Description

NEUROTHERAPEUTIC AZOLE COMPOUNDS

Technical Field

[1] The present invention is directed to neurotherapeutic azole compounds containing a carbamoyl group which are useful as anticonvulsant agents.

[2]

Background Art

[3] Many reports have disclosed that arylalkyl azole compounds are effectively used as anticonvulsant, antimicrobial and hypoglycemic agents. One of the structurally distinct classes of antiepileptic drugs is the (arylalkyl) imidazoles.

[4] J. Med. Chem., 24, 67 (1981) and J. Med. Chem., 24, 727 (1981) disclose

Nafimidone (2-(lH-imidazole-l-yl)-l-(2-naphthalenyl) ethanone) and denzimol ( a

-(4-(2-phenylethyl)phenyl)-lH-imidazole-l-ethanol) are two independently discovered representatives of this group and protect mice and rats against maximal electroshock- or pentylenetetrazole-induced tonic seizures but do not antagonize clonic seizures induced by pentylenetetrazole, strychnine, bicuculline, or picrotoxin. These indicated that denzimol and nafimidone possess a profile of activity similar to that of phenytoin or carbamazepine but distinct from those of barbiturates or valproic acid. Moreover, both agents display acceptable therapeutic ratios and protective indices. Although formal accounts of carefully controlled clinical trials have not been reported, preliminary communications indicate these drugs are effective in epileptic patients. Structure-activity relationship studies show that anticonvulsant properties of this group are associated with the presence of a small oxygen functional group (such as carbonyl, ethylene dioxy, methoxy, acyloxy, and hydroxy substituents) in the alkylene bridge in addition to imidazole ring and lipophilic aryl portion facilitating penetration of the blood-brain barrier.

[5] J. Med. Chem., 24, 67 (1981) discloses anticonvulsive l-(naphthylalkyl)-lH-imidazole derivatives represented by the following general structural formula (I) and (II):

[6]

[7] wherein, A is O, -OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ CH ₂ O-, -OCH(CH ₃ )CH ₂ CH ₂ O-, -OCH ₂

C(CH ) CH O-, (OCH ) , -SCH CH S-, -SCH CH CH S-, (SCH ) , (SC H ) , (S-n-C H

3 2 2 3 2 2 2 2 2 2 3 2 2 5 2 3

7 ) 2 , (S-ϊ-C 3 H7 )2 , (S-i-C 4 H9 )2 , (SC 6 H5 )2 , (SCH 2 C6 H5 )2 , or (H) 2 ;

[8] Alkyl chain is substituted at 1 or 2-position of the naphthalene ring;

[9] R is H, 6-Cl, 6-Br, 6-CH ₃ , 6-C ₂ H ₅ , 6,7-(CH3) ₂ , 6-OCH ₃ , 1-CH ₃ , 7-CH ₃ , 7-C ₃ H ₅ ,

4-CH(CH ₃ ) ₂ , or 6,7-(OCH ₃ ) ₂ ; and [10] n is an integer from 0 to 2;

[H]

[12] wherein, X is OH, OCH , OC H , O-n-C H , OC H , p-OC H Cl, o-OC H CH ,

3 3 5 4 9 6 5 ^ 6 4 6 4 3

OCOC 2H 5, OCOC 6H 5, SCH 3, SOCH 3, or SO 2CH 3;

[13] Alkyl chain is substituted at 1 or 2-position of the naphthalene ring;

[14] R is H, 6-Cl, 6-Br, 6-CH ₃ , 6-C ₂ H ₅ , 6,7-(CH ₃ ) ₂ , 6-OCH ₃ , 1-CH ₃ , 7-CH ₃ , 7-C ₃ H ₅ ,

4-CH(CH ₃ ) ₂ , or 6,7-(OCH ₃ ) ₂ ; and [15] n is an integer from 1 to 2.

[16] J. Med. Chem., 24, 727 (1981) discloses anticonvulsant activity of N-(benzoylalkyl) imidazoles and N-(ω-phenyl-ω-hydroxyalkyl)imidazoles represented by the following general structural formula (HI) and (IV): [17]

[ 18] wherein, R is 3,4-(HO) ₂ , 4-HO, 4-NO ₂ , 4-NH ₂ , 4-CH ^ CONH, 4-CH ₃ SO ₂ NH, 4-C ₈

H O, 4-(t-C H ), 4-(s-C H ), 4-(c-C H ), 2-C H , 3-C H , or 4-C H CH CH ; and

5 4 9 4 9 6 11 6 5 6 5 6 5 2 2

[19] X is CH , CHCH , CH CCH , CH CH , or CH(CH )CH ;

2 3 3 3 2 2 3 2

[20]

[21] wherein, R is 3,4-(HO) , 4-HO, 4-NO , 4-NH , 4-CH CONH, 4-CH SO NH, 4-C H

O, 4-(t-C H ), 4-(s-C H ), 4-(c-C H ), 2-C H , 3-C H , or 4-C H CH CH ; and

4 9 4 9 6 11 6 5 6 5 6 5 2 2

[22] X is CH 2 , CHCH 3 , CH 3 CCH 3 , CH 2 CH 2 , or CH(CH 3 )CH 2.

[23]

[24] J. Med. Chem., 29, 1577 (1986) discloses structure-activity relationships of anticonvulsive (arylalkyl)imidazoles represented by the following general structural formula (V) and (VI):

[25]

CV)

[26] wherein, Ar is benzo[b]thien-2-yl, benzo[b]thien-3-yl, benzofuran-2-yl, phenanthren-2-yl, 9, 10-dihydτophenanthren-2-yl, 9, 10-dihydrophenanthren-3-yl, naphthalen-2-yl, or naphthalene-3-yl; and

[27] X is O or (H, OH);

[28]

[29] wherein, X is O, (H, OH), (H, OCOPh), (CH ₃ , OH), -SCH ₂ CH ₂ S-, -OCH ₂ CH ₂ O-, -

OCH CH CH O-, -OCH(CH )CH O-, -OCH C(CH ) CH O-,or (H, H);

2 2 2 3 2 2 3 2 2

[30] Alkyl chain is substituted at 1,2 or 4-position of the fluorenyl ring ;

[31] R ₁ is H, 9-CH ₃ , 7-CH ₃ , 7-C ₂ H ₅ or 7-OCH ₃ , 7-(Oy ₂ CH, or 7-Br;

[32] R ₂ is H or 9-CH ₃ ;

[33] R ₃ is H, CX-CH ₃ , or CX-C ₂ H ₅ ;

[34] R is H, 2-CH , 2-C H , 4-CH , or 4-C H ; and

4 3 2 5 3 6 5

[35] n is an integer from 1 to 3.

[36] This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent anti-electroshock activity, little or no activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. AU active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450.

[37] Eur. J. Med. Chem., 28, 749 (1993) discloses anticonvulsant activity of

1 -(4-methylphenyl)-2-( lH-imidazol- 1 -yl)ethanol.

[38] Eur. J. Med. Chem., 36, 421 (2001) discloses some l-(2-naphtyl)-2-(imidazole-l-yl)ethanone oxime and oxime ether derivatives of the following general structural formula (VII) and pharmaceutical acceptable salts thereof possessing both anticonvulsant and antimicrobial activities:

[39]

CVIi)

[40] wherein, R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, allyl, cyclohexyl, benzyl, 4-chlorobenzyl, and 2,4-dichlorobenzyl.

[41] U.S. Pat. No. 3,415,840 discloses pyrazole-1-ethanol derivatives of the following general structural formula (VIII) possessing useful pharmacological effects as hypoglycemic agents and anticonvulsant agents:

[42]

(VIII)

[43] wherein, R stands for a member of the group consisting of hydrogen and methyl, Rl stands for a member of the group consisting of phenyl and phenoxymethyl while R2 represents a member of the group consisting of hydrogen and phenyl; and the nontoxic acid addition salts thereof.

[44] Active research and development efforts have been and continues to be directed to the application of azole compounds containing carbamoyl group for the treatment of CNS disorders such as anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, cognitive impairment, stroke, neurodegeneration and muscle spasm.

[45]

Disclosure of Invention Technical Solution

[46] This invention is directed to azole compounds containing carbamoyl group having formula (IX) and their pharmaceutically acceptable salts: [47]

[48] wherein, G is a ring selected from the group consisting of piperonyl, indanyl, naphtyl, phenyl and phenoxy methyl which ring may be substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, perfluoroalkyl, phenoxy, pheny- lalkyloxy of 1 to 8 carbon atoms or phenoxyalkyl of 1 to 8 carbon atoms, wherein the phenyl moiety of phenoxy, phenoxyalkyl and phenylalkyloxy is unsubstituted or

substituted with amino, mono- or di-substituted amino with lower alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms;

[49] m is an integer from 0 to 6;

[50] Y is selected from the group consisting of hydrogen, halogen, and lower alkyl of 1 to 8 carbon atoms;

[51] n is an integer from 0 to 6;

[52] A is azole group represented by the following structural formula (X-I) or (X-2):

[53]

(X-I) (X-2)

[54] wherein, Al is selected from the group consisting of nitrogen atom and CH;

[55] Q is selected from the group consisting of hydrogen, perfluoroalkyl, halogen, amino, mono- or di-substituted alkyl amino with alkyl of 1 to 8 carbon atoms, amido, linear or branched alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, arylalkyl, morpholino, piperidino, pyrrolidino, thioalkoxy of 1 to 8 carbon atoms, benzylthio, thienyl, aminoalkyl, hydroxyalkyl, styryl, carboxylic, pyridyl, un- substituted phenyl and phenyl substituted with one or more identical or different sub- stituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, arylalkyl, halogen, alkoxy containing 1 to 8 carbon atoms, phenoxy, amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, nitro, hydroxy, thioalkoxy, furanyl, sulfonamido, and perfluoroalkyl;

[56] R and R are independently selected from the group consisting of hydrogen,

C(=O)NH , lower alkyl of 1 to 8 carbon atoms, non-substituted or substituted phenyl, and non-substituted or substituted phenylalkyl of 1 to 8 carbon atoms, or taken together with attached nitrogen form a imidazole, piperazine or phenyl piperazine ring or cyclic amine ring represented by the following structural formula (XI):

[57]

(XI)

[58] wherein, A is selected from the group consisting of nitrogen atom and carbon atom; [59] E and U may and are independently selected from the group consisting of hydrogen, hydroxy and O-carbamoyl or taken together form oxo;

[60] W is selected from a ring consisting of piperonyl, indanyl, naphtyl, tetrazolyl, triazolyl, pyridyl and phenyl which ring may be substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phe- noxyalkyl of 1 to 8 carbon atoms, where the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di- substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, hydroxy, or perfluoroalkyl of 1 to 8 carbon atoms;

[61] j is an integer from 0 to 4; and

[62] t is an integer from 0 to 4, preferably from 0 to 2.

[63] In one embodiment, the compound containing carbamoyl group has the following structural formula (XVII):

[64]

[65] wherein, X is selected from the group consisting of lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, or phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di- substituted amino with lower alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms;

[66] X and X may be the same with or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with lower alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms;

[67] m is an integer from 0 to 6;

[68] Y is selected from the group consisting of hydrogen and lower alkyl of 1 to 8 carbon atoms;

[69] n is an integer from 0 to 6;

[70] A is azole group represented by the following structural formula (X-I) or (X-2):

(X-I) (X-2)

[72] wherein, A is selected from the group consisting of nitrogen atom and CH;

[73] Q is as above; and

[74] R and R are as above.

[75] In another embodiment, azole compound containing carbamoyl group has the following formula (XVIII): [76]

(XVIII)

[77] wherein, X and X are independently selected from the group consisting of lower

4 6 alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms;

[78] X and X may be the same with or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with , amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms;

[79] m is an integer from 0 to 6;

[80] 1 is an integer from 1 to 6;

[81] A is azole group represented by the following structural formula (X-I) or (X-2):

[82]

(X-I) (X-2)

[83] wherein, A is selected from the group consisting of nitrogen atom and CH; and

[84] Q, R and R are as above.

[85] In another embodiment, the azole compound containing carbamoyl group has the following structural formula (XIX): [86]

(XIX)

[87] wherein, X and X are independently selected from the group consisting of

8 9 hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, hydroxy, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms or phenoxyalkyl of 1 to 8 carbon atoms wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with, amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, or perfluoroalkyl of 1 to 8 carbon atoms;

[88]

[89] m is an integer from 0 to 6;

[90] Y is selected from the group consisting of hydrogen and lower alkyl of 1 to 8 carbon atoms;

[91] n is an integer from 0 to 6; and

[92] A, R 1 and R 2 are as above.

[93] In another embodiment, the azole compound containing carbamoyl group has the following structural formula (XX): [94]

[95] wherein, Ph is phenyl, piperonyl, indanyl or naphtyl which may be substituted with one or more identical or different substituents selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen, alkoxy containing 1 to 8 carbon atoms, thioalkoxy containing 1 to 8 carbon atoms, phenoxy, phenylalkyloxy of 1 to 8 carbon atoms, phenoxyalkyl of 1 to 8 carbon atoms, wherein the phenyl moiety of phenoxy, phenylalkyloxy and phenoxyalkyl is unsubstituted or substituted with amino, mono- or di-substituted amino with alkyl of 1 to 8 carbon atoms, amido, sulfonamido, nitro, carboxyl, hydroxy, or perfluoroalkyl of 1 to 8 carbon atoms;

[96] 1 is an integer from 1 to 6; and

[97] A, R 1 and R 2 are as above.

[98] In another embodiment compound containing carbamoyl group is structural formula

(XXI): [99]

[100] wherein, E, U, W, A , A, G, j and t are as above and

[101] 1 is an integer from 1 to 4;

[102] and pharmaceutically useful salts thereof.

[103] The compounds of this invention includes all optical and stereo isomeric including mixture racemates as well as substantially pure enantiomers such as the R and S enantiomers. With respect to pure enantiomers, preferably the optical purity of these enantiomers of the containing carbamoyl group represented by the following general structural formula (IX) and their pharmaceutically acceptable salts is greater than 60% , more preferably greater than 95% , and most preferably greater than 98% . The term "ee" means enantiomeric excess. For instance, one enantiomer of a specific compound is present in a mixture of the enantiomers for that compound at a greater amount relative to the other enantiomer. An enantiomerically enriched form may include a mixture of enantiomers of a specific compound in which the concentration of a single enantiomer of that compound is greater than 50%, more typically greater than 60%, 70%, 80%, or 90%, or higher (e.g., >95%, >97%, >99%, >99.5%), relative to the other enantiomer of that compound.

[104] These compounds represented by the formula (IX) are active as anticonvulsive agents. Such agents are utilized in the treatment of central nervous system diseases, particularly, as anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, cognitive impairment, stroke, neurodegeneration and centrally acting muscle spasm.

[105]

Best Mode for Carrying Out the Invention

[106] In accordance with the present invention, the compound represented by the general formula (IX) and their pharmaceutically acceptable salts thereof can be prepared by the following steps starting from the racemic or enantiomerically enriched alcohol compounds represented by the following general structural formula (XII):

[107]

(XII)

[108] wherein, G, m, Y, n and A are as above.

[109] The two methods for preparing the alcohol compounds represented by the general structural formula (XII) will be described below in detail. [110] Method I

[111] Reacting an epoxide of by the following general structural formula (XIII);

[112] o

³ 4~k< _γ j (XIII)

[113] wherein, G, m and Y are as above with azole of the formula (XTV);

[114]

N'^NH (XIV)

Q

[115] wherein, A and Q are as above to synthesize the racemic or enantiomerically enriched alcohol compounds represented by the general structural formula (XII): [116]

(XII)

[117] wherein, G, Y, A, m and n are as above.

[118] It should be noted that the stereochemistry of the product represented by the general formula (IX) depends on that of the starting material represented by the general structural formula (XIII) and intermediates represented by the general structural formula (XII); a starting material represented by the general structural formula (XTII) with an (/?)-configuration yields only a alcohol compound represented by the general structural formula (XII) with (^-configuration and a starting material represented by the general structural formula (XIII) with an (S)-configuration yields only a intermediate represented by the general structural formula (XII) with (S)-configuration. In the preparation of azole compounds containing carbamoyl group represented by the general structural formula (TX) (Reaction Scheme 1 and 2), alcohol intermediates represented by the general structural formula (XB) with an (^-configuration yields only a product represented by the general structural formula (TX) with (R )-configuration and alcohol intermediates represented by the general structural formula

(XII) with an (S)-configuration yields only a product represented by the general structural formula (IX) with (S)-configuration.

[119] Details of the reaction conditions described in Method I are as follows. To a solution of azole derivative of the general structural formula (XIV) (0.5 - 10 equiv) and base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate (0 - 100 equiv), pyridine, diethyl amine, diisopropylethyl amine, and triethylamine in organic solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, DMSO, acetonitrile, DMF, NMP, acetone, methylene chloride, chloroform, MIBK, DME, ethyl acetate, THF, 1,4-dioxane, benzene, toluene, xylene, hexane, heptane and cyclohexane (0 - lOOOOeq), racemic or enantiomerically enriched epoxide derivative of the general structural formula (XIII) was slowly added. The reaction was warmed to 40 - 189°C for 0.1 - 240 hours and then cooled to 25 ⁰ C. Organic solvent such as ethyl acetate, diethyl ether, benzene, toluene, xylene, methylene chloride, chloroform, heptane, cyclohexane and hexane was added to this mixture and organic layer was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This residue was consisting of two regio-isomers, one is azol-lyl compound (hereinafter referred to as "lN-azole" and another is azol-2-yl compound (hereinafter referred to as "2N-azole". They were separated by column chromatography, eluting with an increasing ratio of ethyl acetate in hexane.

[120] Method II

[121] Reacting Alkyl halide represented by the following general structural formula

(XV);

[122]

(XV)

[123] wherein, G, Y and m are as above;

[124] n is an integer from 0 to 6; and

[125] X is halogen such as Cl, Br and I;

[126] with azole represented by the general structural formula (XIV) and then treat with sodium borohydride to synthesize alcohol compounds represented by the general structural formula (XII).

[127] Details of the reaction conditions described in Method II are as follows. To a solution of azole derivative of the general structural formula (XIV) (0.5 - 10 equiv) and base such as sodium hydride, sodium methoxide sodium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate (0 - 100 equiv),

pyridine, diethyl amine, diisopropylethyl amine, and triethylamine in organic solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, DMSO, acetonitrile, DMF, NMP, acetone, methylene chloride, chloroform, MIBK, DME, ethyl acetate, THF, 1,4-dioxane, benzene, toluene, xylene, hexane, heptane and cyclohexane (0 ~ 10000 equiv), alkyl halide derivative of the general structural formula (XV) was slowly added. The reaction was warmed to 40 ~ 189 ⁰ C for 0.1 ~ 240 hours and then cooled to 25 ⁰ C. Organic solvent such as ethyl acetate, diethyl ether, benzene, toluene, xylene, methylene chloride, chloroform, heptane, cyclohexane and hexane was added to this mixture and organic layer was washed with brine. The crude product was dissolved in methyl alcohol (1~ 10000 equiv) and then sodium borohydride (1 - 100 equiv) was added to this solution slowly. After 0.1 - 24 hours stirring at room temperature, the reaction mixture was concentrated in vacuo. Organic solvent such as ethyl acetate, diethyl ether, benzene, toluene, xylene, methylene chloride, chloroform, heptane, cyclohexane and hexane was added to this mixture and organic layer was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This residue was consisting of lN-azole and 2N-azole. They were separated by column chromatography, eluting with an increasing ratio of ethyl acetate in hexane.

[128] There are several pathways to introduce carbamoyl group to alcohol compounds such as l,r-carbonyldiimidazole-amine, sodium cyanate-acid, carbamoyl chloride, chlorosulfamoyl isocyanate-water, disuccimidyl carbonate-amine, phosgene-amine, triphosgene-amine, chloroformate-amine, trichloroacetylchloride-amine, trichloroactylisocyanate, trimethylsilylisocyanate,

1-chlorocarbonylbenzotriazole-amine and so on. Some of pathways to prepare azole compounds containing carbamoyl group represented by the general structural formula (IX) are summarized as set forth in Reaction Scheme 1 and Reaction Scheme 2 below.

[129]

Reaction Scheme 1

1 ) 1 ,1'-Carbonyldιιmidazole R ₁ R ₂ N Λ O 2) R ₁ R ₂ NH (XVI) r-Tm γ L J _n A J _χ)

[130] wherein, G, Y, A, R 1 , R 2, m and n are as above.

[131] The azole compounds containing carbamoyl group represented by the general structural formula (IX) were prepared by reacting alcohol compounds represented by the general structural formula (XII) with l,l'-carbonyldiimidazole and then with amine base represented by the general structural formula (XVI);

[132] R R NH (XVI)

[133]

[134] wherein,

[135] R 1 and R 2 are as above.

[136] Details of the reaction conditions described in Reaction Scheme I are as follows.

For the conversion of the racemic or enantiomerically enriched alcohol compounds of the general structural formula (XII) to the racemic or enantiomerically enriched azole compounds containing carbamoyl group of the general structural formula (IX), the concentration of the alcohol compounds of the general structural formula (XII) is about 0.005 to 0.1 moles with l,l'-carbonyldiimidazole ranging from about 1.0 to 3.5 equivalents. This reaction is preferably carried out at a temperature of -10 to 66 ⁰ C. Without purification, the resulting intermediate is treated with 1 to 1,000 equivalents of amine base represented by the general structural formula (XVI) at a temperature of -10 to 3O ⁰ C to give the compound represented by the general structural formula (IX). For this carbamoylation, an ethereal solvent such as diethyl ether and tetrahydrofuran, a halogenated hydrocarbon solvent such as dichloromethane and chloroform, or the mixture thereof may be used.

[137]

[138] wherein, G, Y, A, R , R , m and n are as above.

1 2

[139] Details of the reaction conditions described in Reaction Scheme 2 are as follows.

For the conversion of the racemic or enantiomerically enriched alcohol compounds represented by the general structural formula (XII) to the racemic or enantiomerically enriched azole compounds containing carbamoyl group represented by the general structural formula (IX), the concentration of alcohol compounds represented by the general structural formula (XII) is about 0.005 to 0.1 moles with sodium cyanate ranging from about 0.5 to 4.0 equivalents and acid ranging from about 0.5 to 4.0 equivalents. This reaction is preferably carried out at a temperature of -10 to 66 ⁰ C to give the compound represented by the general structural formula (IX). For this carbamoylation, an ethereal solvent such as diethyl ether and tetrahydrofuran, a halogenated hydrocarbon solvent such as dichloromethane and chloroform, or the mixture thereof may be used.

[140] Among the preferred embodiments of the compounds of formula (IX) are included compounds of the formula:

[141]

IX-A

[142] wherein, Y is as above;

[143] A 3 , A 4 and A 5 are independently selected from the group consisting of CH or N, with at least one of A , A and A being CH; and at least one of the other of A , A and A

3 4 5 ° 3 4 5 being N; [144] R and R are selected from the group consisting of hydrogen, halogen, per-

6 7 fluoroalkyl, alkyl of from 1 to 8 carbon atoms, thioalkoxy, and alkoxy; [145] R and R are alkyl, hydrogen,

-C-NH ₂ O

, or taken together

[146] with the attached nitrogen atom form an imidazole, or phenyl piperazine ring; and

[147] y is an integer of from 0 to 4, preferably from 0 to 2 or pharmaceutically acceptable salts thereof;

[148] a compound of the formula:

[149]

[150] wherein R 3 , R 4 , R 6 , R 7 ,' Y,' y ^J ,' A3 , A 4 and A 5 are as above;and

[151] p is an integer of from 0 to 1;

[152] or pharmaceutically acceptable salts thereof; and

[153] a compound of the formula:

[154]

[155] wherein R and R taken together with the attached nitrogen atom form a substituent

8 9 of the formula:

[156]

[157] wherein E, U, A 2 , A 3 , A 4 and A 5 are as above; [158] k and v are an integer from 0 to 1 ; [159] Z is a phenyl, phenoxy, alkyl or phenylalkyloxy substitued where the phenyl moiety of said substitutent is unsubstituted or substituted with from one to three substituents selected from the group consisting of halogen, alkyl, perfluoroalkyl or alkoxy;

[160] Y is a hydrogen, halogen or alkyl; [161] y is an integer of from 0 to 1 ; [162] R and R are selected from the group consisting of hydrogen, halogen, per-

6 7 fluoroalkyl, thioalkoxy, alkoxy and alkyl.

[163] Another group of preferred compounds are the following: [164]

[165] wherein A is as above; R and R are hydrogen, halogen, lower alkoxy, lower alkyl,

1 8 9 hydroxy, trifluromethyl, amino, mono or dilower alkyl amino, nitro or R and R when

8 9 substituted on adjacent carbon atoms and when R is hydrogen can be taken together to form a cyclolower alkyl, phenyl or heterocyclolower alkyl ring; R is lower alkoxy, phenyloxy, phenylalkoxy, hydrogen, cycloloweralkyl, halogen, hydroxy, lower alkyl, nitro, trifluoromethyl, mono or lower dikalkyl amino or amino; R is hydrogen, lower alkyl, phenyl or phenyl lower alkyl wherein the phenyl group can be unsubstituted or

mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, or halo; R is hydrogen or lower alkyl or R taken together with R and their attached nitrogen atom form a 4 to 6 membered heteroarmatic ring containing at most 3 additional hetero nitrogen atoms ; R is hydrogen, amino carbonyl or lower alkyl: R is hydrogen,

14 13 lower alkyl, amino, mono or dilower alkylamino hetero aromatic, amino carbonyl or phenyl where the phenyl group can be unsubstituted or mono or disubstituted with a lower alkyl, hydroxy, lower alkoxy, or halo,; and 0 and p are integers from 0-1.

[166]

wherein

[167] a 4 to 6 membered a heterocycloalkyl ring containing at most 1 additional hetero nitrogen atom; A is as above; R , R ,R , R and R are as above; 0, z and p are

1 8 9 10 13 14 integers from 0-1 ; R is phenyl, phenyl carbonyl, a five or six membered hetero

16 aromatic ring containing from 1 to 4 nitro heteroatoms, wherein said phenyl and het- eroaromatic rings can be unsubstituted or mono or di-substituted with hydroxy, hydroxy lower alkyl, lower alkoxy, halogen, phenyl or trifloromethyl.

[168]

[169] wherein A is as above; R , R and R are as above; and R' and R' when taken

1 11 12 13 15 16 together with their attached carbon atoms form a cycloalkyl or phenyl ring which can

be unsubstituted or substituted with halo, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl.

[170] The compounds of IX-A, IX-B, IX-C, IX-D, IX-E and IX-F constitute preferred embodiments of the compound of formula IX. Particularly preferred embodiments of the compounds of formula IX-A, IX-B, IX-C, IX-D, IX-E and IX-F are those compounds where the nitrogen containing ring is a tetrazole or triazole ring. The triazoles are those compounds where one of A , A , A and A is nitrogen and the others are CH. The tetrazoles of the compounds of formula IX-A, IX-B, IX-C, IX-D, IX-E and IX-F are those compounds where two of A , A , A and A are nitrogen and the other is CH. Generally, among the triazoles and tetrazoles of the compounds of formula IX-A, IX-B and IX-C are those compounds where R and R are selected from the group consisting of hydrogen, halogen, perfluoroalkyl, alkyl and alkoxy. Where R and R in the compound of formula IX, are substituted phenyl or substituted phenylalkyl, the phenyl moiety can be substituted in one or more positions, preferably from one to three positions with amino, mono- or di-substituted alkyl amino, amido, alkyl, alkoxy and nitro.

[171] The compounds of formula IX, IX-A, IX-B, IX-C, IX-D, IX-E and IX-F include all forms of these compounds including these stereo, geometric and optical isomeric forms. The compounds of formula IX, IX-A, IX-B, IX-C, IX-D, IX-E and IX-F can exist as a racemate, as well as any mixture of these stereo, geometric or optical isomeric forms. In accordance with a preferred embodiment of this invention, the compounds of IX, IX-A, IX-B, IX-C, IX-D, IX-E and IX-F exist in pure isomeric form substantially free of these other isomeric forms. By substantially free, it is meant, that the specific isomer exists in its pure isomeric form such as a pure enantiomer with at least 95% by weight with at most 5% by weight of the other isomeric forms such as its other enantiomer.

[172] As used in the specification, the term "alkyl", alone or in combination, means a monovalent straight or branched-chain saturated hydrocarbon alkyl group containing from one to eight carbon atoms, preferably lower alkyl containing from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

[173] The term "alkoxy" means a straight or branched-chain alkoxy group formed from alkyl containing from one to eight carbon atoms, preferably from one to six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.

[174] The term "aryl" means a monovalent mono- or bicyclic unsubstituted aromatic hydrocarbon ring such as phenyl or naphthyl, with phenyl being preferred.

[175] The term "perfluoro-lower alkyl" means any lower alkyl group wherein all the

hydrogens of the lower alkyl group are substituted or replaced by fluorine. Among the prefered perfluoro-lower alkyl groups are trifluoromethyl, pentafluroethyl, heptaflu- oropropyl, etc with trifluromethyl being especially preferred.

[176] The term "cycloalkyl" means a cyclolower alkyl substituent which designates a monovalent unsubstituted 3- to 6-membered saturated carbocylic hydrocarbon ring. Among the preferred cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclohexyl, etc.

[177] The term "heterocycloalkyl" refers to a 4 to 6 membered monocyclic saturated ring containing 3 to 4 carbon atoms and one to three hetero nitrogen or oxygen atoms.

[178] The term "heteroaromatic ring" refers to a monovalent 4 to 6 membered monocyclic heteroaromatic ring containing from 4 to 5 carbon atoms and from 1 to 4 hetero nitrogen.

[179] The term "pharmaceutically acceptable salts" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formulae IX, IX-A, IX-B, IX-C, IX-D, IX-E and IX-F are formed from suitable non-toxic organic or inorganic acids, or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygro- scopicity, flowability and solubility of compounds. See, e.g., H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.

[ 180] Representative examples of the racemic or enantiomerically enriched azole compounds containing carbamoyl group represented by the general structural formula (IX) are selected from the group consisting of

[181]

[182] Table 1

# Compound name

Carbamic acid l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-methoxy-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-phenyl-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-methoxy-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-phenyl-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-p-tolyl-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(3-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(4-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-p-tolyl-ethyl ester

Carbamic acid l-o-tolyl-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(4-nitro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(4-nitro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-fluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-fluoro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(3-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-m-tolyl-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-m-tolyl-ethyl ester

Carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid (S)-l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-o-tolyl-ethyl ester

Carbamic acid l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-(3-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid 2-[l,2,3]triazol-2-yl-l-(3-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid l-(2,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-(4-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid 2-[l,2,3]triazol-2-yl-l-(4-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid 2-[l,2,3]triazol-2-yl-l-(2-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid 2-chloro-l-phenyl-2-tetrazol-l-yl-ethyl ester

Carbamic acid (S)-l-(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-l-(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2-chloro-phenyl)-2-(5-methyl-tetrazol-2-yl)-ethyl ester

Carbamic acid l-(2-chloro-phenyl)-2-(5-methyl-tetrazol-l-yl)-ethyl ester

Methyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Ethyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Phenyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-2-tetrazol-2-yl-l-(2-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid (S)-2-tetrazol-2-yl-l-(2-trifluoromethyl-phenyl)-ethyl ester

Carbamic acid l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Methyl-carbamic acid l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Cyclopropyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Methyl-carbamic acid (R)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Carbamic acid l-phenyl-3-tetrazol-2-yl-propyl ester

Carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-2-yl ]-ethyl ester

Methyl-carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-2-yl ] -ethyl ester

Carbamic acid l-(4-hydroxy-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Methyl-carbamic acid (S)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Carbamic acid (S)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-l-yl)-ethyl ester

Methyl-carbamic acid (S)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol- 1 -yl)-ethyl ester

Carbamic acid l-phenyl-3-tetrazol-l-yl-propyl ester

Carbamic acid l-phenyl-3-tetrazol-l-yl-propyl ester

Carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-l-yl ]-ethyl ester

Methyl-carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-l-yl ] -ethyl ester

Carbamic acid l-(3-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

Methyl-carbamic acid l-(3-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

Carbamic acid l-(3-chloro-phenyl)-2-tetrazol-l-yl-propyl ester

Carbamic acid l-(2-chloro-phenyl)-3-[l,2,3]triazol-2-yl-propyl ester

Carbamic acid l-(2-chloro-phenyl)-2-(5-pyridin-2-yl-tetrazol-2-yl)-ethyl ester

Carbamic acid 2-(5-amino-tetrazol-2-yl)-l-(2-chloro-phenyl)-ethyl ester

Carbamic acid l-(3-chloro-phenyl)-2-[l,2,3]triazol-2-yl-propyl ester

Methyl-carbamic acid l-(3-chloro-phenyl)-2-[l,2,3]triazol-2-yl-propyl ester

Ethyl-carbamic acid 1 -(2-chloro-phenyl)-2-(5-pyridin-2-yl-tetrazol-2-yl)-ethyl ester

Carbamic acid l-(4-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

Methyl-carbamic acid l-(4-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

Carbamic acid l-(4-chloro-phenyl)-2-tetrazol-l-yl-propyl ester

Methyl-carbamic acid l-(4-chloro-phenyl)-2-tetrazol-l-yl-propyl ester

Carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester

Methyl-carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester

Carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-l-yl-propyl ester

Methyl-carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-l-yl-propyl ester

Carbamic acid l-(3,4-dimethoxy-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-l-(4-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (R)-l-(4-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (S)-l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (R)-l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2,5-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid (R)-l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (R)-l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid l-(4-phenoxy-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-phenoxy-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-(2,5-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (S)-l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-l-(3,4-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2,6-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(2,6-dichloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid l-(2,4-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-naphthalen-2-yl-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-naphthalen-2-yl-2-tetrazol-l-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-(2,3,4-trimethoxy-phenyl)-ethyl ester

Carbamic acid 2-tetrazol-l-yl-l-(2,3,4-trimethoxy-phenyl)-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-(3,4,5-trimethoxy-phenyl)-ethyl ester

Carbamic acid l-benzo[l,3]dioxol-5-yl-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-benzo[l,3]dioxol-5-yl-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-(4-dimethylamino-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-(2,4,6-trimethyl-phenyl)-ethyl ester

Carbamic acid 2-tetrazol-l-yl-l-(2,4,6-trimethyl-phenyl)-ethyl ester

Carbamic acid (S)-l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-l-(2,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid (R)-l-(2,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid 2-phenyl-l-tetrazol-2-ylmethyl-ethyl ester

Carbamic acid 2-phenyl-l-tetrazol-l-ylmethyl-ethyl ester

Carbamic acid l-(4-tert-butyl-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-tert-butyl-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-(4-chloro-3-trifluoromethyl-phenyl)-2-[l,2,3]triazol-2-yl- ethyl ester

Carbamic acid l-(4-chloro-3-trifluoromethyl-phenyl)-2-[l,2,3]triazol-l-yl- ethyl ester

Carbamic acid (S)-l-(2,6-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid (R)-l-(2,6-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-indan-5-yl-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-indan-5-yl-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-l-(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-l-(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-(2,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

O-l-(2-Chloro-phenyl)-2-tetrazol-2-yl ethyl allophanate

Carbamic acid (R)-l-(2,4-dichloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid l-phenyl-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-(3,4-difluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(3,4-difluoro-phenyl)-2-tetrazol-l-yl-ethyl ester

Carbamic acid l-(3,4-difluoro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

Carbamic acid l-(3,4-difluoro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

Carbamic acid l-(2-fluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2-fluoro-phenyl)-2-tetrazol-l-yl-ethyl ester

4-Benzyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-Phenyl-piperazine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-Phenyl-piperazine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester

4-(4-Fluoro-benzoyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester

l-Benzyl-4-[l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethoxycarbon yl]-piperazin-l-ium

Carbamic acid 2-(3,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

Imidazole- 1 -carboxylic acid 2-(3 ,4-dichloro-phenoxy)- 1 -tetrazol- 1 -ylmethyl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-l -tetrazol- 1 -ylmethyl-ethyl ester

Imidazole- 1 -carboxylic acid 2-(4-chloro-phenoxy)- 1 -tetrazol- 1 -ylmethyl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

4-Benzyl-piperidine-l -carboxylic acid l-phenyl-2-tetrazol-l-yl-ethyl ester

4-Benzyl-piperidine-l -carboxylic acid l-phenyl-2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-(2-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid 2-(2-chloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(2-chloro-phenoxy)-l-tetrazol-l-ylmethyl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid 2-(2-chloro-phenoxy)- 1 -tetrazol- 1 -ylmethyl-ethyl ester

Carbamic acid l-(2,4-difluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2,4-difluoro-phenyl)-2-tetrazol-l-yl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid (S)- l-(2-chloro-phenyl)-2-[ 1,2,3] triazol- 2-yl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid

(R)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(2,4-dimethyl-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid (S)-I -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[2-(3,4-Dihydτoxy-phenyl)-ethyl]-carbamic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[2-(3,4-Dihydτoxy-phenyl)-ethyl]-carbamic acid 1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester

4-Benzyl-piperidine-l-carboxylic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3] triazol- 2-yl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-l-[l,2,3]triazol-l-ylmethyl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid 2-(4-chloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester

4-B enzyl-piperidine- 1 -carboxylic acid 2-(4-chloro-phenoxy)- 1 -tetrazol- 1 -ylmethyl-ethyl ester

4-(4-Methoxy-benzyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-Pyridin-4-ylmethyl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Fluoro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-(4-Fluoro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Chloro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-(4-Chloro-phenyl)-pyrrolidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-[ 1 ,2,3]Triazol-2-ylmethyl-piperidine- 1-carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-Tetrazol-2-ylmethyl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-[ 1 ,2,3]Triazol-2-ylmethyl-piperidine- 1-carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-Benzoyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Chloro-benzoyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Methoxy-benzoyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-[ 1 ,2,3]Triazol- 1 -ylmethyl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-Tetrazol-2-ylmethyl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-[ 1 ,2,3]Triazol-2-yl-piperidine- 1-carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(5-Phenyl-tetrazol-2-yl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-[ 1 ,2,3]Triazol- 1 -yl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 1 -(3 ,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-(4-Chloro-benzyl)-pyrrolidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3,5-Bis-trifluoromethyl-benzyl)-piperidine-l-carboxyli c acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-(5-Methyl-tetrazol-2-ylmethyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(5-Methyl-tetrazol-2-ylmethyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-l -carboxylic acid l-(2-chloro-phenyl)-2-[l,2,3] triazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid

1 -(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid

1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid

1 -(3 ,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid 2-(2-chloro-phenoxy)-l-[l,2,3] triazol- 2-ylmethyl-ethyl ester

3-Phenethyl-pyrrolidine-l-carboxylic acid 2-(2,4-dichloro-phenoxy)-l-[l,2,3] triazol-2-ylmethyl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid 2-(3 ,4-dichloro-phenoxy)- 1 - [ 1 ,2, 3] triazol-2-ylmethyl-ethyl ester

3-Phenethyl-pyrrolidine- 1 -carboxylic acid 2-(2,5-dichloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(2-chloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(3,4-dichloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(2,4-dichloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(2,5-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

4-(4-Fluoro-benzoyl)-piperidine- 1 -carboxylic acid 1 -(3 ,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Fluoro-benzoyl)-piperidine- 1 -carboxylic acid 1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Fluoro-benzoyl)-piperidine- 1 -carboxylic acid 1 -(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 2-(2-chloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 2-(2,4-dichloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 2-(3 ,4-dichloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester

3-[2-(4-Methoxy-phenyl)-ethyl]-pyrrolidine-l-carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3 ,4-Dichloro-benzyl)-piperidine- 1 -carboxylic acid 1 -phenyl-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-benzyloxy-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-benzyloxy-phenyl)-2-tetrazol-l-yl-ethyl ester

methyl-carbamic acid -l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

methyl-carbamic acid (S) -l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-benzyl-piperidine- 1 -carboxylic acid- 1 -(2-chloro-phenyl)-2- [ 1 ,2,3] triazol- 2-yl-ethyl ester

4-benzyl-piperidine- 1 -carboxylic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3] triazol- 2-yl-ethyl ester

[183] [184] In utilizing the compounds of the invention represented by the general structural formula (IX) for the treatment of diseases of the central nervous system, particularly the treatment of anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, cognitive impairment, stroke and muscle spasm, it is preferred to administer the compounds orally. For oral administration, the compounds of formula (IX) are preferably combined with a pharmaceutical carrier. The ratio of the carrier to a compound of formula (IX) is not critical to achieve the desired effects on the central nervous system of the host requiring such treatment, and can vary considerably, depending on whether the composition is to be filled into capsules or formed into tablets. In tableting, it is usually desirable to employ at least as much pharmaceutical carrier as the pharma-

ceutically active ingredients. Various pharmaceutical carriers or mixtures thereof can be used. Suitable carriers, for example, comprise mixtures of lactose, dibasic calcium phosphate and corn starch. Other pharmaceutically acceptable ingredients can be further added, including lubricants such as magnesium stearate.

[185] The compounds of formula (IX) can be formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms that are suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions, and the like. Furthermore, the compounds of the invention can be administered in the form of hard or soft capsules. Examples of suitable inert adjuvant materials that can be used in formulating the compounds of formula (IX) into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, and the like. Moreover, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, and the like, can be incorporated, if desired, into such formulations.

[186] The therapeutic use of the racemic or enantiomerically enriched compounds of general structural formula(IX) and their pharmaceutically useful salts have been established by the following tests.

[ 187] Light-Dark Box Test Methods

[188] Light-Dark Box (LDB) test, one of the unconditioned conflict tests, was used to investigate anxiolytic activity for several drugs such as Diazepam, Buspirone, etc (Allikmets et al, 1996; Belzung and Griebel, 2001; Cutler and Aitken, 1991; Leyre et al, 2004). In the present study, anxiolytic effect of azole compounds containing carbamoyl group represented by general structural formula (IX) was investigated on the LDB test in mice.

[189] The animals were treated with compound 30 min prior to testing. The light-dark box consisted of a plexiglas apparatus measuring 45cmx7cmx7cm (LxWxH), and was partitioned into two compartments, one fully opaque (dark compartment made of black plexiglas : 18cm of total length of apparatus), while the second was lit from the compartment ceiling by a IOOW bulb. A small opening (7x7cm) in the partition wall allowed free passage between the light and dark compartments.

[190] Animals were placed at the lit compartment first, and the latency for escape into dark was checked and tested in the LDB for 5 min after the first entering into dark box. The animal, which the latency was over 2 min, was excluded from the test. Total time spent in the light compartment was counted. Movement of animal was checked through the TV-CCD camera by an experienced observer blind to the conditions of the experiment. A mouse whose four paws were in the new box was considered as having changed box.

[191] The compounds with a higher % duration value in the light box are more potent as anxiolytics. [192] Maximal Electro Shock-induced Tonic Seizure Test Methods

[193] The "Maximal ElectroShock (MES)" test is a well-established pharmacological screening method for anticonvulsants against tonic-clonic seizures. The procedure employed in the MES test for anticonvulsants is as follows. The compounds to be tested were dissolved in 30% PEG400 and administered ip and po into animals. After the designated number of hours, maximal electroshock (50 mA, 60 Hz, 0.2 sec) was applied into animals via corneal electrodes using IITC Life Science model 1 IA Shocker. Anticonvulsant activity is demonstrated by the protection against MES- induced hindlimb tonic extension. Median efficacy dose (ED50) levels were determined using three different dose levels with at least 8 mice in each group. Compounds with smaller ED50 value and higher protection rate are more potent as anticonvulsants.

[194] Pentylenetetrazol-induced Clonic Seizure Test Methods

[195] The "Pentylenetetrazol (PTZ)" test for anticonvulsant and antianxiety activity was also carried out. Compounds that antagonize the effects of subcutaneous PTZ-induced clonic seizures are known to elevate the seizure threshold, hence are generally useful in preventing absence seizures.

[196] The procedure employed in the PTZ test is as follows. The compounds to be tested were dissolved in 30% PEG400 and administered ip and po into animals. After the designated number of hours, each animal was injected subcutaneously with 100 mg/kg of PTZ (CD97 dose) and observed for up to 30 minutes for the presence or absence of clonic spasms over 5 seconds. Median efficacy dose (ED50) levels were determined using three different dose levels with 8 mice in each group. The compounds with a smaller ED50 value and higher protection rate are more potent as anticonvulsant and anxiolytics.

[197] Forced Swimming Test Methods

[198] The "Forced swimming test (FST)" for antidepressant activity was also carried out.

The procedure employed in the FST for antidepressant is as follows. The compounds to be tested were dissolved in 30% PEG400 and administered ip and po into animals. 30 min later, the immobility time during post 4 minutes of 6 minutes experiment time was measured. The compounds with a higher reduction % value of immobility are more potent as antidepressants

[199] GABA-A receptor (TBPS site) Binding Assay Methods

[200] Compounds of the inventions were tested for specific binding to TBPS (t-butyl bi- cyclophosphorothionate) site, an allosteric modulator site of GABA-A receptor as modified from G. Maksay and M. Simonyi, Eur. J. Pharmacol. 1985, 117(2), 275. and

Gee, K.W. et al., J. Pharm. Exp. Ther. 1988, 246, 803.

[201] This binding assay was performed using [35S] TBPS as radioligand in washed crude membrane homogenate from rat brains. Membrane preparations were carried out according to procedure described below. Sprague-Dawley (SD) rat weighting 23Og were killed by decapitation and their whole brains were rapidly removed and its cerebellums were excluded. The dissected brains were homogenized for 30 sec in 10 volumes (W/V) of ice-cold 0.32 M Sucrose and 5OmM Tris-citrate buffer pH 7.4 using glass homogenate. The homogenate was centrifuged at 2,000xg for 5 min at 4°C. And the supernatant re-centrifuged at 50,000xg for 20 min at 4°C. The supernatant was discarded and the resulting pellets were resuspended in 10 volumes (WfV) of ice-cold 5OmM Tris-citrate buffer pH 7.4. And then the suspended pellet was centrifuged at 50,000xg for 20 min at 4°C. The resulting pellets were suspended again in 32 volumes (W/V) of ice-cold 5OmM Tris-citrate buffer pH 7.4 with 0.05% Triton X-100 and then incubated in 37°C for 60 min using a water bath. The incubated suspension was centrifuged at 50,000xg for 20 min at 4°C. Resuspending and centrifugation step of the remained pellets were repeated twice at the same manner and final pellets were re- suspended in 10 volumes(W/V) of ice-cold 5OmM Tris-citrate buffer pH 7.4 to enable distribution of 2 ml aliquot in microcentrifuge tube, which were used immediately or kept at -80°C for no more than 1 month before use.

[202] For TBPS site binding assay, 50 D of the tested compound were added to IOOD membrane protein suspended in 0.15ml of 5OmM Tris-citrate buffer with 20OmM NaCl pH 7.4 in presence of 2 nM of [35S] TBPS. The incubation of mixtures were carried out for 1.5 hours at 25°C and then rapidly filtered over Whatman GF/C glass fiber filters, followed by twice 4.5ml rinses with ice-cold incubation buffer. The filters were placed in counting vials and 4 ml scintillation solution. The vials were counted in a Beckman scintillation counter. Non-specific binding was determined in parallel incubations with lOOμM picrotoxin.

[203] IC50 values for TBPS site binding assay was calculated using Graphpad PRISM v.3.00. The compounds with a smaller IC50 value or higher inhibition % are more potent as GABA allosteric modulator.

[204] Dopamine Transport Assay Methods (Measurement of Dopamine uptake)

[205] The "Dopamine Transport (DAT)" assay for dopamine uptake inhibition was also carried out. In order to test dopamine uptake inhibition, compounds of the inventions were assayed as modified from Zhaoping Liu et. al., Neuropharmacology, 2001, 41, 464.

[206] Cultured CHO cells were infected with recombinant plasmid, DAT-pCDNA3, which encodes rat dopamine transporter. Several subclones were selected and assayed for [3H] dopamine uptake. The clone with the highest uptake, designated D8, was

chosen for Dopamine transport assay of compounds.

[207] For the Dopamine transport assay, D8 cells were cultured in 48-well plate using RMPI 1640 containing 10% FCS. D8 cells, grown to 60,000 cells per well, each wells were rinsed once with phosphate buffered saline (PBS) and pre-incubated in 100 D Hank's balanced salt solution (HBSS) for 10 min at room temperature. The buffer was then changed to 50 D HBSS containing the tested compounds and 350 D HBSS containing reaction components ([3H] dopamine, ascorbic acid and pargyline). Final concentrations of [3H] dopamine, ascorbic acid and pargyline are 151 nM, 100 μM and 100 μM, respectively. The cells were incubated for 20 min at room temperature and the reaction was terminated by aspiration of the buffer and washed three times with ImI cold PBS. The cells were then solubilized in 2N NaOH and an aliquot was measured by liquid scintillation counting to quantify the uptake of [3H] dopamine. The compounds with higher inhibition % are more potent as dopamine uptake inhibitor.

[208] Test results obtained with the compounds of general structural formula (IX) and pharmaceutically useful salts of the invention are set forth in Table 2.

[209] [210] Table 2

[211]

[213] As described hereinbefore, the racemic or enantiomerically enriched azole compounds containing carbamoyl group represented by the general structural formula (IX) and pharmaceutically useful salts thereof of the present invention were observed to have anxiolytic and anticonvulsant activity in the LDB test, MES test, PTZ test and TBPS assay. The compounds showing GABA-related activities can be applied to the treatment of sleep disorder or muscle spasms. Furthermore, the racemic or enantiomerically enriched azole compounds containing carbamoyl group represented by the general structural formula (IX) and pharmaceutically useful salts thereof of the present invention were also observed to have antidepressant activity and affinity to dopamine uptake inhibition. Also the compounds acting as dopamine reuptake inhibitors can be developed for the treatment of ADHD, obesity or abuse syndromes of drugs or smoking. The compounds with the anticonvulsant and/or antiepileptic activities may also be used for the treatment of bipolar disorders, migraine prophylaxis, and neuropathic pain as their additional indications. Accordingly the racemic or enantiomerically enriched azole compounds containing carbamoyl group represented by the general structural formula (IX) and pharmaceutically useful salts thereof of the present invention can be used in the treatment of disorders of the central nervous system, especially as anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, cognitive impairment, stroke, neurodegeneration and muscle spasm.

[214] The amount of a compound of general structural formula (IX) and pharmaceutically useful salts thereof, which is present in any of the above-described dosage forms, is variable. In the systemic treatment of CNS diseases with an active amount of compounds of the general structural formula (IX) and pharmaceutically useful salts thereof, the dosage is typically from about 0.02mg to about 250 mg/kg/day

(0.001 ~12.5g/day in a typical human weighing 50kg) in single or divided doses, regardless of the route of administration. A more preferred dosage range is from about 0.15mg/kg/day to about 250mg/kg/day. Of course, depending upon the exact compound and the exact nature of the individual illness, doses outside this range may be prescribed by the attending physician.

[215] The examples, which follow further, illustrate the invention. AU parts are by weight and all temperatures are in degrees centigrade, unless otherwise mentioned. Moreover, unless otherwise stated, NMR spectra were obtained at 200MHz.

[216]

Mode for the Invention

[217] A better understanding of the present invention may be obtained in light of following examples that are set forth to illustrate, but are not to be construed to limit, the present invention.

[218] Preparation of azole compounds containing carbamoyl group of the general structural formula (IX).

[219] Example 1

[220] Carbamic acid l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[221] To a solution of 2-bromo-2'-chloroacetophenone (2mmol) and sodium carbonate

(4mmol) in toluene (100ml), lH-l,2,3-triazole (4mmol) was added. The reaction was refluxed for 4h and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in methanol (50ml) and was added with sodium borohydride (8mmol) slowly at O ⁰ C to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2Λf-l,2,3-triazole. After Ih stirring at room temperature, this solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 4h, followed by the addition of excess ammonium hydroxide (50ml). After 4h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 2) and give carbamic acid l-(2-chloro-phenyl)-2-[ 1,2,3] triazol-2-yl-ethyl ester.

[222] ¹ H-NMR (CDCl ₃ ) δ7.62 (s, 1Η), 7.21-7.38 (m, 4Η), 6.55 (m, IH), 5.09 (br, 2H),

4.8 (m, 2H)

[223] Example 2

[224] Carbamic acid l-(4-methoxy-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[225] The procedure given in Example 1 was followed using

2-bromo-4'-methoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(4-methoxy-phenyl)-2-[l,2,3] triazol-2-yl-ethyl ester. [226] ¹ H-NMR (Acetone-d ₆ ) δ7.65 (s, 2H), 7.35 (d, 2H), 6.92 (d, 2H), 6.15 (m, IH),

5.75-6.1 (br, 2H), 4.7 (m, 2H), 3.81 (s, 3H) [227] Example 3

[228] Carbamic acid l-phenyl-2-[l,2,3]triazol-2-yl-ethyl ester

[229] The procedure given in Example 1 was followed using 2-bromo acetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid l-phenyl-2-[l,2,3]triazol-2-yl-ethyl ester. [230] ¹ H-NMR (CDCl ₃ ) δ7.62(s, IH), 7.37(br, 5H), 6.21(m, IH), 4.98(br, 2H), 4.8(m,

2H)

[231] Example 4

[232] Carbamic acid l-(3-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[233] The procedure given in Example 1 was followed using

2-bromo-3'-chloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3-chloro-phenyl)-2-[l,2,3] triazol-2-yl-ethyl ester [234] ¹ H-NMR (Acetone-d ₆ ) δ7.67(s, 2H), 7.6-7.2(m, 4H), 6.25(m, IH), 6.15(br, 2H),

4.8 l(m, 2H) [235] Example 5

[236] Carbamic acid l-(4-nitro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[237] The procedure given in Example 1 was followed using

2-bromo-4'-nitroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(4-nitro-phenyl)-2-[ 1,2,3] triazol-2-yl-ethyl ester.

[238] ¹ H-NMR (DMSO-d ₆ ) δ8.15(s, 2H), 7.5 (m, 4H), 6.19 (m, 3H), 4.6- 4.95 (m, 2H)

[239] Example 6

[240] Carbamic acid l-(4-fluoro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[241] The procedure given in Example 1 was followed using

2-bromo-4'-fluoroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(4-fluoro-phenyl)-2-[l,2,3] triazol-2-yl-ethyl ester. [242] ¹ H-NMR (Acetone-dp δ7.66(s, 2H), 7.2-7.5(m, 4H), 6.3(m, IH), 5.8-6.6(br, 2H),

4.7(m, 2H)

[243] Example 7

[244] Carbamic acid l-m-tolyl-2-[l,2,3]triazol-2-yl-ethyl ester

[245] The procedure given in Example 1 was followed using

2-bromo-3'-methylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-m-tolyl-2-[l,2,3] triazol-

2-yl-ethyl ester. [246] ¹ H-NMR (Acetone-d ₆ ) δ7.67(s, 2H), 7.1-7.35(m, 4H), 6.2(m, IH), 5.7-6.3(br, 2H),

4.7(m, 2H)

[247] Example 8

[248] Carbamic acid l-(3,4-dichloro-phenyl)-2-[l^,3]triazol-2-yl-ethyl ester

[249] The procedure given in Example 1 was followed using

2-bromo-3',4'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester. [250] ¹ H-NMR (Acetone-dp δ7.67(s, 2H), 7.57(m, 2H), 7.36(m, IH), 6.19(m, IH),

5.9-6.3(br, 2H), 4.8-4.9(m, 2H) [251] Example 9

[252] Carbamic acid 2-[l,2^]triazol-2-yl-l-(3-trifluoromethyl-phenyl)-ethyl ester

[253] The procedure given in Example 1 was followed using

2-bromo-3'-(trifluoromethyl)acetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid 2-[ 1,2,3] triazol-

2-yl- 1 -(3-trifluoromethyl-phenyl)-ethyl ester.

[254] ¹ H-NMR (Acetone-dp δ7.67 (m, 6H), 6.30(m, IH), 5.9-6.4(br, 2H), 4.87(m, 2H)

[255] Example 10

[256] Carbamic acid l-(2,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[257] The procedure given in Example 1 was followed using

2-bromo-2',4'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,4-dichloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [258] ¹ H-NMR (Acetone-d^ δ7.68(s, 2H), 7.5(m, 3H), 6.50(m, IH), 5.9-6.4(br, 2H),

4.8(m, 2H)

[259] Example 11

[260] Carbamic acid 2-[l,2^]triazol-2-yl-l-(4-trifluoromethyl-phenyl)-ethyl ester

[261] The procedure given in Example 1 was followed using

2-bromo-4'-(trifluoromethyl)acetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid 2-[ 1,2,3] triazol-

2-yl- 1 -(3-trifluoromethyl-phenyl)-ethyl ester. [262] ¹ H-NMR (Acetone-d ) δ7.72 (m, 6H), 6.29(m, IH), 5.8-6.8(br, 2H), 4.8(m, 2H)

6

[263] Example 12

[264] Carbamic acid 2-[l,2^]triazol-2-yl-l-(2-trifluoromethyl-phenyl)-ethyl ester

[265] The procedure given in Example 1 was followed using

2-bromo-2'-(trifluoromethyl)acetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid 2-[ 1,2,3] triazol-

2-yl- 1 -(2-trifluoromethyl-phenyl)-ethyl ester.

[266] ¹ H-NMR (Acetone-d ₆ ) δ7.7 (m, 6H), 6.64(m, IH), 5.7-6.4(br, 2H), 4.75(m, 2H)

[267] Example 13

[268] Carbamic acid l-(2-chloro-phenyl)-3-[l,2,3]triazol-2-yl-propyl ester

[269] The procedure given in Example 1 was followed using methanesulfonic acid

3-(2-chloro-phenyl)-3-hydroxy-propyl ester as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(2-chloro-phenyl)-3-[l,2,3] triazol-2-yl-propyl ester without carbonyl reduction. [270] ¹ H-NMR (Acetone-dp δ7.87 (d, 2H), 8-7(m, 4H), 6.27(br, 2H), 6.00(m, IH),

4.64(m, 2H), 2.4(m, 2H) [271] Example 14

[272] Carbamic acid l-(3-chloro-phenyl)-2-[l,2,3]triazol-2-yl-propyl ester

[273] The procedure given in Example 1 was followed using

2-Bromo-l-(3-chloro-phenyl)-propan-l-one as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3-chloro-phenyl)-2-[l,2,3] triazol-2-yl-propyl ester. [274] ¹ H-NMR (Acetone-dp δ8.09(s, IH), 7.68(s, IH), 7.3(m, 4H), 5.9-6.6(br, 2H),

6.07(m, IH), 5.2 (m, IH), 1.57(d, 3H) [275] Example 15

[276] Methyl-carbamic acid l-(3-chloro-phenyl)-2-[l,2,3]triazol-2-yl-propyl ester

[277] The procedure given in Example 14 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid

1 -(3-chloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-propyl ester. [278] ¹ H-NMR (Acetone-dp δ8.06(s, IH), 7.65(s, IH), 7.3(m, 4H), 6.5(br, IH), 6.05(m,

IH), 5.2 (m, IH), 2.66(m, 3H), 1.54(d, 3H) [279] Example 16

[280] Carbamic acid l-(2,5-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[281] The procedure given in Example 1 was followed using

2-bromo-2',5'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,5-dichloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [282] ¹ H-NMR (Acetone-dp δ7.69(s, 2H), 7.46(m, 3H), 6.35(m, IH), 5.9-6.58(br, 2H),

4.84(m, 2H)

[283] Example 17

[284] Carbamic acid l-(2,6-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[285] The procedure given in Example 1 was followed using

2-bromo-2',6'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,6-dichloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [286] ¹ H-NMR (Acetone-d ₆ ) δ7.68(s, 2H), 7.37-7.6(m, 3H), 6.9 (m, IH), 5.8-6.25(br,

2H), 4.96(m, 2H) [287] Example 18

[288] Carbamic acid l-(4-chloro-3-trifluoromethyl-phenyl)-2-[l,2,3] triazol-

2-yl-ethyl ester [289] The procedure given in Example 1 was followed using

2-bromo-4'-chloro-3'-(trifluoromethyl)acetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(4-chloro-3-trifluoromethyl-phenyl)-2-[l,2,3]triazol-2-yl- ethyl ester. [290] ¹ H-NMR (Acetone-dp 07.9-7.6 (m, 5H), 6.26(m, IH), 6.2(br, 2H), 4.88(m, 2H)

[291] Example 19

[292] Carbamic acid l-(2,4-dimethyl-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[293] The procedure given in Example 1 was followed using

2-bromo-2'-4'-dimethylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(2,4-dimethyl-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester. [294] ¹ H-NMR (Acetone-dp δ7.93(s, IH), 7.63(s, IH), 7.46 (d, IH), 7.1(m, 2H), 5.35(br,

2H), 5.0(m, IH), 4.55(m, 2H), 2.33(s, 3H), 2.30(s, 3H) [295] Example 20

[296] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester [297] The procedure given in Example 1 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [298] ¹ H-NMR (Acetone-d^ δ7.9(s, 2H), 7.48(m, 3H), 7.36(s, IH), 7.22(d, 2H), 7.02(s,

IH), 4.07(d, 2H), 3.15(t, 2H), 2.68(d, 2H), 1.76(m, 4H), 1.33(m, 4H) [299] Example 21

[300] Carbamic acid l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

[301] To a solution of 2-bromo-2'-chloroacetophenone (2mmol) and sodium carbonate

(4mmol) in toluene (100ml), lH-l,2,3-triazole (4mmol) was added. The reaction was refluxed for 4h and then cooled to 25°C. This solution was then concentrated on a

rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in methanol (50ml) and was added with sodium borohydride (8mmol) slowly at 0°C to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is lN-l,2,3-triazole.. After Ih stirring at room temperature, this solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 4h, followed by the addition of excess ammonium hydroxide (50ml). After 4h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo.

[302] The preparation procedure of lN-azole is same as that of 2N-azole in example 1 except the ratio of mobile phase of column chromatography. lN-Azole is more polar than 2N-azole in chromatographic condition and separated by eluting with an increasing ratio of ethyl acetate in hexane after elution of 2N-azole to give carbamic acid l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester.

[303] ¹ H-NMR (CDC13) δ7.57(s, IH), 7.53(s, IH), 7.05-7.35(m, 4H), 6.20(m, IH),

5.64(br, 2H), 4.66(m, 2H)

[304] Example 22

[305] Carbamic acid l-(2,6-dichloro-phenyl)-2-[l^,3]triazol-l-yl-ethyl ester

[306] The procedure given in Example 21 was followed using

2-bromo-2',6'-dichloroacetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 1 -(2,6-dichloro-phenyl)-2- [ 1 ,2,3]triazol- 1 -yl-ethyl ester.

[307] ¹ H-NMR (Acetone-d ₆ ) δ8.05(s, IH), 7.69(s, IH), 7.40-7.89(m, 3H), 6.97(m, IH),

5.82-6.64(br, 2H), 5.58-5.52 (m, 2H)

[308] Example 23

[309] Carbamic acid l-(4-chloro-3-trifluoromethyl-phenyl)-2-[l,2,3] triazol-

1-yl-ethyl ester

[310] The procedure given in Example 21 was followed using

2-bromo-4'-chloro-3'-(trifluoromethyl)acetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid l-(4-chloro-3-trifluoromethyl-phenyl)-2-[l,2,3]triazol-l-yl- ethyl ester.

[311] ¹ H-NMR (Acetone-dp δ7.99 (d, IH), 7.81(s, IH), 7.68-7.65(m, 3H), 6.20(m, 3H),

4.93(dd, 2H)

[312] Example 24

[313] Carbamic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[314] To a solution of 2-bromo-2'-chloroacetophenone (2mmol) and sodium carbonate

(4mmol) in toluene (100ml), lH-tetrazole (4mmol) was added. The reaction was refluxed for 4h and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in methanol (50ml) and was added with sodium borohydride (8mmol) slowly at O ⁰ C to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2N-tetrazole. After Ih stirring at room temperature, this solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 4h, followed by the addition of excess ammonium hydroxide (50ml). After 4h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 2) and give acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

[315] ¹ H-NMR (Acetone-dp 68.71 (s, 1Η), 7.32-7.51 (m, 4Η), 6.56 (m, IH), 6.18 (br,

2H), 5.09 (m, 2H)

[316] Example 25

[317] Carbamic acid l-(4-methoxy-phenyl)-2-tetrazol-2-yl-ethyl ester

[318] The procedure given in Example 24 was followed using

2-bromo-4'-methoxyacetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 1 -(4-methoxy-phenyl)-2-tetrazol-2-yl-ethyl ester.

[319] ¹ H-NMR (Acetone-dp 08.45 (s, IH), 7.30 (d, 2H), 6.90 (d, 2H), 6.18 (m, IH),

4.18-5.19 (m, 4H), 3.83 (s, 3H)

[320] Example 26

[321] Carbamic acid l-phenyl-2-tetrazol-2-yl-ethyl ester

[322] The procedure given in Example 24 was followed using 2-bromo acetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 1 -phenyl-2-tetrazol-2-yl-ethyl ester.

[323] ¹ H-NMR (Acetone-dp 08.55 (s, IH), 7.41 (s, 5H), 6.15 (m, IH), 4.9-5.1 (m, 2H),

4.7-4.95 (br, 2H)

[324] Example 27

[325] Carbamic acid l-(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[326] The procedure given in Example 24 was followed using

2-bromo-4'-chloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [327] ¹ H-NMR (Acetone-d ₆ ) δ8.73 (s, IH), 7.47 (m, 4H), 6.3 (m, IH), 5.8-6.3 (br, 2H),

5.13 (m, 2H) [328] Example 28

[329] Carbamic acid 2-tetrazol-2-yl-l-p-tolyl-ethyl ester

[330] The procedure given in Example 24 was followed using

2-bromo-4'-methylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid 2-tetrazol-2-yl-l-p-tolyl-ethyl ester. [331] ¹ H-NMR (Acetone-d ₆ ) δ8.54(s, IH), 7.15-7.4(m, 4H), 6.19(m, IH), 4.95(m, 2H),

4.6-5.2(br, 2H), 2.38(s, 3H) [332] Example 29

[333] Carbamic acid l-(4-nitro-phenyl)-2-tetrazol-2-yl-ethyl ester

[334] The procedure given in Example 24 was followed using

2-bromo-4'-nitroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-nitro-phenyl)-2-tetrazol-2-yl-ethyl ester. [335] ¹ H-NMR (Acetone-d ₆ ) δ8.77(s, IH), 8.3(m, 2H), 7.75(m, 2H), 6.4(m, IH),

6.0-6.6(br, 2H), 5.23(m, 2H) [336] Example 30

[337] Carbamic acid l-(4-fluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

[338] The procedure given in Example 24 was followed using

2-bromo-4'-fluoroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-fluoro-phenyl)-2-tetrazol-2-yl-ethyl ester. [339] ¹ H-NMR (Acetone-d^ δ8.72(s, IH), 7.5 l(m, 2H), 7.22(m, 2H), 6.35(m, IH),

5.8-6.4(br, 2H), 5.13(m, 2H) [340] Example 31

[341] Carbamic acid l-(3-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[342] The procedure given in Example 24 was followed using

2-bromo-3'-chloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(3-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [343] ¹ H-NMR (Acetone-dp δ8.47(s, IH), 7.12-7.38(m, 4H), 6.15(m, IH), 5.2-5.4(br,

2H), 4.9(m, 2H)

[344] Example 32

[345] Carbamic acid 2-tetrazol-2-yl-l-m-tolyl-ethyl ester

[346] The procedure given in Example 24 was followed using

2-bromo-3'-methylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid 2-tetrazol-2-yl-l-m-tolyl-ethyl ester. [347] ¹ H-NMR (Acetone-d ₆ ) δ8.50(s, IH), 7.16-7.29(m, 4H), 6.18(m, IH), 4.8-5.2(br,

2H), 4.90(m, 2H) [348] Example 33

[349] Carbamic acid 2-tetrazol-2-yl-l-o-tolyl-ethyl ester

[350] The procedure given in Example 24 was followed using 2-bromo

2'-methylacetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 2-tetrazol-2-yl-l-o-tolyl-ethyl ester. [351] ¹ H-NMR (CDCl ₃ ) δ8.55(s, IH), 7.25-7.43(m, 4H), 7.05(br, 2H), 6.66(m, IH),

5.25(m, 2H)

[352] Example 34

[353] Carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[354] The procedure given in Example 24 was followed using

2-bromo-3',4'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [355] ¹ H-NMR (Acetone-d ₆ ) δ8.78(s, IH), 7.38-7.68(m, 3H), 6.25(m, IH), 5.89-6.62(br,

2H), 5.18(m, 2H) [356] Example 35

[357] Carbamic acid 2-tetrazol-2-yl-l-(3-trifluoromethyl-phenyl)-ethyl ester

[358] The procedure given in Example 24 was followed using

2-bromo-3'-trifluoromethylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid 2-tetr azol-

2-yl- 1 -(3-trifluoromethyl-phenyl)-ethyl ester. [359] ¹ H-NMR (Acetone-d^ δ8.78(s, IH), 7.58-7.80(m, 4H), 6.38(m, IH), 5.78-6.52(br,

2H), 5.20(m, 2H) [360] Example 36

[361] Carbamic acid l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[362] The procedure given in Example 24 was followed using 2-bromo

2',4'-dichloroacetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [363] ¹ H-NMR (Acetone-dp δ8.74(s, IH), 7.5(m, 3H), 6.53(m, IH), 5.9-6.5(br, 2H),

5.12(m, 2H)

[364] Example 37

[365] Carbamic acid 2-tetrazol-2-yl-l-(4-trifluoromethyl-phenyl)-ethyl ester

[366] The procedure given in Example 24 was followed using

2-bromo-4'-trifluoromethylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

2-tetrazol-2-yl- 1 -(4-trifluoromethyl-phenyl)-ethyl ester. [367] ¹ H-NMR (Acetone-d ₆ ) δ8.69(s, IH), 7.20-7.49(m, 4H), 6.36(m, IH), 5.90-6.5(br,

2H), 4.95(m, 2H) [368] Example 38

[369] Carbamic acid l-phenyl-3-tetrazol-2-yl-propyl ester

[370] The procedure given in Example 24 was followed using 3-chloropropiophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -phenyl-3-tetrazol-2-yl-propyl ester. [371] ¹ H-NMR (Acetone-dp δ8.73(s, IH), 7.44-7.31(m, 5H), 6.66(br, 2H), 5.75(q, IH),

4.80(m, 2H), 2.55(m, 2H) [372] Example 39

[373] Carbamic acid l-(4-hydroxy-phenyl)-2-tetrazol-2-yl-ethyl ester

[374] The procedure given in Example 24 was followed using

2-bromo-4'-hydroxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-hydroxy-phenyl)-2-tetrazol-2-yl-ethyl ester. [375] ¹ H-NMR (Acetone-dp δ9.04(s, IH), 7.28(m, 2H), 6.87(m, 2h), 5.92(m, IH),

5.65-6.25(br, 2H), 4.74(m, 2H), 3.05(br, IH) [376] Example 40

[377] Carbamic acid l-(2-chloro-phenyl)-3-tetrazol-2-yl-propyl ester

[378] The procedure given in Example 24 was followed using methanesulfonic acid

3-(2-chloro-phenyl)-3-hydroxy-propyl ester as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(2-chloro-phenyl)-3-tetrazol-2-yl-propyl ester without carbonyl reduction. [379] ¹ H-NMR (Acetone-d^ δ8.74(s, IH), 7.56-7.30(m, 4H), 6.20(br, 2H), 6.00(m, IH),

4.93(m, 2H), 2.55(m, 2H) [380] Example 41

[381] Carbamic acid l-(3-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

[382] The procedure given in Example 24 was followed using

2-bromo-l-(3-chloro-phenyl)-propan-l-one as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(3-chloro-phenyl)-2-tetrazol-2-yl-propyl ester. [383] ¹ H-NMR (Acetone-d ) δ8.74(s, IH), 7.4(m, 4H), 6.08(m, IH), 5.6-6.2(br, 2H), 5.5

6

(m, IH), 1.52(d, 3H) [384] Example 42

[385] Methyl-carbamic acid l-(3-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

[386] The procedure given in Example 24 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid

1 -(3-chloro-phenyl)-2-tetrazol-2-yl-propyl ester. [387] ¹ H-NMR (Acetone-d ₆ ) δ8.73(s, IH), 7.45(m, 4H), 6.2(m, IH), 5.8-6.1(br, IH), 5.5

(m, IH), 2.58(d, 3H), 1.52(d, 3H) [388] Example 43

[389] Carbamic acid l-(4-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

[390] The procedure given in Example 24 was followed using

2-bromo-l-(4-chloro-phenyl)-propan-l-one as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-chloro-phenyl)-2-tetrazol-2-yl-propyl ester. [391] ¹ H-NMR (Acetone-dp δ8.75(s, IH), 7.45(m, 4H), 6.10(d, IH), 6.08(br, 2H),

5.52(m, IH), 1.51(d, 3H) [392] Example 44

[393] Methyl-carbamic acid l-(4-chloro-phenyl)-2-tetrazol-2-yl-propyl ester

[394] The procedure given in Example 43 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid

1 -(4-chloro-phenyl)-2-tetrazol-2-yl-propyl ester. [395] ¹ H-NMR (Acetone-dp δ8.76(s, IH), 7.8-7(m, 4H), 6.35(br, IH), 6.12(d, IH),

5.51(m, IH), 2.58(d, 3H), 1.50(d, 3H) [396] Example 45

[397] Carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester

[398] The procedure given in Example 24 was followed using

2-Bromo-l-(3,4-dichloro-phenyl)-propan-l-one as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester. [399] ¹ H-NMR (Acetone-dp δ8.75(s, IH), 7.8-7.2(m, 3H), 6.12(d, IH), 6.1(br, 2H),

5.57(m, IH), 1.57(d, 3H) [400] Example 46

[401] Methyl-carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester

[402] The procedure given in Example 45 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester. [403] ¹ H-NMR (Acetone-dp δ8.74(s, IH), 7.8-7.2(m, 3H), 6.35(br, IH), 6.12(d, IH),

5.55(m, IH), 2.60(d, 3H), 1.55(d, 3H)

[404] Example 47

[405] Carbamic acid l-(3,4-dimethoxy-phenyl)-2-tetrazol-2-yl-ethyl ester

[406] The procedure given in Example 24 was followed using

2-bromo-3',4'-dimethoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-dimethoxy-phenyl)-2-tetrazol-2-yl-ethyl ester. [407] ¹ H-NMR (Acetone-d ₆ ) δ8.04(s, IH), 7.35-8.15(m, 3H), 6.7(m, IH), 6.2(br, 2H),

4.92(m, 2H), 1.35(m, 6H) [408] Example 48

[409] Carbamic acid l-(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[410] The procedure given in Example 24 was followed using

2-bromo-2',5'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [411] ¹ H-NMR (Acetone-dp δ8.74(s, IH), 7.25-7.63(m, 3H), 6.53(m, IH), 5.8-6.57(br,

2H), 5.15(m, 2H) [412] Example 49

[413] Carbamic acid l-(4-phenoxy-phenyl)-2-tetrazol-2-yl-ethyl ester

[414] The procedure given in Example 24 was followed using

2-bromo-4'-phenoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-phenoxy-phenyl)-2-tetrazol-2-yl-ethyl ester. [415] ¹ H-NMR (Acetone-dp δ8.73(s, IH), 7.49(m, 4H), 6.95-7.25(m, 5H), 6.26(m, IH),

5.8-6.39(br, 2H), 5.12(m, 2H) [416] Example 50

[417] Carbamic acid l-(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[418] The procedure given in Example 24 was followed using

2-bromo-2',6'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [419] ¹ H-NMR (Acetone-dp δ7.99(s, 2H), 7.2-7.7(m, 3H), 6.95(m, IH), 5.8-6.4(br, 2H),

4.86(m, 2H)

[420] Example 51

[421] Carbamic acid l-naphthalen-2-yl-2-tetrazol-2-yl-ethyl ester

[422] The procedure given in Example 24 was followed using 2-bromo-2'-acetonaphtone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -naphthalen-2-yl-2-tetrazol-2-yl-ethyl ester. [423] ¹ H-NMR (Acetone-d ) δ8.75(s, IH), 7.91-7.98(m, 4H), 7.52-7.65(m, 3H), 6.47(q,

IH), 6.19(br, 2H), 5.21 (m, 2H). [424] Example 52

[425] Carbamic acid 2-tetrazol-2-yl-l-(2,3,4-trimethoxy-phenyl)-ethyl ester

[426] The procedure given in Example 24 was followed using

2-bromo-2',3',4'-trimethoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

2-tetrazol-2-yl-l-(2,3,4-trimethoxy-phenyl)-ethyl ester. [427] ¹ H-NMR (Acetane-d) δ8.70(s, IH), 7.03(d, IH), 6.83(d, IH), 6.41(m, IH),

6.00(br, 2H), 5.07(m, 2H), 3.99(s, 3H), 3.87(s, 3H), 3.84(s, 3H) [428] Example 53

[429] Carbamic acid 2-tetrazol-2-yl-l-(3,4,5-trimethoxy-phenyl)-ethyl ester

[430] The procedure given in Example 24 was followed using

2-bromo-3',4',5'-trimethoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

2-tetrazol-2-yl-l-(3,4,5-trimethoxy-phenyl)-ethyl ester. [431] ¹ H-NMR (Acetone-dp δ8.73(s, IH), 6.79(s, 2H), 6.21(m, IH), 6.07(br, 2H),

5.03(m, 2H), 3.85(s, 6H), 3.74(s, 3H) [432] Example 54

[433] Carbamic acid l-benzo[l,3]dioxol-5-yl-2-tetrazol-2-yl-ethyl ester

[434] The procedure given in Example 24 was followed using as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-benzo[l,3] dioxol-

5-yl-2-tetrazol-2-yl-ethyl ester. [435] ¹ H-NMR (Acetone-dp δ8.72(s, IH), 6.99-6.86(m, 3H), 6.18(m, IH), 6.12(br, 2H),

6.04(s, 2H), 5.09(m, 2H) [436] Example 55

[437] Carbamic acid l-(4-dimethylamino-phenyl)-2-tetrazol-2-yl-ethyl ester

[438] The procedure given in Example 24 was followed using

2-bromo-4'-(dimethylamino) acetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-dimethylamino-phenyl)-2-tetrazol-2-yl-ethyl ester. [439] ¹ H-NMR (Acetone-d^ δ8.86(s, IH), 6.78-7.34(m, 4H), 6.12(m, IH), 5.7-6.25(br,

2H), 5.02(m, 2H), 1.35 (s, 6H) [440] Example 56

[441] Carbamic acid 2-tetrazol-2-yl-l-(2,4,6-trimethyl-phenyl)-ethyl ester

[442] The procedure given in Example 24 was followed using

2-bromo-2',4',6'-trimethylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

2-tetrazol-2-yl- 1 -(2,4,6-trimethyl-phenyl)-ethyl ester.

[443] ¹ H-NMR (Acetone-dJ δ8.79(s, IH), 7.56(s, 2H), 6.25(m, IH), 5.66-6.39(br, 2H),

5.04(m, 2H), 1.36(s, 9H) [444] Example 57

[445] Carbamic acid l-(4-tert-butyl-phenyl)-2-tetrazol-2-yl-ethyl ester

[446] The procedure given in Example 24 was followed using

2-bromo-4'-tert-butylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-tert-butyl-phenyl)-2-tetrazol-2-yl-ethyl ester. [447] ¹ H-NMR (Acetone-d^ δ9.07(s, IH), 7.44(m, 4H), 6.25(m, IH), 5.75-6.2(br, 2H),

4.96(m, 2H), 1.33(s, 9H) [448] Example 58

[449] Carbamic acid l-indan-5-yl-2-tetrazol-2-yl-ethyl ester

[450] The procedure given in Example 24 was followed using

2-bromo-l-indan-5-yl-ethanone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -indan-5-yl-2-tetrazol-2-yl-ethyl ester. [451] ¹ H-NMR (Acetone-dp δ8.72(s, IH), 7.31-7.22(m, 3H), 6.21(t, IH), 6.01(br, 2H),

5.06(m, 2H), 2.17-1.75(m, 6H) [452] Example 59

[453] Carbamic acid l-(3,4-difluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

[454] The procedure given in Example 24 was followed using

2-bromo-3',4'-difluoroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-difluoro-p henyl)-2-tetrazol-2-yl-ethyl ester.

[455] ¹ H-NMR (Acetone-dp δ8.78(s, IH), 7.46(m, 3H), 5.50-6.34(br, 3H), 5.13(m, 2H)

[456] Example 60

[457] Carbamic acid l-(2-fluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

[458] The procedure given in Example 24 was followed using

2-bromo-2'-fluoroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2-fluoro-phenyl)-2-tetrazol-2-yl-ethyl ester. [459] ¹ H-NMR (Acetone-d^ δ8.74(s, IH), 7.44(m, 4H), 5.60-5.81(m, IH), 5.13(br, 2H),

4.97(m, 2H)

[460] Example 61

[461] 4-Benzyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [462] The procedure given in Example 24 was followed using excess 4-benzyl piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [463] ¹ H-NMR (CDCl ₃ ) δ7.86(s, IH), 7.08-7.34(m, 9H), 4.1(m, 2H), 2.97(m, 2H), 2.6(m,

2H), 1.77(m, 4H), 1.267(m, 4H) [464] Example 62

[465] 4-Phenyl-piperazine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [466] The procedure given in Example 24 was followed using excess 4-phenyl piperazine as a reactant, instead of excess ammonium hydroxide, to give

4-phenyl-piperazine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [467] ¹ H-NMR (Acetone-dp δ8.77(s, IH), 7.54-6.82(m, 9H), 6.63(t, IH), 5.19(d, 2H),

3.73-2.89(d, 8H) [468] Example 63

[469] 4-(4-Fluoro-benzoyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [470] The procedure given in Example 24 was followed using excess

4-(4-fluoro-benzoyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(4-fluoro-benzoyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [471] ¹ H-NMR (Acetone-dp δ8.75(s, IH), 8.18-7.30(m, 8H), 6.61(t, IH), 5.19(d, 2H),

4.29(m, IH), 4.03(m, 2H), 3.68(m, IH) 2.01-1.18(m, 5H) [472] Example 64

[473] l-Benzyl-4-[l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethoxycarbon yl] - piperazin-1-ium [474] The procedure given in Example 24 was followed using excess 4-benzyl-piperazine as a reactant, instead of excess ammonium hydroxide, to give

4-Benzyl-piperazine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

This compound was dissolved in methylene chloride and added HCl gas to give

1 -benzyl-4- [ 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethoxycarbonyl] -piperazin- 1 -ium. [475] ¹ H-NMR (CDCl ₃ ) δ8.50(s, IH), 7.6-7.2(m, 9H), 6.58(m,lH), 5.087(d, 2H), 2.47(m,

4H), 1.73(m, 6H) [476] Example 65

[477] 4-Benzyl-piperidine-l-carboxylic acid l-phenyl-2-tetrazol-2-yl-ethyl ester

[478] The procedure given in Example 26 was followed using excess 4-benzyl piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine-l-carboxylic acid l-phenyl-2-tetrazol-2-yl-ethyl ester. [479] ¹ H-NMR (Acetone-dp δ8.74(s, IH), 7.47-7.20(m, 12H), 6.26(m, IH), 5.14(m, 2H),

4.07(m, IH), 2.55(m, 2H), 1.70(m, 3H), 1.10(m, 3H) [480] Example 66

[481] Carbamic acid l-(2,4-difluoro-phenyl)-2-tetrazol-2-yl-ethyl ester

[482] The procedure given in Example 24 was followed using

2-bromo-2',4'-difluoroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,4-difluoro-phenyl)-2-tetrazol-2-yl-ethyl ester. [483] ¹ H-NMR (Acetone-d ₆ ) δ9.13(s, IH), 7.5(s, IH), 7.05(m, 2H), 5.6-6.2(br, 2H),

5.45(m, IH), 4.82(m, 2H) [484] Example 67

[485] [2-(3,4-Dihydroxy-phenyl)-ethyl]-carbamic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [486] The procedure given in Example 24 was followed using excess

2-(3,4-dihydroxy-phenyl)-ethyl amine as a reactant, instead of excess ammonium hydroxide, to give [2-(3,4-dihydroxy-phenyl)-ethyl]-carbamic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [487] ¹ H-NMR (Acetone-dp δ8.76(s, IH), 7.50-6.60(m, 7H), 6.50(t, IH), 5.09(d, 2H),

3.23(m, 2H), 2.60(t, 2H) [488] Example 68

[489] 4-(4-Methoxy-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [490] The procedure given in Example 24 was followed using excess

4-(4-methoxy-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(4-methoxy-benzyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [491] ¹ H-NMR (Acetone-d ) δ7.96(s, IH), 7.41(m, IH), 7.17(m, 3H), 7.08(m, IH),

6.92(m, 3H), 4.08(d, 2H), 3.82(s, 3H), 3.08(t, 2H), 2.57(d, 2H), 1.75(m, 4H), 1.37(m,

4H)

[492] Example 69

[493] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [494] The procedure given in Example 24 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [495] ¹ H-NMR (Acetone-dp δ7.91(s, IH), 7.5 l(m, 3H), 7.36(s, IH), 7.25(m, 2H), 7.02(s,

IH), 4.05(d, 2H), 3.09(t, 2H), 2.65(d, 2H), 1.75(m, 4H), 1.35(m, 4H) [496] Example 70

[497] 4-Pyridin-4-ylmethyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[498] The procedure given in Example 24 was followed using excess 4-pyridin-4-yl methyl-piperidine as a reactant, instead of excess ammonium hydroxide, to

4-pyridin-4-ylmethyl-piperidine- 1 -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [499] ¹ H-NMR (Acetone-d ₆ ) δ8.50 (d, 2H), 7.91(s, IH), 7.26(m, 6H), 4.05(d, 2H), 3.09(t,

2H), 2.66(d, 2H), 1.75(m, 4H), 1.36(m, 4H) [500] Example 71

[501] 4-(4-Fluoro-benzyl)-piperidine-l-carboxylic acid l-(2-chloro - phenyl)-2-tetrazol-2-yl-ethyl ester [502] The procedure given in Example 24 was followed using excess

4-(4-fluoro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(4-fluoro-benzyl)-piperidine-l -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [503] ¹ H-NMR (Acetone-dp δ7.91(s, IH), 7.37(s, IH), 7.28(m, 6H), 7.02(s, IH), 4.06(d,

2H), 3.06(t, 2H), 2.62(d, 2H), 1.75(m, 4H), 1.35(m, 4H) [504] Example 72

[505] 3-(4-Fluoro-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [506] The procedure given in Example 24 was followed using excess

3-(4-fluoro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 3-(4-fluoro-benzyl)-piperidine-l -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [507] ¹ H-NMR (Acetone-dp δ7.88(s, IH), 6.99-7.32 (m, 8H), 3.95(d, 2H), 3.06(t, IH),

2.95(t, IH), 2.61(d, 2H), 1.75(m, 2H), 1.31(m, 6H) [508] Example 73

[509] 4-(4-Chloro-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [510] The procedure given in Example 24 was followed using excess

4-(4-chloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(4-chloro-benzyl)-piperidine-l -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [511] ¹ H-NMR (Acetone-dp δ7.92(s, IH), 7.31 (m, 6H), 7.04(s, 2H), 4.05(d, 2H), 3.06(t,

2H), 2.61(d, 2H), 1.75(m, 4H), 1.33(m, 4H) [512] Example 74

[513] 3-(4-Chloro-phenyl)-pyrrolidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [514] The procedure given in Example 24 was followed using excess

3-(4-chloro-phenyl)-pyrrolidine as a reactant, instead of excess ammonium hydroxide,

to give 3-(4-chloro-phenyl)-pyrrolidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [515] ¹ H-NMR (Acetone-dJ δ8.09(s, IH), 7.56(s, IH), 7.42(m, 6H), 7.01(s, IH), 4.05(t,

IH), 3.84(d, 2H), 3.68(m, 6H), 2.4(m, IH) [516] Example 75

[517] S-Phenethyl-pyrrolidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [518] The procedure given in Example 24 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give

3-phenethyl-pyrrolidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [519] ¹ H-NMR (Acetone-d ₆ ) δ8.06(s, IH), 7.51(s, IH), 7.24(m, 7H), 7.01(s, IH), 3.86(t,

IH), 3.68(d, 2H), 2.71(t, 2H), 2.25(m, 3H), 1.82(m, 6H) [520] Example 76

[521] 4-[l^,3]Triazol-2-ylmethyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [522] The procedure given in Example 24 was followed using excess 4-[l,2,3] triazol-

2-ylmethyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4- [ 1 ,2, 3]triazol-2-ylmethyl-piperidine- 1 -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [523] ¹ H-NMR (Acetone-d ₆ ) δ7.92(s, IH), 7.7 l(s, 2H), 7.37(s, 2H), 7.03(s, 2H), 4.42(d,

2H), 4.05(d, 2H), 3.15(t, 2H), 1.75(m, 4H), 1.33(m, 4H) [524] Example 77

[525] 3-Tetrazol-2-ylmethyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [526] The procedure given in Example 24 was followed using excess

3-tetrazol-2-ylmethyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give 3-tetrazol-2-ylmethyl-piperidine-l -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [527] ¹ H-NMR (Acetone-d^ δ8.78(s, IH), 7.91(s, IH), 7.35(s, 2H), 7.01(s, 2H), 4.79(d,

2H), 3.97(d, 2H), 3.15(m, 2H), 1.82(m, 2H), 1.4(m, 6H) [528] Example 78

[529] 3-[l^,3]Triazol-2-ylmethyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [530] The procedure given in Example 24 was followed using excess 3-[l,2,3] triazol-

2-ylmethyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

3- [ 1 ,2,3]triazol-2-ylmethyl-piperidine- 1 -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

[531] ¹ H-NMR (Acetone-dJ δ7.89(s, IH), 7.70(s, 2H), 7.30(s, 2H), 7.0(s, 2H), 4.45(d,

2H), 3.9(d, 2H), 3.15(m, 2H), 1.85(m, 2H), 1.3(m, 6H) [532] Example 79

[533] 4-Benzoyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [534] The procedure given in Example 24 was followed using excess

4-benzoyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzoyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [535] ¹ H-NMR (Acetone-d^ δ8.1 (m, 2H), 7.95(s, IH), 7.63(m, 3H), 7.42(s, 2H), 7.0(s,

2H), 4.1 l(d, 2H), 3.85(m, IH), 3.38(t, 2H), 2.09(m, 2H), 2.06(m, 2H), 1.83(m, 4H) [536] Example 80

[537] 4-(4-Chloro-benzoyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [538] The procedure given in Example 24 was followed using excess 4-(4 - chloro-benzoyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(4-chloro-benzoyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [539] ¹ H-NMR (Acetone-dp 68.11 (m, 2H), 7.95(s, IH), 7.59(m, 2H), 7.41(s, 2H),

7.03(s, 2H), 4.1 l(d, 2H), 3.85(m, IH), 3.38(t, 2H), 2.09(m, 2H), 2.07(m, 2H), 1.83(m,

4H)

[540] Example 81

[541] 4-(4-Methoxy-benzoyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [542] The procedure given in Example 24 was followed using excess

4-(4-methoxy-benzoyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(4-methoxy-benzoyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [543] ¹ H-NMR (Acetone-d^ δ8.06(m, 2H), 7.95(s, IH), 7.41(m, 2H), 7.05(d, 4H),

4.15(d, 2H), 3.92(s, 3H), 3.87(m, IH), 3.35(t, 2H), 203(m, 2H), 1.98(m, 2H), 1.81(m,

4H)

[544] Example 82

[545] 4-[l,2,3]Triazol-l-ylmethyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [546] The procedure given in Example 24 was followed using excess . 4-[l,2,3] triazol-

1-ylmethyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4- [ 1 ,2, 3]triazol- 1 -ylmethyl-piperidine- 1 -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [547] ¹ H-NMR (Acetone-d 6 ) δ8.0(s, 2H), 7.96(s, IH), 7.7 l(s, 2H), 7.39(s, IH), 7.05(s,

IH), 4.05(d, 2H), 3.89(m, IH), 3.15(t, 2H), 2.23(m, 2H), 1.99(m, 2H), 1.86(m, 4H) [548] Example 83

[549] 4-Tetrazol-2-ylmethyl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[550] The procedure given in Example 24 was followed using excess

4-tetrazol-2-ylmethyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-tetrazol-2-ylmethyl-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [551] ¹ H-NMR (Acetone-d ₆ ) δ7.97(s, IH), 7.7(s, IH), 7.42(s, 2H), 7.09(s, 2H), 4.96(d,

2H), 4.15(d, 2H), 3.18(t, 2H), 2.17(m, 2H), 2.14(m, 2H), 1.97(m, 4H) [552] Example 84

[553] 4-[l,2,3]Triazol-2-yl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [554] The procedure given in Example 24 was followed using excess 4-[l,2,3] triazol-

2-yl-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4- [1,2,3] triazol-2-yl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [555] ¹ H-NMR (Acetone-dp δ7.99(s, IH), 7.73(s, 2H), 7.45(s, 2H), 7.05(s, 2H), 4.15(d,

2H), 3.17(t, 2H), 2.14(m, 4H), 2.04(m, 4H) [556] Example 85

[557] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester [558] The procedure given in Example 48 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

1 -(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [559] ¹ H-NMR (Acetone-dp δ7.9(s, IH), 7.47(d, 2H), 7.37(s, IH), 7.23(d, 2H), 7.02(s,

IH), 4.05(d, 2H), 3.05(t, 2H), 2.65(d, 2H), 1.75(m, 4H), 1.35(m, 4H) [560] Example 86

[561] 4-(5-Phenyl-tetrazol-2-yl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [562] The procedure given in Example 24 was followed using excess

4-(5-phenyl-tetrazol-2-yl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(5-phenyl-tetrazol-2-yl)-piperidine-l -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [563] ¹ H-NMR (Acetone-dp δ8.18 (m, 2H), 8.1(s, IH), 7.57(m, 6H), 7.07(s, IH), 5.3(m,

IH), 4.25(d, 2H), 3.56(t, IH), 2.45(m, 6H), 1.31(m, 2H) [564] Example 87

[565] 4-[l,2,3]Triazol-l-yl-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[566] The procedure given in Example 24 was followed using excess 4-[l,2,3] triazol-

1-yl-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4- [1,2,3] triazol- 1 -yl-piperidine- 1 -carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [567] ¹ H-NMR (Acetone-d ₆ ) δ8.09(s, IH), 7.98(s, IH), 7.7 l(s, IH), 7.45(s, 2H), 7.05(s,

2H), 4.98(m, IH), 4.25(d, 2H), 3.4(t, IH), 2.25(m, 6H), 1.31(m, 2H) [568] Example 88

[569] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester [570] The procedure given in Example 36 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [571] ¹ H-NMR (Acetone-dp δ7.9(s, IH), 7.49(d, 2H), 7.35(s, IH), 7.25d, 2H), 7.01(s,

IH), 4.06(d, 2H), 3.10(t, 2H), 2.65(d, 2H), 1.75(m, 4H), 1.35(m, 4H) [572] Example 89

[573] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester [574] The procedure given in Example 34 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [575] ¹ H-NMR (Acetone-dp δ7.9(s, IH), 7.49(d, 2H), 7.36(s, IH), 7.26(d, 2H), 7.02(s,

IH), 4.10(d, 2H), 3.1(t, 2H), 2.65(d, 2H), 1.77(m, 4H), 1.35(m, 4H) [576] Example 90

[577] 3-(4-Chloro-benzyl)-pyrrolidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [578] The procedure given in Example 24 was followed using excess

3-(4-chloro-benzyl)-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give 3-(4-chloro-benzyl)-pyrrolidine-l -carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [579] ¹ H-NMR (Acetone-dp δ8.0(s, IH), 7.50(s, IH), 7.34(m, 6H), 6.99(s, IH), 3.42(t,

IH), 2.84(d, 2H), 2.61(m, 3H), 2.09(m, 6H) [580] Example 91

[581] 4-(3,5-Bis-trifluoromethyl-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[582] The procedure given in Example 24 was followed using excess

4-(3,5-bis-trifluoromethyl-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-(3,5-bis-trifluoromethyl-benzyl)-piperidine-l-carboxyli c acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [583] ¹ H-NMR (Acetone-d ₆ ) δ7.95(s, IH), 7.90(m, 4H), 7.37(s, 2H), 7.02(s, IH), 4.1(d,

2H), 3.1(t, 2H), 2.91(d, 2H), 1.77(m, 4H), 1.48(m, 4H) [584] Example 92

[585] 4-(5-Methyl-tetrazol-2-ylmethyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [586] The procedure given in Example 24 was followed using excess

4-(5-methyl-tetrazol-2-ylmethyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(5-methyl-tetrazol-2-ylmethyl)-piperidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [587] ¹ H-NMR (Acetone-dp δ7.9(s, IH), 7.37(s, 2H), 7.01(s, 2H), 4.6(d, 2H), 4.08(d,

2H), 3.14(t, 2H), 2.48(s, 3H), 1.73(m, 4H), 1.52(m, 4H) [588] Example 93

[589] S-Phenethyl-pyrrolidine-l-carboxylic acid l-(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester [590] The procedure given in Example 48 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give

3-phenethyl-pyrrolidine- 1 -carboxylic acid

1 -(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [591] ¹ H-NMR (Acetone-dp δ8.05(s, IH), 7.52(s, IH), 7.28(m, 6H), 7.00(s, IH), 3.8(t,

IH), 3.34(d, 2H), 2.72(t, 2H), 2.15(m, 3H), 1.70(m, 6H) [592] Example 94

[593] 3-Phenethyl-pyrrolidine-l-carboxylic acid l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester [594] The procedure given in Example 36 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give

3-phenethyl-pyrrolidine- 1 -carboxylic acid

1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [595] ¹ H-NMR (Acetone-d^ δ8.05(s, IH), 7.51(s, IH), 7.28(m, 6H), 7.01(s, IH), 3.75(t,

IH), 3.34(d, 2H), 2.74(t, 2H), 2.20(m, 3H), 1.75(m, 6H) [596] Example 95

[597] S-Phenethyl-pyrrolidine-l-carboxylic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester [598] The procedure given in Example 34 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give

3-phenethyl-pyrrolidine- 1 -carboxylic acid l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [599] ¹ H-NMR (Acetone-d ₆ ) δ8.05(s, IH), 7.51(s, IH), 7.27(m, 6H), 7.00(s, IH), 3.76(t,

IH), 3.35(d, 2H), 2.72(t, 2H), 2.20(m, 3H), 1.75(m, 6H) [600] Example 96

[601] 3-[2-(4-Methoxy-phenyl)-ethyl]-pyrrolidine-l-carboxylic add l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [602] The procedure given in Example 24 was followed using excess

3-[2-(4-methoxy-phenyl)-ethyl]-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give 3-[2-(4-methoxy-phenyl)-ethyl]-pyrrolidine-l-carboxylic acid

1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [603] ¹ H-NMR (Acetone-d ₆ ) δ8.05(s, IH), 7.51(s, 2H), 7.17(m, 2H), 7.00(s, 2H), 6.86(m,

2H), 3.78(s, 3H), 3.67(d, 2H), 3.32(t, IH), 2.65(t, 2H), 2.36(m, 3H), 1.71(m, 6H) [604] Example 97

[605] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-phenyl-2-tetrazol-2-yl-ethyl ester [606] The procedure given in Example 26 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

1 -phenyl-2-tetrazol-2-yl-ethyl ester. [607] ¹ H-NMR (Acetone-d ₆ ) δ7.9(s, IH), 7.48(m, 4H), 7.36(s, IH), 7.24(m, 2H), 7.01(s,

IH), 4.07(d, 2H), 3.15(t, 2H), 2.66(d, 2H), 2.08(m, 2H), 1.77(m, 2H), 1.38(m, 4H) [608] Example 98

[609] Carbamic acid l-(4-benzyloxy-phenyl)-2-tetrazol-2-yl-ethyl ester

[610] The procedure given in Example 24 was followed using

2-bromo-4'-benzyloxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-benzyloxy-phenyl)-2-tetrazol-2-yl-ethyl ester. [611] ¹ H-NMR (Acetone-d ₆ ) δ8.7(s, IH), 7.46(m, 7H), 7.05(m, 2H), 6.23(m, IH),

5.85-6.4(br, 2H), 5.16(s, 2H), 5.08(m, 2H) [612] Example 99

[613] Carbamic acid l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[614] To a solution of 2-bromo-2'-chloroacetophenone (2mmol) and sodium carbonate

(4mmol) in toluene (100ml), lH-tetrazole (4mmol) was added. The reaction was refluxed for 4h and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine.

The resulting organic layer was dried and concentrated in vacuo. The crude product

was dissolved in methanol (50ml) and was added with sodium borohydride (8mmol) slowly at O ⁰ C to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is lN-tetrazole. After Ih stirring at room temperature, this solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 4h, followed by the addition of excess ammonium hydroxide (50ml). After 4h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo.

[615] The preparation procedure of lN-azole is same as that of 2N-azole in example except the ratio of mobile phase of column chromatography. lN-azole is more polar than 2N-azole in chromatographic condition and separated by eluting with an increasing ratio of ethyl acetate in hexane after elution of 2N-azole to give carbamic acid l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[616] ¹ H-NMR (Acetone-dp δ9.13(s, IH), 7.3-7.54(m, 4H), 6.41(m, IH), 5.9-6.8(br,

2H), 5.01(m, 2H)

[617] Example 100

[618] Carbamic acid l-phenyl-3-tetrazol-l-yl-propyl ester

[619] The procedure given in Example 99 was followed using 3-chloropropiophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 1 -phenyl-3-tetrazol- 1 -yl-propyl ester.

[620] ¹ H-NMR (Acetone-dp δ9.13(s, IH), 7.38-7.32(m, 5H), 6.08(br, 2H), 5.71(m, IH),

4.63(m, 2H), 2.53(m, 2H)

[621] Example 101

[622] Carbamic acid l-(3-chloro-phenyl)-2-tetrazol-l-yl-propyl ester

[623] The procedure given in Example 99 was followed using

2-bromo-l-(3-chloro-phenyl)-propan-l-one as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 1 -(3-chloro-phenyl)-2-tetrazol- 1 -yl-propyl ester.

[624] ¹ H-NMR (Acetone-d^ δ9.1(s, IH), 7.1-7.4(m, 4H), 5.95-6.5(br, 2H), 6.0(m, IH),

5.3 (m, IH), 1.65(d, 3H)

[625] Example 102

[626] Carbamic acid l-(4-chloro-phenyl)-2-tetrazol-l-yl-propyl ester

[627] The procedure given in Example 99 was followed using

2-bromo-l-(4-chloro-phenyl)-propan-l-one as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-chloro-phenyl)-2-tetrazol- 1 -yl-propyl ester. [628] ¹ H-NMR (Acetone-dJ δ9.20 (d, IH), 7.6-7(m, 4H), 6.4(br, 2H), 6.05(m, IH),

5.35(m, IH), 1.66(m, 3H) [629] Example 103

[630] Methyl-carbamic acid l-(4-chloro-phenyl)-2-tetrazol-l-yl-propyl ester

[631] The procedure given in Example 102 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid

1 -(4-chloro-phenyl)-2-tetrazol- 1 -yl-propyl ester. [632] ¹ H-NMR (Acetone-d^ δ9.17 (d, IH), 7.6-7(m, 4H), 6.72(br, IH), 6.07(m, IH),

5.34(m, IH), 2.67(m, 3H), 1.65(m, 3H) [633] Example 104

[634] Carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-l-yl-propyl ester

[635] The procedure given in Example 99 was followed using

2-bromo-l-(3,4-dichloro-phenyl)-propan-l-one as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-dichloro-phenyl)-2-tetrazol-l-yl-propyl ester. [636] ¹ H-NMR (Acetone-dp δ9.12 (d, IH), 7.7-7.1(m, 3H), 6.354(br, 2H), 6.03(m, IH),

5.38(m, IH), 1.7(m, 3H) [637] Example 105

[638] Carbamic acid l-(2,5-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[639] The procedure given in Example 99 was followed using

2-bromo-2',5'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,5-dichloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [640] ¹ H-NMR (Acetone-dp δ9.17(s, IH), 7.25-7.63(m, 3H), 6.37(m, IH), 5.8-6.7(br,

2H), 5.03(m, 2H) [641] Example 106

[642] Carbamic acid l-(4-phenoxy-phenyl)-2-tetrazol-l-yl-ethyl ester

[643] The procedure given in Example 99 was followed using

2-bromo-4'-phenoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-phenoxy-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [644] ¹ H-NMR (Acetone-d^ δ9.09(s, IH), 7.42(m, 4H), 6.90-7.22(m, 5H), 6.14(m, IH),

5.92-6.45(br, 2H), 4.97(m, 2H) [645] Example 107

[646] Carbamic acid l-(2,4-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[647] The procedure given in Example 99 was followed using

2-bromo-2',4'-dichloroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2,4-dichloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [648] ¹ H-NMR (CDCl ₃ ) δ9.16(s, IH), 7.60(d, IH), 7.39(dd, IH), 7.26(m, IH), 6.36(m,

3H), 5.02(m, 2H) [649] Example 108

[650] Carbamic acid l-naphthalen-2-yl-2-tetrazol-l-yl-ethyl ester

[651] The procedure given in Example 99 was followed using 2-bromo-2'-acetonaphtone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -naphthalen-2-yl-2-tetrazol- 1 -yl-ethyl ester. [652] ¹ H-NMR (Acetone-d^ δ9.10(s, IH), 7.88-7.98(m, 4H), 7.53-7.58(m, 3H), 6.31(t,

IH), 6.28(br, 2H), 5.09(d, 2H) [653] Example 109

[654] Carbamic acid 2-tetrazol-l-yl-l-(2,3,4-trimethoxy-phenyl)-ethyl ester

[655] The procedure given in Example 99 was followed using

2-bromo-2',3',4'-trimethoxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

2-tetrazol- 1 -yl- 1 -(2,3 ,4-trimethoxy-phenyl)-ethyl ester. [656] ¹ H-NMR (Acetone-dp δ9.04(s, IH), 6.87(d, IH), 6.75(d, IH), 6.25(t, IH), 6.20(br,

2H), 4.90(d, 2H), 4.00(s, 3H), 3.85(s, 3H), 3.84(s, 3H) [657] Example 110

[658] Carbamic acid l-benzo[l,3]dioxol-5-yl-2-tetrazol-l-yl-ethyl ester

[659] The procedure given in Example 99 was followed using l-benzo[l,3] dioxol-

5-yl-2-bromo-ethanone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid l-benzo[l,3]dioxol-5-yl-2-tetrazol-l-yl-ethyl ester [660] ¹ H-NMR (Acetone-dp δ9.06(s, IH), 6.85-6.91(m, 3H), 6.17(br, 2H), 6.03(s, 2H),

6.02(m, IH), 4.94(m, 2H) [661] Example 111

[662] Carbamic acid 2-tetrazol-l-yl-l-(2,4,6-trimethyl-phenyl)-ethyl ester

[663] The procedure given in Example 99 was followed using 2-bromo-2', 4',

6'-trimethylacetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid 2-tetrazol- l-yl-l-(2,4,6-trimethyl-phenyl)-ethyl ester. [664] ¹ H-NMR (Acetone-d^ δ9.14(s, IH), 7.59(s, 2H), 6.18(ml IH), 5.65-6.40(br, 2H),

5.10(m, 2H), 1.35(s, 9H) [665] Example 112

[666] Carbamic acid l-(4-tert-butyl-phenyl)-2-tetrazol-l-yl-ethyl ester

[667] The procedure given in Example 99 was followed using

2-bromo-4'-tert-butylacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-tert-butyl-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [668] ¹ H-NMR (Acetone-dJ δ8.74(s, IH), 7.46(m, 4H), 6.1 l(m, IH), 5.80-6.2(br, 2H),

5.10(m, 2H), 1.34(s, 9H) [669] Example 113

[670] Carbamic acid l-indan-5-yl-2-tetrazol-l-yl-ethyl ester

[671] The procedure given in Example 99 was followed using

2-bromo-l-indan-5-yl-ethanone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -indan-5-yl-2-tetrazol- 1 -yl-ethyl ester [672] ¹ H-NMR (Acetone-d^ δ9.05(s, IH), 7.25-7.16(m, 3H), 6.08(m, 3H), 4.95(m, 2H),

2.1-2.03(m, 6H) [673] Example 114

[674] Carbamic acid l-phenyl-2-tetrazol-l-yl-ethyl ester

[675] The procedure given in Example 99 was followed using 2-bromo acetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -phenyl-2-tetrazol- 1 -yl-ethyl ester. [676] ¹ H-NMR (Acetone-dp δ9.04(s, IH), 7.44(m, 3H), 6.07(m, IH), 5.57-6.45(br, 2H),

5.03(m, 2H)

[677] Example 115

[678] Carbamic acid l-(3,4-difluoro-phenyl)-2-tetrazol-l-yl-ethyl ester

[679] The procedure given in Example 99 was followed using 2-bromo-3',

4'-difluoroacetophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid l-(3,4-difluoro-phenyl)-2-tetrazol-l-yl-ethyl ester.

[680] ¹ H-NMR (Acetone-dp δ9.04(s, IH), 7.44(m, 3H), 5.57-6.45(br, 3H), 5.03(m, 2H)

[681] Example 116

[682] Carbamic acid l-(2-fluoro-phenyl)-2-tetrazol-l-yl-ethyl ester

[683] The procedure given in Example 99 was followed using

2-bromo-2'-fluoroacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(2-fluoro-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [684] ¹ H-NMR (Acetone-d^ δ9.14(s, IH), 7.29(m, 4H), 5.6-6.17(br, 2H), 5.32(m, IH),

4.84(m, 2H)

[685] Example 117

[686] 4-Phenyl-piperazine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester [687] The procedure given in Example 99 was followed using excess 4-phenyl-piperazine as a reactant, instead of excess ammonium hydroxide, to give

4-phenyl-piperazine- 1-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-l -yl-ethyl ester.

[688] ¹ H-NMR (Acetone-dJ δ9.24(s, IH), 7.85-7.38(m, 9H), 6.54(t, IH), 5.10(d, 2H),

4.28-3.55(d, 8H) [689] Example 118

[690] 4-Benzyl-piperidine-l-carboxylic acid l-phenyl-2-tetrazol-l-yl-ethyl ester

[691] The procedure given in Example 114 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine-l-carboxylic acid l-phenyl-2-tetrazol-l-yl-ethyl ester. [692] ¹ H-NMR (Acetane-d) δ9.06(s, IH), 7.45-7.20(m, 12H), 6.19(t, IH), 5.01(d, 2H),

4.05(m, IH), 2.55(m, 2H), 1.75(m, 3H), 1.10(m, 3H) [693] Example 119

[694] Carbamic acid l-(2,4-difluoro-phenyl)-2-tetrazol-l-yl-ethyl ester

[695] The procedure given in Example 99 was followed using 2-bromo-2', 4'-difluoroacet ophenone as a reactant, instead of 2-bromo-2'-chloroacetophenone, to give carbamic acid l-(2,4-difluoro-phenyl)-2-tetrazol-l-yl-ethyl ester. [696] ¹ H-NMR (Acetone-dp δ9.12(s, IH), 7.55(m, IH), 7.05(m, 2H), 5.85(br, 2H),

5.41(m, IH), 4.8(m, 2H) [697] Example 120

[698] [2-(3,4-Dihydroxy-phenyl)-ethyl]-carbamic acid l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester [699] The procedure given in Example 99 was followed using excess

2-(3,4-dihydroxy-phenyl)-ethyl amine as a reactant, instead of excess ammonium hydroxide, to give [2-(3,4-dihydroxy-phenyl)-ethyl]-carbamic acid

1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [700] ¹ H-NMR (Acetone-dp δ9.14(s, IH), 7.50-6.56(m, 7H), 5.53(t, IH), 5.07(d, 2H),

3.25(m, 2H), 2.57(m 2H) [701] Example 121

[702] Carbamic acid l-(4-benzyloxy-phenyl)-2-tetrazol-l-yl-ethyl ester

[703] The procedure given in Example 99 was followed using

2-bromo-4'-benzyloxyacetophenone as a reactant, instead of

2-bromo-2'-chloroacetophenone, to give carbamic acid

1 -(4-benzyloxy-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [704] ¹ H-NMR (Acetone-dp δ9.05(s, IH), 7.42(m, 7H), 7.04(m, 2H), 6.09(m, IH),

5.9-6.3(br, 2H), 5.15(s, 2H), 5.04(m, 2H) [705] Example 122

[706] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester [707] The procedure given in Example 99 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium

hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid 1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester.

[708] ¹ H-NMR (CDCl ₃ ) δ7.92(s, IH), 7.48(m, 3H), 7.37(s, IH), 7.25(d, 2H), 7.03(s, IH),

4.07(d, 2H), 3.08(t, 2H), 2.67(d, 2H), 1.75(m, 4H), 1.34(m, 4H)

[709] Example 123

[710] Carbamic acid l-(2-chloro-phenyl)-2-(5-methyl-tetrazol-2-yl)-ethyl ester

[711] To a solution of 2-bromo-2'-chloroacetophenone (2mmol) and sodium carbonate

(4mmol) in toluene (100ml), 5-methyl-lH-tetrazole (4mmol) was added. The reaction was refluxed for 7h and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in methanol (50ml) and was added with sodium borohydride (2.4mmol) slowly at O ⁰ C to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2Λf-5-methyl tetrazole. After 2h stirring at room temperature, this solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 0.5h, followed by the addition of excess ammonium hydroxide (50ml). After 4h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 2) and give carbamic acid 1 -(2-chloro-phenyl)-2-(5-methyl-tetrazol-2-yl)-ethyl ester.

[712] ¹ H-NMR (Acetone-d ₆ ) δ7.37-7.61(m, 4Η), 6.58(m, IH), 6.15(br, 2H), 4.97(m, 2H),

2.47(s, 3H)

[713] Example 124

[714] Carbamic acid l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

[715] The procedure given in Example 123 was followed using 5-phenyl-lH-tetrazole as a reactant, instead of 5-methyl-lH-tetrazole, to give carbamic acid 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester.

[716] ¹ H-NMR (Acetone-d ₆ ) 08.0-8.4 (m, 2Η), 7.2-7.8(m, 7H), 6.67(t, IH), 6.2(br, 2H),

5.14(d, 2H)

[717] Example 125

[718] Methyl-carbamic acid l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

[719] The procedure given in Example 124 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give Methyl-carbamic acid

1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester. [720] ¹ H-NMR (Acetone-dJ 68.1-8.25 (m, 2H), 7.3-7.7(m, 7H), 6.7(t, IH), 6.55(br, IH),

5.12(d, 2H), 2.65(d, 3H) [721] Example 126

[722] Carbamic acid l-(2-chloro-phenyl)-2-[5-(2^-dichloro-phenyl)-tetrazol-2-yl] - ethyl ester [723] The procedure given in Example 123 was followed using 5-(2,3-dichlorophenyl)-l

H-tetrazole as a reactant, instead of 5-methyl-lH-tetrazole, to give carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-2-yl ]-ethyl ester. [724] ¹ H-NMR (Acetone-d^ 07.38-7.85 (m, 7Η), 6.63(t, IH), 6.24(br, 2H), 5.21(d, 2H)

[725] Example 127

[726] Methyl-carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-2-yl ]-ethyl ester [727] The procedure given in Example 126 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-2-yl ]-ethyl ester. [728] ¹ H-NMR (Acetone-dp 07.35-7.85 (m, 7H), 6.68(t, IH), 6.57(d, IH), 5.20(d, 2H),

2.68(d, 3H)

[729] Example 128

[730] Carbamic acid l-(2-chloro-phenyl)-2-(5-pyridin-2-yl-tetrazol-2-yl)-ethyl ester

[731] The procedure given in Example 123 was followed using 5-pyridin-2-yl-lH - tetrazole as a reactant, instead of 5-methyl-lH-tetrazole, to give carbamic acid

1 -(2-chloro-phenyl)-2-(5-pyridin-2-yl-tetrazol-2-yl)-ethyl ester. [732] ¹ H-NMR (Acetone-dp δ9.28(s, 1Η), 8.75(m, 1Η), 8.43(d, 1Η), 7.62-7.40(m 5Η),

6.64(m, IH), 6.25(br, 2H), 5.18(d, 2H) [733] Example 129

[734] Ethyl-carbamic acid l-(2-chloro-phenyl)-2-(5-pyridin-2-yl-tetrazol-2-yl)-ethyl ester [735] The procedure given in Example 128 was followed using excess ethylamine as a reactant, instead of excess ammonium hydroxide, to give ethyl-carbamic acid

1 -(2-chloro-phenyl)-2-(5-pyridin-2-yl-tetrazol-2-yl)-ethyl ester. [736] ¹ H-NMR (Acetone-d^ δ9.28(s, IH), 8.75(dd, IH), 8.41(m, IH), 7.62-7.40(m, 5H),

6.66(t, IH), 6.58(br, IH), 5.17(d, 2H), 2.07(m, 3H) [737] Example 130

[738] Carbamic acid 2-(5-amino-tetrazol-2-yl)-l-(2-chloro-phenyl)-ethyl ester

[739] The procedure given in Example 123 was followed using 5-amino-lH-tetrazole as a reactant, instead of 5-methyl-lH-tetrazole, to give carbamic acid

2-(5-amino-tetrazol-2-yl)- 1 -(2-chloro-phenyl)-ethyl ester.

[740] ¹ H-NMR (Acetone-dJ 67..20-7..76 (m, 4H), 6.5(m, IH), 6.12(br, 2H), 5.46(br, 2H),

4.75(m, 2H)

[741] Example 131

[742] Carbamic acid l-(2-chloro-phenyl)-2-(5-methyl-tetrazol-l-yl)-ethyl ester

[743] To a solution of 2-bromo-2'-chloroacetophenone (2mmol) and sodium carbonate

(4mmol) in toluene (100ml), 5-methyl-lH-tetrazole (4mmol) was added. The reaction was refluxed for 7h and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in methanol (50ml) and was added with sodium borohydride (2.4mmol) slowly at O ⁰ C to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is lΛf-5-methyl tetrazole. After 2h stirring at room temperature, this solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 0.5h, followed by the addition of excess ammonium hydroxide (50ml). After 4h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo.

[744] The preparation procedure of lN-azole is same as that of 2N-azole in example except the ratio of mobile phase of column chromatography. lN-azole is more polar than 2N-azole in chromatographic condition and separated by eluting with an increasing ratio of ethyl acetate in hexane after elution of 2N-azole to give carbamic acid l-(2-chloro-phenyl)-2-(5-methyl-tetrazol-l-yl)-ethyl ester

[745] ¹ H-NMR (Acetone-d ₆ ) 07.35-7.59 (m, 4Η), 6.44(m, IH), 5.99-6.4(br, 2H), 4.82(m,

2H), 2.537(s, 3H)

[746] Example 132

[747] Carbamic acid l-(2-chloro-phenyl)-2-[5-(2^-dichloro-phenyl)-tetrazol-l-yl] - ethyl ester

[748] The procedure given in Example 131 was followed using 5-(2,3-dichlorophenyl)-l

H-tetrazole as a reactant, instead of 5-methyl-lH-tetrazole, to give carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-l-yl ]-ethyl ester.

[749] ¹ H-NMR (Acetone-dp 07.37-7.95 (m, 7Η), 6.26(t, IH), 6.20(br, 2H), 4.79(d, 2H)

[750] Example 133

[751] Methyl-carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-l-yl ]-ethyl ester

[752] The procedure given in Example 132 was followed using excess methylamine as a

reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid l-(2-chloro-phenyl)-2-[5-(2,3-dichloro-phenyl)-tetrazol-l-yl ]-ethyl ester.

[753] ¹ H-NMR (Acetone-d ₆ ) 07.36-7.94 (m, 7H), 6.47(br, IH), 6.29(t, IH), 4.79(d, 2H),

2.65(d, 3H)

[754] Example 134

[755] Carbamic acid (R)-(+)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[756] To a solution of lH-tetrazole (2.4mmol) and lithium carbonate (4.8mmol) in DMF

(100ml), (R)-2-chlorostyrene oxide (2mmol) was slowly added to give enan- tiomerically (R)-configured alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2N- tetrazole. The reaction was stirred for 4h at 12O ⁰ C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 3h, followed by the addition of excess ammonium hydroxide (50ml). After 5h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 2) and recrystallized from dichloromethane and ethyl ether (1 : 1) to give carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

[757] Optical purity was more than 98%ee. The optical purity was measured by ΗPLC

(Chiracel OD-Η column, Mobile phase = acetonitrile + water with 0.1% trifluoroacetic acid).

δ8.74(s, 1Η), 7.38-7.54(m, 4Η), 6.59(m, IH), 6.16(br, 2H),

5.09(m, 2H)

[760] Example 135

[761] Carbamic acid (S)-(-)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[762] The procedure given in Example 134 was followed using (S)-2-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give Carbamic acid (S)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

[763] ¹ H-NMR (Acetone-d^ δ8.74(s, IH), 7.39-7.52(m, 4H), 6.57(m, IH), 6.18(br, 2H),

5.11(m, 2H)

[764] Example 136

[765] Carbamic acid (S)-l-(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[766] The procedure given in Example 134 was followed using (S)-4-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give Carbamic acid

(S)- 1 -(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [767] ¹ H-NMR (CDCl ₃ ) δ8.54(s, IH), 7.29-7.41 (m, 4H), 6.21(m, IH), 6.04(br, 2H),

4.87(m, 2H)

[768] Example 137

[769] Carbamic acid (R)-l-(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[770] The procedure given in Example 134 was followed using (R)-4-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give Carbamic acid

(R)- 1 -(4-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [771] ¹ H-NMR (CDCl ₃ ) δ8.54(s, IH), 7.29-7.41 (m, 4H), 6.21(m, IH), 6.04(br, 2H),

4.87(m, 2H)

[772] Example 138

[773] Methyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[774] The procedure given in Example 134 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid

(R)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [775] ¹ H-NMR (Acetone-dp δ8.75(s, IH), 7.2-7.8(m, 4H), 6.65(dd, IH), 6.5(br, IH),

5.1(m, 2H), 2.65(d, 3H) [776] Example 139

[777] Ethyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[778] The procedure given in Example 134 was followed using excess ethylamine as a reactant, instead of excess ammonium hydroxide, to give ethyl-carbamic acid

(R)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [779] ¹ H-NMR (CDCl ₃ ) δ8.57(s, IH), 8.15-8.47(m, 4H), 5.12(m, IH), 3.40(m, 2H),

3.0-3.2(br, IH), 1.22(t, 3H), 1.09(t, 2H) [780] Example 140

[781] Phenyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[782] The procedure given in Example 134 was followed using excess phenylamine as a reactant, instead of excess ammonium hydroxide, to give phenyl-carbamic acid

(R)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [783] ¹ H-NMR (CDCl ₃ ) 07.17-8.53 (m, 10H), 6.55(m, IH), 6.42-6.86(br, IH), 5.12(m,

2H)

[784] Example 141

[785] Cyclopropyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[786] The procedure given in Example 134 was followed using excess cyclopropylamine as a reactant, instead of excess ammonium hydroxide, to give cyclopropyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [787] ¹ H-NMR (Acetone-dp δ8.75(s, IH), 7.45-8.24(m, 4H), 6.5 l(m, IH), 6.20-6.65(br,

Ih), 4.85(m, 2H), 1.6-1.84(m, 5H)

[788] Example 142

[789] Carbamic acid (R)-2-tetrazol-2-yl-l-(2-trifluoromethyl-phenyl)-ethyl ester

[790] The procedure given in Example 134 was followed using (R)-2-trifluorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)-2-tetrazol-2-yl- 1 -(2-trifluoromethyl-phenyl)-ethyl ester. [791] ¹ H-NMR (Acetone-d ₆ ) δ8.72(s, IH), 7.10-7.83(m, 4H), 6.67(m, IH), 6.05-6.87(br,

2h), 4.86(m, 2H) [792] Example 143

[793] Carbamic acid (S)-2-tetrazol-2-yl-l-(2-trifluoromethyl-phenyl)-ethyl ester

[794] The procedure given in Example 134 was followed using (S)-2-trifluorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)-2-tetrazol-2-yl- 1 -(2-trifluoromethyl-phenyl)-ethyl ester. [795] ¹ H-NMR (Acetone-dp δ8.74(s, IH), 7.10-7.85(m, 4H), 6.58(m, IH), 6.15-6.80(br,

2h), 4.87(m, 2H) [796] Example 144

[797] Carbamic acid (R)-l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[798] The procedure given in Example 134 was followed using (R)-3,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)- 1 -(3 ,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [799] ¹ H-NMR (Acetone-dp δ8.73(s, IH), 7.8-7.2(m, 3H), 6.25(m, IH), 6.2(br, 2H),

5.18(m, 2H)

[800] Example 145

[801] Carbamic acid (S)-l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[802] The procedure given in Example 134 was followed using (S)-3,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)-l-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [803] ¹ H-NMR (Acetone-dp δ8.73(s, 2H), 7.8-7.2(m, 3H), 6.26(m, IH), 6.23(br, 2H),

5.17(m, 2H)

[804] Example 146

[805] Carbamic acid (R)-l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[806] The procedure given in Example 134 was followed using (R)-2,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)- 1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [807] ¹ H-NMR (Acetone-dp δ8.74(s, IH), 7.47-7.63(m, 3H), 6.53(m, IH), 6.24(br, 2H),

5.13(m, 2H)

[808] Example 147

[809] Carbamic acid (S)-l-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[810] The procedure given in Example 134 was followed using (S)-2,4-dichlorostyrene

oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)- 1 -(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [811] ¹ H-NMR (Acetone-d ₆ ) δ8.74(s, IH), 7.58-7.42(m, 3H), 6.53(t, IH), 6.27(br, 2H),

5.13(m, 2H)

[812] Example 148

[813] Carbamic acid 2-phenyl-l-tetrazol-2-ylmethyl-ethyl ester

[814] The procedure given in Example 134 was followed using 2-benzyl-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

2-phenyl- 1 -tetrazol-2-ylmethyl-ethyl ester. [815] ¹ H-NMR (CDCl ₃ ) δ8.52(s, IH), 7.34-7.27(m, 5H), 5.42(m, IH), 4.81(m, 2H),

4.74(m, 2H), 2.98(m, 2H) [816] Example 149

[817] Carbamic acid 2-(2,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

[818] The procedure given in Example 134 was followed using

2-(2,4-dichloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(2,4-dichloro-phenoxy)-l -tetrazol-2-ylmethyl-ethyl ester. [819] ¹ H-NMR (Acetone-dp δ8.76(s, IH), 7.38(m, 3H), 5.03(m, 2H), 4.89(m, IH),

4.71-5.01(br, 2H), 4.31(m, 2H) [820] Example 150

[821] Carbamic acid 2-(3,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

[822] The procedure given in Example 134 was followed using

2-(3,4-dichloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(3,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester. [823] ¹ H-NMR (Acetone-dp δ8.75(s, IH), 7.53-7.02(m, 3H), 6.07(br, 2H), 5.56(t, IH),

5.15(d, 2H), 4.35(m, 2H) [824] Example 151

[825] Carbamic acid 2-(4-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

[826] The procedure given in Example 134 was followed using

2-(4-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(4-chloro-phenoxy)-l -tetrazol-2-ylmethyl-ethyl ester. [827] ¹ H-NMR (Acetone-d^ δ8.76(s, IH), 7.50(m, IH), 7.27(m, IH), 7.04(m, IH),

6.07(br, 2H), 5.56(t, IH), 5.15(d, 2H), 4.35(m, 2H) [828] Example 152

[829] Carbamic acid 2-(2-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

[830] The procedure given in Example 134 was followed using

2-(2-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene

oxide, to give carbamic acid 2-(2-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester. [831] ¹ H-NMR (Acetone-d ₆ ) δ8.76(s, IH), 7.47-6.98(m, 4H), 6.07(br, 2H), 5.60(t, IH),

5.20(d, 2H), 4.39(m, 2H) [832] Example 153

[833] 4-Benzyl-piperidine-l-carboxylic acid

2-(2-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester [834] The procedure given in Example 152 was followed using 4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine- 1 -carboxylic acid

2-(2-chloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester. [835] ¹ H-NMR (Acetane-d) δ8.77(s, IH), 7.48-6.99(m, 1 IH), 5.30(t, IH), 5.25(d, 2H),

4.44(d, 2H), 3.95(m, IH), 2.54(m, 3H), 1.66(m, 3H), 1.04(m, 2H) [836] Example 154

[837] 4-Benzyl-piperidine-l-carboxylic acid

(R)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [838] The procedure given in Example 134 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine- 1 -carboxylic acid (R)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [839] ¹ H-NMR (Acetone-dp δ7.91(s, IH), 7.28(m, 7h), 7.03(s, 2H), 4.0 (d, 2H), 3.12( t,

2H), 2.6( d, 2H) , 1.74 (m, 4H), 1.33(m, 4H) [840] Example 155

[841] 4-Benzyl-piperidine-l-carboxylic acid

(S)-l-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester [842] The procedure given in Example 135 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine- 1 -carboxylic acid (S)- 1 -(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester. [843] ¹ H-NMR (Acetone-d^ δ7.90(s, IH), 6.95-7.5(m, 7h), 7.02(s, 2H), 4.05 (d, 2H),

3.08(t, 2H), 2.63( d, 2H) , 1.75 (m, 4H), 1.35(m, 4H) [844] Example 156

[845] 4-Benzyl-piperidine-l-carboxylic acid

2-(4-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester [846] The procedure given in Example 151 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine- 1 -carboxylic acid

2-(4-chloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester. [847] ¹ H-NMR (Acetone-d 6 ) δ7.92(s, IH), 7.37(s, IH), 7.28(m, 7H), 7.03(s, IH), 4.05(d,

2H), 3.08(t, 2H), 2.59(d, 2H), 2.06(m, 2H), 1.75(m, 4H), 1.35(m, 4H) [848] Example 157

[849] Carbamic acid 2-(2,5-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

[850] The procedure given in Example 134 was followed using

2-(2,5-dichloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(2,5-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester. [851] ¹ H-NMR (Acetone-d ₆ ) δ8.76(s, IH), 7.49(d, IH), 7.29(s, IH), 7.05(d, IH), 6.08(br,

2H), 5.62(m, IH), 5.21(d, 2H), 4.46(m, 2H) [852] Example 158

[853] S-Phenethyl-pyrrolidine-l-carboxylic acid

2-(2,5-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester [854] The procedure given in Example 157 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give

3-phenethyl-pyrrolidine- 1 -carboxylic acid

2-(2,5-dichloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester. [855] ¹ H-NMR (Acetone-dp δ8.06(s, IH), 7.52(s, IH), 7.29(m, 6H), 7.02(s, IH), 3.82(m,

IH), 3.37(d, 2H), 2.99(d, 2H), 2.71(t, 2H), 2.2(m, 3H), 1.77(m, 6H) [856] Example 159

[857] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid

2-(2-chloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester [858] The procedure given in Example 152 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

2-(2-chloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester. [859] ¹ H-NMR (Acetone-dp δ7.9(s, IH), 7.47(m, 3H), 7.36(s, IH), 7.22(m, 2H), 7.02(s,

IH), 4.05(d, 2H), 3.1(t, 2H), 2.65(d, 2H), 2.05 (m, 2H), 1.76(m, 4H), 1.3(m, 4H) [860] Example 160

[861] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid

2-(2,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester [862] The procedure given in Example 149 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid

2-(2,4-dichloro-phenoxy)- 1 -tetrazol-2-ylmethyl-ethyl ester. [863] ¹ H-NMR (Acetone-dp δ7.91(s, IH), 7.50(m, 2H), 7.36(s, IH), 7.23(m, 2H), 7.02(s,

IH), 4.05(d, 2H), 3.08(t, 2H), 2.66(d, 2H), 2.08(m, 2H), 1.76(m, 4H), 1.37(m, 4H) [864] Example 161

[865] 4-(3,4-Dichloro-benzyl)-piperidine-l-carboxylic acid

2-(3,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester

[866] The procedure given in Example 150 was followed using excess

4-(3,4-dichloro-benzyl)-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-(3,4-dichloro-benzyl)-piperidine-l-carboxylic acid 2-(3,4-dichloro-phenoxy)-l-tetrazol-2-ylmethyl-ethyl ester.

[867] ¹ H-NMR (Acetone-d ₆ ) 67.9 l(s, IH), 7.47(m, 2H), 7.35(s, IH), 7.23(m, 2H), 7.02(s,

IH), 4.08(d, 2H), 3.10(t, 2H), 2.65(d, 2H), 1.99(m, 2H), 1.75(m, 4H), 1.3(m, 4H)

[868] Example 162

[869] Carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[870] To a solution of lH-tetrazole (2.4mmol) and lithium carbonate (4.8mmol) in DMF

(100ml), (R)-2-chlorostyrene oxide (2mmol) was slowly added to give enan- tiomerically (R)-configured alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is IN- tetrazole. The reaction was stirred for 4h at 12O ⁰ C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 3h, followed by the addition of excess ammonium hydroxide (50ml). After 5h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo.

[871] The preparation procedure of lN-azole is same as that of 2N-azole in example except the ratio of mobile phase of column chromatography. lN-Azole is more polar than 2N-azole in chromatographic condition and separated by eluting with an increasing ratio of ethyl acetate in hexane after elution of 2N-azole to give carbamic acid (R)-l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester.

[872] ¹ H-NMR (Acetone-d^ δ9.14(s, 1Η), 7.31-7.59(m, 4Η), 6.42(m, IH), 6.0-6.75(br,

2H), 5.03(m, 2H)

[873] Example 163

[874] Carbamic acid (S)-l-(2-chloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[875] The procedure given in Example 162 was followed using (S)-2-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid (S)- 1 -(2-chloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester.

[876] ¹ H-NMR (CDCl ₃ ) δ8.75(s, IH), 7.10-7.4(m, 4H), 6.35(m, IH), 5.67(br, 2H),

4.83(m, 2H)

[877] Example 164

[878] Carbamic acid (S)-l-(3,4-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[879] The procedure given in Example 162 was followed using (S)-3,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)- 1 -(3,4-dichloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [880] ¹ H-NMR (Acetone-d ₆ ) δ9.16(s, IH), 7.59(m, 2H), 7.35(dd, IH), 6.39(br, 2H),

6.17(t, lH),5.05(d, 2H) [881] Example 165

[882] Carbamic acid 2-phenyl-l-tetrazol-l-ylmethyl-ethyl ester

[883] The procedure given in Example 162 was followed using 2-benzyl-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

2-phenyl- 1 -tetrazol- 1 -ylmethyl-ethyl ester. [884] ¹ H-NMR (CDCl ₃ ) δ8.62(s, IH), 7.39-7.27(m, 5H), 5.29(m, IH), 4.78(br, 2H),

4.60(m, 2H), 2.90(m, 2H) [885] Example 166

[886] Carbamic acid (S)-l-(2,6-dichloro-phenyl)-2-tetrazol-l-yl-ethyl ester

[887] The procedure given in Example 162 was followed using (S)-2,6-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)- 1 -(2,6-dichloro-phenyl)-2-tetrazol- 1 -yl-ethyl ester. [888] ¹ H-NMR (CDCl ₃ ) δ8.8(s, IH), 7.4-7.2(m, 3H), 6.72(m, IH), 5.29-4.87(m, 2H),

5.08(br, 2H)

[889] Example 167

[890] Carbamic acid 2-(4-chloro-phenoxy)-l-tetrazol-l-ylmethyl-ethyl ester

[891] The procedure given in Example 162 was followed using

2-(4-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(4-chloro-phenoxy)-l -tetrazol- 1 -ylmethyl-ethyl ester. [892] ¹ H-NMR (Acetone-d ₆ ) δ9.17(s, IH), 7.32(m, 2H), 7.04(m, 2H), 6.18(br, 2H),

5.44(t, IH), 5.00(d, 2H), 4.22(d, 2H) [893] Example 168

[894] Carbamic acid 2-(2-chloro-phenoxy)-l-tetrazol-l-ylmethyl-ethyl ester

[895] The procedure given in Example 162 was followed using

2-(2-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(2-chloro-phenoxy)-l -tetrazol- 1 -ylmethyl-ethyl ester. [896] ¹ H-NMR (Acetone-d^ δ9.20(s, IH), 7.47-6.98(m, 4H), 6.19(br, 2H), 5.50(t, IH),

5.05(d, 2H), 4.30(m, 2H) [897] Example 169

[898] 4-Benzyl-piperidine-l-carboxylic acid

2-(2-chloro-phenoxy)-l-tetrazol-l-ylmethyl-ethyl ester [899] The procedure given in Example 168 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine- 1 -carboxylic acid 2-(2-chloro-phenoxy)- 1 -tetrazol- 1 -ylmethyl-ethyl ester.

[900] ¹ H-NMR (Acetone-dJ δ9.26(s, IH), 7.36-7.01(m, 1 IH), 5.52(t, IH), 5.05(d, 2H),

4.41(m, 2H), 3.14-1.22(m, 9.H)

[901] Example 170

[902] 4-Benzyl-piperidine-l-carboxylic acid

2-(4-chloro-phenoxy)-l-tetrazol-l-ylmethyl-ethyl ester

[903] The procedure given in Example 167 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give 4-benzyl-piperidine- 1 -carboxylic acid 2-(4-chloro-phenoxy)- 1 -tetrazol- 1 -ylmethyl-ethyl ester.

[904] ¹ H-NMR (Acetone-d ₆ ) δ8.02(s, IH), 7.45 (s, IH), 7.29(m, 7H), 7.01(s, IH), 4.05(d,

2H), 3.07(t, 2H), 2.63(d, 2H), 2.07(m, 2H), 1.75(m, 4H), 1.34(m, 4H)

[905] Example 171

[906] Carbamic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[907] To a solution of lH-l,2,3-triazole (2.4mmol) and lithium carbonate (4.8mmol) in

DMF (100ml), (R)-2-chlorostyrene oxide (2mmol) was slowly added to give enan- tiomerically (R)-configured alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2N - 1,2,3-triazole. The reaction was stirred for 4h at 12O ⁰ C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 3h, followed by the addition of excess ammonium hydroxide (50ml). After 5h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 2) and recrystallized from dichloromethane and ethyl ether (1 : 1) to give carbamic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester.

[908] ¹ H-NMR (Acetone-d ₆ ) δ7.69(s, 2Η), 7.6-7.2(m, 4H), 6.59(dd, IH), 6.1 l(br, 2H),

4.78(d, 2H)

[909] Example 172

[910] Carbamic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[911] The procedure given in Example 171 was followed using (S)-2-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid (S)- l-(2-chloro-phenyl)-2-[ 1 ,2,3]triazol-2-yl-ethyl ester.

[912] ¹ H-NMR (Acetone-d ) δ7.71(s, 2H), 7.7-7.1(m, 4H), 6.60(dd, IH), 6.14(br, 2H),

6

4.79(d, 2H)

[913] Example 173

[914] Carbamic acid (S)-l-(4-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[915] The procedure given in Example 171 was followed using (S)-4-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)- l-(4-chloro-phenyl)-2-[ 1 ,2,3]triazol-2-yl-ethyl ester. [916] ¹ H-NMR (Acetone-d ₆ ) δ7.68(s, 2H), 7.41 (m, 4H), 6.23(m, IH), 6.15(br, 2H),

4.82(m, 2H)

[917] Example 174

[918] Carbamic acid (R)-l-(4-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[919] The procedure given in Example 171 was followed using (R)-4-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)- 1 -(4-chloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [920] ¹ H-NMR (Acetone-dp δ7.67(s, 2H), 7.41 (m, 4H), 6.22(m, IH), 6.09(br, 2H),

4.80(m, 2H)

[921] Example 175

[922] Carbamic acid (S)-l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[923] The procedure given in Example 171 was followed using (S)-3,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)- 1 -(3,4-dichloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [924] ¹ H-NMR (Acetone-dp δ7.67(s, 2H), 7.7-7.2(m, 3H), 6.19(m, IH), 6.16(br, 2H),

4.84(m, 2H)

[925] Example 176

[926] Carbamic acid (R)-l-(3,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[927] The procedure given in Example 171 was followed using (R)-3,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)- l-(3,4-dichloro-phenyl)-2-[ 1 ,2,3]triazol-2-yl-ethyl ester.

[928] ¹ H-NMR (Acetone-dp δ8-7(m, 5H), 6.18(m, IH), 6.16(br, 2H), 4.84(m, 2H)

[929] Example 177

[930] Carbamic acid (S)-l-(2,4-dichloro-phenyl)-2-[l,2^]triazol-2-yl-ethyl ester

[931] The procedure given in Example 171 was followed using (S)-2,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(S)- 1 -(2,4-dichloro-phenyl)-2- [ 1 ,2,3]triazol-2-yl-ethyl ester. [932] ¹ H-NMR (Acetone-dp δ7.68(s, 2H), 7.60-7.44(m, 3H), 6.5 l(t, IH), 6.18(s, 2H),

4.79(d, 2H)

[933] Example 178

[934] Carbamic acid (R)-l-(2,4-dichloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester

[935] The procedure given in Example 171 was followed using (R)-2,4-dichlorostyrene

oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)- l-(2,4-dichloro-phenyl)-2-[ 1 ,2,3]triazol-2-yl-ethyl ester. [936] ¹ H-NMR (Acetone-d ₆ ) δ7.68(s, 2H), 7.55-7.4(m, 3H), 6.51(dd, IH), 6.12(br, 2H),

4.8 l(d, 2H)

[937] Example 179

[938] 4-Benzyl-piperidine-l-carboxylic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3] triazol-

2-yl-ethyl ester [939] The procedure given in Example 172 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine-l-carboxylic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3] triazol-

2-yl-ethyl ester. [940] ¹ H-NMR (Acetone-d ₆ ) δ7.91(s, 2H), 7.3(m, 7h), 7.03 (s, 2H), 4.05 (d, 2H), 3.08( t,

2H), 2.63( d, 2H) , 1.74 (m, 4H), 1.35(m, 4H) [941] Example 180

[942] 4-Benzyl-piperidine-l-carboxylic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3] triazol-

2-yl-ethyl ester [943] The procedure given in Example 171 was followed using excess

4-benzyl-piperidine as a reactant, instead of excess ammonium hydroxide, to give

4-benzyl-piperidine- 1-carboxylic acid (R)- l-(2-chloro-phenyl)-2-[ 1,2,3] triazol-

2-yl-ethyl ester. [944] ¹ H-NMR (Acetone-d ₆ ) δ7.98(s, 2H), 7.2-7.55(m, 7h), 7.08 (s, 2H), 4.05 (d, 2H),

3.02( t, 2H), 2.59( d, 2H) , 1.70 (m, 4H), 1.29(m, 4H) [945] Example 181

[946] Carbamic acid 2-(4-chloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

[947] The procedure given in Example 171 was followed using

2-(4-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(4-chloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester. [948] ¹ H-NMR (Acetone-d^ δ7.70(s, 2H), 7.3(d, 2h), 7.0 (d, 2H), 5.7-6.3(br, 2H), 5.5(t,

IH), 4.83(d, 2H), 4.22(m, 2H) [949] Example 182

[950] Carbamic acid 2-(2-chloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

[951] The procedure given in Example 171 was followed using

2-(2-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(2-chloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester. [952] ¹ H-NMR (Acetone-dp δ7.71(s, 2H), 7.25(m, 4H), 6.0(br, 2H), 5.56(m, IH), 4.9(d,

2H), 4.3(m, 2H)

[953] Example 183

[954] S-Phenethyl-pyrrolidine-l-carboxylic acid 2-(2-chloro-phenoxy)-l-[l,2,3] triazol-2-ylmethyl-ethyl ester

[955] The procedure given in Example 182 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give 3-phenethyl-pyrrolidine-l-carboxylic acid 2-(2-chloro-phenoxy)-l-[l,2,3] triazol- 2-ylmethyl-ethyl ester.

[956] ¹ H-NMR (Acetane-d) δ8.06(s, 2H), 7.51(s, IH), 7.25(m, 7H), 7.01(s, IH), 3.75(m,

IH), 3.34(d, 2H), 3.01(d, 2H), 2.7(t, 2H), 2.15(m, 3H), 1.82(m, 6H)

[957] Example 184

[958] Carbamic acid 2-(2,4-dichloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

[959] The procedure given in Example 171 was followed using

2-(2,4-dichloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(2,4-dichloro-phenoxy)-l-[l,2,3] triazol- 2-ylmethyl-ethyl ester.

[960] ¹ H-NMR (Acetone-dp δ7.71(s, 2H), 7.5(s, IH), 7.36(d, IH), 7.19(d, IH), 6.01(br,

2H), 5.55(m, IH), 4.88(d, 2H), 4.32(m, 2H)

[961] Example 185

[962] 3-Phenethyl-pyrrolidine-l-carboxylic acid 2-(2,4-dichloro-phenoxy)-l-[l,2,3] triazol-2-ylmethyl-ethyl ester

[963] The procedure given in Example 184 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give 3-phenethyl-pyrrolidine- 1-carboxylic acid 2-(2,4-dichloro-phenoxy)-l-[l,2,3] triazol- 2-ylmethyl-ethyl ester.

[964] ¹ H-NMR (Acetone-dp δ8.05(s, 2H), 7.51(s, IH), 7.28(m, 6H), 7.01(s, IH), 3.77(m,

IH), 3.35(d, 2H), 3.03(d, 2H), 2.73(t, 2H), 2.15(m, 3H), 1.79(m, 6H)

[965] Example 186

[966] Carbamic acid 2-(3,4-dichloro-phenoxy)-l-[l,2,3]triazol-2-ylmethyl-ethyl ester

[967] The procedure given in Example 171 was followed using

2-(3,4-dichloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(3,4-dichloro-phenoxy)-l-[l,2,3] triazol- 2-ylmethyl-ethyl ester.

[968] ¹ H-NMR (Acetone-d^ δ7.71(s, 2H), 7.50(s, IH), 7.34(d, IH), 7.19(d, IH), 6.03(br,

2H), 5.56(m, IH), 4.89(m, 2H), 4.35(m, 2H)

[969] Example 187

[970] S-Phenethyl-pyrrolidine-l-carboxylic acid 2-(3,4-dichloro-phenoxy)-l-[l,2,3] triazol-2-ylmethyl-ethyl ester

[971] The procedure given in Example 186 was followed using excess

3-phenethyl-pyrrolidine as a reactant, instead of excess ammonium hydroxide, to give S-phenethyl-pyrrolidine-l-carboxylic acid 2-(3,4-dichloro-phenoxy)-l-[l,2,3] triazol- 2-ylmethyl-ethyl ester.

[972] ¹ H-NMR (Acetone-d ₆ ) δ8.06(s, 2H), 7.52(s, IH), 7.28(m, 6H), 7.01(s, IH), 3.80(m,

IH), 3.35(d, 2H), 3.02(d, 2H), 2.7(t, 2H), 2.16(m, 3H), 1.78(m, 6H)

[973] Example 188

[974] Carbamic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

[975] To a solution of lH-l,2,3-triazole (2.4mmol) and lithium carbonate (4.8mmol) in

DMF (100ml), (R)-2-chlorostyrene oxide (2mmol) was slowly added to give enan- tiomerically (R)-configured alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is IN- 1,2,3-triazole. The reaction was stirred for 4h at 12O ⁰ C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 3h, followed by the addition of excess ammonium hydroxide (50ml). After 5h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo.

[976] The preparation procedure of lN-azole is same as that of 2N-azole in example except the ratio of mobile phase of column chromatography. lN-azole is more polar than 2N-azole in chromatographic condition and separated by eluting with an increasing ratio of ethyl acetate in hexane after elution of 2N-azole to give carbamic acid (R)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester.

[977] ¹ H-NMR (CDCl ₃ ) δ7.61(s, 1Η), 7.61(s, 1Η), 7.20-7.38(m, 4Η), 6.35(m, IH),

5.38(br, 2H), 4.75(m, 2H)

[978] Example 189

[979] Carbamic acid (S)-l-(2-chloro-phenyl)-2-[l,2,3]triazol-l-yl-ethyl ester

[980] The procedure given in Example 188 was followed using (S)-2-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid (S)- 1 -(2-chloro-phenyl)-2-[ 1 ,2,3]triazol- 1 -yl-ethyl ester.

[981] ¹ H-NMR (CDCl ₃ ) δ7.53(s, IH), 7.48(s, IH), 6.92-7.37(m, 4H), 6.17(m, IH),

5.72(br, 2H), 4.65(m, 2H)

[982] Example 190

[983] Carbamic acid (R)-l-(3,4-dichloro-phenyl)-2-[l,2^]triazol-l-yl-ethyl ester

[984] The procedure given in Example 188 was followed using (R)-3,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid

(R)- l-(3,4-dichloro-phenyl)-2-[ 1 ,2,3]triazol- 1-yl-ethyl ester.

[985] ¹ H-NMR (Acetone-d ₆ ) δ7.98(s, IH), 7.67(s, IH), 7.8-7. l(m, 3H), 6.34(br, 2H),

6.12(m, IH), 4.90(d, 2H)

[986] Example 191

[987] Carbamic acid (R)-l-(2,4-dichloro-phenyl)-2-[l,2^]triazol-l-yl-ethyl ester

[988] The procedure given in Example 188 was followed using (R)-2,4-dichlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid (R)- 1 -(2,4-dichloro-phenyl)-2-[ 1 ,2,3]triazol- 1 -yl-ethyl ester.

[989] ¹ H-NMR (Acetone-dp δ8.78(s, IH), 7.46(m, 3H), 5.98(m, IH), 5.50-6.34(br, 2H),

5.13(m, 2H)

[990] Example 192

[991] Carbamic acid 2-(4-chloro-phenoxy)-l-[l,2,3]triazol-l-ylmethyl-ethyl ester

[992] The procedure given in Example 188 was followed using

2-(4-chloro-phenoxymethyl)-oxirane as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid 2-(4-chloro-phenoxy)-l-[l,2,3]triazol-l-ylmethyl-ethyl ester.

[993] ¹ H-NMR (Acetone-dp δ8.0(s, IH), 7.70(s, IH), 7.34(d, 2h), 7.0 (d, 2H), 5.9-6.4(br,

2H), 5.41(t, IH), 4.86(d, 2H), 4.16(m, 2H)

[994] Example 193

[995] Carbamic acid (R)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

[996] To a solution of 5-phenyl-lH-tetrazole (2.4mmol) and lithium carbonate (4.8mmol) in DMF (100ml), (R)-2-chlorostyrene oxide (2mmol) was slowly added to give enan- tiomerically (R)-configured alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2N - 5-phenyl-tetrazole. The reaction was stirred for 4h at 12O ⁰ C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 3h, followed by the addition of excess ammonium hydroxide (50ml). After 5h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 2) and recrystallized from dichloromethane and ethyl ether (1 : 1) to give carbamic acid (R)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester.

[997] ¹ H-NMR (Acetone-dp δ8.1-8.3(m, 2Η), 7.2-7.8(m, 7H), 6.67(t, IH), 6.25(br, 2H),

5.14(d, 2H)

[998] Example 194

[999] Carbamic acid (S)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

[1000] The procedure given in Example 193 was followed using (S)-2-chlorostyrene oxide as a reactant, instead of (R)-2-chlorostyrene oxide, to give carbamic acid (S)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester.

[1001] ¹ H-NMR (Acetone-d ₆ ) 68.11 (dd, 2H), 7.57-7.40(m, 7H), 6.65(t, IH), 6.24(br, 2H), 5.13(d, 2H)

[1002] Example 195

[1003] Methyl-carbamic acid (R)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

[1004] The procedure given in Example 193 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid (R)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester.

[1005] ¹ H-NMR (Acetone-d ₆ ) δ8.05-8.25(m, 2H), 7.3-7.7(m, 7H), 6.7(t, IH), 6.55(br, IH), 5.13(d, 2H), 2.64(d, 3H)

[1006] Example 196

[1007] Methyl-carbamic acid (S)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

[1008] The procedure given in Example 194 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid (S)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester.

[1009] ¹ H-NMR (Acetone-d ₆ ) δ8.14 (m, 2H), 7.59-7.39(m, 7H), 6.67(t, IH), 6.54(br, IH), 5.14(m, 2H), 2.64(d, 3H)

[1010] Example 197

[1011] Carbamic acid (S)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-l-yl)-ethyl ester

[1012] To a solution of 5-phenyl-lH-tetrazole (2.4mmol) and lithium carbonate (4.8mmol) in DMF (100ml), (S)-2-chlorostyrene oxide (2mmol) was slowly added to give enan- tiomerically (S)-configured alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is IN- 5-phenyl-tetrazole. The reaction was stirred for 4h at 12O ⁰ C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was added l,l'-carbonyl diimidazole (8mmol). The reaction mixture was stirred at room temperature for 3h, followed by the addition of excess ammonium hydroxide (50ml). After 5h stirring at room temperature, the organic layer was isolated and washed with brine. The resulting organic layer was dried and concentrated in vacuo.

[1013] The preparation procedure of lN-azole is same as that of 2N-azole in example

except the ratio of mobile phase of column chromatography. lN-azole is more polar than 2N-azole in chromatographic condition and separated by eluting with an increasing ratio of ethyl acetate in hexane after elution of 2N-azole to give carbamic acid (S)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol- 1 -yl)-ethyl ester.

[1014] ¹ H-NMR (Acetone-d ₆ ) 07.75-7.60 (m, 4H), 7.36(s, 3H), 7.44(m, IH), 6.18(br, 2H), 4.96(t, 2H)

[1015] Example 198

[1016] Methyl-carbamic acid (S)-l-(2-chloro-phenyl)-2-(5-phenyl-tetrazol-l-yl)-ethyl ester

[1017] The procedure given in Example 197 was followed using excess methylamine as a reactant, instead of excess ammonium hydroxide, to give methyl-carbamic acid (S)- 1 -(2-chloro-phenyl)-2-(5-phenyl-tetrazol- 1 -yl)-ethyl ester.

[1018] ¹ H-NMR (Acetone-d ₆ )δ7.75-7.60(m, 4H), 7.34(m, 3H), 6.45(m, IH), 6.38(br IH), 4.97(m, 2H), 2.63(d, 3H)

[1019] Example 199

[1020] 0-l-(2-Chloro-phenyl)-2-tetrazol-2-yl ethyl allophanate

[1021] To a solution of lH-tetrazole (2.4mmol) and lithium carbonate (4.8mmol) in DMF (100ml), 2-chlorostyrene oxide (2mmol) was slowly added to give alcohol compound represented by the general formula (XII) where in, G is 2-chlorophenyl, m is 0, Y is hydrogen, n is 0 and A is 2N- tetrazole. The reaction was stirred for 4h at 120°C and then cooled to 25 ⁰ C. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine. The resulting organic layer was dried and concentrated in vacuo. This alcohol compound was dissolved in methylene chloride (50ml) and was slowly added methanesulfonic acid (20mmol) and sodium cyanate (20mmol) at O ⁰ C. After 5hr stirring at room temperature, brine was added to terminate the reaction. The resulting organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate : hexane = 1 : 1) to give O-l-(2-Chloro-phenyl)-2-tetrazol-2-yl ethyl allophanate.

[1022] ¹ H-NMR (DMSO-d ₆ ) δ8.75(s, IH), 8.1 l(s, IH), 748(m, 3H), 6.67(m, IH), 5.59-6.55(br, 2H), 5.46(m, 2H).

[1023]

Structure IUPAC

Carbamic acid i-(2-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(2-chloro-phenyl)-2- O ¹ tetrazol-2-yl-ethyl ester

Carbamic acid i-(4-methoxy-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-phenyl-2-tetrazol-2-yl ethyl ester

Carbamic acid i-(4-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(4-methoxy-phenyl)-2 ri,2,λltriazol-2-vl-ethvl ester

Carbamic acid i-phenyl-2-[l,2,3]triazol-2- yl-ethyl ester

Carbamic acid i-p-tolyl-2-[i,2,3]triazol-2- yl-ethyl ester

Carbamic acid i-(3-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(4-chloro-pheπyl)-2-

[i,2,3]triazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-p-tolyl-ethyl ester

Carbamic acid i-o-tolyl-2-[l,2,3]triazol-2- yl-ethyl ester

Carbamic acid i-(4-nitro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(4-nitro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(4-fluoro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(4-fluoro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

¹ V Carbamic acid i-(3-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-m-tolyl-2-[i,2,3]triazol-2- yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-l-m-tolyl- ethyl ester

n, Carbamic acid (R)-i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

O Carbamic acid (S)-i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid (R)-l-(2-chloro-pheny])-2- tetrazol-i-yl-ethyl ester

Carbamic acid (S)-i-(2-chloro-phenyl)-2- tetrazol-i-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-o-tolyl-ethyl ester

Carbamic acid i-(3,4-dichloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(3,4-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-(3- trifluoromethyl-phenyl)-ethyl ester

r> Carbamic acid 2-[i,2,3]triazol-2-yl-i-(3- trifluoromethyl-phenyl)-ethyl ester

Carbamic acid i-(2,4-dichloro-phenyl)-2- [l,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(2,4-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-(4- trifluoromethyl-phenyl)-ethyl ester

Carbamic acid 2-[i,2,3]triazol-2-yl-i-(4- trifluoromethyl-phenyl)-ethyl ester

Carbamic acid (R)-i-(2-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid (S)-i-(2-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(2-chloro-pheπyl)-2- tetrazol-i-yl-ethyl ester

Carbamic acid (R)-i-(2-chloro-phenyl)-2- [i,2,3]triazol-i-yl-ethyl ester

¹ V Carbamic acid (S)-i-(2-chloro-phenyl)-2- [i,2,3]triazol-i-yl-ethyl ester

Carbamic acid i-(2-chloro-phenyl)-2- [i,2,3]triazol-i-yl-ethyl ester

Carbamic acid 2-[l,2,3]triazol-2-yl-i-(2- trifluoromethyl-phenyl)-ethyl ester

¹ V Carbamic acid 2-chloro-i-phenyl-2-tetrazol- l-yl-ethyl ester

,x

O Carbamic acid (S)-i-(4-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid (R)-i-(4-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

°< rC Carbamic acid l-(2-chloro-phenyl)-2-(5- methyl-tetrazol-2-yl)-ethyl ester

Carbamic acid i-(2-chloro-phenyl)-2-(5- methyl-tetrazol-l-yl)-ethyl ester

Methyl-carbamic acid (R)-i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

Ethyl-carbamic acid (R)-i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

Pheπyl-carbamic acid (R)-i-(2-chloro- Λ ^, Λ. ^j <~τf pheny])-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-2-tetrazol-2-y]-i-(2- trifluoromethyl-phenyl)-ethyl ester

Carbamic acid (S)-2-tetrazol-2-yl-i-(2- tτifluoromethyl-phenyl)-ethyl ester

Carbamic acid i-(2-chloro-phenyl)-2-(5- phenyl-tetrazol-2-yl)-ethyl ester

Methyl-carbamic acid i-(2-chlorc-phenyl)- 2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Cyclopropyl-carbamic acid (R)-i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid (R)-i-(2-chloro-phenyl)-2- (5-phenyl-tetrazol-2-yl)-ethyl ester

Methyl-carbamic acid (R)-i-(2-chloro- phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Jk m, Carbamic acid i-phenyl-3-tetrazol-2-yl-

Cr ^{^} ύ propyl ester

Carbamic acid l-(2-chloro-phenyl)-2-[5-

(2,3-dichloro-phenylJ-tetrazol-a-yl]-ethyl ester

Methyl-carbamic acid i-(2-chloro-phenyl)-

2-[5-(2,3-dichloro-phenyl)-tetrazol-2-yl]- ethyl ester

Carbamic acid i-(4-hydroxy-phenyl)-2- tetrazol-2-yl-ethyl ester

Λ,

Carbamic acid (S)-i-(2-chloro-phenyl)-2-(5-

U phenyl-tetrazol-2-yl)-ethyl ester

X Methyl-carbamic acid (S)-i-(2-chloro-

^• 3-O phenyl)-2-(5-phenyl-tetrazol-2-yl)-ethyl ester

Carbamic acid (S)-i-(2-chloro-phenyl)-2-(5- phenyl-tetrazol-l-yl)-ethyl ester

Methyl-carbamic acid (S)-i-(2-chloro- phenyl)-2-(5-phenyl-tetrazol-i-yl)-ethyl ester

Carbamic acid i-phenyl-3-tetrazol-i-yl- propyl ester

Carbamic acid i-phenyl-3-tetrazol-i-yl- propyl ester

Carbamic acid i-(2-chloro-phenyl)-2-[5-

(2,3-dichloro-phenyl)-tetrazol-i-yl]-ethyl ester

Methyl-carbamic acid i-(2-chloro-phenyl)-

2-[5-(2,3-dichloro-phenyl)-tetrazol-i-yl]- ethyl ester

Υγ'γ* _' Carbamic acid i-(3-chloro-phenyl)-2-

I ₁₁ J tetrazol-2-yl-propyl ester

Methyl-carbamic acid i-(3-chloro-phenyl)- 2-tetrazol-2-yl-propyl ester

Λ Carbamic acid i-(3-chloro-phenyl)-2-

Λ tetrazol-i-yl-propyl ester

Carbamic acid i-(2-chloro-phenyl)-3- [i,2,3]triazol-2-yl-propyl ester

Carbamic acid i-(2-chloro-phenyl)-2-(5- pyridin-2-yl-tetrazol-2-yl)-ethyl ester

Carbamic acid 2-(5-amino-tetrazol-2-yl)-i- (2-chloro-phenyl)-ethyl ester

Carbamic acid i-(3-chloro-phenyl)-2- [i,2,3]triazol-2-yl-propyl ester

Methyl-carbamic acid i-(3-chloro-phenyl)- 2-[i,2,3]triazol-2-yl-propyl ester

Ethyl-carbamic acid i-(2-chloro-phenyl)-2- (5 -pyridin- 2 -yl-tetrazol-2-yl) -ethyl ester

Carbamic acid i-(4-chloro-phenyl)-2- tetrazol-2-yl-propyl ester

Methyl-carbamic acid l-(4-chloro-phenyl)- 2-tetrazol-2-yl-propyl ester

Carbamic acid i-(4-chloro-phenyl)-2- tetrazol-i-yl-propyl ester

Methyl-carbamic acid i-(4-chloro-phenyl)- 2-tetrazol-i-yl-propyl ester

" _N X/LC" Carbamic acid i-(3,4-dichloro-phenyl)-2- _a X.J ^< * ^> tetrazol-2-yl-propyl ester

Methyl-carbamic acid i-(3,4-dichloro- phenyl)-2-tetrazol-2-yl-propyl ester

Carbamic acid i-(3,4-dichloro-phenyl)-2- tetrazol-i-yl-propyl ester

Methyl-carbamic acid i-(3,4-dichloro- phenyl)-2-tetrazol-i-yl-propyl ester

Carbamic acid l-(3,4-dimethoxy-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid (S)-i-(4-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid (R)-l-(4-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid (S)-i-(3,4-dichloro-phenyl)- 2-[i,2,3]triazol-2-yl-ethyl ester

Carbamic acid CR)-i-(3,4-dichloro-phenyl)- 2-tetrazol-2-yl-ethy] ester

Carbamic acid i-(2,5-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(2,5-dichloro-phenyl)-2- tetrazol-i-yl-ethyl ester

Carbamic acid (R)-i-(3,4-dichloro-phenyl)- 2-[i,2,3]triazo]-2-yl-ethyl ester

Carbamic acid (R)-i-(3,4-dichloro-phenyl)- 2-[i,2,3]triazol-i-yl-ethyl ester

Carbamic acid i-(4-phenoxy-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(4-phenoxy-phenyl)-2- tetrazol-i-yl-ethyl ester

Carbamic acid i-(2,5-dichloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

A C=V Carbamic acid (S)-i-(3,4-dichloro-phenyl)- XT" 2-tetrazol-2-yl-ethyl ester

πr- ¹ Carbamic acid (S)-i-(3,4-dichloro-phenyl)- 2-tetrazol-i-yl-ethyl ester

Carbamic acid i-(2,6-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

^ n Carbamic acid i-(2,6-dichloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(2,6-dichloro-phenyl)-2- [i,2,3]triazol-i-yl-ethyl ester

A. Carbamic acid l-(2,4-dichloro-phenyl)-2- o tetrazol-i-yl-ethyl ester

Carbamic acid i-naphthalen-2-yl-2-tetrazol- 2-yl-ethyl ester

Carbamic acid (R)-i-(2,4-dichloro-phenyl)- 2-tetrazol-2-yl-ethyl ester

Carbamic acid i-naphthalen-a-yl-2-tetrazol- l-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-(2,3,4- trimethoxy-phenyl)-ethyl ester

Carbamic acid 2-tetrazol-i-yl-i-(2,3,4- trimethoxy-ρhenyl)-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-(3,4,5- trimethoxy-phenyl)-ethyl ester

Carbamic acid i-benzo[i,3]dioxol-5-yl-2- tetrazol-2-yl-ethyl ester

_<χr w Carbamic acid i-benzo[i,3]dioxol-5-yl-2- tetrazol-i-yl-ethyl ester

Carbamic acid i-(4-dimethylamiπo-phenyl)- 2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i-(2,4,6- trimethyl-phenyl)-ethyl ester

Carbamic acid 2-tetrazol-i-yl-i-(2,4,6- trimethyl-phenyl)-ethyl ester

Carbamic acid (S)-i-(2,4-dichloro-phenyl)- 2-tetrazol-2-yl-ethyl ester

XT Carbamic acid (S)-i-(2,4-dichloro-phenyl)- rζy 2-[i,2,3]triazol-2-yl-ethyl ester

Carbamic acid (R)-i-(2,4-dichloro-phenyl)- 2-[i,2,3]triazol-2-yl-ethyl ester

1 _^ ? i "^ ¹ Carbamic acid 2-phenyl-i-tetrazol-2-

¹⁴ ° ylmethyl-ethyl ester

^ I "' Carbamic acid 2-phenyl-i-tetrazol-i- ylmethyl-ethyl ester

Carbamic acid i-(4-tert-butyl-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(4-tert-butyl-phenyl)-2- tetrazol-i-yl-ethyl ester

Carbamic acid i-(4-chloro-3- ^v ' trifluo >rroommeetthhyyll--pphheennyyll))--22--[[i] ,2,3]triazol-2-

<ζy yl-ethyl ester

Carbamic acid i-(4-chloro-3- trifluoromethyl-phenyl)-2-[i,2,3]triazol-i- yl-ethyl ester

Carbamic acid (S)-i-(2,6-dichloro-phenyl)- 2-tetrazol-i-yl-ethyl ester

Carbamic acid (R)-l-(2 _; 6-dichloro-phenyl)- 2-tetrazol-i-yl-ethyl ester

Carbamic acid i-indan-5-yl-2-tetrazol-i-yl-

^ ethyl ester

Carbamic acid i-indan-5-yl-2-tetrazol-2-yl- ethyl ester

Carbamic acid (R)-i-(2,6-dichloro-phenyl)- 2-tetrazol-2-yl-ethyl ester

Carbamic acid (S)-i-(2,6-dichloro-phenyl)- 2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-(2,4-dichloro-phenoxy)-l- tetrazol-2-ylmethyl-ethyl ester

O-i-(2-Chloro-phenyl)-2-tetrazol-2-yl ethyl allophanate

Carbamic acid (R)-i-(2,4-dichloro-phenyl)- O* 2-[i,2,3]triazol-i-yl-ethyl ester

Carbamic acid i-phenyl-2-tetrazol-i-yl-ethyl ester

Carbamic acid i-(3,4-difluoro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(3,4-difluoro-pheny])-2- tetrazol-i-yl-ethyl ester

Carbamic acid i-(3,4-difluoro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

Carbamic acid i-(3,4-difluoro-phenyl)-2- [i,2,3]triazol-i-yl-ethyl ester

Carbamic acid i-(2-fluoro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid l-(2-fluorophenyl)-2- tetrazol-i-yl-ethyl ester

4-Benzyl-piperidine-i-carboxylic acid 1 (2- chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid 7-nitro-2-tetrazol-2-yl- 1,2,3,4-tetrahydro-naphthalen-i-yl ester

Carbamic acid 5,7-dimethyl-2-tetrazol-2-yl~ 1,2,3,4-tetrahydro-πaphthalen-l-yl ester

I j*\ Carbamic acid 7-nitro-2-tetrazol-l-yl- i,2,3,4-tetrahydro-naphthalen-i-yl ester

Carbamic acid 5,7-dimethyl-2-tetrazol-i-yl- 1,2,3,4-tetrahydro-naphthalen-i-yl ester

4-Phenyl-piperazine-i-carboxylic acid i-{2- chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-Phenyl-piperazine-i-carboxylic acid i-(2- chloro-phenyl)-2-tetrazol-i-yl-ethyl ester

4-(4-Fluoro-benzoyl)-piperidine-l- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-Benzyl-piperidine-l-carboxylic acid i-(2- chloro-phenyl)-2-tetrazol-i-yl-ethyl ester

i-Benzyl-4-[x-(2-chloro-phenyl)-2-tetrazol- 2-yl-ethoxycarbonyl]-piperazin-i-ium

Carbamic acid 2-(3,4-dichloro-phenoxy)-i- tetrazol-2-ylmethyl-ethyl ester

Imidazole-i-carboxylic acid 2-(3,4-dichloro- phenoxy)-i-tetrazol-i-ylmethyl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-i- tetrazol-i-ylmethyl-ethyl ester

Imidazole-l-carboxylic acid 2-(4-chloro- phenoxy)-l-tetrazol-i-y]methyl-ethyl ester

X

OJO Carbamic acid 2-(4-chloro-phenoxy)-i- tetrazol-2-ylmethyl-ethyl ester

X,

OJO 4-Beπzyl-piperidine-i-carboxylic acid l- ύ phenyl-2-tetrazol-i-yl-ethyl ester

JOJD 4-Benzyl-piperidiπe-i-carboxylic acid l- ^u ό phenyl-2-tetrazol-2-yl-ethyl ester

Carbamic acid 2-(2-chloro-phenoxy)-i- tetrazol-2-ylmethyl-ethyl ester

4-Benzyl-piperidiπe-i-carboxylic acid 2-(2- chloro-phenoxy)-i-tetrazol-2-ylmethyl-ethyl ester

,vA _r ^» , _N Carbamic acid 2-(2-chloro-phenoxy)-i- tetrazol-i-ylmethyl-ethyl ester

4-Benzyl-piperidine-i-carboxylic acid 2-(2- chloro-phenoxy)-i-tetrazol-i-ylmethyl-ethyl ester

Carbamic acid 2-tetrazol-2-yl-i,2,3,4- tetrahydro-naphthalen-i-yl ester

Carbamic acid 2-tetrazol-l-yl- 1,2,3,4- tetrahydro-naphthalen-i-yl ester

~r Carbamic acid i-(2,4-difluoro-phenyl)-2- tetrazol-2-yl-ethyl ester

Carbamic acid i-(2,4-difluoro-pheπyl)-2- tetrazol-i-yl-ethyl ester

4-Benzyl-piperidine-i-carboxylic acid (S)-i- C2-chloro-phenyl)-2-[l,2,3]triazol-2-yI-ethyl

4-Benzyl-piperidiπe-i-carboxylic acid (R)-I- (2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

Carbamic acid i-(2,4-dimethyl-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

4-Benzyl-piperidine-l-carboxylic acid (S)-i- (2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

[2-(3,4-Dihydroxy-phenyl)-ethyl]-carbamic acid i-(2-chloro-ρhenyl)-2-tetrazol-2-yl- ethyl ester

[2-(3,4-Dihydroxy-phenyl)-ethyl]-carbamic acid i-(2-chloro-phenyl)-2-tetrazol-i-yl- ethyl ester

4-Benzyl-piperidine-i-carboxylic acid (R)-i- (2-chloro-phenyl)-2-[i,2,3]triazol-2-yl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-i~ [i,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(4-chloro-phenoxy)-i- [i,2,3]triazol-i-ylmethyl-ethyl ester

4-Benzyl-piperidine-i-carboxylic acid 2-(4- chloro-phenoxy)-i-tetrazol-2-ylmethyl-ethyl ester

4-Benzyl-piperidine-i-carboxylic acid 2-(4~ chloro-phenoxy)-i-tetrazol-i-ylmethyl-ethyl ester

4-(4-Methoxy-beπzyl)-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(3 _J 4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-Pyridin-4-ylmethyl-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(4-Fluoro-benzyl)-piperidine-i-carboxylic acid i-(2-chloro-phenyl)-2-tetrazol-2-yl- ethyl ester

3-(4-Fluoro-benzyl)-piperidiπe-i-carboxylic acid i-(2-chloro-phenyl)-2-tetrazol-2-yl- ethyl ester

4-(4-Chloro-beπzyl)-piperidine-i-carboxylic acid i-(2-chloro-phenyl)-2-tetrazol-2-yl- ethyl ester

3-(4-Chloro-phenyl)-pyrrolidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

3-Phenethyl-pyτrolidine-i-carboxylic acid l- (2-chloro-phenyI)-2-tetrazol-2-yl-ethyl ester

4-[i,2,3]Triazol-2-ylmethyl-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

3-Tetrazol-2-ylmethyl-piperidine-i- carboxylic acid i-(2-chloro-phenyl>2- tetrazol-2-yl-ethyl ester

3-[i,2,3]Triazol-2-ylmethyl-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-Benzoyl-piperidine-i-carboxylic acid i-(2- chloro-phenyl)-2-tetrazol-2-yl-ethyl ester

4-(4-Chloro-benzoyl)-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

A 4-(4-Methoxy-benzoyl)-piperidine-i-

O carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

A 4-[i _J 2 ₎ 3]Triazol-i-ylmethyl-piperidine-i-

O carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-Tetrazol-2-ylmethyl-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-[i,2,3]Triazol-2-yl-piperidine-i-carboxylic acid i-(2-chloro-phenyl)-2-tetrazol-2-yl- ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-(2,5-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(5-Phenyl-tetrazol-2-yl)-piperidiπe-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-[i,2,3]Triazol-i-yl-piperidine-i-carboxylic acid i-(2-chloro-phenyl)-2-tetrazol-2-yl- ethyl ester

4-(3 _» 4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-(2,4-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-(3,4-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

3-(4-Chloro-benzyl)-pyrrolidine-i- carboxylic acid l-(2-chloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(3,5-Bis-trifluoromethyl-benzyl)- piperidine-i-carboxylic acid i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

3-(5-Methyl-tetrazol-2-ylmethyl)- piperidine-i-carboxylic acid i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

4-(5-Methyl-tetrazol-2-ylmethyl)- piperidine-i-carboxylic acid i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- [i,2,3]triazol-2-yl-ethyl ester

[1055] [1056]

4-(3 _; 4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-(2-chloro-phenyl)-2- tetrazol-i-yl-ethyl ester

S-Phenethyl-pyrrolidine-i-carboxylic acid i- (2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

S-Phenethyl-pyrrolidine-l-carboxylic acid i-

(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

s-Phenethyl-pyrrolidine-i-carboxylic acid i- (3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester

s-Phenethyl-pyrrolidine-i-carboxylic acid 2-(2-chloro-phenoxy)-i-[i,2,3]triazol-2- ylmethyl-ethyl ester

S-Phenethyl-pyrrolidine-l-carboxylic acid

2-(2,4-dichloro-phenoxy)-i-[i,2,3]triazol-2- ylmethyl-ethyl ester

S-Phenethyl-pyrrolidine-i-carboxylic acid

2-(3,4-dichloro-phenoxy)-i-[l,2,3]triazol-2- ylmethyl-ethyl ester

s-Phenethyl-pyrrolidine-i-carboxylic acid 2-(2,5-dichloro-ρhenoxy)-i-tetrazol-2- ylmethyl-ethyl ester

K Carbamic acid 2-(2-chloro-phenoxy)-i-

*ζy [i,2,3]triazol-2-ylmethyl-ethyl ester

YykΛ A _" , Carbamic acid 2-(3,4-dichloro-phenoxy)-i-

⁰¹ ^ "ζ _j f [i,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(2,4-dichloro-phenoxy)-i- [i,2,3]triazol-2-ylmethyl-ethyl ester

Carbamic acid 2-(2,5-dichloro-phenoxy)-i- tetrazol-2-ylmethyl-ethyl ester

j 4-(4-Fruoro-benzoyl)-piperidine-l-

A _, Ox _x iJ' carboxylic acid i-(3,4-dichloro-phenyl)-2-

<( _j " " ° tetrazol-2-yl-ethyl ester

[1058]

4-(4-Fluoro-benzoyT)-piperidine-i- carboxylic acid i-(2,4-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(4-Fluoro-benzoyl)-piperidine-i- carboxylic acid i-(2,5-dichloro-phenyl)-2- tetrazol-2-yl-ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-i- carboxylic acid 2-(2-chloro-phenoxy)-i- tetrazol-2-ylmethyl-ethyl ester

4-(3 _; 4-Dichloro-benzyl)-piperidine-i- carboxylic acid 2-(2,4-dichloro-phenoxy)-l- tetrazol-2-ylmethyl-ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-i- carboxylic acid 2-(3,4-dichloro-phenoxy)-l- tetrazol-2-ylmethyl-ethyl ester

3-[2-(4-Methoxy-phenyl)-ethyl]- pyrrolidine-i-carboxylic acid i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

4-(3,4-Dichloro-benzyl)-piperidine-i- carboxylic acid i-phenyl-2-tetrazol-2-yl- ethyl ester

Carbamic acid i-(4-benzyloxy-phenyl)-2-

(T tetrazol-2-yl-ethyl ester

Carbamic acid l-(4-benzyloxy-phenyl)-2- tetrazol-l-yl-ethyl ester

methyl-carbamic acid -i-(2-chloro-phenyl)- 2-tetrazol-2-yl-ethyl ester

methyl-carbamic acid (S)-i-(2-chloro- phenyl)-2-tetrazol-2-yl-ethyl ester

4-benzyl-piperidine-i-carboxylic acid-i-(2- chloro-phenyl)-2-[i _; 2,3]triazol-2-yl-ethyl ester

4-benzyl-piperidine-i-carboxylic acid (S)-i-

(2-chloro-phenyl)-2-[l,2,3]triazol-2-yl-ethyl ester