 to about 30 weight %, more preferably about 1 to about 25 weight 90, and for the still better result, about 1 to about 20 weight % based on the total weight of the composition. When the viscogenic agent is dispersed in the coating material of the composition comprising the polyglycerol fatty acid ester or the lipid, the proportion of the viscogenic agent is also about 0.005 to about 95 weight %, preferably about 0.5 to about 30 weight %, more preferably about 1 to about 25 weight %, and for the still better result, about 1 to about 20 weight % based on the total composition.

When the gastrointestinal mucosa-adherent matrix is a matrix comprising said polyglycerol fatty acid ester and the viscogenic agent or a matrix comprising said lipid and the viscogenic agent, the amount of the polyglycerol fatty acid ester or the lipid is about 5 to about 98 weight %, preferably about 20 to about 95 weight %, and more preferably about 40 to about 95 weight % based on the total weight. And the proportion of the polyglycerol fatty acid

ester or the lipid relative to the active ingredient is about 0.01 to about 15,000 parts by weight, preferably about 0.1 about to 1,000 parts by weight, and more preferably about 0.1 to about 100 parts by weight.

The matrix prepared by using said polyglycerol fatty acid ester may be supplemented with said lipid. The lipid which can be used is a pharmaceutically acceptable water-insoluble substance which is capable of regulating the rate of release of the active ingredient, and the specific lipids mentioned hereinbefore, for instance, can be employed.

When the lipid and the polyglycerol fatty acid ester are used together, the amount of the polyglycerol fatty acid ester and the lipid together is about 5 to about 98 weight %, preferably about 20 to about 95 weight %, more preferably about 40 to about 95 weight % based on the total weight.

And the amount of the lipid should be within the range not detracting from the adhesion of the composition to the gastrointestinal mucosa, and may range from about 0.01 to about 15,000 parts by weight, preferably about 0.1 about to 1,000 parts by weight, more preferably about 0.1 to about 100 parts by weight, relative to the active ingredient.

The liquid or solid pharmaceutical composition of the invention can be administered orally either as it is or as formulated into a preparation which can be manufactured by the established pharmaceutical procedures. The liquid composition can be directly administered via a gastric catheter or a feeding tube or in the form of a hard or soft capsule. The solid composition can be administered orally in the bulk form, as encapsulated, or in the form of a tablet.

Preparations containing the pharmaceutical composition of the invention can be manufactured by basically following the per se known procedures as such or as modified. Moreover, in the manufacture of the oral preparation, a variety of additives which are conventionally formulated in an oral preparation can be

added for controlling the rate of release of the active ingredient or to meet other pharmaceutical needs. Among such additives are excipients (e.g. lactose, corn starch, talc, crystalline cellulose, powdered sucrose, magnesium stearate, mannitol, light silicic anhydride, magnesium carbonate, calcium carbonate, L-cysteine, etc.); binders (e.g. starch, sucrose, gelatin, gum arabic powder, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.); disintegrators (e.g. carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.); anionic surfactants (e.g. sodium alkylsulfonates etc.) and nonionic surfactants (e.g. polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty acid esters, polyethoxylated castor oil derivatives, etc.); antacids and mucosal protectants (e.g. magnesium hydroxide, magnesium oxide, aluminium hydroxide, aluminium sulfate, magnesium aluminometasilicate, magnesium aluminosilicate, sucralfate, etc.); cyclodextrins and cyclodextrincarboxylic acids (e.g. maltosyl-b- cyclodextrin and maltosyl-b-cyclodextrincarboxylic acid); coloring agents; corrigents; adsorbents; antiseptics; lubricants; antistatic agents; and disintegration detardants. The levels of addition of those additives can be respectively selected from the range not detracting from the stability and efficiency of absorption of the active substance.

When, for example, a liquid pharmaceutical composition of the invention is processed into soft capsules, various known forms can be adopted. Thus, the geometry, size, and formulation of the capsule and the manufacturing method can be freely selected. The capsule may for example be spherical, oval, oblong, tubular, spindle-shaped, self-cut, duplex, square, or heart-shaped.

The capsule size is generally selected from the range of about 1 mg to about 10 g in terms of capacity.

The commonest film material that can be used is a mixture of gelatin (e.g. alkalinized gelatin) and a suitable plasticizer, optionally supplemented with a coloring agent, an antiseptic, a flavor, and/or a corrigent.

The capsule manufacturing technology that can be utilized includes the plate method, rotary die method, and seamless method, although the rotary die method is preferred.

The solid pharmaceutical composition of the present invention, either as such or as a uniform mixture of the composition and said additives, can be processed into hard capsules using hard capsule shells. As such capsule shells, hard gelatin capsule shells having capacities within the range of about 0.13 to about 1. 37 ml are generally used and the filling operation can be carried out by means of a disk-type, compress-type, or Auger type filling machine.

Tablets can be manufactured by compressing a powdery mixture containing the pharmaceutical composition of the invention. The tablet shape and size can be freely selected.

For example, ellipsoidal, football-shaped, heart-shaped, and other tablets can be provided, with or without a dividing line. The tablet machine may be an eccentric machine or a rotary machine.

The pharmaceutical composition of the present invention can be coated with an enteric coating material to provide an enteric preparation. The "enteric coating material" means an enteric polymer which is substantially insoluble in the acidic region of pH but at least partially soluble in the weakly acidic to basic region. The term "acid region" is used herein to mean the range of pH about 0.5 to about 4.5, preferably pH about 1.0 to about 2. 0. The "weakly acidic to basic region" means the range of pH about 5.0 to about 9.0, preferably pH about 6.0 to about 7. 5. As

specific examples of said enteric coating material, there can be mentioned cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethyl acetate succinate (Shin-Etsu Chemicals), methacrylic acid copolymers (Eudragit L- 30D-55, L100-55, L100, S100, etc., Röhm-Pharma), among others. Those materials can be safely used as they are in enteric preparation.

The coating technology that can be used includes a variety of per se known methods, such as pan coating, fluidized-bed coating, roll coating, and so on. When the coating material is a solution or dispersion containing water or an organic solvent, the spray coating method can also be employed. The proportion of said water or organic solvent may for example be about 25 to about 99 weight %.

There is no particular limitation on the kind of said organic solvent. Thus, for example, alcohols (e.g. methanol, ethanol, isopropylalcohol, etc.); ketones (e.g. acetone etc.); and halogenated hydrocarbons (e.g. chloroform, dichloromethane, trichloromethane, etc) can be mentioned.

The above-mentioned gastrointestinal mucosa- adherent composition can be used as it is or as processed into gastrointestinal mucosa-adherent preparations.

Furthermore, various additives conventionally incorporated in solid preparations (e.g fine granules, granules, etc.) can be added to the preparation form as well unless they cause an adverse influence. Among such additives are various excipients such as lactose, corn starch, talc, crystalline cellulose (e.g. Avicel), powdered sucrose, magnesium stearate, mannitol, light silicic anhydride, magnesium carbonate, calcium carbonate, L-cysteine, etc.; binders such as starch, sucrose, gelatin, powdered gum arabic, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose,

polyvinylpyrrolidone, pullulan, dextrin, etc.; disintegrators such as carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, hydroxypropylstarch, partially dextrinized starch, etc.; anionic surfactants such as sodium alkylsulfonates etc. and nonionic surfactants such as polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty acid esters, polyethoxylated castor oil derivatives, etc.; antacids and mucosal protectants such as magnesium hydroxide, magnesium oxide, aluminium hydroxide, aluminium sulfate, magnesium aluminometasilicate, magnesium aluminosilicate, sucralfate, etc.; coloring agents; corrigents; adsorbents; antiseptics; lubricants; antistatics; and disintegration detardants. The levels of addition of those additives can be respectively selected from the range not detracting from adhesion of the composition to the mucosa.

The gastrointestinal mucosa-adherent solid composition comprising said viscogenic agent dispersed in a matrix comprising a polyglycerol fatty acid ester and/or lipid may be any dispersion of said polyglycerol fatty acid ester and/or lipid, viscogenic agent, and active ingredient.

Dispersion can be effected by the per se known technology.

The gastrointestinal mucosa-adherent solid composition can be produced by the analogue to the per se known pharmaceutical procedures. A typical process comprises melting the polyglycerol fatty acid ester and/or lipid at a temperature beyond its melting point, adding said viscogenic agent and said active ingredient to the melt, either together or serially to thereby disperse them in the melt, and cooling the dispersion. The heating temperature may for example be about 40 to about 150 C, preferably about 50 to about 110or, and more preferably about 50 to about 90°C. This process can be carried out using a conventional granulating machine and the composition is preferably molded into solid beads (e.g. fine granules etc.) by a spray

granulation technique, for example spray chilling.

The spray chilling method typically comprises dripping a mixed dispersion of the viscogenic agent and active ingredient in a molten polyglycerol fatty acid ester and/or lipid at a constant flow rate onto a rotary disk revolving at a high speed of, for example, about 10 to about 6,000 rpm, preferably about 900 to about 6,000 rpm, more preferably about 1,000 to about 5,000 rpm, furthermore preferably about 2,500 to about 3,000 rpm. The rotary disk may for example be a flat, smooth disk, typically made of aluminum and measuring about 5 to about 100 cm in diameter, preferably about 10 to about 20 cm in diameter. The dripping rate of said molten dispersion can be selected according to the designed particle diameter and is generally about 1 to about 1,000 g/min., preferably about 2 to about 200 g/min., and more preferably about 5 about to 100 g/min. The granules thus obtained are substantially spherical so that a uniform film can be formed on their surface with good efficiency in the subsequent coating step.

When the gastrointestinal mucosa-adherent composition according to the invention is manufactured by the above method, it is possible not only to render the product adherent but also to stabilize the urease inhibitor in the preparation.

An alternative production process comprises kneading the viscogenic agent and active ingredient into the polyglycerol fatty acid ester and/or lipid, and granulating the resulting dispersion. The solvent for use in this process may be a solvent of the common variety (e.g. methanol, acetonitrile, chloroform, etc.).

A further alternative process for producing said solid composition comprises the use of melt granulation technology. A typical melt granulation process comprises heating the polyglycerol fatty acid ester and/or lipid at a temperature near its melting point, for example a

temperature ranging from its melting point to a temperature about 5°C below the melting point, subjecting the resulting melt to granulation, such as the above-mentioned spray chilling, and floating the resulting fine particles together with the viscogenic agent and active ingredient under moderate heating at a suitable temperature to provide an gastrointestinal mucosa-adherent matrix. In this process, the influence of heat on the active ingredient can be mitigated. Therefore, even when the active ingredient is a peptide or a protein, a solid composition can be manufactured without the risk of deactivation of the active ingredient.

The solid composition comprising a matrix made up of a polyglycerol fatty acid ester and/or a lipid and being coated with a viscogenic agent may be one coated with a viscogenic agent as such or preferably one coated with a coating material containing a viscogenic agent. The coating material may be a composition containing at least one member selected from the class consisting of said polyglycerol fatty acid ester, said lipid, and said water-insoluble polymer in addition to said viscogenic agent. When a viscogenic agent which is sparingly compatible or incompatible with the matrix components is employed for coating, the solid composition can be provided with a film in which the viscogenic agent has been strategically dispersed. The coating material may further contain additives. In any of the above manufacturing processes, it is preferable to prevent infiltration of moisture.

The water-insoluble (hydrophobic) polymer includes but is not limited to ethylcellulose (FMC, Asahi Chemical), aminoalkyl methacrylate copolymer (EudragitTM E100, Rhein-Pharma), aminoalkyl methacrylate copolymer (Eudragit RS, RL-100L, RS-300, RL-30D, RL-PO, RS-PO, Röhm-Pharm). Those hydrophobic polymers can be used independently or as a mixture of two or more different

species.

The proportion of the viscogenic agent in the coating material may for example be about 0.005 to about 100 weight %, preferably about 0.05 to about 95 weight %, more preferably about 0.05 to about 30 weight %, and still more preferably about 1 to about 10 weight %, based on the whole solid fraction of the coating material.

When at least one of said polyglycerol fatty acid ester, lipid, and hydrophobic polymer is used in combination with said viscogenic agent for said coating, the proportion of the viscogenic agent based on the total weight of the solid matter of the coating material is about 0.005 to about 95 weight %, preferably about 0.5 to about 30 weight %, and more preferably about 5 to about 25 weight %.

Referring further to the coating material, two or more members selected from the class consisting of the polyglycerol fatty acid ester, lipid, and hydrophobic polymer can be used in combination. In this case, based on each part by weight of the whole polyglycerol fatty acid ester and/or lipid, the remaining component is used in a proportion of about 0.0001 to about 1,000 parts, preferably about 0.01 to about 100 parts, and more preferably about 0.01 to about 10 parts.

The coating amount can be selected according to the desired type of solid preparation and the desired strength of adhesion to the mucosa. For example, the coating amount for a solid preparation may be about 0.1 to about 30 weight %, preferably about 0.5 to about 20 weight %, more preferably about 0.5 to about 10 weight %, for tablets; about 0.1 to about 50 weight %, preferably about 1 to about 20 weight %, for pills and granules; and about 0.1 to about 100 weight %, preferably about 1 to about 50 weight %, for fine granules.

Where necessary, the coating material may be supplemented with common additives such as those mentioned hereinbefore. The coating material and the additive may be applied together or serially. The proportion of the

additive relative to the solid matter of the coating material is about 0.1 to about 70 weight %, preferably about 1 to about 50 weight %, and more preferably about 20 to about 50 weight %.

The coating technology that can be used includes a variety of per se known methods, such as pan coating, fluidized-bed coating, roll coating, and so on. When the coating material is a solution or dispersion containing water or an organic solvent, the spray coating method can also be employed. The proportion of said water or organic solvent may for example be about 25 to about 99 weight %.

There is no particular limitation on the kind of said organic solvent. Thus, for example, alcohols such as methanol, ethanol, isopropyl alcohol, etc.; ketones such as acetone etc.; and halogenated hydrocarbons such as chloroform, dichloromethane, trichloroethane, etc. can be employed.

When the polyglycerol fatty acid ester and/or lipid is used for coating, the objective coated composition can be obtained by melting the polyglycerol fatty acid ester and/or lipid, optionally together with other additives, under heating, emulsifying the melt with water, spray- coating the surface of a solid composition with the resulting emulsion, and drying the coat. An alternative procedure comprises adding the coating material to the substrate solid composition preheated by hot air in a coating pan or the like and melt-spreading the coating.

The solid composition is coated generally at a temperature of about 25 to about 60°C and preferably at about 25 to about 40or.

The coating time can be judiciously selected with reference to the coating method, the characteristics and amount of the coating material, and characteristics of the substrate solid preparation.

Insofar as a sufficient adhesion to the gastrointestinal mucosa can be assured, the

gastrointestinal mucosa-adherent solid composition may, if necessary, be further coated with a conventional gastric coating agent or a water-soluble coating agent.

The gastrointestinal mucosa-adherent solid preparation includes but is not limited to fine granules, granules, pills, tablets manufactured by compressing said fine granules or granules with a tablet machine, and capsules manufactured by filling said fine granules or granules into suitable capsule shells. Among those preparations, fine granules and granules are preferred.

The particle size distribution of said fine granules may for example be: particles measuring 10 to about 500 llm in diameter accounting for not less than 75 weight %, particles larger than 500 Fm accounting for not more than 5 weight %, and particles smaller than 10 m accounting for not more than 10 weight %. The preferred distribution is 105 to about 500 Inm in diameter accounting for not less than 75 weight %, particles larger than500 llm accounting for not more than 5 weight %, and particles smaller than 74 µm accounting for not more than 10 weight %. The particle size distribution of said granules may for example be about 500 to about 1410 m accounting for not less than 90 weight % and smaller than 177 µm accounting for not more than 5 weight %.

The amount of the urease inhibitor in the pharmaceutical composition of the invention can be selected according to the intended dosage form and may for example be about 0.01 to about 95 weight %, preferably about 1 to about 95 weight %, more preferably about 10 to about 90 weight %, and for still better results, about 10 to about 50 weight %.

The pharmaceutical composition of the invention can be provided in a non-oral preparation. The non-oral preparation includes suppositories and preparations for external application.

The suppositories may be rectal suppositories or

vaginal suppositories, and the preparations for external application may for example be ointments (inclusive of creams), preparations for vaginal administration, transnasal or transdermal DDSs, etc.

Suppositories can be provided in oil-based or water-based solid, semi-solid, or liquid forms according to the per se known technologies.

The composition of the present invention is useful for the treatment of Helicobacter pvlori-harboring mammals (e.g. feline, canine, bovine, equine, goat, monkey, human being, etc.). Any of the above-mentioned preparations exhibits marked efficacy in the clearance of Helicobacter pylori in such animals. The indication includes but is not limited to gastritis and gastrointestinal ulcer, stomach cancer, and a particularly remarkable response can be obtained in the treatment of gastrointestinal ulcer.

The pharmaceutical preparation of the present invention are only sparingly toxic and can be administered orally or otherwise to mammals including human beings. The dosage of the preparation varies with different dosage forms, methods of administration, or species of active ingredient. In accordance with the present invention, the dosage of the urease inhibitor can be reduced to about one-half through about one-tenth of the usual dosage required. For use in adult patients with gastric ulcer or duodenal ulcer, the preparation containing a compound of formula (I) is preferably administered in a daily dose of about 0.05 to about 100 mg/kg, preferably about 0.2 to about 100 mg/kg, more preferably about 0.2 to about 20 mg/kg, furthermore preferably about 0.1 to about 10 mg/kg, and for the still better result, about 0.5 to about 10 mg/kg in terms of the active ingredient.

The pharmaceutical preparation of the present invention may further contain other active ingredient, such as antiulcerative agents, antimicrobial agents having anti-HP activity, antacids, gastric acid antisecretory

agents, etc. for the symptomatic relief or cure of gastrointestinal ulcers. As an alternative, the preparation of the invention can be used in combination with other independent preparations containing such other active drugs.

The antacid mentioned above includes but is not limited to aluminum hydroxide gel, sodium bicarbonate, aminoacetic acid, aluminum silicate, magnesium aluminometasilicate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate, and calcium carbonate.

The gastric acid antisecretory agent mentioned above includes but is not limited to gastric proton pump inhibitors, histamine, and H2 blockers. The proton pump inhibitor is any drug substance which inhibits secretion of gastric acid through direct or indirect inhibition of H/K-ATPase which is functioning as a proton pump in the acid secretory cells (parietal cells) of the gastric mucosa. As such, the proton pump inhibitor includes lansoprazole, omeprazole, pantoprazole, pariprazole sodium, leminoprazole, TY-11345, TU-199, FPL-65372, BY-686, tannic acid, ellagic acid, ebselen, AHR-9294, cassigarol-A, bafilomycin, Y-25942, xanthoangelol E, SKF-96356, epigallocatechingallate, WY-27198, T-330, andSK&F-20054.

The H2 blocker includes but is not limited to cimetidine, ranitidine, amotidine, loctidine, and their derivatives and salts. Those H2 blockers can be produced by the processes described in USP 3,950,333, USP 4,283,408, USP 4,128,658, etc. or any processes analogous thereto.

The antimicrobial agents having anti-HP activity and antiulcerative agents which can be used include the following and other substances.

The antimicrobials mentioned above include but are not limited to penicillins (e.g. amoxicillin, benzylpenicillin, piperacillin, mecillinam, etc.), cephalosporins, macrolides (e.g. erythromycin,

clarithromycin, roxithromycin, azithromycin, etc.), tetracyclines (e.g. tetracycline, minocycline, etc.), aminoglycosides (e.g. gentamicin, amikacin, streptomycin, etc.), bismuth salts (e.g. bismuth acetate, bismuth citrate, bismuth salicylate, etc.), imidazoles (metronidazole, tinidazole, miconazole, etc.), quinolones (e.g. ofloxacin, cyproxane, etc.), and tryptophanyl-t-RNA synthase inhibitors (e.g. indolmycin etc.). Particularly preferred are penicillins, macrolides, imidazole compounds, and tryptophanyl-t-RNA synthase inhibitors. In particular, amoxicillin, clarithromycin and indolmycin are preferred.

As said antiulcerative agents, mucosal protectant antiulcerative agents, for instance, can be used. The mucosal protectant antiulcerative agent which can be used includes but is not limited to (z)-7-[(lR,2R,3R)-2- <BR> <BR> <BR> [(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-3-methyl-5- oxocyclopentyl]-5-heptenoic acid (trimoprostil, ulstar), l-butyric acid-7-(L-2-aminobutyric acid)-26-L-aspartic acid-27-L-valine-29-L-alaninecalcitonin (elcatonin), 3- ethyl-7-isopropyl-1-azulene sulfonate sodium (egualen sodium).

The pharmaceutical preparations of the present invention can also be used in conjunction with other preparations containing the above active ingredients.

As described above, the pharmaceutical preparations of the present invention are effective in the prevention and treatment of various gastrointestinal diseases (e.g. gastritis, duodenal ulcer, stomach ulcer, chronic gastritis, etc.) associated with microorganisms inducing toxic reactions in the gastrointestinal tract, particularly Helicobacter pylori, at low doses.

Furthermore, in accordance with the present invention, phosphoric amide derivatives which are unstable to water and acid can be pharmaceutically stabilized.

MODE OF WORKING THE INVENTION The following reference examples, working examples, and test examples illustrate the present invention in further detail, however these examples should by no means be construed as limiting the scope of the invention.

Reference Example 1 5-Methyl-2-thiophenecarboxamide To 50 ml of acetic acid were added 2.6 g (0.1 M) of 5-methyl-2-thiophenecarbaldehyde, 8.3 g (0.12 M) of hydroxylamine hydrochloride, and 9.8 g (0.12 M) of sodium acetate, and the mixture was refluxed for 13-15 hours.

After the starting compound ceased to be detected by liquid chromatography (HPLC) (retention time ca 13 min.), the reaction mixture was concentrated under reduced pressure to about half its initial volume. To this concentrate was added 100 ml of concentrated hydrochloric acid and the reaction was carried out at 60°C for 4 hours. After completion of the reaction, the reaction mixture was diluted with 100 ml of water and stirred under ice cooling for 30 minutes. The resulting crystals were collected by filtration and rinsed with 100 ml of iced water to provide 11.6 g (82%) of 5-methyl-2-thiophenecarboxamide (HPLC retention time: ca 4 min.).

HPLC conditions Column: GL Science's Inertsil ODS-3, 5 Fm, 4.6 x 150 mm Eluent: acetonitrile:0.05 M potassium dihydrogen phosphate/water = 30:70 Detection wavelength: 231 nm Flow rate: 1.0 ml/min.

1H-NMR (DMSO-d6) #: 2.54 (3H, d, CH3), 7.01 (111, dd, thiophene-4-H), 7.78 (1H, dd, thiophene-3-H).

Reference Example 2 N-(diaminophosphinyl)-5-methyl-2-

thiophenecarboxamide In 50 ml of toluene was suspended 7.6 g (47 mM) of 5-methyl-2-thiophenecarboxamide and while this suspension was stirred vigorously at room temperature, 10.9 g (50 mM) of phosphorus pentachloride was added. The mixture was heated at 650C and stirred for 30 minutes. Then, under ice cooling, 2.0 ml of formic acid was added dropwise. The mixture was stirred at 25°C for 30 minutes and then concentrated under reduced pressure to remove the toluene.

The residue was dissolved in 100 ml of tetrahydrofuran (THF), and 17.1 ml of 25% aqueous ammonia was added under ice cooling. The mixture was stirred at 25°C for 30 minutes, after which 100 ml of toluene was added, and the resulting crystals were recovered by filtration. The crystals were rinsed with 50 ml of THF and 50 ml of water and dried in vacuo to provide 6.78 g (64%) of N-(diaminophosphinyl)- 5-methyl- 2 - thiophenecarboxamide. m.p. 285-297°C (decomp.) Reference Example 3 5-methyl-3-furancarboxylic acid The mixture of 299 g of ethyl laevulinate, 142 g of ethylene glycol, 338 g of ortho triethyl formate, and 1 g of paratoluene sulfonic acid mono hydrate was stirred for 72 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with 500 ml of ethyl ether, followed by rince with 1N sodium hydroxide, saturated sodium carbonate, and then water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 374 g of the colorless oily compound. 168 g of potassium t-butoxide was added portionwise to a diethylether solution of 181 g of the above-described compound and 222 g of ethyl formate at room temparature, then after addition, stirred for 15 hours at room temparature. The reaction mixture was added to ice, then was acidified with conc-hydrochloric acid under ice

cooling. After separation, the aqueous layer was extracted with ethyl ether. The organic layer was combined, and was concentrated under reduced pressure. 400 ml of acetone and 40 ml of 0.5 N sulfuric acid was added to the residue, and was refluxed for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was added to water and extracted with ethyl ethter. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in 100 ml of ethyl ether. The solution was added to 200 g of anhydrous polyphosphate and stirred for 20 min at 50 C. The reaction mixture was cooled to room temparature and then iced water was added, and then the mixture was stirred for 10 min, extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate, and then removed solvent. To give 95 g of brown oily substance, to the substance was added 300 ml of water and 35 g of sodium hydroxide and then stirred for 2 hours at room temparature. The reaction mixture was cooled and acidified with conc-hydrochloric acid and then stirred for 2 hours under ice cooling. To provide 44 g of 5-methyl-3-furancarboxylic acid as a colorless crystals, the precipitated solid was filtered.

Reference Example 4 5-methyl-3-furancarboxamide 5-methyl-3-furancarboxylic acid (0.95 g) was dissolved in tetrahydrofuran (30 ml), and N,N- dimethylformamide (3 drops) was added. Oxalyl chloride (1.0 g) was added dropwise at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (30 ml) and ethyl acetate (100 ml) with stirring under ice-cooling. The resulting mixture was stirred at

room temperature for 3 hours, and then the mixture was washed with water and dried over anhydrous magnesium sulfate to remove the solvent. The residue was crystallized from aceton-isopropylether to provide 240 mg of 5-methyl-3-furancarboxamide. mp 123-124 oC.

1H-NMR (CDCl3) b: 2.22 (3H, d, J=1.2 Hz), 5.80 (2H, br, s), 7.23(1h, J=1.2 Hz), 7.85 (1H, D, J=1.2Hz) Reference Example 5 N-(diaminophosphinyl)-5-methyl-3-furancarboxamide 5-Methyl-3-furancarboxamide (0.94 g) was suspended in toluene (10 ml), and phosphorus pentachloride (1.6 g) was added portionwise. The mixture was heated to 70 C, stirred for 30 minutes and then cooled to room temperature.

Formic acid (0.35 g) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. Then, hexane (30 ml) was added, and the mixture was stirred for 15 minutes. Precipitated crystals were collected by filtration, washed with hexane, and dried to give 1.1 g of crystals. The crystals were dissolved in tetrahydrofuran (50 ml) and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 50 minutes. Ethyl ether (50 ml) was added and stirred for 20 minutes. Precipitate was collected by filtration, washed with water, and dried. The obtained solid was recrystallized from methanol-ethyl ether to give N- (diaminophosphinyl) -5-methyl-3-furancarboxamide (0.39 g) as colorless crystals. mp 168-170 oC.

Elemental analysis for C6H10N303P Calcd : C, 35.48; H, 4.96; N, 20.69.

Found : C, 35.42; H, 4.90; N, 20.42.

1H-NMR (DMSO-d6) 6 : 2.12(3H,s), 4.12(4H,brs), 7.48(1H,s), 8.44(1H,s), 9.07(1H,d,J=7.6Hz).

Reference Example 6 2-methyl- 3 -furancarboxylic acid 2-Methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (70 ml), and 1N aqueous sodium hydroxide (78 ml) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration with diisopropyl ether to give 2-methyl-3-furancarboxylic acid (5.5 g) as crystals. mp 101-102 oC.

Reference Example 7 2-methyl-3-furancarboxamide 2-methyl-3-furancarboxamide was synthesized in the similar manner as Reference Example 4. mp 87-88 oC.

Reference Example 8 N-(diaminophosphinyl)-2-methyl-3-furancarboxamide 2-Methyl-3-furancarboxamide (2.0 g) was suspended in toluene (30 ml), and phosphorus pentachloride (3.5 g) was added portionwise. The mixture was heated to 70 C, stirred for 30 minutes, and then cooled to room temperature. Formic acid (0.74 g) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added, and the resulting mixture was stirred for 10 minutes. Precipitated crystals were collected by filtration, washed with hexane and dried to give 3.3 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml), and ammonia gas was introduced under ice-cooling

for 30 minutes. The mixture was stirred at room temperature for 1 hour, and diethyl ether (100 ml) was added. The resulting mixture was stirred for 10 minutes, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from methanol to give N-(diaminophosphinyl)-2-methyl-3- furancarboxamide (0.85 g) as colorless crystals. mp 249-253 C (decomp.).

Elemental Analysis for C6H10N303P Calcd : C, 35.48; H, 4.96; N, 20.69.

Found : C, 35.41; H, 4.86; N, 20.68.

1H-NMR (DMSO-d6) 6 : 2.52(3H,s), 4.13(4H,s), 7.17(1H,d,J=2.0Hz), 7.50(1H,d,J=2.0Hz), 9.00(1H,d,J=7.4Hz).

Reference Example 9 3.5-dimethvl-2-furancarboxamide 3,5-dimethyl-2-furancarboxamide was synthesized in the similar manner as Reference Example 4. mp 141-142 oC Reference Example 10 N-(diaminophosphinyl)-3,5-dimethyl-2- furancarboxamide N-(diaminophosphinyl)-3,5-dimethyl-2- furancarboxamide was synthesized in the similar manner as Reference Example 5. mp 189-191 oC Elemental Analysis for C7H12N303P Calcd : C, 38.72; H, 5.57; N, 19.35.

Found : C, 38.36; H, 5.31; N, 19.24.

1H-NMR (DMSO-d6) d : 2.24(2H,s), 2.28(3H,s), 4.15(4H, br s), 6.17(1H,S), 8.09(1H,D,J=7.8Hz) Reference Example 11 3,5-dimethyl-2-thiophenecarboxamide

3,5-dimethyl-2-thiophenecarboxamide was synthesized in the similar manner as Reference Example 4. mp 141-142 oC Reference Example 12 N-(dimaminophosphinyl)-3,5-dimethyl-2- thiophenecarboxamide N-(diaminophosphinyl)-3,5-dimethyl-2- thiophenecarboxamide was synthesized in the similar manner as Reference Example 5. mp 160-162 oC Elemental Analysis for C7H12N302 Calcd : C, 36.05; H, 5.91; N, 18.02.

Found : C, 35.86; H, 5.16; N, 17.97.

1H-NMR (DMSO-d6) # : 2.37(3H,s), 2.41(3H,s), 4.13(4H, br s), 6.68(1H,S), 8.31(1H,br s) Example 1 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB3lOTM, Sakamoto Yakuhin Kogyo Co., Ltd.) (86.0 g) was melted at 840(3.

To this melt, 4.0 g of N- (diaminophosphinyl)-5-methyl- 2-thiophenecarboxamide (hereinafter referred to as compound-A) and 10.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 84°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby spherical fine granules passing through a 42-mesh sieve but failing to pass through a 60-mesh sieve (hereinafter referred to briefly as 42/60-mesh) were obtained.

Example 2 Production of a urease inhibitor-containing gastric

mucosa-adherent preparation.

A mixture of hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (63.0 g) and behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (5.0 g) was melted at 84°C. To this melt, 4.0 g of compound-A, 8.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 20.0 g of Curdlan (Takeda Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 84C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 3 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

A mixture of hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (63.0 g) and behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (5.0 g) was melted at 84°C. To this melt, 4.0 g of compound-A) 8.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 2.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 84C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 4 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (81.5 g) was melted at 84°C.

To this melt, 0.5 g of compound-A, 8.0g of acrylic polymer

(HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 10.0 g of Curdlan (Takeda Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 84C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 5 Production of a urease inhibitor-containing gastric mucosa-adherent preparation.

A mixture of hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (54.0 g) and behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (1.0 g) was melted at 84°C. To this melt, 35.0 g of compound-A, 5.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) amd 5.0 g of Curdlan (Takeda Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 84C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 6 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

A mixture of hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (35.0 g) and behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (1.0 g) was melted at 84°C. To this melt, 35.0 g of compound-A, 5.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 5.0 g of low substituted <BR> <BR> <BR> <BR> hydroxypropylcellulose (LH31TM, Shin-EtsuChemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 84°C for 15 minutes. This

molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 7 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

A mixture of hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (54.0 g) and behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (1.0 g) was melted at 84°C. To this melt, 35.0 g of compound-A, 5.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 5.0 g of low substituted <BR> <BR> <BR> <BR> hydroxypropylcellulose (LH-31TM. Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 84C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 8 Production of a urease inhibitor-containing gastric mucosa-adherent preparation.

Hydrogenated castor oil (Lubri wax TM 101, Freund Industrial Co. Ltd.) (76.0 g) was melted at 84C. To this melt, 4.0 g of compound-A, 10.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 10.0 g of low substituted hydroxypropylcellulose (LH31Th, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 840(3 for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Example 9

Production of a urease inhibitor-containing gastric mucosa-adherent preparation.

Hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (78.0 g) was melted at 84(3. To this melt, 4.0 g of compound-A, 8.0g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 10.0 g Curdlan (Takeda Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 84C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 1950 rpm at a flow rate of 10 g/min, whereby 42/60-mesh spherical fine granules were obtained.

Test Example 1 The fine granules obtained in Example 9 were stored in a tight container at 40C for 6 weeks and the stability of compound-A was investigated after 2, 4, and 6 weeks of storage.

Table 1 Storage period (weeks) Content of compound-A (t) 0 100.0 2 99.1 4 103.4 6 100.0 It can be seen from Table 1 that compound-A remained stable in the preparation for 6 weeks.

Example 10 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310Th, Sakamoto Yakuhin Kogyo Co., Ltd.) (8.4 g) was melted at 80°C.

To this melt, 0.1 g of N-(diaminophosphinyl)-2-methyl- 3-furancarboxamide (hereinafter referred to as compound-B), 1. 5g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical

Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

ExamDle 11 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310Th, Sakamoto Yakuhin Kogyo Co.. Ltd. )(8.4 g) was melted at80C.

To this melt, 0.1 g of compound-B, 1.5g of acrylic polymer ammonium salt (HIVISWAKOTM 204, Wako Pure Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 12 Production of a urease inhibitor-containinq gastrointestinal mucosa-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co.. Ltd. )(8.4 g) was melted at80C.

To this melt, 0.1 g of compound-B, 1.5g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 13 Production of a urease inhibitor-containing

gastrointestinal mucosa-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (7.9 g) was melted at 800(3.

To this melt, 0.1 g of compound-B, 1.0g of acrylic polymer <BR> <BR> <BR> <BR> ammonium salt (HIVISWAKO 204, Wako Pure Chemical Industries, Ltd.) and 1.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 14 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

A mixture of behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co., Ltd.)(8.0 g) and hydrogenated castor oil (Lubri wax TM 101, Freund Industrial Co. Ltd.) (0.1 g) was melted at 85°C. To this melt, 0.1 g of compound-B, 0.8 g of acrylic polxmer ammonium salt (HIVISWAKOTM 204, Wako Pure Chemical Industries, Ltd.) and 1.0 g of low substituted hydroxypropylcellulose (LH31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 800(3 for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 15 Production of a urease inhibitor-containing gastrointestinal mucosa-adherent preparation.

A mixture of behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (8.0 g) and hydrogenated castor oil (Lubri waxTM 101, Freund Industrial

Co. Ltd.) (0.1 g) was melted at 85C. To this melt, 0.1 g of N-(diaminophosphinyl)-5-methyl-3-furancarboxamide (hereinfater referred to as compound-C), 0.8 g of acrylic polymer ammonium salt (HIVISWAKOTM 204, Wako Pure Chemical Industries, Ltd.) and 1.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 85°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 16 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

A mixture of behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (8.0 g) and hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (0.1 g) was melted at 85°C. To this melt, 0.1 g of compound-B, 0.8 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 1.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 85°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 17 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

A mixture of behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co., Ltd.)(8.0 g) and hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (0.1 g) was melted at 85°C. To this melt, 0.1

g of compound-C, 0.8 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 1.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 85°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3,600 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 18 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB3lOTM, Sakamoto Yakuhin Kogyo Co., Ltd.) (56.0 g) was melted at 80°C.

To this melt, 39.0 g of compound-B, 5.0 g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 19 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (56.0 g) was melted at 80 C.

To this melt, 39.0 g of compound-B, 5.0 g of acrylic polymer ammonium salt (HIVISWAKOTM 204, Wako Pure Chemical Industries, Ltd.) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 20 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (56.0 g) was melted at 80°C.

To this melt, 39.0 g of compound-B, 5.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 21 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (50.5 g) was melted at 800(3.

To this melt, 39.0 g of compound-B, 4.0 g of acrylic polymer (HIVISWAKOTM 104, Wako Pure Chemical Industries, Ltd.) and 6.5 g of low substituted hydroxypropylcellulose (LH3lTM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 22 Production of a urease inhibitor-containinq gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (50.5 g) was melted at 800(3.

To this melt, 39.0 g of compound-B, 4.0 g of acrylic polymer ammonium salt (HIVISWAKOTM 204, Wako Pure Chemical

Industries, Ltd.) and 6.5 g of low substituted hydroxypropylcellulose (LH-31TM, Shin~Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 23 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (50.5 g) was melted at 800(3.

To this melt, 39.0 g of compound-B, 4.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 6.5 g of low substituted hydroxypropylcellulose (LH31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 24 Production of a urease inhibitor-containinq gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (50.5g) was melted at 80 C.

To this melt, 39.0 of compound-B, 2.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 8.5 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules

were obtained.

Example 25 Production of a urease inhibitor-containinq gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (60.0 g) was melted at 80%.

To this melt, 30.0 g of compound-B, 6.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 4.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 26 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (70.0 g) was melted at 800(3.

To this melt, 20.0 g of compoound-B, 6.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 4.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 80°C for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 27 Production of a urease inhibitor-containing gastrointestinal-adherent preparation.

Behenic acid hexa (tetra) glyceride (HB310TM,

Sakamoto Yakuhin Kogyo Co., Ltd. ) (60.0 g) was melted at 80°C.

To this melt, 30.0 g of compound-B, 2.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 8.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 800(3 for 15 minutes. This molten mixture was dropped onto a 15 cm (di.) aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Example 28 Production of a urease inhibitor-containinq gastrointestinal-adherent preparation.

A mixture of behenic acid hexa (tetra) glyceride (HB-310TM, Sakamoto Yakuhin Kogyo Co., Ltd.) (20.0 g) and hydrogenated castor oil (Lubri waxTM 101, Freund Industrial Co. Ltd.) (29.0 g) was melted at 85°C. To this melt, 39.0 g of compound-B, 4.0 g of acrylic polymer sodium salt (EX214TM, The B.F. Goodrich Company) and 8.0 g of low substituted hydroxypropylcellulose (LH-31TM, Shin-Etsu Chemicals) were serially added and the mixture was stirred for dispersion at a constant temperature of 85°C for 15 minutes. This molten mixture was dropped onto a 15cm (di.) <BR> <BR> <BR> aluminum disk rotating at 3960 rpm at a flow rate of 50 g/min, whereby 42/119-mesh spherical fine granules were obtained.

Test Example 2 In vivo anti-Helicobacter Dvlori effect of the urease inhibitor -containing gastrointestinal-adherent preparation.

Mongolian gerbils (MON/Jms/Gbs) infected with Helicobacter pylori (hereinafter sometimes referred to briefly as HP) were subcutaneously dosed with a lansoprazole (hereinafter referred to briefly as LPZ)- containing 0.5% methylcellulose suspension. At 30 minutes

after administration, compound-B-containing gastrointestinal-adherent preparations obtained in Example 13, 14 (AdMMS-13, -14 in Table 2) or a 1.0% NaHCO3/0.5% methylcellulose suspension containing compound-B (Suspension in Table 2) was orally administered twice a day for 3 consecutive days at a dose of 0.3 mg/kg as compound-B for AdMMS or 3 mg/kg as compound B for the suspension. At 16 hours after the final dose, the stomach was excised and the gastric wall was homogenized and serial dilutions were plated on the HP selective medium. The inoculated medium was incubated for 4 days at 37C under microaerobic conditions and the number of viable cells was counted. The results are shown in Table 2.

Table 2 Dose (mg/kg) Clearance rate Formulation Cleared/total Indolmycin (%) Control oo Suspension 3 40 AdMMS-12 0.3 40 AdMMS-13 0.3 40 The compound-B-containing gastrointestinal- adhesive preparations showed an equivalent anti-HP effect at the dose of one tenth of the suspension.

INDUSTRIAL APPLICABILITY According to the present invention, phosphoric amide derivatives which are inherently unstable to moisture and acid can be stabilized in pharmaceutical composition.

Those preparations are pharmaceutically meritorious in that an internal milieu with a relative humidity of not over 15% can be maintained over a long period of time under the usual storage conditions and, in addition, can be administered by the oral route.

Furthermore, the pharmaceutical composition or preparation provided with the property to adhere to the gastrointestinal mucosa in accordance with the present invention is capable of staying in the stomach to constantly release the active substance and, therefore, is very useful for the prevention and treatment of various gastrointestinal diseases associated with Helicobacter pylori, the microorganism known to do harm in the gastrointestinal, (such as gastritis, duodenal ulcer, stomach ulcer, and chronic gastritis).