WO1995003299A1

WO1995003299A1 - 1,5-benzodiazepine derivatives useful as cck or gastrin antagonists

Info

Publication number: WO1995003299A1
Application number: PCT/EP1994/002351
Authority: WO
Inventors: Robert James Barnaby; Paolo Cassara
Original assignee: Glaxo S.P.A.
Priority date: 1993-07-20
Filing date: 1994-07-18
Publication date: 1995-02-02
Also published as: GB9314977D0; AU7228994A

Abstract

Compounds of general formula (I) wherein R1 represents a phenyl, C¿3-7?cycloalkyl, C7-11 bridgedcycloalkyl or C1-6alkyl group which alkyl group may be substituted by a hydroxy, phenyl, C1-6alkoxycarbonyl, C3-7cycloalkyl, or C7-11 bridgedcycloalkyl group; R?2¿ represents a phenyl group optionally substituted by 1 or 2 substituents selected from, halogen, C¿1-4?alkyl, C1-4alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH2)nR?4¿ or O(CH¿2)pR?4 wherein R4 represents hydroxy, C¿1-4?alkoxy, CO2R?5 or NR6R7¿; n is zero or 1; p is an integer from 1 to 4; R3 represents the group (CH¿2?)qR?8; R5¿ represents hydrogen or C¿1-4?alkyl; R?6¿ represents hydrogen or C¿1-4?alkyl; R?7¿ represents hydrogen, C¿1-4?alkyl, acyl, or C2-6alkyl substituted by one or more hydroxy, carboxyl, and/or amino groups or R?6 and R7¿ together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C¿1-4?alkyl or hydroxy groups. R?8¿ represents a saturated 5-7 membered nitrogen containing ring linked to the rest of the molecule via a carbon atom in the ring and which ring may also contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C¿1-4?alkyl groups or R?8¿ represents a nitrogen containing 5-6 membered heteroaryl group which may also have an additional heteroatom selected from O, N or S and which heterocyclic ring may also be substituted by one or more C¿1-4?alkyl groups; q is zero or an integer from 1 to 6; R?9¿ represents hydrogen or a halogen atom; m is zero, 1 or 2. X is oxygen or NH; and pharmaceutically acceptable salts and/or metabolically labile esters thereof are antagonists of gastrin and/or CCK.

Description

1,5-BENZODIAZEPINE DERIVATIVES USEFUL AS CCK OR GASTRIN ANTAGONISTS

This invention relates to novel 1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

Cholecystokinins (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 carboxy terminal octapeptide sulphate, 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-NH₂(CCK-4), which is the common structual 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. CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal and central nervous systems of animals, and more particularly humans.

US Patent No. 4,988,692 describes a group of 3-acylamino 1-alkyl-5-phenyl 1 ,5- benzodiazepine derivatives as cholecystokinin antagonists. Further the specification teaches that the compounds have a significantly greater affinity for the CCK-A receptor over the CCK-B receptor.

We have now found a novel group of 3-substituted 1 ,5-benzodiazepine compounds which are potent and specific antagonists of gastrin and/or CCK and in particular antagonists of gastrin and /or CCK at the CCK-B receptor which exhibit a particularly advantageous profile of activity.

Thus, the invention provides compounds of general formula (I)

wherein R¹ represents a phenyl, C3_7cycloalkyl, Cj-^ bridgedcycloalkyl or C-j^alkyl group which alkyl group may be substituted by a hydroxy, phenyl, C-|_ βalkoxycarbonyl, C3_7cycloalkyl, or C7_ι -| bridgedcycloalkyl group; R² represents a phenyl group optionally substituted by 1 or 2 substituents selected from, halogen, C^alkyl, C-^alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH₂)nR^{4 or} O(CH₂)pR⁴ wherein R⁴ represents hydroxy, C^ ₄alkoxy, CO₂R⁵ or NR⁶R⁷; n is zero or 1; p is an integer from 1 to 4; R³ represents the group (CH₂)qR⁸; R⁵ represents hydrogen or C^alkyl; R⁶ represents hydrogen or C^alkyl; R⁷ represents hydrogen, C^alkyl, acyl, or C₂_₆alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C-^alkyl or hydroxy groups. R⁸ represents a saturated 5-7 membered nitrogen containing ring linked to the rest of the molecule via a carbon atom in the ring and which ring may also contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C-^alkyl groups or R⁸ represents a nitrogen containing 5-6 membered heteroaryl group which may also have an additional heteroatom selected from O, N or S and which heteocyclic ring may also be substituted by one or more C-|_4alkyl groups; q is zero or an integer from 1 or 6;

R⁹ represents hydrogen or a halogen atom; m is zero, 1 or 2. X is oxygen or NH; and pharmaceutically acceptable salts and or metabolically labile esters thereof.

It will be appreciated that compounds of formula (I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 3-position of the diazepine ring) and the compounds of the invention thus include all stereoisomers and mixtures thereof including the racemates.

In the compounds of formula (I) 'alkyl' when used as a substituent or part of a substituent group means that the group may be straight or branched. Thus, C-]_ 6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,3-dimethylbutyl, 3,3- dimethylbutyl, 2,3-dimethylbutyl.

For the group R¹ the term C3_7cycloalkyl as a group or part of a group refers to a monocyclic alkyl group such as cyclopropyl, cylobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term C7_-| - bridged cycloalkyi refers to groups such adamantyl, norbornanyl or norbornenyl.

For the groups R⁵. R⁶. R⁷ R⁸ and R⁹ the term C-|_ alkyl includes 3-4- cycloalkyi (e.g. cyclopropyl or cyclobutyl) as well as straight or branched chain alkyl groups as defined above.

Halogen in the definition of compounds of formula (I) may represent a fluoro, chloro, bromo or iodo substituent.

When R-2 is a phenyl group substituted by a single substituent this may be in the ortho, or more preferably in the meta or para position.

When the group R⁶ and R⁷ together with the nitrogen atom represent a saturated heterocylic group examples of suitable groups include morpholino, 2,6-dimethylmorpholino, thiomorpholino, piperidino, 4,4-dimethylpiperidino and pyrrolidino.

When R⁷ represents acyl this may be for example C^alkanoyl e.g. formyl or acetyl.

When R⁷ represents C₂^,hydroxyalkyl this may be for example 2-hydroxyethyl, 3-hydroxyρropyl or 2,3-dihydroxypropyl.

When R⁸ is as saturated heterocylic group linked to the rest of the molecule via a carbon ring member examples of suitable R⁸ groups include piperidine, pyrrolidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydropyranone, 2-oxazolidone.

When R⁸ is a heteroaryl group examples of suitable groups R⁸ include imidazolyl, N-methylimidazolyl, thiazolyl, N-linked imidazole e.g. 1-4 methylimidazole, pyridone or pyrimidinone, furanyl, thienyl, oxazolyl, pyridinyl and pyrimidinyl.

When R⁹ is halogen this is preferably chlorine or fluorine.

When m is 1 or 2 the halogen atom(s) e.g. chlorine or fluorine are preferably in the 7 and/or 8 positions.

When q is an integer it is preferably from 1 to 4 e.g. 2,

When R1 represents an alkyl group substituted by a hydroxyl group this is preferably a C3_6alkyl group substituted by hydroxy. Examples of such groups include 2-hydroxypropyl, 2-hydroxy-3-methylbutyl and 2-hydroxy-3,3- dimethylbutyl of which 2-hydroxy-3-methylbutyl, and 2-hydroxy-3,3-dimethylbutyl are particularly preferred.

When R1 represent an alkyl group substituted by a C3_7cycloalkyl group this is preferably a C2-3alkyl group such as ethyl or 1-methylethyl, substituted by a C3_7cycloalkyl group such as cyclopentyl. When Rl is a bridged C7_-| -| cycloalkyi group this may be for example an adamantyl group such as 1 -adamantyl or 2-adamantyl group or a 2-norbornanyl group.

When R¹ is an alkyl group substituted by a bridged C7_-| -j cycloalkyi group this is preferably an ethyl group or more especially a methyl group substituted by a bridged C7..-11 cycloalkyi group. Examples of suitable briged cycloalkyi groups include adamantyl such as 1 -adamantyl or 2-adamantyl, 2-norbornanyl or 5- norbomenyl. Most preferably R¹ represents 1-adamantylmethyl. e.g. 1- adamantylmethyl

When R¹ is alkyl substituted by phenyl this may be for example benzyl or phenethyl.

When R1 is alkyl substituted by alkoxycarbonyl this is preferably methyl substituted by alkoxycarbonyl such methoxycarbonyl or as t-butoxycarbonyl.

A preferred class of compounds of formula (I) is that in which R^ represents a phenyl, adamantyl, norbomanyl, phenethyl, C ^alkyl e.g. n- butyl, 3-methyl butyl, 3,3-dimethyl butyl, 1,3-dimethylbutyl, 2,3- dimethylbutyl, C3_e hydroxy alkyl e.g. 2-hydroxypropyl, 2-hydroxy-3- methylbutyl, 2-hydroxy-3,3- dimethylbutyl, C«|_2alkyl substituted by a bridged C7_--|ocycloalkyl group e.g. 2- norbomanylmethyl, 5-norbomenylmethyl, 2-adamantylmethyl, 2-adamantylethyl, 2-(1-adamantyl)ethyl, 1-adamantylmethyl, alkoxycarbonylalkyl, e.g. methoxycarbonylmethyl or t-butyoxycarbonylmethyl, or 2-cyclopentylethyl.

A particularly preferred class of compounds of formula (I) is that in which R¹ is 3-methylbutyl or more especially adamantylmethyl. e.g. 1-adamantyimethyl.

A further preferred class of compounds of formula (I) is that in which R² is phenyl or phenyl substituted by a single substitutent e.g. fluorophenyl.

Another preferred class of compounds of formula (I) are those wherein X represents NH. Compounds wherein R⁹ is a hydrogen atom represents a further preferred class of compounds of formula (I).

Compounds wherien R⁸ is a heteroaryl group repesents yet a further preferred class of compounds of formula (I). Within this class particularly preferred compounds include those wherein R⁸ represents imidazolyl e.g. 4-imidazolyl.

Compounds wherein R³ represents 2-(4-imidazolyl)ethyl represent a further preferred class of compound according to the invention.

A preferred group of compounds of formula (I) are those wherein R1 represents 1-adamantylmethyl R³ represents 2-(4-imidazolyl)ethyl. X is NH, R⁹ is hydrogen and R² is phenyl optionally substituted by fluorine.

Particularly preferred compounds of the invention include:

N-[1 -(1 -Adamantylmethyi)2,4-dioxo-5-[2-(1 H-imidazol-4-yl)ethyl]-2,3,4,5- tetrahydro-1 H-1 ,5-benzodiazepin-3-yl]-N'-phenylurea;

N-[1 -(1 -Adamantylrτϊethyl)2,4-dioxo-5-[2-(1 H-imidazol-4-yl)ethyl]-2,3,4,5- tetrahydro-1 H-1 ,5-benzodiazepin-3-yl]-N'-(4-fluoro)phenylurea; and enantiomers thereof.

The pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed for example from pharmaceutically acceptable inorganic or organic acids as well as quaternary ammonium acid addition salts. 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. The compounds of formula (I) in which R⁵ represents hydrogen may form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g calcium or magnesium) cations.^"

Salts may also be formed with organic bases e.g. N-methylglucamine. The invention also includes metabolically labile esters of compounds of formula (I) wherein R^ represents hydrogen. Examples of such metabolically labile esters include C-_|_4alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholino)ethyl esters) or acyloxyalkyi esters such as, acyloxymethyl or 1- acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymeth l, 1- acetoxyethyl, 1 -methoxy-1 -methyl-ethylcarbonyloxyethyl, 1 -benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1 -isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4- tetrahydropyranyloxycarbonyloxyethyl) or 1 -(4-tetrahydropyranylcarbonyloxy)- ethyl.

The compound of formula (i) and salts and metabolically labile esters thereof may from solvates e.g. hydrates and the invention includes such solvates.

The compounds of the invention are potent and specific antagonists of gastrin and/or CCK and in particular gastrin and or CCK at the CCK-B-receptor. Thus compounds of the invention have been shown to be antagonists of CCK, particularly at CCK-B receptors as demonstrated for example by the compound's ability to inhibit the contractile actions of CCK-4 in the presence of a CCK-A antagonist, in the guinea-pig isolated ileum longitudinal muscle- myenteric plexus.

Compounds of the invention have also been found to have a significantly weaker activity at CCK-A receptors compared with their activity at gastrin and/or CCK-B receptors, as demonstrated by their ability to inhibit the contractile activity of CCK-8 in guinea-pig isolated ileum longitudinal muscle-myenteric plexus. The preparation and use of guinea-pig isolated ileum longitudinal muscle- myenteric plexus has been described by K-H Buchheit et al in Nauyn- Schmeideberg's Arch. Pharmacol, (1985), 329, p36-41 and by V.L. Lucaites et al (1991 ) in J. Pharmacol. Exp. Ther., 256, 695-703.

The compounds of the invention have also been shown to be antagonists of gastrin as demonstrated by their ability to inhibit pentagasthn-stimulated acid secretion from rat isolated gastric mucosa using the procedure described by J.J. Reeves and R. Stables in Br. J. Pharmacol.. 1985, 86, p.677-684.

The greater affinity of the compounds of the invention for the CCK-B receptor over the CCK-A receptor has also been established using the CCK receptor binding assays described by G Dal Forno et al., J. Pharmcol. Exp & Ther. 261. 1056-1063, 1992.

The compounds of the invention are therefore useful for the treatment and/or prevention of disorders in mammals, especially humans, where modification of the effects of gastrin or CCK is of therapeutic benefit. Thus the compounds of the invention are useful for the treatment of central nervous system disorders where CCK and/or gastrin are involved. For example anxiety disorders (including panic disorder, agoraphobia, social phobia, simple phobia, obsessive compulsive disorders, post traumatic stress disorder, and general anxiety disorder), tardive dyskinesia, depression, Parkinson's disease or psychosis. The compounds of the invention are also useful for the treatment of gastrointestinal disorders especially those where there is an advantage in lowering gastric acidity. Such disorders include peptic ulceration, reflux oesophagitis and Zollinger Ellison syndrome. They may also be useful for the treatment of gastrointestinal disorders such as irritable bowel syndrome, excess pancreatic secretion, acute pancreatitis, motility disorders, antral G cell hyperplasia, fundic mucosal hyperplasia or gastrointestinal neoplasms. They may also be useful for the treatment of dependency on drugs or substances of abuse and withdrawal, Gilles de la Tourette syndrome, or dysfunction of appetite regulatory systems; as well as the treatment of certain tumours of the lung, lower oesophagus, pancreas, stomach, intestines and colon. Compounds of the invention are also useful for directly inducing analgesia, or enhancing opiate or non-opiate mediated analgesia, as well as anaesthesia or loss of the sensation of pain.

The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.

According to another aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of conditions where modification of the effects of gastrin and/or CCK is of therapeutic benefit.

According to a further aspect of the invention we provide a method for the treatment of a mammal, including man, in particular in the treatment of conditions where modification of the effects of gastrin and/or CCK is of therapeutic benefit which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the patient.

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.

It will further 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 0.01- 2000mg per day e.g 0.01 -500mg 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. Because the compounds of the invention antagonise the function of CCK in animals, they may also be used as feed additives to increase the food intake in animals in daily dosages of around 1mg/kg to 10mg/kg.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefor 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.

The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, implant, or rectal administration. Oral administration is preferred.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, accacia, gelatin, sorbitol, tragacanth, hydroxypropyl cellulose, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, hydrogenated vegetable oils, 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. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or 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, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p_-hydroxybenzoates or sorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in prefilled syringes, vials and ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form which may be obtained by freeze drying for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3- 50% for liquid preparations.

Compounds of general formula (I) and salts thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups R¹-R9 are as defined for the compounds of formula (I) unless otherwise stated. Compounds of formula (I) may be prepared by reacting a compound of formula (II) wherein the groups R¹ R⁹ and m have the meanings defined above and R³ _a has the meaning defined for R³ or is a protected derivative thereof

with an isocyanate of formula (V)

0=C=N-R² (III)

or a acyl chloride of formula (IV)

CICO(X)R² (IV)

followed if necessary by removal of any protecting group.

The reaction conveniently takes place in the presence of a suitable solvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g tetrahydrofuran) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature in the range of 0°C to 80°C.

In the above process for the preparation of a compound of formula (I) wherein the group R³ contains an NH grouping in the heterocyclic ring it may be desirable to carry out the process using a compound of formula (II) wherein R³ _a is a protected derivative thereof. Suitable nitrogen protecting groups include trialkylsilylethoxymethyl groups e.g. trimethylsiiylethoxymethyl

The protecting group R³ _a may then be removed by conventional procedures. Thus the trimethylsiiylethoxymethyl group may be removed by hydrolysis with a mineral acid hydrochloric acid. Compounds of formula (II) may be prepared by reduction of compounds of formula (V)

The reduction may be carried out by reaction with zinc and acetic acid. This reaction may be carried out a temperature with the range 0-50^.

Compounds of formula (V) may be prepared by reaction of the ortho- phenylenediamine (VIII) with the diacid chloride (VII), in a suitable solvent such as an ether e.g. tetrahydorfuran

R¹

^αoc\

(VI) (VI!)

Compounds of formula (VII) are either known compounds or may be prepared by analogous methods. Thus for example a compound of formula (VII) may be prepared by alkylation of the amine (VIII).

Thus the amine (VIII) may be reacted with the compound R¹ L, in which L is a leaving group e.g. chlorine or bromine, optionally in the presence of sodium iodide in a solvent such as N,N-dimethylformamide. Alternatively the group R¹ may be introduced by reaction of the amine (VIII) with an appropriate aldehyde under standard reductive alkylation condition.

The diamine (VIII) may be prepared from the corresponding nitro derivative

by standard procedures. Thus the nitro group may be reduced by reaction with Na2S2θ4

The compounds of formula (IX) are either known compounds or may be prepared by analogous methods to those used for preparing the known compounds. Thus for example by reaction of the fluoro derivative (X) with the amine R³ _aNH₂

The metabolically labile esters of the compounds of formula (I) may be prepared from the corresponding carboxylic and by conventional means. For example by reaction of the carboxylic acid with carbonyl diimidazole followed by reaction with the appropriate alcohol.

Compounds of formula (I) contain at least one asymmetric carbon atom, namely the carbon atom of the diazepine ring to which the grouping NHCOXR² is attached. Specific enantiomers of the compounds of formula (I) may be obtained by resolution of the racemic compound using conventional procedures such as chiral HPLC.

In the Preparations and Examples, unless otherwise stated: Melting points (m.p.) were determined on a Bϋchi m.p. apparatus and are uncorrected.

All temperatures refer to oc.

Infrared spectra were measured in chloroform-dι solutions on ά FT-IR instrument. Proton Magnetic Resonance (1 H-NMR) spectra were recorded at

300MHz as solutions in chloroform-dι . Chemical shifts are reported in ppm downfield ( ) from Me4Si as an internal standard .

Column chromatography was carried out over silica gel (Merck AG Darmstadt,

Germany). Solutions were dried over anhydrous sodium sulphate.

"Petrol" refers to petroleum ether,b.p.40-60θC

Methylene chloride was redistilled over calcium hydride; tetrahydrofuran was redistilled over sodium; diethyl ether was redistilled over sodium and ethyl acetate was dried over activated molecular sieves. The following abbreviations are used in the text. EA = ethyl acetate, CH = cyclohexane, P = petroleum ether 40-60OC, THF = tetrahydrofuran, DCM = dichloromethane MeOH = methanol, EE = ethyl ether, DMF = dimethylformamide.

Tic refers to thin layer chromatography on silica plates. All the compounds are intended as racemic mixtures unless otherwise indicated.

Intermediate 1 f2-(1 H-imidazol-4-vhethylK2-nitro-phenvπamine

A solution of 2-nitrofluoro benzene (5.1 ml) was dropped into a suspension of histamine dihydrochloride (10g) and potassium carbonate (22g) in dry ethanol (150ml) , at 230 under a nitrogen atmosphere. The mixture was stirred at 70° for 12h; then it was allowed to cool to 23o, filtered and concentrated under vacuum to give a residue which was purified by chromatography on silica eluting with DCM-MeOH (20:1.5) to give the title compound as an orange solid (3.9g). T.l.c. DCM-MeOH (20:1.5), Rf 0.46. M.p. 100-102O.

Intermediate 2

2-ri-(2-(trimethylsilvπethoxymethvhimidazol-4-vnethyl(2-nitrophenvπamine Intermediate 1 (0.400g) was added to a suspension of sodium hydride (0.058g) in dry DMF (3ml) previously cooled to 0o . The solution was stirred at 230 for 15min, then allowed to cool to 0°. 2-(Trimethylsilyl)ethoxymethyl chloride (0.294 ml) was then added and the mixture was stirred at 23° for 1 h. The mixture was diluted with ethyl acetate (50 ml) and washed with water ( 50ml ); the organic extracts were washed with brine (50ml), dried and concentrated in vacϋo to an oil, which was purified by flash chromatography (eluting with DCM-MeOH 20:0.5) to give the title compound as an orange solid (0.220g). T.l.c. DCM- MeOH 20:0.5 , Rf 0.67.

Intermediate 3 2-f1-(2-(thmethylsilvπethoxymethvπimidazol-4-vnethyl(2-aminophenvnamine

A solution of potassium carbonate (40g) and sodium hydrosulfite (38g) in water (50ml) was added to a mixture of intermediate 2 (17.5g) in ethanol (100ml) and water (50ml). The mixture was stirred at 230 for 20min, then acidified with cone, hydrochloric acid until pH=3. The mixture was then basified with a 10% sodium hydroxide solution until pH=10 and concentrated to half volume. The residue was extracted with ethyl acetate (2x300ml); the combined extracts were washed with brine (150ml),dried and concentrated in vacuo to a residue, which was purified by flash chromatography (eluting with DCM-MeOH 10:1) to give the title compound as a grey^'solid (11.8g). T.l.c. DCM-MeOH (10:1), Rf 0.63.

Intermediate 4

N-(1-Adamantylmethyl)-N'2-f1-(2-(trimethylsilvπethoxymethyl)-imidazol-4-vn- ethyll-1.2-phenylendiamine

To a solution of intermediate 3 (5.8g) in methanol (100ml) 1- adamantylcarboxaldehyde (2.86g), acetic acid (1.09ml ) and sodium cyanoborohydride ( 2.2g ) were added . The reaction mixture was left at 230 for 2h . The solution was , diluted with water (70ml) and extracted with ethyl acetate (2x80ml). The combined organic extracts were washed with brine (100ml), dried and concentrated in vacuo to an oil, which was purified by flash chromatography (eluting with DCM-MeOH 10-0.5) to give the title compound as a yellow oil (7.6g). T.l.c. DCM-MeOH (10-0.5), Rf=0.6

Intermediate 5 1 -M -Adamantylmethvn-2.4-dioxo-5-r2-f 1 -(2-

(trimethylsilvπethoxymethvπimidazol-4-yllethvn-3-phenylhvdrazono-2.3.4.5- tetrahvdro-1 H-1.5-benzodiazepine

To the solution of the intermediate 4 (7.4g) in dichloromethane ( 75ml ), ^' the 2- phenylhydrazonomalonyldichloride (4.15g) in dichloromethane ( 75ml ) was added. After complete addition the solution was heated at 40° for 2h. The solution was washed with saturated NaHCO3 solution ( 100ml ), brine ( 100ml ) dried and concentrated in vacuo; the residue( 12g ) was purified by flash chromatography (eluting with DCM/MeOH 10:0.5) to give the title compound as a yellow foam (8.6g). M.p. 80-2O. T.l.c. DCM/MeOH 10:0.5, Rf 0.50.

Intermediate 6

1 -M -Adamantylmethvn-3-amino-2,4-dioxo-5-r2-M -(2-

(trimethylsilyl)ethoxymethyl)imidazol-4-vnethvn-2.3.4.5-tetrahvdro-1 H-1.5- benzodiazepine

Zinc dust (6.4g) was added to a solution of the intermediate 5 (8.34g) in glacial acetic acid (100ml). The mixture was stirred at 230 for 5h, then decanted from zinc. The filtrate was basified until pH=9 with 10% sodium hydroxide solution, then extracted with ethyl acetate (100ml). The organic layer was washed with brine (100ml), dried and concentrated in vacuo to a yellow oil, which was purified by flash chromatography (eluting with DCM /MeOH 10:0.5) to give the title compound as a pale yellow foam (3.3g). M.p.50-2o. T.l.c. MC-MeOH 10:0.5, Rf 0.24.

intermediate 7

N-π-f1-Adamantylmethyl-2.4-dioxo-f 5-241 -(2-(trimethylsilvπethoxymethvn- imidazol-4-yl1ethvn-2.3.4,5-tetrahvdro-1 H-1.5-benzodiazepin-3-vn-N'-phenylurea Phenyl isocyanate (0.1ml) was added to a solution of the intermediate 6 (0.500g) in dichloromethane (20ml). The reaction mixture was stirred at 23o for 30 min., then concentrated in vacuo to an oil, which was purified by flash chromatography (eluting with DCM /MeOH 10:0.5) to give the title compound as a white solid (0.336g). M.p.128-30o. T.l.c. MC-MeOH 10:0.5, Rf 0.25.

intermediate 8 N-π -(1 -Adamantylmethyl)-2.4-dioxo-5-f2-π -(2-(trimethylsilyl)ethoxymethyl)- imidazol-4-vn-ethvπ-2,3.4,5-tetrahvdro-1 H-1 ,5-benzodiazepin-3-vn-N'(4-fluoro)- phenylurea

4-Fluorophenyl isocyanate (0.111ml) was added to a solution ^'of the intermediate 6 (0.500g) in dichloromethane (30ml). The reaction mixture was stirred at 23° for 1h., then concentrated in vacuo to give the title compound as a pale yellow foam (0.660g). T.l.c. DCM-MeOH 10: 1 , Rf 0.72.

EXAMPLE 1 N-f1-(1-Adamantylmethvn-2.4-dioxo-5-r2-(1 H-imidazol-4-vnethvn-2.3.4.5- tetrahvdro-1 H-1 ,5-benzodiazepin-3-vn-N'-phenylurea

A 10N solution of hydrochloric acid (25ml) was added to a solution of intermediate 7 (0.260g) in ethanol (25ml). The resulting solution was diluted with ethyl acetate ( 150 ml ), washed with 10% sodium hydroxide solution ( 50 ml ) , 10% potassium carbonate solution ( 100ml ) brine ( 100 ml ), dried and then concentrated in vacuo. The residue was taken up with methanol ( 2ml ) and diethyl ether ( 20ml ) was added ; the title compound was collected and filtered as a white solid (0.100g). M.p.204o. T.l.c. DCM-MeOH 10:1 , Rf 0.55 IR: 3140 (NH), 17111,1641 (C=O) cm-1; 1 H-NMR: 11.892 (bs); 9.15 (s ); 7.72 (m); 7.56 (s); 7.40 (m); 7.30 (d); 7.19 (t); 6.88 (m); 4.80 (d); 4.20 (d); 4.06 (m); 3.44 (d); 2.94(bm); 1.76(bm); 1.6-1.3 (m).

EXAMPLE 2 N-π-π-Adamantylmethvn-2.4-dioxo-5-r2-(1 H-imidazol-4-vnethvn-2.3.4.5- tetrahvdro-1 H-1 ,5-benzodiazepin-3-vH-N'-(4-fluoro)phenylurea

A 10N solution of hydrochloric acid (50ml) was added to a solution of intermediate 8 (0.600g) in ethanol (50ml). The resulting solution was diluted with ethyl acetate ( 150 ml ), washed with 10% sodium hydroxide solution ( 50 ml ) , 10% potassium carbonate solution ( 100ml ) brine ( 100 ml ), dried and then concentrated in vacuo. The residue was taken up with methanol ( 2ml ) and diethyl ether (15ml ) and ethyl acetate( 5ml ) were added ; the title compound was collected and filtered as a white solid (0.170g). M.p.>255o. T.l.c. DCM-MeOH 10:1, Rf 0.52 IR: 3138(NH), 1740,1678 (C=O) cm-1; 1 H- NMR: 9.34(bs ); 8.93 (bs); 7.73 (m); 7.58 (m); 7.53 (bs); 7.41 (m); 7.32 (m); 7.03 (t); 6.84 (d); 4.81 (d); 4.19 (d); 4.20 (m); 4.00 (m);3.3 (d); 3.19(m); 1.76(bm); 1.46 (sist AB); 1.16 ( sist.AB) .

Pharmacy Example

Capsules or Tablets mg/dosage form

Active ingredient 0.1

Polyethyleneglycol 15.0

Lactose 52.4

Starch 30.0

Magnesium stearate 0.5

Silicon dioxide 1.0

Sodium Lauryl Sulphate 1.0

100.0

The active ingredient is dispersed in a suitable solvent (e.g. ethanol) together with polyethyleneglycol. The solvent is removed. The powder so obtained is blended with the other excipients. The blend can be used to fill gelatine capsules or compressed using appropriate punches. The tablets can be coated using conventional techniques and coatings.

Active ingredient 0.1

Povidone 15.4

Lactose 74.0

Hydrogenated vegetable oils 3.0

Silicon dioxide 1.0

Sodium Laauryl sulphate 1.5

Crospovidone 5.0

100.0

The active ingredient is dispersed in a suitable solvent (e.g. ethanol) together with povidone. The solution is sprayed on to lactose and the solvent removed. The powder obtained is blended with the other excipients. The blend is used to fill gelatine capsules or comprssed using appropriate punches. The tablet can be coated using conventional techniques and coatings.

Oral liquid

Active ingredient 70-100 micrograms/dose ethanol 5-15%

Sodium sacchahnate 0.1 -1 %

Propylene glycol 10-100% Purified water qb 100% Pack; plastic or glass bottle or other suitable pack

Injection Formulation

Active ingredient 0.1 -100 micrograms Sodium phosphate 1.50 mg/ml

NaOH qs desired pH (range 3-9) propylene glycol 10-500 mg/ml water for injection qs to 0.5-10ml

Pack: glass (ampules) with a rubber stopper (vials, syringes) and a plastic/metal overseal (vials only) or other suitable pack . An inert gas atmosphere (for example nitrogen) may be introduced into head space of ., container.

CCK - Receptor Binding

The binding affinity of the compounds of the invention for the CCK-A receptor (Pancreas Assay) and CCK-B receptor (guinea pig cortex assay) was determined using the procedure of G Dal Forno et al J. Pharmacol. Exp & Ther. 261 - 1056-1063. The pKi values determined with respresentative compounds of invention were as follows: Compound Ex No F )Ki

CCK-A CCK-B

1 6.5 9.8

2 5.7 9.5

The compounds of the invention are essentially non-toxic and therapeutically useful doses.

Claims

(I) Compounds of general formula (I)

NHCOXR

(I)

wherein

R1 represents a phenyl, C3_7cycloalkyl, C7_-| -| bridgedcycloalkyl or C-|_ealkyl group which alkyl group may be substituted by a hydroxy, phenyl, C«|_

bridgedcycloalkyl group;

R² represents a phenyl group optionally substituted by 1 or 2 substituents selected from, halogen, C^alkyl, C_1-4alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH₂)nR⁴ or O(CH₂)pR⁴ wherein R⁴ represents hydroxy, C^ ₄alkoxy, CO₂R⁵ or NR⁶R⁷; n is zero or 1 ; p is an integer from 1 to 4; R³ represents the group (CH₂)qR⁸;^~ R⁵ represents hydrogen or C^alkyl; R⁶ represents hydrogen or C^alkyl;

R⁷ represents hydrogen, C₁_₄alkyi, acyl, or C^alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C_1-4alkyl or hydroxy groups. R⁸ represents a saturated 5-7 membered nitrogen containing ring linked to the rest of the molecule via a carbon atom in the ring and which ring may also contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C^alkyl groups or R⁸ represents a nitrogen containing 5-6 membered heteroaryl group which may also have an additional heteroatom selected from O, N or S and which heteocyclic ring may also be substituted by one or more Cι_4alkyl groups; q is zero or an integer from 1 or 6;

2. Compounds as claimed in Claim 1 wherein X is NH.

3. Compounds as claimed in Claim 1 or Claims 2 wherein R⁹ represents hydrogen.

4. Compounds as claimed in any of Claims 1 to 3 wherein R⁸ represents a 5 or 6 membered heteroaryl group.

5. Compounds as claimed in any of Claims 1 to 4 wherein R⁸ represents imidazolyl.

6. Compounds as claimed in any of Claims 1 to 5 wherein q is 2.

7. Compounds as claimed in any of Claims 1 to 6 wherein R¹ represents 1- adamantylmethyl.

8. Compounds as claimed in any of Claims 1 to 6 wherein R² represents phenyl or fluorophenyl.

9. The compounds :

N-[1 -(1 -Adamantylmethyl)2,4-dioxo-5-[2-(1 H-imidazol-4-yl)ethyl]-2,3,4,5- tetrahydro-1 H-1 ,5-benzodiazepin-3-yl]-N'-phenylurea;

N-[1 -(1 -Adamantylmethyl)2,4-dioxo-5-[2-(1 H-imidazol-4-yl)ethyl]-2,3,4,5- tetrahydro-1 H-1 ,5-benzodiazepin-3-yl]-N'-(4-fluoro)phenylurea; and enantiomers thereof.

10. Compounds as claimed in any of Claims 1 to 9 for use in therapy.

11. The use of a compound as claimed in any of Claims 1 to 9 in the manufacture of a medicament for the treatment of conditions where a modification of the effects of gastrin and or CCK is of therapeutic benefit.

12. Pharmaceutical compositions comprising a compound as claimed in any of Claims 1 to 9 in admixture with one or more physiologically acceptable carriers or excipients.

13. A method of treatment of a mammal including man for conditions where modification of the effect of gastrin and or CCK is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in any of Claims 1 to 9.

14. A process for the preparation of compounds of formula (I) which comprises (a) reacting a compound of formula (II) wherein R¹, R¹⁰ and m have the meanings defined in formula (I) and R³ _a has the meanings defined for R³ or is a protected derivative thereof.

with an isocyanate (III) or an acyl chloride (IV)

R²NCO (III) R²XCOCI (IV)

followed if necessary by removal of any protecting groups.