HUT74091A - 1,5-benzodiazepine derivatives having cck and/or gastrin antagonistic activity - Google Patents

Description

1,5-benzodiazepine derivatives having CCK and / or gastrin antagonist activity

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

Cholecystokinin (CCK) and gastrin are structurally related peptides that occur in gastrointestinal tissue and in the central nervous system. Cholecystokinin contains CCK-33, originally a 33-amino acid neuropeptide, a carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in the form of 34, 17 and 14 amino acids with a minimal active sequence of the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH ₂ (CCK-4), which is common to both CCK and gastrin. structural element.

CCK and gastrin are gastrointestinal hormones and neurotransmitters of the neural and peripheral systems and play their biological role by binding to specific receptors located at various locations in the body.

82539-5194-KY / KMO

At least two subtypes of CCK-A and CCK-B terminating with cholecystokinin receptors are distinguished and both are located in the peripheral and central nervous systems.

CCK and gastrin receptor antagonists are known to prevent and treat CCK-related and / or gastrin-related gastrointestinal and CNS disorders in animals and humans.

U.S. Pat. No. 4,988,692 describes a class of 3-acylamino-1-alkyl-5-phenyl-1,5-benzodiazepine derivatives as cholecystokinin antagonists. Further, the disclosure also teaches compounds which exhibit significantly greater affinity for the CCK-A receptor than for the CCK-B receptor. It has now been found that a new class of 3-ureido-1,5-benzodiazepine compounds are potent and specific gastrin and / or CCK antagonists, and in particular gastrin and / or CCK antagonists at the CCK-B receptor.

The present invention thus relates to novel compounds of formula I and their physiologically acceptable salts, wherein NR ₁ R _{2 is a} 5-7 membered saturated heterocyclic ring which may be substituted by one or two methyl groups;

R _{3 is C} 1-6 alkyl, C 3-6 cycloalkyl or phenyl optionally substituted with one or two halogen atoms,

R ₄ is phenyl or phenyl optionally substituted with one or two halogen atoms, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy or (CH ₂ ) _n R 5 wherein n is 0 or 1, and

- R ₅ represents -1 -4 alkoxy, hydroxy, nitro, cyano,

CO ₂ R ₆ , S (O) _p CH ₃ , NR ₇ R ₈ , CONR ₇ R ₈ or SO ₂ NR ₇ CO (C 1 -C 4 alkyl), tetrazolyl, carboxamidodetrazolyl or 3-trifluoromethyl; 1,2,4-triazolyl group,

R ₈ is hydrogen, C 1-4 alkyl or benzyl,

R ₇ is hydrogen or C 1-4 alkyl,

R ₈ is hydrogen, C 1-4 alkyl, SO ₂ CH ₃ or

Group SO ₂ CF ₃ ,

X is hydrogen or halogen or C1-C4 alkyl, m is 0, 1 or 2 and p is 0, 1 or 2.

The compounds of the invention contain at least one asymmetric carbon atom and include both enantiomers and mixtures thereof, including the racemate.

Alkyl refers to straight or branched chain alkyl groups, for example, C 1-6 alkyl may be methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, t-butyl or hexyl.

Halogen also includes fluorine, chlorine, bromine or iodine.

When R ₅ is tetrazolyl, carboxamido-tetrazolyl or 3-trifluoromethyl-1,2,4-triazolyl, they are attached to the remainder of the molecule via carbon and the invention includes all tautomers and is 1 - N-substituted derivatives of C 4 alkyl. Includes (1 H) -tetrazole3 · ·

-5-yl, carboxamido-1 H -tetrazol-5-yl, 2-methyltetrazol-5-yl, and (3-trifluoromethyl) -1,2,4-triazol-5-yl. -group.

NRiFU is attached to the rest of the molecule via nitrogen, such as pyrrolidino, piperidino, hexamethyleneimino,

2,5-dimethyl-1-pyrrolidino-, 3,3-dimethyl-piperidin-1, 2,6-dimethyl-

-piperidino or 4,4-dimethylpiperidino.

When R ₃ is phenyl optionally substituted by halogen, it may be optionally substituted phenyl, such as phenyl, 2-fluorophenyl or 4-fluorophenyl.

When R _{3 is C} 3 -C 6 cycloalkyl, it may be cyclopropyl, cyclopentyl or cyclohexyl.

When R _{3 is C} 1-6 alkyl, these include methyl, ethyl, propyl, butyl, 3-methylbutyl or 3,3-dimethylbutyl.

R ₄ can be, for example, optionally halogen such as fluorine, alkyl such as methyl, alkoxy such as methoxy, nitro, cyano, thiomethyl, carboxamido, carboxyl, dimethylamino, cyanomethyl, 1H. phenyl substituted with -tetrazol-5-yl, carboxymethyl or N-methanesulfonylcarboxamido.

A preferred group of compounds of the invention wherein NR ₁ R ₂ is pyrrolidino, piperidino, 3,3-dimethylpiperidino,

4,4-dimethylpiperidino, 2,6-dimethylpiperidino or 2,5-dimethylpyrrolidino. NR 4 also includes pyrrolidino, piperidino or 3,3-dimethylpiperidino.

Preferably X is halogen, for example bromine, fluorine or especially hydrogen.

A preferred group of compounds of formula I are those wherein R ₃ is phenyl, 2-fluorophenyl or cyclohexyl, in particular 2-fluorophenyl or cyclohexyl.

Another preferred group of compounds of formula I are those wherein R _{4 is} phenyl or methyl substituted phenyl, such as 3-methylphenyl or 3,5-dimethylphenyl, 3-dimethylaminophenyl or a phenyl substituted by a fluorine atom such as 4-fluorophenyl or methoxy substituted phenyl such as 3-methoxyphenyl or 4-methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl, 3-carboxamidophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or 3 (1H) -tetrazol-5-yl-phenyl.

Particularly preferred compounds are those wherein NR ₁ R ₂ is pyrrolidino, piperidine or 3,3-dimethyl, piperidino, R ₃ is 2-fluorophenyl or cyclohexyl, and X is hydrogen. Particularly preferred within this group are those compounds wherein R ₄ is phenyl, 4-fluorophenyl, 3-dimethylaminophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or 3-. (1 H) -tetrazolyl-5-yl-phenyl.

Particularly preferred is the following compound:

- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b] [1 , 4] diazepin-3-yl] -3- (4-fluorophenyl) urea and its enantiomers.

Other preferred compounds include:

3- {3- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b ] [1,4] diazepin-3-yl] ureido} benzoic acid;

3- {3- [1- (2-Fluoro-phenyl) -2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro- 1H-benzo [b] [1,4] diazepin-3-yl] -ureido} -phenyl) -acetic acid;

3- {3- [1- [2- (3,3-Dimethyl-piperidin-1-yl) -2-oxo-ethyl] -5- (2-fluoro-phenyl) -2,4-dioxo-2, 3,4 _{L of} 5-tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] -ureido] -benzoic acid and its enantiomers.

Physiologically acceptable salts of the compounds of formula (I) include, for example, pharmaceutically acceptable inorganic or organic acids, and quaternary ammonium acid addition salts. Examples of such salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, malic acid, malonic acid, hydroxy, salts of glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid. Other acids, such as oxalic acid, which are not pharmaceutically acceptable per se, may also be useful in the preparation of salts useful as intermediates in the preparation of the compounds, as well as in the preparation of pharmaceutically acceptable salts thereof.

Accordingly, the present invention provides compounds of formula (I), pharmaceutically acceptable salts and solvates thereof.

The compounds of the invention modulate the action of gastrin and / or CCK in mammals. In particular, the compounds of the invention are gastrin and / or CCK antagonists.

The compounds of the invention are CCK antagonists, particularly at CCK-B receptors, as exemplified by

its ability to inhibit the constrictive effect of CCK-4 in the presence of a CCK-A antagonist in the longitudinal musculoskeletal plexus of isolated guinea pig ileum.

The preparation and use of the longitudinal musculoskeletal plexus of isolated guinea-pig ileum is described by K-H Buchheit et al., Nauyn-Schmeidergs Arch. Pharmacol., 329: 36-41 (1985). page, and V.L. Lucaites et al., J. Pharmacol. Exp. Ther., (1991) 256, 695-703. literature.

The compounds of the invention also show greater affinity for the CCK-B receptor than for the CCK-A receptor. This can be determined by the CCK receptor binding assay described in Fornos et al., J. Pharmacol. Exp. Ther., 261: 1056-1063 (1992).

The binding affinity of the compounds of the invention for CCK-A and CCK-B receptors can also be determined using HelA cell membranes transfected with human CCK-B receptor or using COS-M6 cell membranes transiently transfected with human CCK-A receptor.

The compounds of the invention are also gastrin antagonists, as demonstrated by their ability to inhibit pentagastrin-stimulated acid secretion from the rat mucosa of isolated stomachs by J.J. Reeves and R. Stables, Br. J. Pharmac. (1985) 86, 677-684. 4, p.

The compounds of the invention also inhibit pentagastrin-induced acid secretion in conscious gastric ulcer rats, Hedges and Parsons, Journal of

Phisiology 1977, 267, 181-194. page.

The compounds of the present invention can therefore be used to treat and / or prevent disorders in mammals, particularly humans, wherein the therapeutic effect consists in modifying the effect of gastrin or CCK. Thus, the compounds of the present invention can be used to treat gastrointestinal disorders, particularly in those cases where a reduction in gastric acidity is beneficial. Examples of such disorders are gastric or duodenal ulcer, reflux oesophagitis, and Zollinger Ellison syndrome. They can also be used to treat gastrointestinal disorders such as irritable abdominal syndrome, excessive pancreatic secretion, acute pancreatitis, motility disorders, secondary G-cell hyperplasia, fundamental mucosal hyperplasia, or gastric neoplasm. The compounds of the invention may also be used to treat disorders of the central nervous system where CCK and / or gastrin are involved. For example, anxiety disorders including panic disorder agoraphobia, social phobia, simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder and general anxiety disorder! and depression, Parkinson's disease or psychosis, and delayed dyskinesia. They can also be used in drug addiction or drug withdrawal, in Gilles de la Tourette syndrome, or in malfunctioning of the appetite control system, and in the treatment of certain tumors of the low oesophagus, stomach, intestines, and colon. The compounds of the present invention may be used directly to induce analgesia or to enhance opioid or non-opium mediated analgesia, and to anesthetize or reduce pain.

The compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are thus useful in medicine, especially in human medicine.

Another aspect of the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a condition; wherein the therapeutic effect is to modify the effect of gastrin and / or CCK.

In particular, the mammals, including humans, of the present invention may be treated by modifying the effect of gastrin and / or CCK is a therapeutic effect, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. to the patient.

It will be apparent to those skilled in the art that the treatment extends to prevention as well as to the treatment of established diseases or symptoms.

The compound of the invention is administered in an amount that will vary with the condition being treated, the age and condition of the patient, and will be at the discretion of the physician or veterinarian. However, in general, in the treatment of human adults, the dosage will usually be 1 to 2000 mg / day, for example 10 to 500 mg / day.

The desired dose may be administered in single or divided doses at appropriate intervals, for example, two, three, four or more times daily.

The compounds of the invention which antagonize CCK function in animals may also be used as a feed additive to increase the food intake of the animals at a daily dose of about 1 mg / kg to about 10 mg / kg.

The compound of the present invention may also be administered in the form of a crude chemical in medicine, but it is preferable to administer the active ingredient in the form of a pharmaceutical.

The invention thus also relates to pharmaceutical compositions comprising the compounds of the formula I or their pharmaceutically acceptable salts and one or more carriers, which may optionally contain other pharmaceutical and / or prophylactic agents. The carriers are necessarily acceptable or compatible with the other components and must not be deleterious to the patient.

The compositions of the invention may be suitable for oral, buccal, parenteral, implant or rectal administration, with oral administration being preferred. Tablets and capsules for oral administration may contain the usual excipients such as excipients such as syrup, gum arabic, gelatin sorbitol, tragacanth gum, starch gum or polyvinylpyrrolidone, fillers such as lactose, sugar, microcrystalline cellulose, ; a lubricant such as magnesium stearate, stearic acid, talc, polyethylene glycol or silica, a disintegrant such as potato starch or sodium starch glycolate or a wetting agent such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be, for example, aqueous or

- 11 - ........

oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product to be diluted with water or other suitable solvent before use. Such liquid formulations may contain conventional additives such as suspending agents, for example sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, such as lecithin, sorbitan monooleate or gum arabic, anhydrous solvents which may also contain edible oils, such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, and preservatives such as methyl or propyl parahydroxybenzoate or ascorbic acid. The compositions may also be presented in the form of suppositories, for example suppositories containing a conventional suppository base such as cocoa butter or other glycerides.

Oral administration may take the form of tablets or lozenges formulated in conventional manner.

The compositions of the invention may be formulated for parenteral administration by injection or continuous infusion. Injections are prepared in unit dosage form in ampoules or in multidose containers with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions, in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. The active ingredient may also be in powder form for constitution with a suitable solvent, for example sterile pyrogen-free water, before use.

The composition of the invention may also be prepared in a preserved form. Such sustained release formulations may be administered, for example, by implantation, for example, subcutaneously or intramuscularly, or by intramuscular injection. For example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials, for example in the form of an emulsion in a suitable oil, or using ion-exchange resins or slightly soluble derivatives, such as slightly soluble salts.

The compositions may contain from 0.1 to 99% by weight of the active ingredient, preferably from 30 to 95% for tablets, similarly for capsules, and from 3 to 50% for liquid preparations.

The compounds of formula (I) and salts thereof may be prepared by other general methods. In the following description, R 1 to R ₈ and X are as defined for compounds of formula (I).

In the first method a) the compound of formula (I) may be prepared by amine wherein R ι, R _2, R _3, X and m are as stated above, _R4 -Y formula (II) of the formula with a compound wherein R _{4 is} -Y isocyanate of formula (III), carbamoyl chloride of formula (IV) or imidazolide of formula (V) or optionally substituted phenylcarbamate of formula (VI) wherein R _a is optionally phenoxy.

The reaction may be carried out in a suitable solvent such as a replacement hydrocarbon such as dichloromethane or ether such as tetrahydrofuran or nitrile such as acetonitrile or a mixture thereof at a temperature of 0 to 80 ° C.

Isocyanates of formula (III) may be obtained or prepared by reacting an amine of formula H ₂ NR ₄ with phosgene or triphosgene in a suitable solvent such as methylene chloride. The carbamoyl chlorides of formula (IV) may also be prepared by reacting an amine of formula H ₂ NR ₄ with phosgene or triphosgene in a suitable solvent such as methylene chloride. The imidazolides of formula VI are prepared by treating an amine of formula H ₂ NR ₄ with carbonyldiimidazole in a suitable solvent such as dichloromethane, ether or tetrahydrofuran at 0-80 ° C, preferably at room temperature. The formula, optionally of the formula (VI) substituted phenyl carbamate is prepared by an H ₂ NR ₄ amine corresponding RaCOCI chloroformate ester, methylthio ester is reacted with a base such as pyridine or triethylamine, in a suitable solvent such as dichloro- in methane at 0-50 ° C.

In process b), the compound of formula (I) is prepared by reacting an intermediate of formula (VII) wherein Y is -NCO, -NHCOCI or NHCOR _a , wherein R _is an optionally substituted phenoxy group or an imidazole group, The reaction is carried out with an amine of formula (VIII) and optionally in the presence of a base such as tertiary amine such as triethylamine.

The reaction is preferably carried out in a suitable solvent such as a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran or an amide such as N, N-dimethylformamide, optionally from room temperature to the reflux temperature of the solvent.

• «

Preferably, the compound of formula (VII) is prepared in situ starting from the amine of formula (II).

In one embodiment _of process b), when Y is NHCOR _a and R _a is 1-imidazole, the imidazolid of formula VII may be formed in situ, in which case the amine of formula VIII will be formed in general formula II in the presence of carbonyldiimidazole under the above conditions.

When Y is NHCOR _a and R _is an optionally substituted phenoxy group, the reaction of process variant B with the primary amine (VIII) is preferably carried out in the presence of a base such as tertiary amine such as triethylamine.

In process b), when Y is an isocyanate group, the reaction with the primary amine of formula VIIIa is carried out in an aprotic solvent such as a halogenated hydrocarbon such as methylene chloride, the isocyanate is prepared in situ before the primary amine of formula VIIIa is added. .

Compounds of formula (VII) wherein R _is an optionally substituted phenoxy may be prepared from the primary amine of formula (II) by reaction with a suitable optionally substituted phenyl formic acid in the presence of a base such as pyridine. The reaction may be carried out in a solvent such as a halogenated hydrocarbon such as dichloromethane at 0-50 ° C.

Compounds of formula (VII) wherein R _a is 1-imidazole can be prepared by reacting a compound of formula (II) with carbonyldiimidazole in a suitable solvent such as a halogenated hydrocarbon such as dichloro-15-.

methane or ether such as tetrahydrofuran at 0 to 80 ° C, preferably at room temperature.

Compounds of formula (VII) wherein Y is an isocyanate group or carbamoyl chloride may be prepared from the primary amine of formula (II) by reaction with phosgene or triphosgene in a suitable solvent such as methylene chloride.

In a further process c), the compounds of formula I may also be prepared by reacting a compound of formula IX with a halide of formula R ₂ R ₁ CON ₂ CH ₂ Z wherein Z is a leaving group such as bromine, chlorine or iodine.

The reaction is preferably carried out by reacting the compound (IX) is treated with a strong base such as sodium hydride in a polar aprotic solvent such as N, N-dimethylformamide and then reacted with an alkylating agent of the formula RIR ₂ NCOCH ₂ Z.

Compounds of formula (II) are prepared by reducing a compound of formula (X) wherein W is CH-N3 or C = N-NHPh.

Compounds of formula (X) wherein W is CH-N3 may be reduced to compounds of formula (II) by hydrogenation in the presence of a suitable catalyst such as palladium / carrier such as carbon or calcium carbonate or platinum (IV) oxide. The reaction is preferably carried out in the presence of a solvent such as an alkanol such as ethanol or an ester such as ethyl acetate or acetic acid.

Compounds of formula (X) wherein W is C = N-NHPh may be reduced to compounds of formula (II) with zinc and acetic acid. This reaction is carried out at 0 to 50 ° C.

The compounds of formula (X) wherein W is CHN _{3 can be} prepared from a compound of formula (X) wherein W is CH _{2 by treatment} with a strong base such as sodium hydride or potassium tert-butoxide followed by triisopropyl. with benzenesulfonyl azide. The reaction is preferably carried out in a solvent such as ether such as tetrahydrofuran at -78 to 20 ° C.

Compounds of formula (X) wherein W is C = NNHPh may be prepared by reacting an orthophenylene diamine of formula (XI) with diacid chloride of formula (XII) in a suitable solvent, such as an ether such as tetrahydrofuran.

Compounds of formula (X) wherein W is CH ₂ may be prepared by reacting a compound (XI) with diacid chloride (XIII).

Compounds of formula (XI) are known or may be prepared in an analogous manner, for example, a compound of formula (XI) may be prepared by alkylation of an amine of formula (XIV).

Thus, the amine of formula (XIV) may be reacted with a compound of formula R ₁ R ₂ NCOCH ₂ Z, wherein Z is chlorine or bromine, optionally in the presence of sodium iodide in a solvent such as N, N-dimethylformamide.

The compounds of formula (III), (IV), (V) and (VI) are generally known or may be prepared by known methods.

In a further process d), compounds of formula I can be prepared from compounds of formula XV wherein R _b is hydrogen by reacting its activated derivative with an amine of formula R 1 R ₂ NH. The reaction is usually carried out using an acid in the presence of a diimide such as dicyclohexylcarbodiimide and hydroxybenzotriazole in a solvent, e.g.

for example dichloromethane or in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline in a solvent such as dimethoxyethane.

Compounds of formula XV wherein R _{b is} hydrogen may be prepared by hydrolyzing the corresponding compound XV where R _b is a t-butyl group, for example, by reaction with trifluoroacetic acid. Compounds of formula XV wherein R _{b is} t-butyl can be prepared by alkylation of the corresponding compound of formula IX with Z-CH ₂ CO ₂ R _b where Z is halogen. Compound (XV) wherein R _b is t-butyl can also be prepared by Methods A and B starting from the corresponding N-substituted benzodiazepine derivative.

In a further process (e), the compounds of formula (I) can be converted to other compounds of formula (I) in a known manner. Thus, the R ₄ is prepared a compound of formula (I) containing carboxy or carboxymethyl-substituted phenyl group by hydrolyzing the corresponding compound (I) wherein R ₄ is phenyl, alkoxycarbonyl or alkoxycarbonyl methyl is substituted with.

Compounds of formula (IX) may be prepared from diamine of formula (XIV) wherein the primary amino group is protected as a para-methoxybenzyl derivative, and the general procedure for the preparation of compounds of formula (I) is starting from phenylenediamine and then removing the N-protecting group, i.e. the para-methoxybenzyl group, by a known method.

The compounds of formula I contain at least one asymmetric carbon atom, namely the carbon atom of the diazepine ring to which the substituted urea group is attached.

Specific enantiomers of the compounds of formula (I) may be prepared by resolution of the racemic compound by known methods, such as chiral HPLC. The desired enantiomer may also be prepared from the corresponding enantiomeric amine of formula (II) by using one of the methods listed above to prepare the compound of formula (I) starting from the amine of formula (II).

The enantiomers of the amine (II) may be prepared from the racemic amine (II) by known methods, for example by salt formation with a suitable optically active acid such as R-camphorsulfonic acid or by preparative chiral HPLC.

The following examples illustrate the invention.

For intermediates and examples, the melting point is determined using a Gallenkamp op apparatus and is uncorrected. Temperatures are given in ° C and column chromatography is carried out on silica gel. Thin layer chromatography is carried out on silica plates, and the term dried refers to solutions which are dried over anhydrous sodium sulfate. The following abbreviations are used: EA = ethyl acetate, DMF = Ν, Ν-dimethylformamide, THF = tetrahydrofuran, DE = diethyl ether, DCM = dichloromethane, MeOH = methanol, AcOH = acetic acid, ee = excess enantiomer, R _T = retention time.

Intermediate 1

A mixture of cyclohexyl- (2-nitrophenyl) -amine g 2-chloronitrobenzene, 35 g potassium carbonate and 1.21 g copper (I) iodide in 43.6 ml cyclohexylamine at 150 ° C heat in a stream of nitrogen for 18 hours. The mixture was allowed to cool to room temperature and adsorbed onto silica. This was chromatographed with 98: 2 hexane-EA as the eluent to afford 22.94 g of the title compound as an orange solid. TLC: (98: 2 hexane-EA) Rf 0.38.

Intermediate 2

A solution of N-cyclohexylbenzene-1,2-diamine g, intermediate 1, in 400 ml of ethyl acetate was hydrogenated at 23 ° C and 1 g of 10% palladium-on-charcoal catalyst for 4 hours. The catalyst was removed by filtration through Hyflo, and the filtrate was evaporated to dryness to give 8.5 g of the title compound as an orange oil.

TLC (9: 1 hexane-ethyl acetate) Rf 0.36.

Intermediate 3

2- (2-Cyclohexylamino-phenylamino) -1-pyrrolidin-1-yl-ethanone

A mixture of 8.5 g of intermediate 2 and 9.4 g of 2-oxo-2- (pyrrolidin-1-yl) ethyl bromide, 18.5 g of potassium carbonate and 250 ml of anhydrous DMF is stirred at 23 ° C. hours in a stream of nitrogen. The mixture was poured into water (600 mL) and extracted with ethyl acetate (3 x 300). The combined extracts were washed with water (3 x 300 mL), brine (200 mL), dried, and concentrated. A brown oil is obtained which is chromatographed on hexane: EA (1: 1) to give 9.8 g of the title compound.

20 g of product are obtained in the form of a cream solid, m.p. 108-11 ° C.

TLC (1: 1 hexane-ethyl acetate) Rf 0.42.

Intermediate 4

-Cyclohexyl-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -3- (phenylhydrazono) -1,5-dihydro-benzo [b] [1,4] diazepi n-2,4-di is

A solution of Intermediate 3 (9.8 g) and 2- (phenylhydrazone) -propanediol dichloride (8.36 g) in dry tetrahydrofuran (75 mL) was added in anhydrous THF (70 mL) cooled to -10 ° C under nitrogen. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 3 hours. The solvent was removed by evaporation to give 19.5 g of the crude title compound as a yellow hard foam. TLC (DE): Rf 0.23.

Intermediate 5

3-Amino-1-cyclohexyl-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -1,5-dihydrobenzo [b] [1,4] diazepine-2,4-dione A solution of intermediate 4 (200 g) in glacial acetic acid (200 ml) was added dropwise to a stirred suspension of zinc powder (15 g) in glacial acetic acid. After stirring for 1.5 hours at 23 ° C, the zinc was removed by filtration through hyflo and the filtrate evaporated to give a red oil which was extracted with 200 ml of water and 75 ml of ethyl acetate. The aqueous portion was adjusted to pH 9 by addition of solid sodium carbonate and extracted with ethyl acetate (4 x 100 mL). The combined organic extracts were dried and evaporated. The resulting brown oil was chromatographed eluting with DCM: MeOH 95: 5. 7.4 g of the title compound are obtained in the form of a pink hard foam.

21 TLC: (DCM-MeOH 95: 5) Rf 0.26.

Intermediate 6

3- {3- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b ] [1,4] diazepin-3-yl] -ureido} -benzoic acid benzyl ester

A mixture of 108 μΙ of triethylamine and 77 mg of triphosgene was successively added to a solution of 177 mg of 3-aminobenzoic acid benzyl ester in 10 ml of anhydrous THF at 0 ° C under a stream of nitrogen. 108 μΙ of additional triethylamine was added and stirred at 0 ° C for 30 minutes. A solution of intermediate 5 (250 mg) in anhydrous tetrahydrofuran (10 mL) was added and stirred at 23 ° C for 18 hours. The mixture was partitioned between 2N hydrochloric acid (50 mL) and ethyl acetate (50 mL), the dried organic extract was evaporated and the residue was chromatographed with EA / hexane (2: 1). 320 mg of the title compound are obtained as a pale yellow solid.

TLC (2: 1 EA-hexane) Rf 0.17.

Ir (solution in chloroform): 3384; 2939; 1690; 1658; 1423 cm ^-1 .

Intermediate 7

3-Nitrobenzoic acid tert-butyl ester

A solution of 1.4 g of 3-nitrobenzoic acid in 10 ml of anhydrous toluene was treated with 10 ml of N, N-dimethylformamide di-tert-butyl acetate. The mixture was heated at reflux for 18 hours, cooled, diluted with ethyl acetate and washed successively with water, 8% sodium bicarbonate, and brine. The dried organic phase was evaporated to give the title compound as a yellow oil (1.02 g).

- 22 ϊ ·. _ · 1 * · ···

..... · ·., · ·. '

TLC (DCM-MeOH 97: 3) Rf: 0.66.

Intermediate 8

A solution of 3-aminobenzoic acid tert-butyl ester intermediate 7 in 20 ml of ethanol was hydrogenated at 23 ° C under 1 atmosphere of 10% palladium on charcoal in 200 ml. After 2 hours, the mixture is filtered through hyflo, the filtrate is evaporated and the residue is chromatographed with 97: 3 DCM-MeOH. 727 mg of the title compound are obtained as a colorless oil.

TLC: (DCM-MeOH 97: 3) Rf: 0.35.

Intermediate 9 (3-Nitrophenyl) acetic acid benzyl ester g 3-nitrophenylacetic acid, 2.9 ml benzyl alcohol and 300 mg 4,4-dimethylaminopyridine in 50 ml anhydrous methane was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (7.4 g). The resulting yellow mixture was stirred at 23 ° C for 3 days and then the solvent was removed in vacuo. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic layer was washed with water (2 x 100 mL) and brine (100 mL), dried and evaporated. The residue was chromatographed (4: 1 hexane: EA) and again eluted with 1: 1 isohexane: DCM to give 2.05 g of the title compound as a light yellow oil.

TLC (hexane: EA 4: 1) Rf: 0.35.

Intermediate 10 (3-Aminophenyl) acetic acid benzyl ester

A solution of Intermediate 9 (2.05 g) in EtOAc (100 mL) was hydrogenated at 23 ° C under 1 atmosphere with 200 mg of 0.5% platinum on charcoal. After 90 minutes, the mixture was filtered through hyflo, and the filtrate was evaporated to give 1.77 g of the title compound as a pale yellow oil.

TLC: (DCM) Rf: 0.35.

Intermediate 11 (2-Fluorophenyl) - (2-nitrophenyl) -amine g 2-fluoroaniline, 2.5 g potassium carbonate and 414 mg copper (I) iodide in 16.9 ml 2-fluoro -Nitrobenzene was heated to 180 ° C under a stream of nitrogen for 18 hours. The cooled mixture was poured into water (300 mL) and extracted with ethyl acetate (2 x 250 mL). The combined extracts were then washed with brine and evaporated. The residual brown oil was azeotroped with ethanol / water and toluene. The residue was chromatographed with hexane / DE (100: 0-95: 5) to give the title compound (3.25 g) as a light orange solid. Melting point: 58-59 ° C.

TLC: (hexane-DE 95: 5) Rf: 0.45.

Intermediate 12

N- (2-Fluoro-phenyl) -benzene-1,2-diamine

A solution of 15.6 g of intermediate 11 in 400 ml of ethyl acetate was hydrogenated at 23 ° C under 1 atmosphere of 2 g of 5% platinum on charcoal and after 1 h

- 24:: ··. The filtrate was filtered through hyflo and the filtrate was evaporated to give 13.45 g of the title compound as a yellow solid. TLC (hexane-DE 9: 1) Rf: 0.25.

Intermediate 13

2- [2- (2-Fluoro-phenylamino) -phenylamino] -1-pyrrolidin-1-yl-ethanone

A solution of 12.8 g of 2-oxo-2- (pyrrolidin-1-yl) ethyl bromide in 60 ml of anhydrous DMF was added dropwise to 13.45 g of intermediate 12 and 27.5 g of potassium carbonate in 100 ml of anhydrous DMF. prepared at 23 ° C under a stream of nitrogen. After stirring at 60 ° C for 4 hours, the mixture was poured into 500 ml of 2N sodium carbonate solution and extracted with 400 ml of ethyl acetate. The organic extract was washed with water (2 x 250 mL) and brine (250 mL), dried, and evaporated. The residue was chromatographed on hexane / DE 50:50 - 0: 100 as eluent. 14.12 g of the title compound are obtained as a light brown solid. TLC: (DE) Rf: 0.53.

Intermediate 14

- (2-Fluoro-phenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -3- (phenyl-hydrazono) -1,5-dihydro-benzo [b] [1,4] diazepine-2,4-dione

A solution of 14.12 g of intermediate 13 and 11.04 g of 2- (phenylhydrazone) -propanediol dichloride in 100 ml of anhydrous THF is added dropwise in an equal amount of anhydrous nitrogen, cooled to -10 ° C. ml of anhydrous THF. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 3.5 hours. Evaporation of the solvent gave 23 g of the crude title compound as a yellowish hard foam.

- TLC: (EA) Rf: 0.5.

Intermediate 15

3-Amino-1- (2-fluorophenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -1,5-dihydrobenzo [b] [1,4] diazepin-2 A solution of 4-dione g, intermediate 14, in 200 ml of glacial acetic acid was added dropwise to a stirred suspension of 22.2 g of zinc powder in 100 ml of glacial acetic acid in a cold water bath. After stirring at 23 ° C for 2.5 hours, the zinc was filtered through hyflo and the filtrate was evaporated. The residue was partitioned between water (150 mL) and ethyl acetate (100 mL) and basified with solid sodium carbonate. The phases are separated, the aqueous phase is further extracted with ethyl acetate, and the combined organic extracts are washed with brine, dried, and evaporated. The residue was chromatographed on EA / MeOH (100: 0 to 95: 5) as eluent followed by DCM: MeOH (80:20). 11.07 g of the title compound are obtained in the form of a beige powder.

TLC: (DCM-MeOH 95: 5) Rf: 0.23.

Intermediate 16 (3- {3- [1- (2-Fluoro-phenyl) -23,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2] , 3,4,5-Tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] -ureido} -phenyl) -acetic acid benzyl ester Intermediate 15 in 40 mL of anhydrous methanol solution was added dropwise to a stirred solution of phosgene in 60 ml of toluene under a stream of nitrogen, the resulting mixture was stirred at 23 ° C for 4 hours, and then nitrogen was bubbled into the ammonia solution for 16 hours. The mixture was evaporated and the residue was dried in vacuo at 60 ° C for 3 hours to give 3.3 g of intermediate.

26 isocyanates were obtained as a beige solid which was used without further identification. A solution of 400 mg of the above isocyanate in 3 ml of anhydrous dichloromethane is added dropwise to a stirred solution of 241 ml of (3-aminophenyl) acetic acid benzyl ester in 2 ml of anhydrous dichloromethane at 23 ° C. After 60 minutes, the solvent was removed in vacuo and the residue was triturated with diethyl ether. The solid was filtered off and dried, yielding 263 mg of the title compound as an off-white solid, mp 104-106 ° C. TLC: (EA) Rf: 0.54.

Intermediate 17

A mixture of 2-bromo-1- (3,3-dimethylpiperidin-1-yl) ethanone g, 3,3-dimethylpiperidine and 12.3 ml of triethylamine in 50 ml of anhydrous dichloromethane is added dropwise, 7 ml of bromoacetyl bromide in ice-cold solution of 100 ml of anhydrous dichloromethane. The mixture was stirred at 23 ° C for 18 hours and then cooled again to 0 ° C. Ice water (200 mL) was added and the layers were separated. The aqueous layer was further extracted with dichloromethane (2 x 200 mL), and the combined extracts were washed with 2N hydrochloric acid (200 mL) and brine (200 mL), dried and evaporated. 17.28 g of the title compound are obtained in the form of a brown oil. TLC: (DE) Rf: 0.49.

Intermediate 18

- (3,3-Dimethyl-piperidin-1-yl) -2- [2- (2-fluoro-phenylamino) -phenylamino] -ethanone g Intermediate 12 and 6.15 g of potassium carbonate in 10 ml of anhydrous DMF with a solution of 3.5 g of 2-bromo-1- (3,3-dimethylpiperidin-1-yl) ethanone in 10 ml of anhydrous DMF

- 27 - and stirred at 23 'C under nitrogen for 3 days. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried, and evaporated. The resulting brown oil was chromatographed with DCM: MeOH (100: 0 to 97: 3) as eluent to give the title compound (3.17 g) as a light brown foam. TLC: (DCM) Rf: 0.23.

Intermediate 19

1- [2- (3,3-Dimethyl-piperidin-1-yl) -2-oxo-ethyl] -5- (2-fluoro-phenyl) -3- (phenyl-hydrazono) -1,5-dihydro- benzo [b] [1,4] diazepine n-2,4-dione

A solution of Intermediate 18 (3.08 g) and 2- (phenylhydrazono) propanediol dichloride (2.12 g) in anhydrous THF (100 mL) was added in an equal amount to anhydrous THF (50 mL) under nitrogen at -10 ° C. cool down. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was evaporated to give 5.25 g of crude title compound as a yellow hard foam. TLC: (DCM-MeOH 95: 5) Rf: 0.68.

Intermediate 20

3-Amino-1- [2- (3,3-dimethyl-piperidin-1-yl) -2-oxo-ethyl] -5- (2-fluoro-phenyl) -1,5-dihydro-benzo [b] [1,4] diazepine n-2,4-dione

A solution of 5.15 g of intermediate 19 in 75 ml of glacial acetic acid is added dropwise to a stirred suspension of 4.47 g of zinc powder in 50 ml of glacial acetic acid in an ice-cold water bath. After stirring at 23 ° C for 6 hours, the zinc was removed by filtration through Hyflo and the filtrate evaporated. The residue was partitioned between water and ethyl acetate, and the aqueous layer was solid sodium carbonate.

Alkaline: The organic extract was washed with brine, dried, and evaporated. The residue was chromatographed on DCM: MeOH 95: 5 to give 2.38 g of the title compound as a light brown solid.

TLC: (DCM-MeOH 95: 5) Rf: 0.18.

Intermediate 21

3- {3- [1- [2- (3,3-Dimethyl-piperidin-1-yl) -2-oxo-ethyl] -5- (2-fluoro-phenyl) -2,4-dioxo-2, 3,4,5-Tetrahydro-1 H -benzo [b] [1,4] diazepin-3-yl] ureido} -benzoic acid tert-butyl ester

Triethylamine (0.31 mL) and triphosgene (217 mg) were added sequentially

423 mg of a solution of 3-aminobenzoic acid tert-butyl ester in 10 ml of anhydrous THF at 0 ° C under a stream of nitrogen. An additional 0.31 mL of triethylamine was added and stirred at 0 ° C for 30 min. A solution of Intermediate 20 (800 mg) in THF (10 mL) was added and stirred at 23 ° C for 18 h. The mixture was then partitioned between pH 6.5 phosphate buffer solution and dichloromethane. The combined organic extracts were washed with brine, dried, and evaporated. The residue was chromatographed, eluting with DCM-MeOH 97: 3, to give a light green solid which was triturated with DE: hexane 1: 1 to give the title compound as a white solid (1.07 g). Melting point: 170 ° C.

TLC: (DCM-MeOH 97: 3) Rf: 0.15.

Example 1

1- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b] [ 1,4] diazepin-3-yl] -3- (4-fluorophenyl) urea

650 µl of 4-fluorophenyl isocyanate was added to a solution of 2 g of intermediate 5 in 50 ml of anhydrous dichloromethane under a stream of nitrogen at 23 ° C. The resulting mixture was stirred for 1 hour then adsorbed onto silica and eluted with EA-MeOH (100: 0 to 95: 5) to give 1.92 g of the title compound as a white solid, m.p. 181-183 ° C. TLC: (EA) Rf: 0.42.

1.7 g of the compound of Example 1 were separated into two enantiomers by separate chiral HPLC (Isomer 1 and Isomer 2).

column: Chiralcel OD 25 cm x 20 mm id eluent: hexane-EtOH (70:30) Flow rate: 20 ml / min

Detection: uv @ 254 nm

452 mg isomer 1, white solid R _T 8.6 min, HPLC> 99.5% ee.

TLC (EA) Rf 0.42.

IR (chloroform solution): 3622; 3091; 2938; 2895; 2403; 1657; 1515; 1425; 1189; 1047; 929 cm ^-1 .

488 mg isomer 2, white solid R _T 15.1 min,

HPLC> 98.8% ee.

TLC (EA) Rf 0.42.

IR (KBr plate): 3366; 2935; 1695; 1657; 1558; 1510; 1422; 1206; 833; 763 cm ^-1 .

Example 2

3- {3- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b ] [1,4] Diazepin-3-yl] -ureido} -benzoic acid

A solution of Intermediate 6 (248 mg) in ethyl acetate (10 mL) and THF (5 mL) was hydrogenated at 23 ° C under 1 atmosphere overnight in the presence of 25 mg of 10% palladium on charcoal. An additional 25 mg of catalyst was added and hydrogenation was continued for 2 hours, then the mixture was filtered through Hyflo and the filtrate was evaporated to give 216 mg of the title compound as a white solid. Melting point: 275-276 ° C. TLC (EA-AcOH 100: 2) Rf 0.25.

Ir (KBr plate): 3369; 2935; 1700; 1659; 1557; 1499; 1431; 1233; 760 cm ^-1 .

Example 3 (3- {3- [1- (2-Fluoro-phenyl) -2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl)] -2,3,4,5-Tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] -ureido} -phenyl) -acetic acid

A solution of Intermediate 16 (177 mg) in THF (10 mL) was hydrogenated at 23 ° C under 1 atmosphere of 10% Pd / C. After 90 minutes, the mixture was filtered through hyflo, and the filtrate was evaporated to give 67 mg of the title compound as a white solid. Melting point: 197-199 ° C.

solid R _t 8.6 min, HPLC> 99.5% ee.

TLC (EA) Rf 0.17.

31 IR (KBr plate): 3331; 1708; 1651; 1562; 1499; 1454; 1403; 1238; 761 cm ^-1 .

Example 4

3- (3- (1- (2- (3,3-Dimethyl-piperidin-1-yl) -2-oxo-ethyl) -5- (2-fluoro-phenyl) -2,4-dioxo) 2,3,4,5-Tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] -ureido} -benzoic acid

A solution of intermediate 21 (400 mg) in dichloromethane (20 mL) was treated with trifluoroacetic acid (1 mL) and stirred at 23 ° C for 1 h under nitrogen. The mixture was concentrated in vacuo and the residue was chromatographed with DCM-MeOH 95: 5 as the eluent to give 344 mg of the title compound as a white solid. Melting point: 225 ° C (with decomposition). TLC (95: 5 DCM-MeOH) Rf 0.26.

A, B, C, and D are also prepared by the above process to produce the following compounds of the invention.

Table 1

A compound of formula (Γ) k Example number X Rs Mp (° C) process 5 H 3,5-diCH ₃ 254-255 THE 6th H 4-OCH ₃ 180-182 THE 7th H 3-F 188-190 THE 8th H 3-NO2 173-175 THE 9th H 3-CH ₂ CN 210-212 THE 10th H H 216-218 THE 11th H 3-CONH ₂ 275-277 THE 12th H 3-N (CH ₃ ) ₂ 251-253 THE

• · ·

- Table 32 (continued)

Example number X r ₅ Mp (° C) process 13th Br 4-F * Rf 0.3 D

★ TLC: cyclohexane: EA: AcOH 1: 1.0: 0.4

Table 2 Compounds of formula (I)

Example number r ₃ Rs Mp (° C) process 14th Ph 3 -tetrazol 243 THE 15th Ph 3-CH ₃ 243-246 THE 16th Ph 3-CONHSO ₂ CH ₃ 199-200 B 17th 2-F-Ph 4-F 155-157 THE 18th 2 F-Ph 3-CH ₃ 195-197 THE 19th 2 F-Ph 3-CO ₂ H -225-227 B

Table 3

(Γ ”) compounds Example number nr, r ₂ Mp (° C) process 20th 240 THE 21st 170 THE 22nd 260 THE 23rd 220-5 ° C (dec.) C 24th 255-258 D

Examples of drug preparation

Tablet

agent 50 mg Anhydrous lactose USP 163 mg Microcrystalline cellulose NF 69 mg Raised starch Ph. Eur. 15 mg Magnesium stearate USP 3 mg Pressing mass 300 mg active ingredient, microcrystalline cellulose, lactose and

screened starch is sieved through a 500 micron sieve and mixed with a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and mixed with a mixture of the active ingredient.

- 34. The mixture is compressed into tablets using a suitable tableting device.

b. Active ingredient50 mg

Lactose Monohydrate USP 120mg

Pregelatinized starch Ph. Eur. 20mg

Crospovidone NF 8mg

Magnesium Stearate USP 2mg

Pressing weight 200mg

The active ingredient, lactose and pregelatinized starch are mixed and granulated with water. The wet mass is dried and ground. The magnesium stearate and crospovidone were sieved through a 250 micron sieve and mixed with the granulate. The resulting mixture is compressed on a suitable tabletting machine.

Capsule

the. Active ingredient50 mg

Pregelatinized starch Ph. Eur. 148mg

Magnesium Stearate USP 2mg

Filling weight 200mg

The active ingredient and the pregelatinized starch were sieved through a 500 micron sieve, mixed and mixed with magnesium stearate through a 250 micron sieve. The mixture is filled into hard gelatin capsules of appropriate size.

- 35 • ·· ·

agent 50 mg Lactose Monohydrate USP 223 mg Povidone USP 12 mg Crospovidone NF 12 mg Seed is watching um-stearate 3 mg filling Weight 300 mg

The active ingredient, lactose, is mixed and granulated with povidone solution. The wet mass is dried and ground. The magnesium stearate and Crospovidone were sieved through a 250 micron sieve and mixed with the granulate. The resulting mixture is filled into hard gelatin capsules of appropriate size.

CCK-B receptor binding affinity

CCK-B receptor binding studies were performed using HeLa cell membranes stably transferred from the cerebral cortex cDNA library to human CCK-B receptor cloned.

Measurement of CCK-B binding affinity

Transfected HeLa cell membranes were incubated with 30 pM [ ¹²⁵ L] BH-sCCK-8 in the presence of various concentrations of test compound at concentrations ranging from 1 pM to 1 pm. The experiments were performed in a 250 μΙ experimental volume, the membranes were collected on GF / C glass fiber filter paper (Whatman, UK) and rapidly filtered using Cell Harvester, Brandel model M-24R and washed three times with HEPES wash buffer cooled to 4 ° C. The accumulated radioactivity on each filter plate was counted in a gamma counter (Mini gamma counter, LKB, Wallac, Finland) for 60 seconds at 77% counting efficiency. A control experiment was also performed in the absence of the test compound.

• · «

Data are analyzed by computer non-linear regression (ALLFIT programmer DeLean et al., 1978). The IC ₅₀ values of test compounds are converted to K i values using the Cheng & Prussof equation (K i = IC ₅₀ o / (1 + [L] / K _D )) (Cheng and Prussof, 1973). The results obtained for the compounds of the invention, expressed as pKi, are given below.

CCK-A receptor binding affinity

CCK-A receptor binding studies were performed using C0S-M6 cell membranes transiently transfected with human gallbladder CCK-A receptor cDNA.

The clone was transiently transferred into COS-M6 cells grown to 80% confluency by the dimethylaminoethyl dextran method by Seed and Araffo. Prov. Natl. Acad. Sci. USA 84, 3365 (1987). The desired transferred cell membranes are then isolated in a known manner.

The affinity of the compounds of the invention for the CCK-A receptor was determined as described below for the CCK-B receptor, but in these experiments, the test compound was tested at a concentration of 10 µM to 10 µM.

CCK-B binding studies

Example number pKi First 8.5 (Isomer 1). 8.5 1st (Isomer 2) 8.1 Second 8.7 Third 8.4 4th 8.8 7th 8.3 8th 8.6 10th 8.4 12th 9.0 14th 8.5 15th 8.8 20th 8.7

The compounds of the invention are substantially non-toxic at the therapeutically effective dose. No undesirable effect was observed when the isomer 1 of Example 1 was administered to rats with gastric ulcer at 0.3 and 1 mg / kg i.v. doses. At these doses, gastric acid secretion was significantly inhibited by the administered substance.

Claims (13)

Claims A compound of the formula I and its physiologically acceptable salts, wherein NR ₁ R _{2 is a} 5-7 membered saturated heterocyclic ring which may be substituted by one or two methyl groups; R _{3 is C} 1-6 alkyl, C 3-6 cycloalkyl or phenyl optionally substituted with one or two halogen atoms, R ₄ is phenyl or phenyl optionally substituted with one or two halogen atoms, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy or (CH ₂ ) _n R 5 wherein n is 0 or 1, and R ₅ is C 1-4 alkoxy, hydroxy, nitro, cyano, CO ₂ R ₆ , S (O) _p CH ₃ , NR ₇ R ₈ , CONR ₇ R ₈ or SO ₂ NR ₇ CO (C 1 -C 4 alkyl), tetrazolyl, carboxamidodetrazolyl or 3-trifluoromethyl-1,2,4-triazolyl, R ₆ is hydrogen, C 1-4 alkyl or benzyl, R ₇ is hydrogen or C 1-4 alkyl, R ₈ is hydrogen, C 1 -C 4 alkyl, SO ₂ CH ₃ or SO ₂ CF ₃ , X is hydrogen or halogen or C 1-4 alkyl, m is 0, 1 or 2 and p is 0, 1 or 2. Compounds according to claim 1, wherein NR ₁ R ₂ is pyrrolidino, 2,5-dimethylpyrrolidino, piperidino, 3,3-dimethyl38 · · · · · · ··· ··· · • * · · ····· * ·· · ν ·· »· ·· · - 39-piperidino, '4,4-dimethylpiperidino or 2,6-dimethylpiperidino. Compounds according to claim 1 or 2, wherein NR ₄ R ₂ is pyrrolidino. 4. Compounds according to any one of claims 1 to ₃ , wherein R ₃ is phenyl, 2-fluorophenyl or cyclohexyl. 5. Compounds according to any one of claims 1 to ₃ , wherein R ₃ is cyclohexyl. 6. Compounds according to any one of claims 1 to 4, wherein R ₄ is phenyl, 3-methylphenyl, 3,5-dimethylphenyl, 3-dimethylaminophenyl, 4-fluorophenyl, 3-methoxyphenyl, , 4-methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl, 3-carboxamidophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or 3- ( 1H) -tetrazol-5-yl-phenyl. 7. Compounds according to any one of claims 1 to 4, wherein R ₄ is phenyl, 4-fluorophenyl, 3-dimethylaminophenyl, 3-carboxylphenyl, 3-carboxymethylphenyl or 3- (1H) -tetrazol-5-yl-1-phenyl. 8. 1- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b] [1,4] Diazepin-3-yl] -3- (4-fluorophenyl) urea and its enantiomers. 9th 3- {3- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-1 H -benzo [b] [1,4] diazepin-3-yl] ureido} benzoic acid; 3- {3- [1- (2-Fluoro-phenyl) -2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro- 1H-benzo [b] [1,4] diazepin-3-yl] -ureido} -phenyl) -acetic acid; - 40 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · all quick all · 3- {3- [1- [2- (3,3-Dimethyl-piperidin-1-yl) -2-oxo-ethyl] -5- (2-fluoro-phenyl) -2,4-dioxo-2, 3,4,5-Tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] -ureido] -benzoic acid and its enantiomers. 10. The use of a compound according to any one of claims 1 to 5 in medicine. 11. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of conditions wherein modifying the effect of gastrin and / or CCK is a therapeutic effect. 12. A pharmaceutical composition, wherein the active ingredient is a compound according to any one of claims 1-9. A compound according to any one of claims 1 to 6 or a salt thereof with one or more physiologically acceptable carriers or excipients. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that (a) a compound of formula (II) - wherein R _1f R ₂ , R ₃ , X and n are as defined above, R ₄ Y with a compound of formula (III), which is selected from the group consisting of isocyanate (III), carbamoyl chloride (IV), imidazolide (V) and phenylcarbamate (VI), wherein R _a is optionally substituted phenoxy and R _{4 is} or (b) a compound of Formula VII: wherein R 1, R ₂ , R ₃ , X and m are as defined above, and Y is NCO, NHCOCl, or NHCOR _a , wherein R _a is optionally substituted phenoxy or an imidazole group, reacting a R ₄ NH ₂ amine of formula (VIII) wherein R ₄ is as defined above, or ··· (c) a compound of formula IX wherein R ₃ , R ₄ , X and m are as defined above, R ₂ RiNCOCH ₂ Z general view or (d) an activated derivative of a compound of Formula XV wherein R ₃ , R _41, X and m are as defined above, and R _{b is a} hydrogen atom, R ₁ R ₂ NH. and optionally before converting the compounds into stereochemically isomeric forms or converting a compound of formula (I) into another compound of formula (I).