This invention relates to a new medical use of 1 ,5-benzodiazepine derivatives which exhibit CCK-A agonist activity. More particularly it relates to the use of such compounds to control gastric emptying in patients having an early non-insulin- dependent diabetic condition.

Cholecysto inins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-Nhtø (CCK-4) which is the common structural element shared by both CCK and gastrin.

CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body. There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B and both are found in the periphery and in the central nervous system.

The CCK-A receptor, commonly referred to as the "peripheral-type" receptor, is primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents.

The CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.

U.S. Patent No. 4,988,692, to Gasc, et al. describes a group of 3-acylamino 1- alkyl-5-phenyl 1,5-benzodiazepine derivatives which behave as cholecystokinin antagonists to reverse or block the effects of the endogenous hormone at its receptors.

US Patent No. 4,490,304 and PTC applications No's WO90/06937 and W091/19733 describe peptide derivatives that exhibit CCK-A agonist activity. Such compounds have been disclosed for appetite regulation as well as the treatment and/or prevention of gastrointestinal disorders or disorders of the central nervous in animals and, more particularly, humans.

US Patent No. 5,187,154 which is incorporated herein by reference describes the use of the neuropeptide cholecystokinin (CCK) to control gastric emptying in patients having an early non-insulin-dependent diabetic condition and exhibiting rapid gastric emptying. Further the specification teaches that compounds which inhibit gastric emptying may be useful to alleviate or eliminate symptoms associated with early or pre-diabetes. Particular symptoms include elevated blood glucose and insulin levels, insulin resistance, increased susceptibility to infection or glycosu a while also maintaining gastric emptying within normal levels.

We have now discovered that a novel group of 3-amino 1 ,5-benzodiazepine compounds which exhibit agonist activity for the CCK-A receptor delay or inhibit gastric emptying and thus may be used to treat patents having non-insulin- dependent diabetic conditions and exhibiting rapid gastric emptying.

The present invention thus provides for the use of compounds of the general Formula (I)

(I)

and physiologically salts and solvate thereof wherein:

X is either hydrogen, trifluoromethyl, alkyl, Ci-4alkylthio, -O(Ci-4alkyl) or halogen;

R ¹ is either Formula II or -NR ⁴ R ⁵ -;

R ² is either:

(1 ) a heterocycle linked at its 2- position and selected from pyrrole, tetrahydropyrrole, indole, benzofuran, thiophene, benzothiophene, indoline, quinoline or 4-oxobenzopyran and wherein said pyrrole, tetrahydropyrrole, indole or indoline may optionally be substituted on the ring nitrogen thereof by the group R ⁸ as defined hereunder and said indole, indoline, quinoline, benzofuran, benzothiophene or 4-oxo-benzopyran may optionally be substituted in the benzo ring thereof by the group R® as defined hereunder or

(2) phenyl or phenyl mono- or disubstituted independently with halogen, hydroxy, cyano, carboxy, -O(Ci-4alkyl), -0(CH2C6H5), -C00(Ci-4alkyl), amino, dimethylamino, -NHR ^{ι n} , 1-pyrrolidinyl or tetrazolyl; or

(3) pyridine or pyridinyl mono- or disubstituted independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, -0(Cι-4 alkyl), -COO(Cι-4alkyl), amino or dimethylamino; or

(4) -NHR ^{1 1} where R ^{1 1} is defined hereinunder or R ^{1 1} is 7-indazolyl containing a group R ^{1 u} at the N-1 position;

R3 is hydrogen, Ci-6alkyl, C3-6cycloalkyl, phenyl or phenyl mono- or disubstituted independently with halogen;

R ⁴ is independently C3-6alkyl, C3-6cycloalkyl, C3-6alkenyl, phenyl, -(CH2)pCN or -(CH2)ρCOO(Ci-4alkyl) and R ⁵ is independently C3-6alkyl, C3-6cycloalkyl, C3-6 alkenyl, benzyl, phenyl or phenyl mono- or disubstituted independently with Ci- 3alkyl, optionally substituted by 1 or more fluorine atoms cyano, hydroxy, dimethylamino, -0(Ci-4alkyl), -0(CH2C6H5), -NH(Ci-4alkyl), -C00(Ci-4alkyl), - N(C- _)^ alkyl) ₂ pyrrolidino, morpholino or halogen or R ⁴ is Ci-2alkyl and R^ is phenyl substituted at the 2- or 4- position with chloro, methyl, methoxy or methoxycarbonyl;

R6 is hydrogen or methyl;

R ⁷ is hydrogen, hydroxy, fluoro, dimethylamino, -0(Ci-4alkyl) or -O(CH2C6H5);

R ⁸ is -(CH2)bCOOH;

R9 is methyl, chloro, nitro, hydroxy, methoxy or -NHR ¹⁰ ;

R ¹⁰ is hydrogen, acetyl, Ci-4alkyl, -SO3H, -SO2CH3, -SO2CF3 or -S02C6H5, C 1 _4alkoxycarbonyl;

R ^{1 1} is phenyl or phenyl mono- or disubstituted independently with fluorine, trifluoromethoxy, Ci-4alkylthio, -(CH2)cCOOH, -(CH2)cCOO(Ci-4alkyl),

-(CH2)cSCH3, -(CH2)cSOCH3, -(CH2) _C S02CH3, -(CH2) _c CONH2, -SCH2COOH,

-CONH(S02CH3), -CONH(S02CF3), -(CH2) _C N(Ci -4alkyl)2,

(CH2)cNH(S02CF3), -(CH2) _C N(Sθ2CF3)(Ci-4alkyl), -(CH2) _C SO2NHCO(Cl-

4alkyl), -(CH2)cSθ2N (C -4alkyl)CO(Ci-4alkyl), -(CH2) _C CONHSθ2(Ci-4alkyl), -(CH2)cCON

(Cl-4alkyl)S02(Ci-4alkyl), -(CH2)cOR ¹² -(CH2)cNHR ¹⁰ or phenyl monosubstituted with -(CH2)c(tetrazolyl), -(CH2)c (carboxamidotetrazolyl) or

-(CH2)c(pyi"rolidinyl) or R ^{1 1} is selected from pyridine or pyridinyl mono- or disubstituted independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, -0(Ci-4 alkyl), amino, dimethylamino, -NHR ¹⁰ ;

R ¹² is hydrogen, C-|^alkyl, C3_6cycloalkyl, -CH2C6H5, -CH2COOH, -CH2CONH2, -CH2CONH(Cι_4alkyl), or

-(CH CO-N O or -(CH,) CO-N N-R

z is 1 or 2;

n is 1 or 2;

p is an integer from 1-4;

b is an integer from 0-3; and

c is 0 or 1,

in the manufacture of a therapeutic agent for controlling gastric emptying in patients having an early non-insulin-dependent diabetic condition and exhibiting rapid gastric emptying.

When R ¹ represents the group of Formula (II), examples of such a group include those wherein R ⁶ is hydrogen or more particularly methyl, R ⁷ is hydrogen, hydroxyl, methoxy, or fluorine, and n is 1.

When R ¹ represents the group NR ⁴ R ⁵ , examples of suitable groups include those wherein R ⁴ represent C3-6 alkyl, such as propyl or isopropyl, cyclohexyl or phenyl and R ⁵ represents C3-6 alkyl, benzyl or phenyl optionally substituted in the para- position by hydroxy, dimethylamino methoxy, trifluoromethyl, fluorine, pyrrolidino or morpholino. Within this group, particularly useful R ¹ groups include those wherein R ⁴ is propyl and, more particularly, isopropyl and R ⁵ represents phenyl or phenyl substituted in the para-position by groups selected from hydroxy, methoxy dimethylamino, fluorine, or morpholino.

Examples of particularly suitable R ¹ groups include those wherein R ¹ is the group of Formula (II) wherein RQ is methyl, n is 1 and R ⁷ is hydrogen, hydroxy, fluorine or methoxy or R ¹ is the group NR ⁴ R^ wherein R ⁴ is propyl or isopropyl and R^ is

phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, trifluoromethyl, dimethylamino, pyrrolidino or morpholino.

When R ² represents a group selected from indole, indoline, benzofuran, benzothiophene, quinoline or 4-oxobenzopyran, the optional substituent R ⁹ is conveniently a group selected from hydrogen, methyl, methoxy, hydroxy, nitro or amino and, where appropriate, the optional substituent on nitrogen, (R ⁸ ), is - CH ₂ C0 ₂ H.

When R ² is an optionally substituted phenyl group, this is conveniently phenyl or phenyl substituted by one or two groups, which may be the same or different and selected from chlorine, fluorine, amino, hydroxy or carboxyl.

When R ² represents the group NHR ¹¹ , R ¹¹ is conveniently phenyl (optionally substituted by fluoro, hydroxy, amino, dimethylamino, trifluoromethylsulphonylamino, C1-4 alkoxycarbonyl, carboxy, 1 H-tetrazol-5-yl, acetylamino or OR ¹² wherein R ¹² represents hydrogen, methyl, benzyl, CH ₂ C0 ₂ H, CH ₂ CONH ₂ , CH ₂ CONHCH ₃ , CH ₂ CON(CH ₃ ) ₂

CH.CON O ' CH.CON NH or CHXON NCO.C(CH ₃

^* \ ^{■■ :} v__ ^* \ / ^*

) or a 7-indazolyl group wherein the N-1 substituent, (R ¹⁰ ), is hydrogen.

When R ¹¹ is a mono substituted phenyl group, the substituted is conveniently in the meta- position.

Examples of particularly suitable R ² groups includes indole, benzofuran, thiophene, benzothiophene, indoline, quinoline, 4-oxobenzopyran, an optionally substituted phenyl group or the group NHR ^{1 1} . Conveniently, R ² is selected from the group indole, indoline or benzofuran, an optionally substituted phenyl group or the group NHR ^{1 1} . More particularly, R ² represents an indole, an optionally substituted phenyl or NHR ¹¹ .

When R3 represents C1-6 alkyl, examples of suitable groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isoamyl.

When R3 represents C3-6 cycloalkyl, examples of suitable groups include cyclopropyl, cyclopentyl or cyclohexyl.

When R3 represents phenyl, mono or disubstituted by independently with halogen, examples of suitable groups include those wherein the halogen substituent is fluorine e.g., 2-fluorophenyl or 4 fluorophenyl.

Examples of particularly suitable R ³ groups include hydrogen, methyl, cyclohexyl, 2-fluorophenyl or phenyl, and more particularly, phenyl.

A particularly useful group of compounds for use according to the invention include those wherein R ¹ represents the group of Formula (II) wherein R ⁶ is methyl, n is 1 and R ⁷ is hydrogen, fluorine, hydroxy or methoxy, or more particularly NR ⁴ R ⁵ wherein R ⁴ is propyl or isopropyl and R ⁵ is phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, dimethylamino or monopholino; R ² represents phenyl (optionally substituted independently by one or two groups selected from chlorine, fluorine, hydroxy, amine or carboxy), NHR ^{1 1} wherein R ¹¹ represents phenyl (optionally substituted by amino, dimethylamino, trifluoromethyl- sulphonylamino, carboxy, 1 H-tetrazol-5- yl, acetylamino or OR ¹² wherein R ² represents hydrogen, methyl, benzyl, CH2CO2H, CH ₂ CONH ₂ , CH ₂ CONHCH ₃ , CH ₂ CON(CH ₃ )2,

CH,CON O ^• CH.CON NH or CH,CON NCO,C(CH ₃ ) ₃ and

\ ^{/' 2} , . ^* \ / ^* wherein the substituent is preferably in the meta- position) or an indole wherein the nitrogen atom is optionally subtituted by the group -CH2CO2H and the benzo ring is optionally substituted by chlorine, methyl, methoxy, nitro, hydroxy or amino; R ³ represents hydrogen, methyl, cyclohexyl, 2- fluorophenyl or phenyl or, more particularly, 2 fluorophenyl or phenyl; and X represents fluorine and z is 1 or, more particularly, X is hydrogen;

A particularly interesting class of compounds for use in the present invention are those wherein R ² is an indole group. A preferred group of compounds within this class are those wherein the indole group is substituted on the nitrogen atom by the group -CH2CO2H or, more preferably, the nitrogen atom is unsubstituted,

and benzo ring of the indole group is optionally substituted by a group selected from chlorine, methyl, methoxy, nitro, hydroxy or ammo.

A particularly preferred compound for use in the invention which is hereinafter referred to as compound 'A' is

1 H-lndole-2-carboxylιc acid {1 -[lsopropyl-(4-methoxyphenyl)carbamoyl-methyl]- 2,4-dιoxo-5-phenyl-2,3,4,5-tetrahydro-1 H-benzo[b][1 ,4]dιazepιn-3-yl}-amide and enantiomers thereof

As provided herein, the term alkyl is generally intended to mean both straight chain and branched chain aliphatic isomers of the corresponding alkyl. For example, C-i-βalkyl is intended to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, etc

The term cycloalkyl, as provided herein, is intended to mean all alicyclic isomers of the corresponding alkyl For example, the term C3.6 alkyl, as provided herein, is intended to include such groups as cyclopropyl, cyclopentyl and cyclohexyl.

The term halogen is intended to mean F, Cl, Br or I

The term tetrazole as a group or part of a group refers to the (1 H)-tetrazol-5-yl grouping and tautomers thereof

Those skilled in the art will recognize that stereocenters exist in compounds of Formula (I) Accordingly, the present invention includes all possible stereoisomers and geometric isomers of Formula (I) and includes not only racemic compounds but also the optically active isomers as well When a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomeπcally pure starting material or any convenient intermediate Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art See, for example, Stereochemistry of Carbon Compounds by E L Eliel

(Mcgraw Hill, 1962) and Tables of Resolving Agents by S H Wilen Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeπc forms of the compounds

It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of Formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids as well as quaternary ammonium acid addition salts. More specific examples of suitable salts include hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, _ benzoic, salicylic, fumaric, toluenesulphonic, methanesulphonic, naphthalene-2-sulphonic, benzenesulphonic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. References hereinafter to a compound according to the invention include both compounds of Formula (I) and their pharmaceutically acceptable salts and solvates.

CCK-A agonist activity of the compounds of formula (I) may be determined by standard procedures.

The relative affinities of compounds of formula (I) for the CCK-A and CCK-B receptors may also be determined using known conventional procedures such as described by Fornos et al J. Pharmacol Exp. Ther., 1992 261., 1056-1063.

The compounds of formula (I) inhibit or delay gastric emptying and thus may be used to alleviate or eliminate symptoms associated with early or prediabetes, particularly for non-insulin dependent diabetes. Such symptoms include elevated blood glucose and insulin levels, insulin resistance, increased susceptibility to infection and/or glycosuria while also maintaining gastric emptying with normal levels.

The ability of compounds of formula (I) to inhibit or delay gastric emptying may be determined using standard tests. Thus for example rats deprived for food for 18hr were pretreated with the test compound administered i.p at a pre-set time (20 mins) before being given a methyl cellulose meal which was administered by the gavage route. The meal contains a marker element such as Phenol Red. After

specific predetermined time intervals the rats are sacrificed and the amount of the meal in the stomach is determined by measuring the concentration of the marker substance present. This value is then compared with a control animal which was not pre-treated with the test compound. In this test the preferred compound of formula (I) compound 'A' when administered i.p at doses of 1μmole/kg 20 min before gavage of test meal (1.5% methyl cellulose), completely inhibited gastric emptying 30mins after administration of the test meal. Lower doses of the compound 'A' 0.01 and O.lμmoles per kg i.p also resulted in a significant reduction in gastric emptying.

According to a further aspect of the present invention, there is provided herein a method for the treatment of a mammal, including man, in particular in the treatment associated with early or prediabetes, particularly noninsuiin-dependent diabetes, the method comprising administering to the patient exhibiting rapid gastric emptying an therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per day, e.g., 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

While it is possible that compounds of formula (I) may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, the present invention further provides for a pharmaceutical formulation for use in the present invention comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s)

must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations of the present invention include those especially formulated for oral, buccal, parenteral, implant, or rectal administration, however, oral administration is preferred. For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulphate. The tablets may be coated according to methods well- known in the art. Such tablet coatings conveniently include conventional enteric coatings known to those skilled in the art e.g. cellulose acetate phthalate, polyvinyl acetate phthalate, shellac, styrene maleic acid copolymers, methyacrylic acid copolymers and hydroxypropyl methyl cellulose phthalate.

Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p_- hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

For oral administration the compounds of formula (I) are preferably formulated as enteric coated tablets or enteric capsules.

Pharmacy

Tablet

Active Ingredient 50 mg

Lactose anhydrous USP 163 mg

Microcrystalline Cellulose NF 69 mg

Pregelatinized starch Ph. Eur. 15 mg Magnesium stearate USP 3 mg

Compression weight 300 mg

The active ingredient, microcrystalline cellulose, lactose and pregletinized starch are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium starate is sieved through a 250 micron sieve and blended with the active blend. The blend is compressed into tablets using suitable punches, then coated in a conventional manner with an enteric coating such as cellulose acetate phthalate.