SK125495A3 - 1,5-benzodiazepine derivatives, manufacturing process, their use and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of general formula (I) and physiologically acceptable salts thereof wherein the group NR1R2 represents a 5-7 membered saturated heterocyclic ring which may be substituted by one or two methyl groups; R3 is C1-6alkyl, C3-6cycloalkyl or phenyl optionally substituted by 1 or 2 halogen atoms; R4 is phenyl or phenyl substituted by one or two groups selected from halogen, C1-4alkyl, trifluoromethyl, trifluoromethoxy or (CH2)nR5 wherein n is zero or 1 and R5 represents C1-4alkoxy, hydroxy, nitro, cyano, CO2R6, S(O)pCH3, NR7R8, CONR7R8, SO2NR7CO(C1-4alkyl), tetrazolyl, carboxamidotetrazolyl, or a 3-trifluoromethyl 1,2,4-triazolyl; R6 is hydrogen, C1-4alkyl or benzyl; R7 is hydrogen or C1-4alkyl, R8 is hydrogen, C1-4alkyl, SO2CH3 or SO2CF3, X represents hydrogen, C1-4alkyl or halogen; m is zero, 1 or 2, and p is zero, 1 or 2; processes for their preparation and their use in medicine as antagonists of gastrin and CCK.

Description

Technical field

The present invention relates to novel 1,5-benzodiazepine derivatives, to a process for the preparation of these substances, to pharmaceutical compositions containing them and to the use of these substances in the manufacture of pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Cholecystokinins CCK and gastrin are structurally related peptides that occur in the digestive tract tissue and the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of 33 amino acid residues in its original isolated form, its carboxyterminal octapeptide CCK-8, which also occurs as a separate neuropeptide, and a form of 39 and 12 amino acid residues. Gastrin is present in forms containing 34, 17 and 14 amino acid residues, with the shortest active chain being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-Nl, CCK-4, which is a common structure found in CCK even in the gastrin.

CCK and gastrin are gastrointestinal hormones and neurotransmitters in both the nervous and peripheral systems, which perform their biological role by binding to the appropriate receptors located at various sites in the body.

There are at least two subtypes of cholecystokinin receptors, referred to as CCK-A and CCK-B, both of which can be detected in the peripheral and central nervous systems. CCK and gastrin receptor antagonists have also been found, which could be used to prevent or treat disorders associated with the secretion of CCK and / or gastrin in the digestive system and in the central nervous system of various animals and especially humans.

U.S. Pat. No. 4,988,692, a group is described

3-acylamino-1-alkyl-5-phenyl-1,5-benzodiazepine derivatives as cholecystokinin antagonists. These agents are reported to have a significantly higher affinity for CCK-A receptors than for CCK-B receptors.

We have now found a class of novel 3-ureido-1,5-benzodiazepine compounds that are potent and specific antagonists of gastrin and / or CCK and, in particular, antagonize gastrin receptors and / or CCK-B receptor for CCK.

SUMMARY OF THE INVENTION

The present invention relates to 1,5-benzodiazepine derivatives

CONR ^ ²

(I) and physiologically acceptable salts of these compounds, wherein NR R represents a saturated 5- to 7-membered heterocyclic ring, optionally substituted with one or two methyl groups, and

R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl, optionally substituted with one or two halogen atoms,

R ⁴ is phenyl, optionally substituted with one or two groups selected from halogen, C 1 -C 4 alkyl, trifluoromethyl, trifluoromethoxy, or (C 1-6 R 6) wherein n is 0 or 1 and R 5 is (C až-C) alkoxy, hydroxy, nitro, cyano, CC ^R ^, S (O) pCH ₃ , NR ⁷ R R, CONRNR®, SO ₂ NR ⁷ CO-alkyl of 1 to 4 carbon atoms in the alkyl moiety, tetrazolyl, carboxamidotetrazolyl or 3-trifluoromethyl-1,2,4-triazolyl,

R ⁶ is hydrogen, C 1 -C 4 alkyl or benzyl,

R ⁷ represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms,

R® is H, C 1 -C 4 alkyl, SO ₂ CH ₃ or SO ₂ CF _3,

X is hydrogen, alkyl of 1 to 4 carbon atoms or halogen, 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 the invention therefore encompasses both individual enantiomers and mixtures including racemates.

The term alkyl refers to straight and branched chain groups. For example, alkyl of 1 to 6 carbon atoms may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or hexyl.

The halogen atom is a fluorine, chlorine, bromine or iodine atom.

When R1 is a tetrazolyl, carboxamidotetrazolyl or 3-trifluoromethyl-1,2,4-triazolyl group, these groups are attached to the remainder of the molecule via one of their carbon atoms, the invention encompassing all tautomers that may be present and also dervates thereof, substituted on the nitrogen atom with a C1-C4 alkyl radical. Examples of such groups are (1 H) -tetrazol-5-yl, carboxamido-1 H -tetrazol-5-yl, 2-methyltetrazol-5-yl and 3-trifluoromethyl-1,2,4-triazol-5-yl .

The -NR R group is bonded to the rest of the molecule via a nitrogen atom. Examples of such groups include pyrrolidine, piperidine, hexamethyleneimino, 2,5-dimethylpyrrolidine, 3,3-dimethylpiperidine, 2,6-dimethylpiperidine or 4,4-dimethylpiperidine, and

When R is phenyl optionally substituted by a halogen atom, examples of such groups may include phenyl optionally substituted by a fluorine atom, for example phenyl, 2-fluorophenyl or 4-fluorophenyl.

Q

When R is C 3 -C 6 cycloalkyl, cyclopropyl, cyclopentyl or cyclohexyl are examples of such groups.

When it is an alkyl group having 1 to 6 carbon atoms, methyl, ethyl, propyl, butyl, 3-methylbutyl or 3,3-dimethylbutyl are examples of such groups.

Examples of useful R ⁴ groups include phenyl optionally substituted by a halogen atom such as fluorine, alkyl such as methyl, alkoxy such as methoxy, nitro, cyano, thiomethylcarboxamido, carboxyl, dimethylamino, cyanomethyl, 1H-tetrazole 5-yl, carboxymethyl or N-methylsulfonylcarboxamido.

A preferred group of compounds of the invention are those wherein the -NR R group is a pyrrolidine, piperidine, 3,3-piperidine, 4,4-dimethylpiperidine, 2,6-dimethylpiperidine or 2,5-dimethylpyrrolidine group.

19th

In this group of substances, the -NR R group is preferably a pyrrolidine, piperidine or 3,3-dimethylpiperidine group.

S preferably represents a halogen atom, for example a bromine atom, a fluorine atom, and in particular a hydrogen atom.

Another preferred group of compounds of the formula

Q

I are those in which R is phenyl, 2-fluorophenyl or cyclohexyl, and in particular 2-fluorophenyl or cyclohexyl.

Another preferred group of compounds of formula I are those wherein R ⁴ is phenyl or phenyl substituted with a methyl group, for example 3-methylphenyl or 3,5-dimethylphenyl, 3-dimethylaminophenyl, phenyl, substituted with a fluorine atom, for example 4-fluorophenyl , phenyl substituted by methoxy, for example 4-fluorophenyl, phenyl substituted by methoxy, for example 3-methoxyphenyl or 4-methoxyphenyl, further 3-nitrophenyl, 3-cyanomethylphenyl, 3-carboxamidophenyl, 3-carboxyphenyl, 3-carboxmethylphenyl or 3- (1) 1 H -tetrazol-5-ylphenyl.

A particularly preferred group of compounds according to the invention is 19.

those in which the -NR group R represents a pyrrolidine, 3 piperidine or 3,3-dimethylpiperidine group, R represents 2-fluorophenyl or cyclohexyl and X represents a hydrogen atom. Particularly preferred compounds within this group are those wherein R ⁴ is phenyl, 4-fluorophenyl, 3-dimethylaminophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or 3 (1H) -tetrazol-5-ylphenyl.

A particularly preferred compound of the invention is 1- [1-cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-ylethyl) -2,3,4,5-tetrahydro-1 H -benzo [b] ] [1,4] diazepin-3-yl] -3- (4-fluorophenyl) urea and its enantiomers.

Other preferred compounds of the present invention include 3- (3- [1-cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-ylethyl) -2,3,4,5- tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] ureido) benzoic acid (3- (3- (1- (2-fluorophenyl) -2,4-dioxo-5- (2))) (oxo-2-pyrrolidin-1-ylethyl) -2,3,4,5-tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] -ureido) phenyl) acetic acid,

- (3- [1- [2- (3,3-dimethylpiperidin-1-yl) -2-oxoethyl] -5- (2-fluorophenyl) -2,4-dioxo-2,3,4,5-tetrahydro 1 H -benzo [b] [1,4] diazepin-3-yl] -ureido) benzoic acid and the enantiomers of these compounds. <

Physiologically acceptable salts of these compounds of formula I include conventional salts formed, for example, using pharmaceutically acceptable inorganic or organic acids, as well as quaternary ammonium salts and acid addition salts. Examples of suitable salts include salts with hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, filmmaker, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartar, citric, pamoic, malonic, hydroxymaleinic, phthalomic acid, phthalominoic, , glutamic, benzoic, salicylic, fumaric, toluenesulfonic, mangansulfonic, naphthalene-2-sulfonic, benzenesulfonic, and the like. Other acids, such as oxalic acid, which are not pharmaceutically acceptable, can be used in the manufacture of salts useful as intermediates in the manufacture of the compounds of the invention and their pharmaceutically acceptable salts.

When referring to the compounds of the present invention, the term includes both compounds of formula I as well as their pharmaceutically acceptable salts and solvates.

The compounds of the invention are capable of modulating the effect 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 have been shown to antagonize CCK, particularly at CCK-B receptors, as demonstrated, for example, by their ability to inhibit the contractile action of CCK-4 in the presence of a CCK-A antagonist on isolated longitudinal muscle and guinea pig myenteric plexus.

The preparation and use of the preparation containing the longitudinal muscle and the guinea pig myentericus plexus has been described by K. H. Buchheit et al., Naunyn-Schiedeberg’s Arch. Pharmacol., 1985, 329, p. 36-41 and V.L. Lucaites et al., J. Pharmacol. Exp. Ther., 1991, 256, 695-703.

The compounds of the invention have also been shown to have a higher affinity for CCK-B receptors than for CCK-A receptors. This can be demonstrated using the CCK receptor binding assays described by Fornos et al., J. Pharmacol. Exp. Ther. 261: 1056-1063.

, 1992.

The affinity of binding of the compounds of the invention to CCK-A and CCK-B receptors can also be determined using HeLa cell membrane membranes that are transfected with human CCK-B receptor or using COS-M6 transient cell membranes. transfection with the human CCK-A receptor.

It has also been shown that the compounds of the invention are capable of antagonizing gastrin because they have the ability to inhibit gastric acid secretion upon stimulation with pentagastrin on an isolated preparation of rat gastric mucosa according to the method of J. J. Reeves and R. Stables, Br. J. Pharmac., 1985, 86, p. 677 to 684.

The compounds of the invention are also capable of inhibiting gastric acid secretion upon pentagastrin stimulation in waking gastric whistle-making rats using procedures described in Hedges and Parsons, Journal of Physiology, 1977, 267, 181-194.

For the above reasons, the compounds of the invention can be used for the treatment and / or prevention of such disorders in mammals, and especially in humans, in which modification of the effects of gastrin or CCK may have a beneficial effect. Thus, the compounds of the present invention can be used to treat gastric and intestinal disorders, particularly those in which it is desirable to reduce the acidity of gastric juice. Some of these disorders include peptic ulcer, esophageal reflux, and Zollinger-Ellison syndrome. However, they can also be used to treat other disorders of the stomach and intestinal system, such as irritable bowel syndrome, excessive pancreatic secretion, acute pancreatitis, gastrointestinal motility disorders, anthra G-cell hyperplasia, fundus mucosal hyperplasia or tumors of the stomach and intestines. However, the compounds of the invention may also be used to treat those central nervous system disorders in which CCK and / or gastrin are involved. These may include, for example, some anxiety disorders including panic disorders, agoraphobia, social phobia, simple phobias, obsessive compulsive disorders, post-traumatic stress related disorders and general anxiety disorders, depression, tardive dyskinesia, Parkinson's and some psychoses. The compounds of the invention can also be used in the case of drug dependence or addictions to certain drugs or addictive substances and in the case of withdrawal syndrome, in the case of Gilles de la Tourette syndrome or in the dysfunction of the appetite control system. The compounds of the invention may also be used to treat some tumors in the lower part of the esophagus, the stomach, the small and large intestine. However, the compounds of the invention are also useful for direct pain relief or for enhancing analgesia when administering opioids and other non-opioid analgesics, and for improving anesthesia or increasing the sensitivity threshold for painful sensations.

Thus, the compounds of formula I and their pharmaceutically acceptable salts or solvates can be used for medical purposes, especially in human medicine.

In particular, the compounds of the invention or their pharmaceutically acceptable salts or solvates can be used in the manufacture of pharmaceutical compositions for the treatment of conditions in which it is desirable to modify the effects of gastrin and / or CCK.

In such cases, an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered.

Obviously, where therapeutic purposes are mentioned, the substance can also be used to prevent and not only alleviate the already developed disease or its symptoms.

It will also be appreciated that the effective amount of the compounds of the invention to be used to achieve a therapeutic effect will vary depending upon the nature of the condition being treated, the age and the condition of the patient, and the resulting dose will be determined by the attending physician or veterinarian. In general, the daily dose for an adult patient will typically be in the range of 1 to 2000, for example 10 to 500 mg of active ingredient.

Said desired daily dose may be administered at once or divided at appropriate intervals, for example in the form of two, three, four or more sub-doses per day.

Compounds of the invention that antagonize CCK function in animals can also be used as an additive in feed where it is desirable to increase food intake in animals, in which case the required daily dose is in the range of 1 mg / kg to 10 mg / kg.

While it is possible to use the compounds of the invention for therapeutic purposes directly as chemical substances, it is preferable to formulate them into the active ingredients of the pharmaceutical compositions.

The present invention also provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) or a salt thereof, pharmaceutically acceptable, together with one or more pharmaceutically acceptable carriers therefor and optionally together with other ingredients for therapeutic and / or prophylactic use. The carrier must be acceptable in the sense of being compatible with the other ingredients of the compositions having no deleterious effects on the body.

The pharmaceutical compositions of the invention include dosage forms especially adapted for oral administration, oral mucosal administration, parenteral administration, implantation or rectal administration. Of these administration routes, oral administration is particularly preferred.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth, starch slime or polyvinylpyrrolidone, as well as fillers such as lactose, sucrose, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol, glidants such as magnesium stearate, stearic acid, talc, polyethylene glycol or silica, disintegrating agents such as potato starch or sodium starch glycolate or wetting agents such as sodium lauryl sulfate. The tablets may be coated in a manner known per se. Liquid compositions for oral administration may be in the form of, for example, a suspension, solution or emulsion in water or an oil, syrup or elixir, but may also be presented in a dry form to be mixed with water or other suitable vehicle before administration. Such liquid compositions may contain conventional additives, for example, suspending agents such as sorbitol syrup, methylcellulose, glucose and sucrose syrup, gelatin, hydroxycellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils, emulsifying agents such as lecithin, sorbitan monooleate or acacia gum, a non-aqueous vehicle, including edible oils such as almond oil, fractionated coconut oil, oil-type esters, propylene glycol or ethyl alcohol, and a preservative such as methyl or propyl p-hydroxybenzoate or ascorbic acid. The pharmaceutical compositions may also be formulated as suppositories, which will contain a conventional suppository base such as cocoa butter or other glycerides.

For oral administration, the pharmaceutical compositions of the invention may take the form of tablets or lozenges formulated in conventional manner.

The pharmaceutical compositions of the invention may also be formulated for parenteral administration by injection or continuous infusion. The injectable compositions may be presented in ampoules containing a unit dose of the active ingredient concerned or in multiple dose vials with the addition of a preservative. These compositions may take the form of a suspension, solution or emulsion in an oily or aqueous medium and may contain excipients such as suspending, stabilizing and / or dispersing agents. However, the active ingredient may also be presented in the form of a powder to be mixed with a suitable environment, for example sterile pyrogen-free water, just prior to administration.

However, the pharmaceutical compositions of the invention may also be formulated as depot sustained release formulations. These compositions may be used in the form of an implant, for example, subcutaneously or intramuscularly, or as an intramuscular injection. For this purpose, for example, the compounds of the invention may be formulated with a suitable polymeric or hydrophobic material, for example, as an emulsion in an acceptable oil or in the form of sparingly soluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions according to the invention may contain 0.1 to 99% by weight of the active ingredient, in the case of tablets and capsules usually 30 to 95% by weight and, in the case of liquid preparations, 3 to 50% by weight.

The compounds of formula (I) and salts thereof can be prepared by the general procedures described below.

R

In these procedures, the groups R to R and X have the meaning given in formula I unless otherwise expressly stated.

Procedure

According to the first general procedure A, compounds of the formula I can be prepared by reacting an amine of the formula II

wherein the symbols are as defined in formula I, with a compound R ^ Y wherein R Y is an isocyanate of formula III, a carbamoyl chloride of formula IV, the imidazolides of formula V, or an optionally substituted phenyl carbamate of the formula VI, wherein R ^and represents a phenoxy group, optionally substituted.

O = C = N-R ⁴

ClCO ⁴ NH (III) (IV) \ = J

(IN)

R ^and CONHR ⁴ (VI)

The reaction is readily carried out in the presence of a suitable solvent such as a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or a nitrile such as acetonitrile or a mixture thereof at 0 to 80 ° C.

The isocyanates of formula III are available or can be prepared by the reaction of amines H 2 N-R ⁴ with phosgene or triphosgene in a suitable solvent such as methylene chloride. Carbamoyl chlorides of the formula IV can also be prepared by reaction of amines of formula H 2 NR ⁴ with phosgene or triphosgene in a suitable solvent such as methylene chloride. The imidazolides of formula V can be obtained by treating the amines of the formula H 2 NR ⁴ treated with carbonyl diimidazole in a suitable solvent such as dichloromethane, ether or tetrahydrofuran at temperatures between 0 and 80 ° C, conveniently at room temperature. Optionally substituted phenylcarbamates of formula VI can be prepared by reacting amines of formula I-NR ⁴ with the appropriate chloroformate of formula R ^and COCl in the presence of a base such as pyridine or triethylamine in a suitable solvent such as dichloromethane at 0 to 50 ° C.

Procedure B

According to a further general procedure (B), compounds of formula (I) may be prepared by reacting an intermediate of formula (VII)

(VII) • \ where

Y is -NCO, is phenoxy, 1-imidazole,

-NHCOCl or -NHCOR ^a , wherein R ^{a is} optionally substituted or with an amine of formula VIII

H ₂ N - R ⁴ (VIII) optionally in the presence of a base, for example a tertiary amine such as triethylamine.

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

Compounds of formula VII may be prepared in situ from amines of formula II.

In a preferred embodiment of Process B wherein Y is -NHCOR ^a , where R ^a is 1-imidazole, an imidazolide of formula VII can be formed in situ, in which case the amine of formula VIII is mixed with a compound of formula II

in the presence of carbonyldiimidazole under the above conditions.

In carrying out process B when Y is -NHCOR ^a , where R ^a is optionally substituted phenoxy, the reaction with a primary amine of formula VIII is preferably carried out in the presence of a base, for example a tertiary amine such as triethylamine.

In the case of process B in which Y is an isocyanate group -N = C = O, the reaction with the primary amine of formula VIII is preferably carried out in an aprotic solvent, for example a halogenated hydrocarbon such as methylene chloride. The isocyanate is preferably formed in situ prior to the addition of the primary amine of formula VIII.

Compounds of formula VII wherein R ^a is an optionally substituted phenoxy group may be prepared from a primary amine of formula II by reaction with the corresponding, optionally substituted phenyl chloroformate 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 a temperature in the range of 0 to 50 ° C.

Compounds of formula (VII) wherein R ^a is

The 1-imidazole group may be prepared by reacting a compound of formula II with carbonyldiimidazole in the presence of a suitable solvent, for example a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran at 0 to 80 ° C, conveniently at room temperature.

Compounds of formula VII in which Y is an isocyanate group -N = C = O or a carbamoyl chloride -NHCOCl moiety can be prepared from a primary amine of formula II by reversible dissolution with phosgene COCl 2 or triphosgene in ice, for example methylene chloride.

Procedure C

According to a further general procedure (C), the compounds of formula (I) may also be prepared by reaction of conventional formula (IX) with compounds of general formula

O ^H /

ΓΎ, 4 (ix) with a halide of formula

R ² R ¹ NC0CHoZ wherein Z is a leaving group, for example a bromine, chlorine or iodine.

The reaction proceeds well by treating the compound of formula IX with a strong base, for example sodium hydrogen in a polar aprotic solvent such as N, N-dimethylformamide, and then reacting with an alkylating agent of formula R R NCOCH 2 Z.

Compounds of formula (II) may be prepared by reduction of compounds of formula (X ⁾

(X) wherein V is CH-N4 or C = N-NHPh.

Compounds of formula X, wherein W is _CH-N3 may be reduced to a compound of formula II by hydrogenation in the presence of a suitable catalyst, for example palladium on a support such as carbon or calcium carbonate, or platinum oxide. The reaction is readily carried out in the presence of a solvent, for example an alkanol such as methanol, an ester such as ethyl acetate or acetic acid.

Compounds of formula X in which V is C = N-NHPh can be reduced to a compound of formula II by reaction with zinc and acetic acid. This reaction can be carried out at a temperature in the range of 0 to 50 ° C.

Compounds of formula X in which V is CHN may be prepared from compounds of formula X in which V is CH ₂ by treatment with a strong base such as sodium hydride or potassium tert-butoxide and then with triisopropylbenzenesulfonyl azide. The reaction is readily carried out in a solvent such as an ether such as tetrahydrofuran at a temperature in the range of -78 to 20 ° C.

Compounds of formula X wherein V is C = NHPh may be obtained by reacting an orthophenylenediamine of formula XI with a diacid chloride of formula XII in a suitable solvent, for example in an ether such as tetrahydrofuran.

conA ²

CH.

I ·

C10 <

CIO

NNHPh (XII)

I

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

(XIII)

Compounds of formula XI are known or possible compounds

J can be prepared by procedures analogous to known procedures. For example, a compound of formula XI can be prepared by alkylating an amine of formula XIV

(Xiv)

Alternatively, the amine of formula (XIV) is reacted with a compound of formula ( ^1), ( ²⁾ or ( ₂₎ , wherein Z is chlorine or bromine.

optionally in the presence of sodium iodide in a solvent such as N, N-dimethylformamide.

The compounds of formulas (III), (IV), (V) and (VI) are known compounds or can be prepared by methods used to produce known compounds.

Procedure D

According to a further procedure (D) of formula (I), a compound of formula (XV) may be prepared with a compound

NHCONHR ⁴ (XV) wherein R * ³ represents a hydrogen atom, by reacting an activated derivative of this compound with an amine of general formula RR NH.

The reaction proceeds well using an acid in the presence of a diimide such as dicyclohexylcarbodiimide and hydroxy19 benzotriazole in a solvent such as dichloromethane or in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone in a solvent such as dimethoxyethane.

The compounds of formula XV, wherein R ³ is H, Sj ^e may be prepared by hydrolysis of a corresponding compound of formula XV, wherein R ^D is t-butyl, for example by treatment with trifluoroacetic acid. A compound of formula XV in which R &lt; ¹ &gt; is tert-butyl can be prepared by alkylation of the corresponding compound of formula IX with a halogenated ester of formula Z-C1-C4-Rb in which. means an atom by preparing a halogen compound. In an alternative embodiment tokens of formula XV, wherein R is tert-butyl ^the general procedures A and B described above for the preparation of compounds of formula I, but starting from the appropriate N-substituted benzodiazepine derivative.

Procedure E

According to another general procedure E, a compound of formula I can be converted to another compound of formula I by conventional means.

Compounds of formula I wherein R ⁴ is phenyl substituted by carboxyl or carboxymethyl may be prepared by hydrolysis of the corresponding compound of formula I wherein R ⁴ is phenyl substituted by alkoxycarbonyl or alkoxycarbonylmethyl.

Compounds of formula IX may be prepared from a diamine of formula XIV in which the primary amino group is protected as a p-methoxybenzyl derivative using the general procedures described above for the preparation of compounds of formula I from the corresponding orthophenylenediamine of formula XI followed by removal of the N-protecting group (p-methoxybenzyl group) using conventional procedures.

The compounds of formula I contain at least one asymmetric carbon atom, in particular a carbon atom of the diazepine ring to which the substituted urea group is attached. Specific enantiomers of compounds of Formula I may be prepared by resolution of the racemic compound using conventional procedures such as chiral HPLC. However, the desired enantiomer may also be prepared from the corresponding enantiomeric amine of formula II using any of the procedures described above for the preparation of compounds of formula I from the amine of formula II. The enantiomers of the amine of formula II may be prepared from the racemic amine of formula II using conventional procedures, for example by salt formation with a suitable optically active acid, for example R-camphorsulfonic acid, or by preparative HPLC HPLC in chiral form.

The following examples illustrate the invention without limiting the scope of the invention in any way.

In describing the intermediates and the resulting compounds, the melting points were determined on a Gallenkamp melting point apparatus and are reported without correction. All temperature data are given in degrees Celsius. Column chromatography was performed using silica gel. Thin layer chromatography t.l.c. was also carried out on silica plates. When the solutions were dried, the solutions were dried over anhydrous sodium sulfate.

The following abbreviations are used throughout the exemplary application:

and

EA = ethyl acetate,

DMF = N, N-dimethylformamide,

THF = tetrahydrofuran,

DE = diethyl ether,

DCM = dichloromethane,

MeOH = methanol,

AcOH = acetic acid, ee = excess of one of the enantiomers,

Ry = retention time

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1

Cyclohexyl- (2-nitro-phenyl) -amine

A mixture of 20 g of 2-chloronitrobenzene, 35 g of potassium carbonate and 1.21 g of copper iodide in 43.6 ml of cyclohexylamine is heated at 150 DEG C. for 18 hours under nitrogen. The mixture was allowed to cool to room temperature and purified by chromatography on silica eluting with hexane / ethyl acetate (98: 2) to give the title compound as an orange solid (22.94 g).

T.l.c. (98: 2, hexane / EA) = 0.38.

Intermediate 2

N-cyclohexyl-benzene-1,2-diamine

In the presence of 1 g of 10% palladium on charcoal, a solution of 10 g of intermediate 1 in 400 ml of ethyl acetate at 23 DEG C. is hydrogenated at 0.1 MPa. The catalyst is removed by filtration through hyflo and the filtrate is evaporated to give 8.5 g of an orange oil. of the title compound.

TLC (9: 1, hexane / ethyl acetate) _Rf = 0.36.

Intermediate 3

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

The mixture was stirred under nitrogen at 23 ° C for 18 hours

8.5 g of intermediate 2, 9.4 g of 2-oxo-2- (pyrrolidin-1-yl) ethyl bromide and 18.5 g of potassium carbonate in 250 ml of anhydrous N, N-dimethylformamide. The mixture is poured into 600 ml of water and extracted three times with 300 ml of ethyl acetate. The combined extracts were washed three times with 300 ml of water, 200 ml of saturated sodium chloride solution, dried and evaporated to give a brown oil which was purified by chromatography eluting with hexane: ethyl acetate 1: 1 to give 9.8 g of a beige solid. mp 108-110 ° C.

T.l.c. (1: 1, hexane / EA) = 0.42.

Intermediate 4 1-Cyclohexyl-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -3- (phenylhydrazone) -1,5-dihydrobenzo [b] [1,4] diazepine-2,4-dione

A solution of 9.8 g of intermediate 3 in 75 ml of anhydrous tetrahydrofuran and 8.36 g of 2- (phenylhydrazone) propanedioyl dichloride in 75 ml of anhydrous tetrahydrofuran was added under nitrogen to 5 ml of anhydrous tetrahydrofuran. After completion of the reaction, the mixture was allowed to warm to room temperature and stirred for three hours. The solvent was removed by evaporation to give 19.5 g of a yellow, brittle foam of the crude title compound.

T.l.c. (DE) _Rf = 0.23.

Intermediate 5

3-amino-l-cyclohexyl-5- (2-oxo-2-pyrrolidin-l-yl-ethyl) -1,5dihydrobenzo [b] [1,4] diazepine-2,4-dione

To a stirred suspension of 15 g of zinc powder in glacial acetic acid was added dropwise a solution of 19 g of intermediate 4 in 200 ml of glacial acetic acid. The resulting mixture was stirred

After stirring at 23 ° C for 1.5 hours, the zinc was removed by filtration through hyflo and the filtrate was evaporated to give a red oil. After partitioning the oil into 200 ml of water and 75 ml of ethyl acetate, the aqueous portion was brought to pH 9 by addition of solid sodium carbonate and extracted four times with 100 ml of ethyl acetate. The combined organic extracts were dried and evaporated to give a brown oil. Chromatography eluting with dichloromethane: methanol (95: 5) gave the title compound as a pink crisp foam (7.4 g).

T.l.c. (2: 1, EA / hexane) Rf = 0.17.

I.R. (solution in chloroform) 3384, 2939, 1690, 1658, 1423 cm -1.

Intermediate 6 3- (3- [1-Cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-17H-benzoic acid benzyl ester) [b] [1,4] diazepin-3-yl] ureido) benzoic acid

To a solution of 177 mg of 3-aminobenzoic acid benzyl ester in 10 ml of anhydrous tetrahydrofuran under nitrogen at 0 ° C was gradually added 108 μΐ of triethylamine and 77 mg of triphosgene. After an additional 108 μ 108 of triethylamine was added, the reaction mixture was stirred at 0 ° C for 30 minutes and then a solution of 250 mg of intermediate 5 in 10 ml of anhydrous tetrahydrofuran was added. The mixture was stirred at 23 ° C for 18 hours and then partitioned between 50 mL of 2M hydrochloric acid and 50 mL of ethyl acetate. The dried organic extract was evaporated and the residue was purified by chromatography eluting with ethyl acetate / hexane (2: 1) to give the title compound as a pale yellow solid (320 mg).

TLC (97: 3, DCM / MeOH) _Rf = 0.66.

Intermediate 7 3-Nitrobenzoic acid tert-butyl ester

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

TLC (97: 3, DCM / MeOH) _Rf = 0.66.

Intermediate 8 3-Aminobenzoic acid tert-butyl ester

A solution of 1 g of intermediate 7 in 20 ml of ethanol is hydrogenated in the presence of 200 mg of 10% palladium on charcoal at 23 ° C and at a pressure of 1 bar. After 2 hours the mixture was filtered through hyflo and the filtrate was evaporated. The resulting residue was purified by chromatography eluting with a 97: 3 mixture of dichloromethane and methanol to give 727 mg of the title compound as a colorless oil.

TLC (97: 3, DCM / MeOH) _Rf = 0.35.

Intermediate 9 (3-Nitrophenyl) acetic acid benzyl ester

A mixture of 5 g of 3-nitrophenylacetic acid, 2.9 ml of benzyl alcohol and 300 ml of 4,4-dimethylaminopyridine in 50 ml of anhydrous dichloromethane is treated with 7.4 g of 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide. The resulting yellow reaction mixture was stirred at 23 ° C for 3 days. After removal of the solvent in vacuo, the residue is partitioned between 100 ml of water and 100 ml of ethyl acetate, and the organic layer is washed twice with 100 ml of water and 100 ml of saturated sodium chloride solution, dried, evaporated and purified by chromatography eluting with hexane. ethyl acetate 4: 1. Elution with 1: 1 isohexane / dichloromethane gave 2.05 g of the title compound as a pale yellow oil.

T.l.c. (4: 1, hexane / EA) = 0.35.

Intermediate 10 (3-Aminophenyl) octanoic acid benzyl ester

A solution of 2.5 g of intermediate 9 in 100 ml of ethyl acetate is hydrogenated in the presence of 200 ml of 5% platinum on activated carbon at 23 ° C and at a pressure of 1 bar. 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

A mixture of 5.0 g of 2-fluoroaniline, 2.5 g of potassium carbonate and 414 mg of copper iodide in 16.9 ml of 2-fluoronitrobenzene was heated at 180 ° C under nitrogen for 18 hours. The cooled mixture was poured into 300 ml of water and extracted twice with 250 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and evaporated. The resulting brown oil was azeotroped with ethanol-water and then toluene. The resulting residue was purified by chromatography eluting with hexane / diethyl ether (100: 0 to 95: 5) to give the title compound as a pale orange solid (3.25 g), m.p. 58-59 ° C.

T.l.c. (95: 5, hexane / DE), Rf = 0.45.

Intermediate 12

N- (2-fluorophenyl) benzene-1,2-diamine

A solution of 15.6 g of intermediate 11 in 400 ml of ethyl acetate is hydrogenated in the presence of 2 g of 5% platinum on activated carbon at 23 ° C and at a pressure of 1 bar. After 1 h, the mixture was filtered through hyflo and the filtrate was evaporated to give 13.45 g of the title compound as a yellow solid.

T.l.c. (9: 1, hexane / DE) Rf 0.25.

Intermediate 13 '

N- [2- (2-fluoro-phenylamino) phenylamino] -1-pyrrolidin-l-yl-ethanone

12.8 g of 2-oxo-2- (pyrrolidin-1-yl) ethyl bromide in 60 ml of dimethylformamide are added dropwise to a mixture of 13.45 g of intermediate 12 and 27.5 g of potassium carbonate in 100 ml of dimethylformamide under nitrogen at 23 ° C. . The mixture was stirred at 60 ° C for 4 hours and then poured into 500 ml of 2 N sodium carbonate solution. After extraction with 400 ml of ethyl acetate, the extracts are washed twice with 250 ml of water and 250 ml of saturated sodium chloride solution, dried and evaporated. The resulting residue was purified by chromatography eluting with 50:50 to 0: 100 hexane / diethyl ether to give the title compound (14.12 g) as a pale brown solid.

T.l.c. (DE) _Rf = 0.53.

Intermediate 14

1- (2-Fluorophenyl) -5- (2-oxo-2-pyrrolidin-1-yl-ethyl) -3- (phenylhydrazone) -1,5-dihydrobenzo [b] [1,4] diazepine-2,4 -dione

A solution of 14.12 g of intermediate 13 in 100 ml of anhydrous tetrahydrofuran and 11.04 g of 2- (phenylhydrazone) propanedioyl dichloride in 100 ml of anhydrous tetrahydrofuran was added dropwise simultaneously in equal amounts at -10 ° C under nitrogen to 100 ml of anhydrous tetrahydrofuran. After completion of the reaction, the mixture was allowed to warm to room temperature and stirred for 3.5 hours. The solvent was removed to give 23 g of a yellow, brittle foam of the title compound.

T.l.c. (EA) _Rf 0.5.

Intermediate 15

3-Amino-1- (2-fluorophenyl) -5- (2-oxo-2-pyrrolidin-l-yl-ethyl) -1,5dihydrobenzo [b] [1,4] diazepine-2,4-dione

To a stirred suspension of 22.2 g of zinc powder in 100 ml of glacial acetic acid was added dropwise a solution of 23 g of intermediate 14 in 200 ml of glacial acetic acid in a cold water bath. The mixture was stirred for 2.5 hours at tep27 Lote 23 ^e C and the zinc was removed by filtration through hyflo and the filtrate evaporated. After partitioning the residue into 150 ml of water and 100 ml of ethyl acetate, the aqueous portion is brought to basic pH by addition of solid sodium carbonate. Separate the portions and extract the aqueous portion with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried and evaporated. Subsequent chromatography with initial elution with ethyl acetate / methanol (100: 0 to 95: 5) followed by elution with dichloromethane / methanol (80:20) gave 11.07 g of the title compound as a pale brown powder.

TLC (95: 5 DCM / MeOH) _Rf = 0.23.

Intermediate 16 3- (3- [1- (2-Fluorophenyl) -2,4-dioxo-5 (2-oxo-2-pyrrolidin-1-yl-ethyl) -2,3,4,5-tetrahydro-benzyl ester) (1H-benzo [b] [1,4] diazepin-3-yl] ureido) phenyl) acetic acid

To a stirred solution of 60 ml of phosgene in toluene was added dropwise a solution of 3 g of intermediate 15 in 40 ml of anhydrous dichloromethane under nitrogen. The resulting mixture was stirred at 23 ° C for 4 hours and then purged with nitrogen for 18 hours. The mixture was evaporated and the residue was dried under vacuum at 60 ° C for 3 hours to give 3.3 g of the intermediate isocyanate as a pale yellow solid. To a stirred solution of 241 mg of (3-aminophenyl) acetic acid benzyl ester in 2 mL of anhydrous dichloromethane under nitrogen at 23 ° C was added dropwise a solution of 400 mg of the intermediate isocyanate in 3 mL of anhydrous dichloromethane. After 60 minutes, the solvent was removed in vacuo and the residue was triturated with diethyl ether. The solid was collected by filtration to give the title compound as an off-white solid (263 mg), mp 104-106 ° C.

T.l.c. (EA) _Rf = 0.54.

Intermediate 17

2-bromo-l- (3,3-dimethyl-1-yl) ethanone

To an ice-cooled solution of 7.7 ml of bromoacetyl bromide in 100 ml of anhydrous dichloromethane is added dropwise a mixture of 10 g of 3,3-dimethylpiperidine and 12.3 ml of triethylamine in 50 ml of anhydrous dichloromethane. The mixture was stirred at 23 ° C for 18 hours and then re-cooled to 0 ° C. After adding 200 ml of ice-water, the aliquots were separated. The aqueous portion was extracted twice with 200 mL of dichloromethane and the combined extracts were washed with 200 mL of 2M hydrochloric acid and 200 mL of saturated sodium chloride solution. Drying and evaporation gave the title compound (17.28 g) as a brown oil.

T.l.c. (DE) _Rf = 0.49.

Intermediate 18

1- (3,3-dimethyl-1-yl) -2- [2- (2-fluoro-phenylamino) phenylamino] -ethanone

A mixture of 3 g of intermediate 12 and 6.15 g of potassium carbonate in 10 ml of anhydrous dimethylformamide is treated with a solution of 3.5 g of 2-bromo-1- (3,3-dimethylpiperidin-1-yl) -ethanone in 10 ml of anhydrous dimethylformamide. The resulting reaction mixture was stirred at 23 ° C under nitrogen for 3 days. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried and evaporated to give a brown oil. Chromatography eluting with dichloromethane: methanol (100: 0 to 97: 3) gave the title compound as a light yellow foam (3.17 g).

TLC (DCM) _Rf = 0.23.

I

Intermediate 19

1- [2- (3,3-dimethylpiperidin-1-yl) -2-oxoethyl] -5- (2-fluoro-29-phenyl) -3- (phenylhydrazone) -1,5-dihydrobenzo [b] [1,4] diazepin2,4-dione

To 50 ml of anhydrous tetrahydrofuran cooled to -10 ° C are added in equal portions under nitrogen a solution of 3.08 g of intermediate 18 in 100 ml of anhydrous tetrahydrofuran and 2.12 g of 2- (phenylhydrazone) propanedioyl dichloride in 100 ml of anhydrous tetrahydrofuran. After completion of the reaction, the mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was removed by evaporation to give 5.25 g of the crude title compound as a yellow brittle foam.

TLC (95: 5 DCM / MeOH) _Rf = 0.68.

ííedziprodukt 20

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

To a stirred suspension of 4.47 g of zinc powder in 50 ml of glacial acetic acid was added dropwise a solution of 5.15 g of intermediate 19 in 75 ml of glacial acetic acid in a cold water bath. The resulting mixture was stirred at 23 ° C for 6 hours and then the zinc was removed by filtration through hyflo and the filtrate was evaporated. After partitioning the residue into water and ethyl acetate, the aqueous portion was brought to basic pH by addition of solid sodium carbonate. The organic extract was washed with saturated sodium chloride solution, dried and evaporated. Subsequent chromatography, eluting with dichloromethane: methanol (95: 5) gave 2.38 g of the title compound as a pale brown solid.

TLC (95: 5 DCM / MeOH) _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-tert-butyl ester , 5-tetrahydro-1 H -benzo [b] [1,4] diazepin-3-yl] ureido) benzoate

To a solution of 423 mg of 3-aminobenzoic acid tert-butyl ester in 10 ml of anhydrous tetrahydrofuran is added successively 0.31 ml of triethylamine and 217 mg of triphosgene under nitrogen at 0 ° C. After an additional 0.31 ml of triethylamine was added, the reaction mixture was stirred at 0 ° C for 30 minutes, then a solution of 800 mg of intermediate 20 and 10 ml of anhydrous tetrahydrofuran was added. The mixture was stirred at 23 ° C for 18 hours and partitioned between phosphate buffer (pH 6.5) and dichloromethane. The combined organic extracts were washed with saturated sodium chloride solution, dried and evaporated. The residue was purified by chromatography eluting with 97: 3 dichloromethane: methanol to give a light green solid which was triturated with 1: 1 diethyl ether: hexane to give the title compound as a white solid (1.07 g, m.p. 170 °). C.

TLC (97: 3, DCM / MeOH) _Rf = 0.15.

Example 1

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

To a solution of 2 g of intermediate 5 in 50 ml of anhydrous dichloromethane under nitrogen at 23 ° C is added 650 μΐ

4-fluorophenyl isocyanate. The resulting mixture was stirred for 1 hour and purified by chromatography on silica eluting with a 100: 0 to 95: 5 mixture of ethyl acetate and methanol. 1.92 g of white solid are obtained, m.p. 181-183 ° C.

T.l.c. (EA) _Rf 0.42.

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

Column: Chiralcel OD 25 cm x 20 mm id.

Elution: 70:30 hexane / ethanol. Flow rate: 20 ml / min.

Detection: UV, = 254 nm.

Isomer 1: 452 mg white solid, retention time 8.6 min, HPLC greater than 99.5% ee. TLC (ethyl acetate) _Rf = 0.42.

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

Isomer 2: 488 mg white solid, retention time 15.1 min, HPLC greater than 98.8% ee. TLC (ethyl acetate) Rf = 0.42.

Ir (potassium bromide, disc) 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-ylethyl) 2,3,4,5-tetrahydro-1 H -benzo [b] [1, 4] diazepin-3-yl] -ureido) benzoic acid

In the presence of 25 mg of 10% palladium on charcoal, a solution of 248 mg of intermediate 6 in 10 ml of ethyl acetate and 5 ml of tetrahydrofuran is hydrogenated overnight at 23 ° C and at 1 bar. After an additional 25 mg of catalyst was added, hydrogenation was continued for 2 hours. The mixture was filtered through hyflo and the filtrate was evaporated to give 216 mg of the title compound as a white solid, mp 275-276 ° C (100: 2, EA / AcOH), R _f = 0.25.

Ir (KBr disc) 3369, 2035, 1700, 1659, 1557, 1499, 1431, 1233, 760 cm ^-1 .

Example 3 (3- (3- (1- (2-fluorophenyl) -2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-ylethyl)) -2,3,4,5-tetrahydro-1 H) benzo [b] [1,4] diazepin-3-yl] ureido) phenyl) acetic acid

In the presence of 10 mg of 10% palladium on charcoal, the solution is hydrogenated at 23 ° C and 1 bar.

177 mg of intermediate 6 in 10 ml of tetrahydrofuran. 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, mp 197-199 ° C.

T.l.c. (EA) _Rf 0.17.

IR (KBr disc) 3331, 1708, 1651, 1562, 1499, 1454, 1403, 1238, 761 cm &lt; ^{-1 &gt};.

Example 4

3- (3- [l- [2- (3,3-dimethyl-1-yl) -2-oxo-ethyl] -5- (2-fluorophenyl) -2,4-dioxo-2,3,4,5-tetrahydro- 1H-benzo [b] [1,4] diazepin-3-yl] ureido) benzoic acid

A solution of 400 mg of intermediate 21 in 20 ml of dichloromethane was treated with 2 ml of trifluoroacetic acid at 23 ° C under nitrogen for 1 hour. The mixture was concentrated in vacuo and the residue was purified by chromatography eluting with dichloromethane: methanol (95: 5) to give the title compound as a white solid (344 mg), mp 225 ° C dec.

TLC (95: 5 DCM / MeOH) _Rf = 0.26.

The following compounds of the present invention are prepared according to general procedures A, B, C and D.

Table 1

Por.číslo X

R ⁵

mp approach

5 H 3,5-diCH ₃ 254-5 ° A 6 H 4-OCH ₃ 180-2 ° A 7 H 3-F 188-90 ° A 8 H 3-NO ₂ 173-5 ° A 9 H _3-CH2 CN 210-2 ° A 10 H H 216-8 °  A 11 H 3-CONH ₂ 275-7 ° A 12 H 3-N (CH ₃ ) ₂ 251-3 ° A 13 br 4-F ‘Rf 0.3 D L C. cyclohexane EA / AcOH 1: 1: 0.0.4

Table 2

Por.číslo R ³ R ⁵ mp approach 14 ph 3-tetrazolyl 243 ° A 15 ph _3-CH3 234-6 ° A 16 ph 3-CONHSO ₂ CH ₃ 199-200 B 17 2-F-Ph 4-F 155-7 ° A 18 2F-Ph _3-CH3 195-7 ° A 19 2F-Ph 3-CO ₂ H -225-7 ° B

- 34 Table 3

NR R. ²

I

WHAT

por.číslo

NR ^X R ²

N

\ _

240 °

N

170 °

N /

n

260 °

220-5 ° dec

255-8 ° \

approach

A!

A

A

C

D

I

Examples of pharmaceutical compositions

tablets

tablets

Mixture a

active ingredient 50 mg anhydrous lactose USP 163 mg microcrystalline cellulose NF 69 mg gelatinized starch Ph.Eur. 15 mg magnesium stearate USP 3 mg weight after pressing 300 mg

The active ingredient, microcrystalline cellulose, lactose and pre-gelatinized starch are sieved through a 500 micron sieve and blended in a suitable machine. The magnesium stearate is passed through a sieve with a 250 micron mesh diameter and blended with the above mixture. The resulting mixture is then compressed into tablets using suitable punches.

Mixture b Active ingredient 50 mg Lactose monohydrate USP 120 mg Gelatinized starch Ph.Eur. 20 mg cross-linked polyvinylpyrrolidone NF 8 mg magnesium stearate USP 2 mg compression weight 200 mg

The active ingredient, lactose and added gelatinized starch are mixed and the mixture is granulated using water. The wet mass is dried and ground. The magnesium stearate and cross-linked polyvinylpyrrolidone are passed through a sieve with a 250 micron mesh diameter and added to the granulate. The resulting mixture is compressed into tablets using suitable punches.

The capsules

Mixture a active ingredient 50 mg gelatinized starch Ph.Eur. 148 mg magnesium stearate USP 2 mg filling weight 200 mg

The active ingredient and the pregelatinized starch are passed through a 500 micron sieve, mixed thoroughly and magnesium stearate passed through a 250 micron sieve is added as a glidant. The resulting mixture is then filled into hard gelatine capsules of appropriate size.

active ingredient 50 mg lactose monohydrate USP 223 mg polyvinylpyrrolidone USP 12 mg cross-linked polyvinylpyrrolidone NF 12 mg magnesium stearate 3 mg filling weight 300 mg

The active ingredient and lactose are mixed and the mixture is granulated after wetting with a polyvinylpyrrolidone solution. The resulting wet mixture is dried and then ground. The magnesium stearate and cross-linked polyvinylpyrrolidone are passed through a sieve with a 250 micron mesh diameter and then added to the granulate. The resulting mixture is then filled into hard gelatin capsules of appropriate size.

Affinity of CCK-B receptor binding

CUK-B receptor binding assays were performed using HeLa cell membranes previously subjected to stable transfection with the human CCK-B receptor cloned from the sleep cortex cDNA bank.

Measurement of binding affinity for CCK-B

The transfected HeLa cell membranes were incubated with 30 µM 125 µL of BH-sCCK-8 in the presence of various concentrations of the test compound in the range of 1 µM to 1 µmol. All experiments were performed in a volume of 250 microns. The membrane material was transferred to GF / C glass fiber filter paper (Vhatman, UK) by rapid filtration using a cell separator (Brandel model M-24R) and then washed three times with HEPES buffer cooled to 4 ° C. The amount of radioactivity retained on the individual rolls of filter paper was counted for 60 seconds using a gamma counter (Mini Gamma Counter, LKB, Valiac, Finland) with an efficiency of 77%. A control experiment was also carried out in the absence of the test substance.

Analysis of the obtained values was performed using nonlinear computer regression (ALLFIT programs DeLean et al., 1978). IC 50 values for the test substances were converted to K 50 values using the Cheng and Prussof equations, K 4 = IC ₃ q [(1+ | L |] K i), (Cheng and Prussof, 1973). The following table shows the results for representative compounds of the invention, expressed as pK 2.

Affinity of binding to CCK-A receptor

CCK-A receptor binding assays were performed using COS-M6 cell membranes after transient transfection of these CCK-A receptor bile cells from human gall bladder.

The clone was used to transiently transfect COS-M6 cells grown to form an 80% continuous layer using the dimethylaminoethyldextran method of Seed and Araffo, Proc. Natl. Acad. Sci., USA 84, 3365, 1987. The desired membranes are then isolated from the cells after transfection by the conventional method. ¹

The affinity of the compounds of the invention for the CCK-A receptor was determined as described above to determine the affinity for the CCK-B receptor, but in these experiments the compounds used were used at concentrations of 10 µM to 10 µM.

CCK-B Binding Assay of Example p _Ki

1 8.5 1 (isomer 1) 8.5 1 (isomer 2) 8.1 2 8.7 3 8.4 4 8.8 7 8.3 8 8.6 10 8.4 12 9.0 14 8.5 15 8.8 20 8.7

The compounds of the invention are substantially non-toxic using therapeutic effective doses. When isomer 1 of the compound of Example 1 was administered to rats with gastric whistles at 0.3 and 1 mg / kg intravenously, there was a substantial inhibition of gastric secretion, but no adverse effects were observed at these doses.

I

Claims (9)

PATENT CLAIMS 1. 1,5-Benzodiazepine derivatives of the general formula I σοΝΕ ¹ ^ ² (I) and their physiologically acceptable salts, in which '10 NR ^A R represents a saturated 5- to 7-membered heterocyclic ring, optionally substituted with one or two methyl groups, Q R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl, optionally substituted with one or two halogen atoms, R 1 is phenyl, optionally substituted with one or two groups selected from halogen, C 1 -C 4 alkyl, trifluoromethyl, trifluoromethoxy or (CH ₂ ) _n R 6, where n is 0 or 1 and R 6 is C1-C4alkoxy, hydroxy, nitro, cyano, CO ₂ R 4, S (O) CH 4, NR ² R ®, CONR ² R ®, SO ₂ NR CO-alkyl of 1 to 4 carbon atoms in the alkyl moiety, tetrazolyl, carboxamidotetrazolyl or The 1,5-benzodiazepine derivative according to claim 1, wherein the -NR 1 R 3 represents a pyrrolidine, 2,5-dimethylpyrrolidine, piperidine, 3,3-dimethylpiperidine, 4,4-dimethylpiperidine or 2,6-dimethylpiperidine group. 3-yl] -3- (4-fluorophenyl) urea and its enantiomers. 9. A compound according to claim 1 selected from the group consisting of: 3- (3- [1-cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-yl) -yl) -2 (3,4,5-tetrahydro-1 H -benzo [b] [1,4] diazepin-3-yl] ureido) benzoic acid (3- (3- [1- (2-fluorophenyl) -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) phenyl) acetic acid 3- (3- [1- [2- (3,3-dimethylpiperidin-1-yl) -2-oxoethyl] 5- (2-fluorophenyl) -2,4-dioxo-2 3,4,5-tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl] ureido) benzoic acid, as well as the enantiomers of these compounds. The 1,5-benzodiazepine derivatives according to any one of claims 1 to 9 for use in therapy. Use of the 1,5-benzodiazepine derivatives according to any one of claims 1 to 9 for the manufacture of pharmaceutical compositions for the treatment of conditions in which the effects of gastrin and / or CCK need to be modified, Pharmaceutical composition, characterized in that it comprises as its active ingredient a 1,5-benzodiazepine derivative according to any one of claims 1 to 9 in admixture with a physiologically acceptable carrier or excipient. A process for the preparation of the 1,5-benzodiazepine derivatives of the general formula I according to claim 1, characterized in that it is: a) reacting a compound of formula II wherein R ¹ , R ² , R 6, X and n are as defined in formula I with a compound of formula R ⁴ Y from isocyanate III, carbamoyl chloride IV, imidazolide V or phenylcarbamate of formula VI (III) C1CONHŔ. ⁴ (IV) (A) R ^and CONHR ⁴ (VI) wherein R ^a R ⁴ is phenoxy which is optionally substituted and is as defined in formula II, B) reacting a compound of formula VII (VII) wherein wherein R, R, R, X and m are as defined in formula I and Y is NCO, NHCOCl or NHCOR ^a , wherein R ^a is phenoxy optionally substituted or an imidazole group, with an amine of formula VIII r ⁴ nh ₂ (VIII) wherein R ⁴ is as defined in formula I, c) reacting a compound of formula IX wherein R ³ , R ⁴ , X and m are as defined in formula I, (ix) with a compound of formula R ² R ¹ NCOCH ₂ Z in which Z is a leaving group or d) reacting an activated derivative of a compound of formula XV (xv) wherein R ³ , R ^b R1, X and m have the meanings given in formula (I) and hydrogen, 3-carboxymethylphenyl or 3- (1H) -tetrazol-5-ylphenyl. The compound according to claim 1 or 2, wherein -NR ^X R is a pyrrolidine group. 3-trifluoromethyl-1,2,4-triazolyl, R @ 1 is hydrogen, C1 -C4 alkyl or benzyl; R represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms, ABOUT R represents a hydrogen atom, an alkyl of 1 to 4 carbon atoms, SO4H4 or SO4F4, X is hydrogen, alkyl of 1 to 4 carbon atoms or halogen, m is 0, 1 or 2 and p is 0, 1 or 2. 4-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl, 3-carboxamidophenyl, 3-carboxyphenyl, 4. 1,5-Benzodiazepine derivatives of the general formula a A compound according to any one of claims 1 to 3, wherein R 1 is phenyl, 2-fluorophenyl or cyclohexyl. 5. 1,5-Benzodiazepine derivatives of the general formula a I, as claimed in any one of claims 1 to 4, wherein R ^is cyclohexyl. 6. 1,5-Benzodiazepine derivatives of the general formula A compound according to any one of claims 1 to 5, wherein R 1 is phenyl, 3-methylphenyl, 3,5-dimethylphenyl, 3-dimethylaminophenyl, A compound according to any one of claims 1 to 6, wherein R 1 is phenyl, 4-fluorophenyl, 3-dimethylaminophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or 3- (1 H) -tetrazole-5. ylphenyl. I A compound of formula I according to claim 1, 1- [1-cyclohexyl-2,4-dioxo-5- (2-oxo-2-pyrrolidin-1-ylethyl) -2,3,4, 5-tetrahydro-lH-benzo [b] [1,4] diazepin41 9 with an amine of the formula R R NH, then optionally before or after resolution into the stereochemical isomers, a compound of the formula I is converted into another compound of the formula I. about