HRP940330A2 - Amine derivatives - Google Patents

Description

This invention relates to new amine derivatives, processes for their preparation, pharmaceutical preparations containing them and their use in medicine.

The invention particularly relates to 5-aminoalkyl-1,4-benzodiazepine derivatives, which regulate the action of gastrin and/or cholecystokinin (CCK) in mammals.

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

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and their physiologically acceptable salts; where R1 represents CH2CONR5R6 or CH2COR7;

R2 represents a phenyl group, optionally substituted with 1 or 2 substituents selected from halogen, alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, substituted amine, hydroxy, alkoxy, methylenedioxy, alkoxycarbonyl, oxazolyl or oxadiazolyl;

A represents a C1-4 straight or branched alkylene chain;

R3 and R4 independently represent hydrogen or alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a saturated 5-7-membered heterocyclic ring, which ring may contain an additional heteroatom selected from oxygen, sulfur or nitrogen;

R5 represents hydrogen or C1-4 alkyl;

R6 represents (C1-4 alkyl or phenyl, optionally substituted with halogen, or R5 and R6, together with the nitrogen atom to which they are connected, represent a saturated 5 to 7-membered heterocyclic ring, which can optionally be substituted with 1 or 2 methyl groups or fused to a benzene ring;

R7 represents a group selected from alkyl, or optionally substituted phenyl;

R8 represents a hydrogen or halogen atom;

n is zero, 1 or 2.

It is recommended that the compounds of formula (I) contain at least one asymmetric carbon atom (ie the carbon atom occupying position 3 of the diazepine ring), so that the compounds according to the invention include all stereoisomers and their mixtures, including racemates.

In the compounds of formula (I), the term alkyl as a group or part of a group represents a straight or branched chain alkyl group containing 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In the definition of the compound of formula (I), halogen may represent a fluorine, chlorine, bromine or iodine substituent.

When R 7 represents C 1-4 alkyl, examples of suitable groups include t-butyl.

When R 7 is optionally substituted phenyl, examples of suitable groups include phenyl or phenyl substituted with a methyl group, eg 2-methylphenyl.

When NR5R6 represents a saturated 5- to 7-membered heterocyclic ring, it can be for example pyrrolidino, piperidino or hexamethyleneimino which rings can be substituted with one or two methyl groups, such as 2,5-dimethyl pyrrolidino, 3,3-dimethylpyrrolidino, 3,3-dimethylpiperidino or 4,4-dimethylpiperidino.

When NR 5 R 6 represents a saturated heterocyclic ring fused to a benzene ring, it may, for example, be a group selected from:

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When NR3R4 represents a 5- to 7-membered saturated heterocyclic ring, it can for example be pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino or their oxides, piperazino or its N-substituted derivative, e.g. N-methyl piperazino or N-alkoxycarbonyl piperazino .

When R 3 and R 4 represent C 1-4 alkyl, examples of suitable groups include methyl, ethyl, isopropyl, propyl or n-butyl.

The alkylene chain A in the compounds of formula (I) is mainly a straight-chain alkylene such as methylene, ethylene, propylene or butylene.

When R 8 represents halogen, examples of suitable groups include chlorine or fluorine.

The term oxazolyl refers to a 1,3-oxazolyl group that is attached to the rest of the molecule via a carbon atom at position 2 or 5.

The term oxadiazolyl refers to a 1,2,4-oxadiazolyl group that is attached to the rest of the molecule via a carbon atom at position 3 or 5.

In the compounds of formula (I), the term substituted amino denotes C1-4 alkylamino (e.g. isopropylamino, diC1-4 alkylamino, e.g. dimethylamino, C1-4 alkanoylamino or alkoxycarbonylamino, e.g. t-butoxycarbonylamino.

When R 2 is phenyl containing one substituent, it is preferably in the meta or para position.

Preferred classes of compounds of formula (I) include those in which R 1 represents the group CH 2 CONR 5 R 6 . Particularly recommended within this class are compounds in which R5 represents methyl or ethyl, and R6 represents phenyl or phenyl substituted with a halogen atom, such as 2-chlorophenyl or better 4-fluorophenyl; or NR 5 R 6 represents a saturated heterocyclic ring selected from pyrrolidino, 2,5-dimethylpyrrolidino, 3,3-dimethylpyrrolidino, piperidino, 3,3-dimethylpiperidino or 1-tetrahydroquinoline.

A further recommended class of compounds of formula (I) is that in which A represents a methylene or ethylene chain, especially a methylene chain.

Compounds of formula (I) where NR 3 R 4 represents a 5- to 7-membered saturated heterocyclic ring selected from pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino or N-methyl piperazino, represent a further recommended class of compounds of formula (I). From this class, the compounds in which NR3R4 is a morpholino are especially recommended.

A further preferred class of compounds of formula (I) are those in which the R 2 phenyl group is optionally substituted with one or two groups selected from halogen, eg fluorine; alkyl, eg methyl; alkoxy, eg methoxy; amino, cyano, hydroxyoxazoles, trifluoromethyl or 1,2,4-oxadiazol-3-yl. Of this class of compounds, those in which the R 2 phenyl group is substituted by fluorine, oxazol-5-yl or even better by methoxy are particularly recommended.

A further preferred class of compounds of formula (I) are those in which R 8 is fluorine or chlorine or, in particular, hydrogen.

A preferred group of compounds of formula (I) is one in which Ri is CH2CONR5R6, where R5 and R6 are as defined above, R8 is hydrogen, A and NR3R4 are as defined above, and R2 is a phenyl group optionally substituted with or two substituents selected from halogen, alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, substituted amino, hydroxy, alkoxy, methylenedioxy and alkoxycarbonyl.

A further preferred group of compounds of formula (I) is one in which it represents the group CH2CONR5R6, A represents a methylene chain, NR3R4 represents a saturated 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, sulfur and nitrogen. Particularly recommended within this group are compounds that include those in which R5 is methyl or ethyl and R6 is phenyl optionally substituted with fluorine or chlorine, or NR5R6 represents pyrrolidino, 2,5-dimethylpyrrolidino, 3,3-dimethylpyrrolidino, piperidino, 3, 3-dimethylpiperidino or 1-tetrahydroquinoline; R 2 is phenyl optionally substituted with one or two groups such as fluorine, methyl, methoxy, trifluoromethyl amino, cyano, hydroxy, oxazol-5-yl or 1,2,4-oxadiazol-3-yl and R 8 is hydrogen or R 8 represents fluorine or chlorine, and n is 1.

Particularly preferred compounds of the invention include:

2-{3-[3-3-methoxy-phenyl-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl} -N-methyl-N-phenyl-acetamide;

N-methyl-2-[5-morpholin-4-yl-methyl-2-oxo-3-(3-phenyl-ureido)-2,3-dihydro-benzo[e][1,4]diazepin-1 - yl]-N-phenylacetamide;

N-methyl-2-{5-morpholin-4-ylmethyl-2-oxo-3-[3-(3-trifluoromethyl-phenyl)-ureido]-2,3-dihydro-benzo[e][1,4] diazepine: 1-yl}-N-phenylacetamide;

2-{3-[3-(3-cyano-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1- yl}-N-methyl-N-phenyl-acetamide;

1-[5-(morpholin-4-yl-methyl)-2-oxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1-H-benzo[e ][1,4]diazepin-3-yl]-3-(3-oxazol-5-yl-phenyl)-urea;

N-ethyl-N-(4-fluoro-phenyl)-2-{3-[3-(4-fluoro-phenyl)-ureido-5-(morpholin-4-yl-methyl)-2-oxo-2, 3-dihydro-benzo[e][1,4]diazepin-1-yl}-acetamide;

and their enantiomers, and their physiologically acceptable salts.

Physiologically acceptable salts of the compounds of formula (I) include conventional salts obtained, for example, from pharmaceutically acceptable organic and inorganic acids, as well as quaternary ammonium acid addition salts. Examples of suitable salts include hydrochloric, hydrobromic, sulfate, phosphate, nitrate, perchloric, fumaric, acetate, propionate, succinic, glycolic, formic, lactic, malic, tartaric, citric, malonic, hydroxymaleic, phenylacetate, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic, etc. Other acids, such as oxalic, although not pharmaceutically acceptable in themselves, can be useful in the preparation of salts that are used as intermediates when obtaining the compounds according to the invention and their pharmaceutically acceptable salts.

In the following text, the reference to the compound according to the invention includes both the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

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

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

It was also shown that the compounds according to the invention are antagonists of CCK, and especially CCK-B receptors, which is manifested, for example, in the ability of the compounds to inhibit the contraction effects of CCK-4 in the presence of CCK-A antagonists, in the isolated longitudinal muscle-myenteric plexus of the intestine guinea pig.

Preparation and use of isolated longitudinal musculo-myenteric bundle of guinea pig intestine was described by K-H Buchheit et al. in Nauyn-Schmeideberg's Arch. Pharmacol., (1985), 329. p. 36-41 and V. L. Lucaites et al. (1991) in J. Pharmacol. Exp. Ther., 256, 695-703.

The affinity of the compound according to the invention for the CCK-B receptor was also determined using experiments on the guinea pig cortex as described by G. Dal Fornoto et al. in J. Pharmacol. Exp. Ther., 261, 1056-1063, 1992.

The compounds according to the invention are therefore useful in the treatment and/or prevention of disorders in mammals, especially humans, in which altering the effects of gastrin or CCK is of therapeutic benefit. Thus, the compounds according to the invention are useful in the treatment of gastrointestinal disorders, especially those in which it is desirable to reduce the acidity of the stomach. Such disorders include peptic ulceration, esophageal reflux, and Zollinger Ellison syndrome. They may also be useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome, increased pancreatic secretion, acute pancreatitis, impaired motility, antral G cell hyperplasia, mucosal hyperplasia, or gastrointestinal neoplasms. The compounds of the invention are also useful in the treatment of central nervous system disorders in which CCK and/or gastrin are involved. For example, fear states (including panic states, agoraphobia, sociophobia, simple phobia, obsessive compulsive neurosis, post-traumatic stress and general fear states), depression, dyskinesia, Parkinson's disease and psychoses. They can also be useful in the treatment of addiction and withdrawal from drugs and unwanted substances, Gilles de la Tourett syndrome or dysfunction of the appetite regulatory system; as well as for the treatment of certain types of tumors of the lower esophagus, stomach, small and large intestine. The compounds according to the invention are also used for directly inducing analgesia, enhancing analgesia induced by opiates or non-opiates, as well as in anesthesia or local anesthesia.

The invention therefore provides a compound of formula (I) or its pharmaceutically acceptable salts and solvates for use in therapy, especially human medicine.

According to another aspect, the invention provides for the use of a compound of formula (I) or its pharmaceutically acceptable salts and solvates for the production of drugs for the treatment of conditions in which a change in the effects of gastrin and/or CCK is of therapeutic benefit.

According to a further aspect of the invention, we provide a method for the treatment of mammals, including humans, particularly in the treatment of conditions in which alteration of the action of gastrin and/or CCK is of therapeutic benefit, which method comprises administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof .

It is recommended to experts that here the term treatment is extended to prophylaxis, as well as the treatment of already established diseases or symptoms.

It is further recommended that the amount of compound according to the invention required for use in treatment varies depending on the nature of the condition being treated, as well as the age and condition of the patient, which will ultimately be decided by the prescribing physician or veterinarian. However, in general the doses used in the treatment of adults will usually be in the range of 1-2000 mg per day, eg 10-500 mg per day.

The desired dose may be conventionally administered as a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

Compounds according to the invention which have an antagonistic effect on the action of CCK in animals can also be used as feed additives to increase food intake in animals at daily doses of about 1 mg/kg to 10 mg/kg.

Although it is possible that, for use in treatment, the compound of the invention is administered as a crude chemical, it is recommended that the active ingredient be provided as a pharmaceutical preparation.

The invention thus further provides a pharmaceutical preparation containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic admixtures. The carrier(s) must be "acceptable" in the sense that they are compatible with the other ingredients and not harmful to the person taking them.

Compositions according to the invention include those in the form specially prepared for oral, buccal, parenteral, injection or rectal administration. Oral administration is recommended.

Tablets and capsules for oral administration may contain common excipients such as binders, for example syrup, acacia, gelatin, sorbitol, starch glue or polyvinylpyrrolidone; fillers, for example lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica gel; disintegrants, for example potato starch or sodium starch glycolate, and wetting agents, for example sodium lauryl sulfate. The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, aqueous or oily suspensions, emulsions, syrups or elixirs, or may be given as a dry product which is reconstituted with water or other suitable vehicle prior to use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan, mono-oleate or acacia; non-aqueous binders (which may include edible oils), for example almond oil, fractionated coconut oil, oil esters, propylene glycol or ethyl alcohol; and preservatives, for example methyl or propyl p-hydroxybenzoates or ascorbic acid. The preparations may also be formulated as suppositories, which, for example, contain conventional suppository bases, such as cocoa butter or other glycerides.

For buccal administration, the preparation can be in the form of tablets or pastilles prepared in the usual way.

The preparation according to the invention can be prepared for parenteral administration by injection or continuous infusion. Preparations for injections can be in the form of unit doses in ampoules, or in packages with multiple doses with the addition of preservatives. The preparations may take such forms as suspensions, solutions or emulsions in oil or water carriers, and may contain a forming agent, such as suspending, stabilizing and/or dispersing agents. If possible, the active ingredient can be in the form of a powder that is prepared with a suitable binder before use, for example sterile, pyrogen-free water.

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

Compositions according to the invention can contain between 0.1 - 99% of the active ingredient, usually from 30 to 95% for tablets and capsules, and 3 - 50% for liquid preparations.

The compounds of general formula (I) and their salts may be prepared by the general methods set forth below. In the description that follows, the groups R1 - R8 are as defined for compounds of formula (I), unless otherwise stated.

Compounds of formula (I) can be prepared by reacting compounds of formula (II)

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where R1; R 3 , R 4 , R 8 and A have the meaning given in formula (I), R 9 is a group which is removed with an amine R 2 NH 2 , where R 2 has the meaning given earlier for formula (I). Examples of suitable R9 leaving groups include 1-imidazole, or an optionally substituted phenoxy group.

The reaction is usually carried out in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran) or an amide (e.g. N,N-dimethylformamide) or a mixture thereof, at a temperature ranging from room temperature to reflux temperature solvents.

In a particular aspect of the process with the compound of formula (II) where R9 is a 1-imidazole group, this compound can be obtained in situ, in which case the amine R2NH2 will react with the compound of formula (III)

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in the presence of carbonyl diimidazole, under the previously mentioned conditions.

Compounds of formula (II) can be prepared from compounds of formula (III). Thus, the compounds of formula (II), where R9 represents 1-imidazole, can be prepared by reacting the compound of formula (III) with carbonyldiimidazole in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or ether (e.g. tetrahydrofuran) at a temperature ranging from 0 °C to 80 °C, usually at room temperature.

Compounds of formula (II), where R1, R3, R4 and A have the meaning defined in formula (I) and R9 is an optionally substituted phenoxy group, can be prepared by reacting a compound of formula (III) with the corresponding haloformate R9COHal, where Hal is chlorine or bromine. The reaction is usually carried out in the presence of a base such as a tertiary amine, for example triethylamine or pyridine, and a solvent such as a halohydrocarbon, for example dichloromethane.

Compounds of formula (I) can also be prepared by reacting a compound of formula (III) where R 1 , R 3 , R 4 and A have the meaning defined as for formula (I), with isocyanate R 2 NCO or carbamoyl chloride R 2 NHCOCl (where R 2 has the meaning defined in formula (I )). The reaction is usually carried out in the presence of a suitable solvent such as a halohydrocarbon (eg dichloromethane), an ether (eg tetrahydrofuran) or a nitrile (eg acetonitrile), or a mixture thereof, at a temperature in the range of 0 °C to 80 °C.

Compounds of formula (III) can be prepared by hydrogenolysis of the corresponding benzyl carbamate of formula (IV), in which R 2 has the meaning defined earlier.

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Hydrogenolysis can be carried out under catalytic hydrogenation conditions with a suitable metal catalyst such as palladium on carbon, in a solvent such as an alcohol, for example methanol.

Usually, the reaction is carried out at a temperature within the range of 20 - 100°C in the presence of ammonium formate.

Compounds of formula (IV) can be prepared by alkylation of the corresponding carbamates of formula (V)

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The alkylation reaction is usually carried out by treating a compound of formula (V) with a strong base such as sodium hydride in a polar aprotic solvent such as N,N-dimethylformamide; followed by reaction with an alkylating agent R1L, where it has the meaning defined in formula (I) and L is a leaving group, such as halogen, eg chlorine or bromine.

The reaction is usually carried out at a temperature within the range of -30 °C to 40 °C.

The compound of formula (V) can be prepared by cyclization of ketone derivative (VI)

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Cyclization can be carried out by treating compound (VI) with ammonia in a suitable solvent such as an ether, eg tetrahydrofuran, followed by reaction with sodium acetate in glacial acetic acid.

Compounds of formula (IV), where A is a methylene group, can also be prepared by reacting compounds of formula (VII), where R 1 is as defined in formula (I)

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with the amine R3R4NH, preferably in a solvent such as a halohydrocarbon, eg dichloromethane.

Compounds of formula (VII) can be prepared by bromination of compounds of formula (VIII)

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The bromination reaction can be carried out using reagents such as N-bromosuccinimide, or 5,5-dibromobarbituric acid.

Compounds of formula (IV) where A is an ethylene group, can be prepared from a compound of formula (VIII) with amine HNR3R4 and formaldehyde, under the usual conditions of the Mannich reaction.

Compounds of formula (VIII) can be prepared by alkylation of compounds of formula (IX)

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using the same conditions as previously described for the preparation of the corresponding compound of formula (IV) from compound (V).

Compounds of formula (VI) can be prepared by condensation of aminoketone (X) with benzotriazole derivative (XI)

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The condensation reaction can be carried out using conventional procedures, for example by reacting (X) with (XI) in the presence of dicyclohexylcarbodiimide in a solvent such as tetrahydrofuran.

Compounds of formula (X) are either already known compounds or can be prepared using methods analogous to those described for the preparation of known compounds.

Compounds of formula (I), where A represents a methylene group, can also be prepared by the reaction of bromomethyl derivative (XII)

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wherein R 1 and R 2 are as defined in formula (I), with amine R 3 R 4 NH, wherein R 3 and R 4 are as defined in formula (I). Preferably, the reaction is carried out in an aprotic solvent such as a halohydrocarbon, eg dichloromethane. Bromomethyl derivatives (XII) can be prepared by bromination of the corresponding methyl compound (XIII)

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The bromination reaction can be carried out using a reagent such as 5,5-dibromobarbituric acid in a solvent such as a halohydrocarbon, eg dichloromethane, or chloroform, or a mixture thereof.

The methyl derivatives (XIII) can be prepared from the corresponding intermediate (VIII) using the general procedures described earlier for the conversion of compounds of formula (IV) to compounds of formula (I).

Compounds according to the invention can be translated into other compounds of the invention. Thus, the compounds of formula (I), where R 2 represents a phenyl group substituted with amino, can be prepared from the corresponding compound, where R 2 is a phenyl group substituted with an alkoxycarbonylamino group, by conventional means, such as acid hydrolysis. For example, compounds in which R2 is phenyl substituted with an amino group can be prepared by reacting the corresponding t-butylcarbonylamino compound with trifluoroacetate in a suitable solvent such as dichloromethane.

Acid addition salts of compounds of formula (I) may be prepared by reaction with suitable physiologically acceptable acids in a suitable solvent, followed, if necessary, by a suitable non-solvent.

The compounds of formulas (II), (III), (IV), (V), (VI) and (VII) are novel and form a further aspect of the invention.

In general, compounds R 2 NH 2 , R 2 NCO or R 2 HNCOCl are either known, or can be prepared according to methods used to prepare known compounds. For example, amines R2NH2 can be prepared by reduction of the corresponding nitro compounds R2NO2. The reduction can for example be carried out by catalytic hydrogenation using a suitable metal catalyst such as palladium on carbon, in a suitable solvent such as an alcohol (eg ethanol) at room temperature.

The compounds of formula (I) contain at least one asymmetric carbon atom, namely the carbon atom of the diazepine ring to which a substituted urea group is attached. Specific enantiomers of compounds of formula (I) can be obtained by resolution of the racemic compound using conventional procedures such as salt formation with a suitable optically active acid, or by applying chiral H.P.L.C. Alternatively, the desired enantiomer can be prepared from the corresponding enantiomeric amines of formula (III) using any of the procedures described earlier for the preparation of compounds of formula (I) from amines (III). Enantiomers of amine (III) can be prepared from racemic amine (III) using conventional procedures, such as salt formation with a suitable optically active acid. In another case, the racemic amine (III) can react with an optically active carbonate ester to give its optically active carbamate. The resulting diastereoisomers can then be separated in the usual way. Each separated diastereoisomeric carbamate can then be converted to the corresponding enantiomeric amine (III) by conventional procedures.

The following non-limiting examples illustrate the invention. Temperatures are in °C. "Dried" refers to drying with anhydrous Mg2SO4. All chromatographies were performed on silica gel. The following abbreviations were used: T. I. c. - thin layer chromatography; CDI - carbonyldiimidazole; DCM - dichloromethane; DE - diethyl ether; THF - tetrachiarofuran; DMF - N,N-dimethylformamide; EA - ethyl acetate; MeOH- methanol; CHCl3 - chloroform; NaH - sodium hydride; ir - infrared spectrum, defined as "muli" in mineral oil, unless otherwise stated.

Intermediary 1

Phenylmethyl [2[(2-acetylphenyl)amino]-1-[(1-methylethyl)thio]-2-oxoethyl] carbamate

A suspension of [(1-methylethyl)thio]-[(phenylmethoxy)carbonyl]amino]acetic acid (10.49 g) in dry DCM (175 ml) at 0° under nitrogen was treated with 4-methylmorpholine (3.93 g), after which isobutyl chloroformate (5.31 g) is added dropwise. The mixture was stirred for 40 min at 0° and a solution of 2-aminoacetophene (5.00 g) in dry DCM (60 ml) was added dropwise. The mixture is stirred at 0° for 1 hour and then at 23° for 18 hours. The mixture is washed with 2N hydrochloric acid, 2N sodium carbonate solution, saturated saline and then dried. Evaporation of the solvent in vacuo gave the title compound (14.82 g) which was used without further purification.

T.I.c. (1:1 DE-hexane) Rf 0.3

Intermediary 2

Phenylmethyl [2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepine-3-yl] carbamate

Ammonia gas was passed through a solution of phenylmethyl[2-[(2-acetylphenyl)amino]-1-[(1-methylethyl)thio]-2-oxoethyl] carbamate (14.74g) in dry THF (250ml) at 0° through 0.5 h. Mercury(II) chloride (10.00g) is added and the mixture is vigorously stirred for 6 hours, while gaseous ammonia is continuously passed through the mixture. The mixture was filtered through hiflo and the solvent was removed from the filtrate by evaporation in vacuo. The residue was treated with acetic acid (290 ml) and sodium acetate (13.35 g) and the resulting mixture was stirred for 18 hours at 23°. The solvent is evaporated in vacuo, and the residue is purified by chromatography. elution with EA gives the title compound (5.70g).

T.I.c. (3:2 EA-hexane) Rf 0.4

Intermediary 3

Phenylmethyl [2,3-dihydro-5-methyl-1-[2-(methylphenylamino)-2-oxoethyl]-2-oxo-1H-1,4-benzodiazepine-3-yl] carbamate

80% sodium hydride in oil (102 mg) is added to a solution of phenylmethyl [2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepine-3-yl] carbamate (1.00 g). in dry DMF (10 ml) under nitrogen. The mixture was stirred for 0.5 h at 23° and treated with a solution of 2-bromo-N-methyl-N-phenylacetamide (707 mg) in dry DMF (1 ml). The mixture is stirred at 23° for 1 hour, divided between phosphate buffer solution (pH 6.5) and EA, the organic phase is washed with water and dried. The solvent is evaporated in a vacuum and the residue is purified by chromatography on aluminum oxide. Elution with MeOH-DCM (1:50) gave the title compound (568 mg).

T.I.c. (1:50 MeOH-DCM) Rf 0.2.

Intermediary 4

3-amino-2,3-dihydro-N,5-dimethyl-2-oxo-N-phenyl-1H-1,4-benzodiazepine-1-acetamide

A mixture of 5% palladium on charcoal (300 mg) and phenylmethyl[2,3-dihydro-5-methyl-1-[2-(methylphenylamino)-2-oxoethyl]-2-oxo-1H-1,4-benzodiazepine- 3-yl] carbamate (500 mg) in MeOH-water 4:1 (40 ml) at 40° under nitrogen is treated with ammonium formate (201 mg) for 1 hour. The mixture is cooled to 23° and filtered through hiflo. The filtrate was evaporated in vacuo and the residue partitioned between 2N sodium carbonate solution and chloroform. The organic phase is dried and the solvent is evaporated in vacuo. The residue was purified by chromatography, eluting with MeOH-DCM to give the title compound (302 mg).

T.I.c. (1:9 MeOH-DCM) Rf 0.3

Intermediary 5

2,3-dihydro-N,5-dimethyl-2-oxo-N-phenyl-[3[[(3-cyanophenyl)amino]carbonyl]amino]-1H-1,4-benzodiazepine-1-acetamide

3-Cyanophenylisocyanate (144 mg) was added to a solution of Intermediate 4 (336 mg) in dichloromethane (10 mL) under nitrogen and the mixture was stirred for 4 hours. The reaction mixture was filtered to give the title compound (305 mg) as a white solid, m.p. 210-211°.

Intermediary 6

2-{5-bromomethyl-3-[3-(3-cyano-phenyl)-ureido]2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl}-N- methyl-N-phenyl-acetamide

A solution of Intermediate 5 (2.99 g) in dry DCM (300 ml) and CHCl3 (100 ml) was treated with 5,5-dibromobarbituric acid (0.93 g) under nitrogen at 23°. After 18 hours, silica gel (Merck 9385; 20 g) is added and the mixture is evaporated under vacuum. The mixture was purified by liquid chromatography eluting with (1 to 2 to 5%) MeOH in DCM to give the title compound as a white powder (1.89 g), m.p. 100° (decomposes).

T.I.c. (5% MeOH-DCM) Rf 0.29

Intermediary 7

Benzyl ester of 5-bromomethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine-3-carbamic acid

5,5-dibromobarbituric acid (5.1 g) is added to a solution of 2,3-dihydro-5-methyl-2-oxo-1H-benzo[e][1,4]-diazepine-3-carbamic acid benzyl ester (11 g) in dry DCM (750 ml) at 23° under nitrogen. The solution becomes increasingly opaque and darker orange in color over 20 hours, after which silica gel (50 g) is added and the mixture is evaporated to dryness. The residue was chromatographed on silica gel (Et3N-deactivated, Merck 9385) with 1% MeOH in DCM as eluent to give the title compound (7.1g) as a pale yellow solid, m.p. 154° (exp.)

T.I.c. Et3N-deactivated SiO2 (100:1 DCM-MeOH) Rf 0.55

Intermediary 8

5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,41]diazepine-3-carbamic acid benzyl ester

Morpholine (7.5 ml) was added to a solution of Intermediate 7 (6.9 g) in dry DCM (190 ml) at 23° under nitrogen. After 3 hours, the cloudy orange mixture is poured into water (200 ml) and the layers are separated. The aqueous phase was extracted with DCM (150 ml) and the combined, dried organic extracts were evaporated. The residue was chromatographed with 2 to 3% MeOH in DCM as eluent to give the title compound (3.38 g) as a cream foam, m.p. 91° asc.;

T.I.c. (95:5 DCM-MeOH) Rf 0.28;

I.r-3235; 1698; 1500; 1456; 1241; 1116 cm-1

Intermediary 9

1-(3-cyano-phenyl)-3-(5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-1 H-benzo[e] [1,4]diazepin-3-yl)- urea

A solution of Intermediate 8 (3.38 g) in absolute EtOH (160 ml) was hydrogenated at 23° and a pressure of 1 atmosphere in the presence of 10% palladium on charcoal as a catalyst (1 g). After 3 hours, the mixture is filtered through hiflo and the filtrate is evaporated to give a purple foam. A solution of the foam in MeCN (54 ml) was treated with 3-cyanophenyl isocyanate (1.21 g) and after 1 hour DE was added to the resulting suspension. The solid was filtered off and dried at 50° in vacuo to give the title compound (1.44 g) as a yellowish-white solid,

d.p. 249-50°.

T.I.c. (9:1 DCM-MeOH) Rf 0.46

Intermediary 10

1 -(3-cyano-phenyl)-3-[1-(3,3-dimethyl-2-oxo-butyl)-5-methyl-2-oxo-2,3-dihydro-1 H-benzo[e] [1,4]diazepin-3-yl]-urea

3-Cyanophenyl isocyanate (278 mg) was added to a solution of 3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)-5-methyl-2-oxo-1 H-1, of 4-benzodiazepine (500 mg) in dry MeCN (13 ml) at 23° under nitrogen. After 30 minutes, the resulting thick mixture was mixed with DE (5 ml), filtered and the precipitate washed with EA and DE, and dried in vacuo at 50° to give the title compound (571 mg) as a white solid, m.p. 246-7°.

T.I.c. (9:1 DCM-MeOH) Rf 0.51.

I.r. 3340; 2229; 1719; 1673; 1646; 1557; 1517 cm-1

Intermediary 11

1-[5-bromomethyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ]-3-(3-cyano-phenin-urea

5,5-Dibromobarbituric acid (38 mg) was added to a suspension of Intermediate 10 (100 mg) in dry DCM (10 ml) at 23° under nitrogen. After 6.5 hours dry THF (4 ml) was added to induce solubility and stirring was continued for 17 hours. Silica gel (2 g) was added to the pale orange solution and the mixture was evaporated to dryness. The residue was chromatographed with 0 to 0.25 to 0.5 to 1 to 2% MeOH in DCM as eluent to give the title compound (80 mg) as a white solid, m.p. 135°, disp. T.I.c.(2% MeOH-DCM) Rf 0.23

Intermediary 12

5-Bromomethyl-1-(methyl-phenyl-carbamoylmethyl)-2-oxo-2,3-dihydro-1 H-benzo[e][1,4]diazepine-3-carbamic acid benzyl ester

A solution of Intermediate 3 (200 mg) in DE (5 ml) and chloroform (5 ml) under nitrogen was treated with 5,5-dibromobarbituric acid (61 mg) and the mixture was stirred at 23° for 18 hours. MeOH (5 ml) and silica gel (1 g) are added and the solvent is evaporated in vacuo. The residue was chromatographed with MeOH-DCM (0.2:10) as eluent to give the title compound (175 mg) as a white foam.

T.I.c. (10:0.5 DCM-MeOH). Rf 0.69.

I.r. 3418; 3325; 1727; 1670; 1496; 1453 cm-1.

Intermediary 13

Benzyl ester 1-(methyl-phenyl-carbamoylmethyl)-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-1 H-benzo[e][1,41 diazepin-3 carbamic acid

A solution of Intermediate 12 (2.75 g) in DCM (50 ml) was treated with samorpholine (2.18 g) and the mixture was stirred at 23° under nitrogen for 1 hour. The mixture is washed with water (2x40 ml) and brine (40 ml), dried and evaporated in a vacuum. The residue was chromatographed with DCM-MeOH (10:0.3) as eluent to give the title compound (2.38 g) as an orange foam,

I.r. (solution in CHCl3) 3425; 1723; 1670; 1497; 1452; 1394 cm-1.

Intermediary 14

2-(3-amino-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yn-N-methyl-N-phenyl-acetamide

A solution of Intermediate 13 (1.82 g) in EtOH (50 ml) was hydrogenated over 10% palladium on carbon (250 mg) at 23° and 1 atm pressure. After 4 hours the mixture was filtered through hyflo and the filtrate evaporated to give the title compound (1.35 g) as a pale yellow foam. T.I.c. (9:1 DCM-MeOH). Rf 0.25.

I.r. (solution in CHCl3) 3395; 1669; 1598; 1497; 1451; 1116 cm-1.

Intermediary 15

R-carbonic acid (4-nitro-phenyl) ester (1-phenyl-ethyl) ester

To a solution of (R)-sec-phenethyl alcohol (500 mg) and pyridine (324 mg) in DCM (15 ml) at 0-5° under nitrogen, a solution of 4-nitrophenyl chloroformate (825 mg) in DCM (10 ml) is added dropwise. . The mixture is allowed to warm to 23° and stirred for 18 hours. The mixture was partitioned between phosphate buffer (pH 6.5) and DCM. The organic phase is washed with 8% sodium bicarbonate solution and dried (Na2SO4). By evaporating the solvent in a vacuum, a residue is obtained which gives an azeotrope with toluene, and then it is purified chromatographically. Elution with EA-hexane (1:9) gave the title compound as a colorless oil (290 mg).

T.I.c. (1:4 EA-hexane). Rf 0.45.

I.r. (film) 3086; 2986; 1765; 1526; 1349; 1258; 1220; 1064; 861; 700 cm-1.

Intermediary 16

R-5-methyl-1 –(methyl-phenyl-carbamoylmethyl)-2-oxo-2,3-dihydro-1 H-benzo[e][1,4]diazepine-3 carbamic acid 1-phenyl-ethyl-ester

A solution of Intermediate 4 (200 mg) and Intermediate 15 (256 mg) in MeCN (14 mL) was treated with Et 3 N (60 mg) under nitrogen and the mixture was heated under reflux for 18 h. The mixture was cooled to 23° and partitioned between phosphate buffer (pH 6.5) and EA. The organic phase is dried (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography. Elution with EA-hexane (7:3) gave the title compound as a white foam (79 mg).

T.I.c. (7:3 EA-hexane). Rf 0.26.

I. r. 3425; 3318; 1724; 1669; 1632; 1596; 1270; 1244; 1206; 1071; 766; 701 cm-1.

Intermediary 17

2-(3-amino-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-methyl-N-phenyl-acetamide (isomer 2)

A solution of Intermediate 16 (442 mg) in EtOH (14 mL) was hydrogenated over 10% palladium on carbon (90 mg). After 7 hours the mixture was filtered through hyflo and the solvent evaporated in vacuo to give the title compound as a white foam (311 mg).

T.I.c. (1.20 MeOH-DCM). Rf 0.24.

I.r. 1660; 1595; 1317; 1275; 1251; 1200; 1122; 964; 770; 724; 702; 558 cm-1.

Intermediary 18

2-{3-[3-(3-methoxy-phenyl)-ureido]-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl-N- methyl-N-phenyl-acetamide (isomer 1)

A solution of Intermediate 17 (208 mg) in DCM (5 ml) under nitrogen was treated with 3-methoxyphenyl isocyanate in vacuo and the residue purified by chromatography. Elution with MeOH-DCM (1:20) gave the title compound as a white solid (221 mg), m.p. 238-9°.

T.I.c. (1:20 MeOH-DCM). Rf 0.30.

I.r. 3311; 1666; 1637; 1612; 1558; 1523; 1496; 1158; 1036; 766; 701; 557 cm-1.

Intermediary 19

Benzyl ester 1-(methyl-phenyl-carbamoylmethyl)-5-(4-methyl-piperazin-1-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3 - carbamic acid

N-methyl piperazine (0.51 ml) was added to a stirred solution of Intermediate 12 (0.5 g) in dry DCM (10 ml) at 23° under nitrogen. After 3 hours the mixture was poured into water (75 ml) and extracted with EA (50 ml x 3). The combined organic extracts are washed with saturated brine, dried and evaporated in a vacuum. The crude product was purified by liquid chromatography on silica gel (Merck 9385-Et3N deactivated) eluting with 2 to 4% MeOH in DCM to give the title compound as an orange foam (385 mg), m.p. 65-70°.

T.I.c. SiO2-Et3N deactivated (2% MeOH-DCM) Rf 0.39.

Intermediary 20

2-{3-[3-(3-methoxy-phenyl)-ureido]-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl}-N -methyl-N-phenyl-acetamide

A solution of intermediate 4 (500 mg) in dry MeCN (10 ml) was treated with 3-methoxyphenylisocyanate (195 μl) and the mixture was stirred at 23° under nitrogen for 5 h. DE (10 ml) was added and the resulting mixture was filtered, the filter cake washed with hexane to give the title compound as a yellowish solid (599 mg), m.p. 215.

T.I.c. (EA) Rf 0.38

Intermediary 21

3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)5-methyl-2-oxo-1H-1,4-benzodiazepine

(a) Benzyl ester N-[5-methyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,3-dihydro-benzo[e][1,4]diazepine-3 -yl] carbamic acid

Sodium hydride (80% in oil, 235 mg) was added to a solution of Intermediate 2 (2g) in dry (DMF) (20 ml) under nitrogen while cooling in an ice bath. After 45 minutes, a solution of 1-brompinacolone (1.23 g) in dry DMF (5 ml) was added and stirred for 2 h 20 min, while the ice water bath was melting. The reaction mixture was partitioned between water (150 ml) and EA (2 x 150 ml) and the combined EA extracts were washed with water (100 ml), saturated brine (100 ml) and dried. The solution was evaporated and chromatographed with hexane-EA (1:2) as eluent to give the title compound (2.47 g) as a white foam, m.p. 68°.

(b). 3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)-5-methyl-2-oxo-1H-1,4-benzodiazepine

The three-necked flask is washed well with nitrogen and filled successively with 5% palladium on carbon (50%) wet paste (1.66 g); water (45 ml), a solution of Intermediate 21a (2.42 g) in methanol (180 ml) and ammonium formate (1.09 g). The mixture is stirred at 40° under nitrogen for 1.5 hours, then it is cooled and filtered through hyflo. The nitrate was evaporated and the residue was partitioned between 2N sodium carbonate solution (100 ml) and EA (2 x 150 ml). The combined organic extracts were washed with saturated brine (100 ml), dried and evaporated to give the title compound (1.63 g) as a yellowish brown solid, m.p. 96-8°.

T.I.c. (9:1 DCM-MeOH) Rf 0.33

Intermediary 22

Benzyl ester N-[5-methyl-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2-oxo-1,3-dihydro-benzo[e][1,4]diazepin-3- yl]-carbamic acid

NaH (80% in oil; 102 mg) was added to a solution of intermediate 2 (1.00 g) in dry DMF (10 mL) at 0°. The mixture was stirred at 0° for 0.5 h and a solution of 2-N-pyrrolidinyl-2-oxo-ethyl bromide (596 mg) in DMF (1 ml) was added. The mixture was stirred at 23° for 4 h. Phosphate buffer (pH 6.5; 50 ml) was added and the mixture was extracted with ethyl acetate (50 ml). The organic phase is washed with water (2x50 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo afforded a residue which was chromatographed with EA then MeOH-EA (1:9) as eluent to give the title compound (959 mg) as a white solid, m.p. 165-6°.

T.I.c. (EA) Rf 0.16

I.r. (solution in CHBr3) 3147; 2974; 2874; 1719; 1683; 1654; 1057; 1449; 1079; 765 cm-1.

Intermediary 23

Benzyl ester N-[5-(bromo-methyl)-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2-oxo-1,3-dihydro-benzo[e][1,4] diazepin-3-yl]-carbamic acid

A solution of intermediate 22 (4.00 g) in DE (50 ml) and CHCl 3 (50 ml) was treated under nitrogen and at 230 with 5,5-dibromobarbituric acid (1.32 g) and the mixture was stirred at 230 for 18 hours. MeOH (20 ml) and silica gel (Merck, 9385; 15 g) were added and the solvent was evaporated in vacuo. The residue was purified by chromatography with MeOH-DCM (0.2:10) as eluent to give the title compound as a white solid (3.88 g).

T.I.c. (10:0.2 DCM-MeOH) Rf 0.36

I.r. 3389; 1733; 1686; 1662: 1650; 1596; 1330; 1217; 1200; 1084; 777 cm-1.

Intermediary 24

Benzyl ester N-[5-(morpholin-4-yl-methyl)-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2-oxo-1,3-dihydro-benzo[e][ 1,4]diazepin-3-yl]-carbamic acids

A solution of Intermediate 23 (3.78 g) in DMF (20 ml) was treated under nitrogen at 23° with morpholine (3.21 g) and the mixture was stirred for 1 hour. Water is added and the mixture is extracted with EA. The extract is washed with water and saturated brine, then dried (Na2SO4). The solvent is evaporated in vacuo and the residue is purified by chromatography. Elution with DCM-MeOH (100:3) gave the title compound as a pale orange foam (1.095 g).

T.I.c. (100:3 DCM - MeOH) Rf 0.27.

I.r. (KBr disc) 3426; 2979; 1723; 1688; 1661; 1510; 1453; 1394; 1323; 1116; 1090; 929 cm-1.

Intermediary 25

3-amino-5-(morpholin-4-yl-methyl)-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzo[e][1,4]diazepine -2-he

A solution of Intermediate 24 (3.584 g) in EtOH (100 ml) was hydrogenated over 10% paldium on carbon (500 mg) at 23°. After 3.5 hours the mixture was filtered through hyflo and the filtrate evaporated in vacuo to give the title compound as a cream foam (2.536 g).

T.I.c. (9:1 DCM-MeOH) Rf 0.22.

I.r (KBr disk) 3396; 2981; 1657; 1448; 1322; 1256, 1116; 865 cm-1.

Intermediary 26

Ethyl-(4-fluoro-phenyl)-amine

Iodethane (3.6 ml) was added to a mixture of 4-fluoroaniline (4.26 ml) and potassium carbonate (6.9 g) in dry DMF (100 ml). After 18.5 h at 23°, the resulting suspension was poured into water (400 ml) and extracted with EA (400 ml). The organic extract is washed with water (200 ml) and saturated brine (200 ml), dried and evaporated. The residual oil was chromatographed with 2 to 3 to 4% EA in hexane as eluent to give the title compound (3.667 g) as a yellow oil.

T.I.c. (4:1 hexane-EA) Rf 0.62

Intermediary 27

2-Bromo-N-ethyl-N-(4-fluoro-phenyl)-acetamide

A solution of bromoacetyl bromide (2.24 ml) in dry DCM (15 ml) was added dropwise over 20 min to a solution of Intermediate 26 (3.58 g) and Et3N (3.59 ml) in dry DCM (30 ml) at 0° under nitrogen. After 2.5 h at 0°, the solution was partitioned between water (200 ml) and DCM (200+100 ml). The combined organic extracts were dried and evaporated and the residue chromatographed with 10 to 15 to 20% EA in hexane as eluent to give the title compound (2.641 g) as a pale orange oil.

T.I.c. (9:1 hexane-EA) Rf 0.15

Intermediary 28

Benzyl ester N-(1-{[ethyl-(4-fluoro-phenyl)-carbamoin-methyl}-5-methyl-2-oxo-1,3-dihydro-benzo[e][1,4]diazepine-3 -yl)-carbamic acid

NaH (80% in oil; 348 mg) was added to a solution of Intermediate 2 (2.92 g) in dry DMF (30 mL) at 0° under nitrogen. After 1 h, the orange solution is treated with a solution of Intermediate 27 (2.608 g) in dry DMF (10 ml). Stirring was continued at 0° for 2 hours, after which the solution was poured into water (200 ml) and extracted with EA (200+100 ml). The combined extracts are washed with saturated brine (200 ml), dried and evaporated. The residue was chromatographed with EA-DCM (4:1) as eluent to give the title compound (3.75 g) as a pale yellow foam.

T.I.c. (4:1) EA-DCM. Rf 0.26.

I.r. (solution in CHCl3) 3425; 1724; 1671; 1515; 1510; 1248; 1094; 845 cm-1.

Intermediary 29

benzyl ester N-{1-[ethyl-(4-fluoro-phenyl)-carbamoyl-methyl]-5-(morpholin-4-yl-methyl)-2-oxo-1,3-dihydro-benzo[e][ 1,4]diazepin-3-yl}-carbamic acid

5,5-Dibromobarbituric acid (765 mg) was added to a solution of Intermediate 28 (2.69 g) in CHCl 3 (30 ml) and DE (30 ml) at 23° under nitrogen. After 30 h, morpholine (2.3 ml) was added and stirring was continued for a further 16 h, after which the cloudy orange liquid was poured into water (100 ml). The layers were separated and the aqueous phase was extracted with CHCl 3 (100 ml). The combined dried organic extracts were evaporated and the residue chromatographed with EA-DCM (3:1) as eluent to give the title compound (2.22 g) as a coarse orange foam.

T.I.c. (4:1 EA-DCM). Rf 0.17

I.r. (solution in CHCl3) 3621; 3425; 1726; 1672; 1510; 1233; 1202; 1116; 845 cm-1.

Intermediary 30

2-[3-amino-5-(morpholin-4-yl-methyl)-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl]-N-ethyl-N -(4-fluoro-phenyl)-acetamide

A solution of intermediate 29 (1.144 g) in absolute EtOH (25 ml) was hydrogenated at 23° and 1 atmosphere in the presence of 10% palladium on activated carbon as a catalyst (160 mg). After stirring for 6 h and standing overnight under hydrogen, the mixture was filtered through hyflo and the filtrate evaporated to give the title compound (879 mg) as a coarse, green-brown foam, m.p. 95-9° disp.

T.I.c. (9:1 DCM-MeOH) Rf 0.18

Intermediary 31

3-(1,2,4-oxadiazol-3-yl)-phenylamine

A solution of 3-(1,2,4-oxidazol-3-yl)nitrobenzene (3.0 g) and EA (50 ml) was hydrogenated at 1 atm and at 23° over Raney nickel (1 full pipette). After 4.5 h, the catalyst is removed by filtration through hiflo. The filtrate was evaporated to give a pale brown solid (2.57g) identified as hydroxylamine.

T.I.c. (1:1 EA-hexane) Rf 0.27.

A solution of hydroxylamine (2.54 g) in EA (40 ml) was further hydrated at room temperature and pressure over Raney nickel (1 full pipette). After 4.5 h, the catalyst is removed by filtration through hiflo and the filtrate is evaporated to give a yellow solid. Crystallization from EA gives the pure product. The mother liquors were chromatographed with hexane-DE (3:1) as eluent to afford more product which combined with the crystallized material to give the title compound (548 mg) as a cream solid.

T.I.c. (2:1 DE-hexane) Rf 0.35.

Example 1

2-{3-[3-(3-cyano-phenyl)-ureido]-2-oxo-5-piperidin-1-ylmethyl-2,3-dihydro-benzo[e][1,4]diazepin-1- yl}-N-methyl-N-phenyl-acetamide

A solution of intermediate 6 (300 mg) in DCM (5 ml) was treated with piperidine (0.27 ml) at 23° under nitrogen. After 2 hours, the mixture was poured into water (75 ml) and extracted with EA (100 ml x 2). The combined organic extracts are washed with saturated brine, dried and evaporated in a vacuum. The crude product was partially purified by liquid chromatography on silica gel (Merck 9385-Et3N deactivated) eluting with 2% MeOH in DCM. Complete purification was achieved by liquid chromatography on silica gel (Merck 9385-Et3N deactivated) eluting with 1 to 2% MeOH in DCM to give the title compound as a cream solid (135 mg), m.p. 145-150°.

I.r. 3260; 2222; 1704; 1686; 1591; 1383; 1223; 1125 cm-1.

Example 2

2-{3-[3-(3-cyano-phenyl)-ureido]-2-oxo-5-pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[e][1,4]diazepin-1- yl}-N-methyl-N-phenyl-acetamide

A solution of intermediate 6 (300 mg) in DCM (5 ml) was treated with pyrrolidine (0.22 ml) at 23° under nitrogen. After 2 hours the mixture was evaporated in vacuo to give a brown oil which was purified by liquid chromatography on silica gel (Merck 9385-Et3N deactivated) eluting with 2% MeOH in DCM. After vacuum evaporation, the product fractions were scraped with EA-hexane. The solid was dissolved in EA-THF (4:1; 100 ml) and the solution was washed with water and saturated brine, then dried and evaporated in vacuo to give the title compound as a pale pink solid (154 mg), m.p. 140-145°, disp.

T.I.c. Et3N deactivated SiO2 (2% MeOH-DCM) Rf 0.22.

I.r. 3342; 2226; 1685; 1593; 1559; 1496; 1381 cm-1.

Example 3

2-{3-[3-(3-cyano-phenyl)-ureido]-5-(isopropylamino-methyl)-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1- yl}-N-methyl-N-phenyl-acetamide

A solution of Intermediate 6 (300 mg) in DCM (5 ml) at 23° under nitrogen is treated with isopropylamine (0.23 ml). After 2 hours, the mixture was evaporated in vacuo to give an oil, which was purified by liquid chromatography on silica gel (Merck 9385-Et3N deactivated) eluting with 2% MeOH-DCM. Trituration with EA-hexane gave a cream solid, which was dissolved in EA-THF (4:1; 100 ml), washed with water (100 ml) and saturated brine, dried and evaporated in vacuo to give the title compound as a cream solid. (132 mg), m.p. 160°, disp.

T.I.c. Et3N deactivated SiO2 (2% MeOH-DCM) Rf 0.16.

I.r. 3316; 2231; 1674; 1591; 1561; 1455; 1432; 1384; 1240; 1198 cm-1.

Example 4

2-{3-[3-(3-cyano-phenyl)-ureido]-2-oxo-5-[1,4]thiazinan-4-ylmethyl-2,3-dihydro-benzo[e][1,4 ]diazepin-1-yl}-N-methyl-N-phenyl-acetamide

A solution of Intermediate 6 (1 g) in dry DCM (20 ml) is treated with thiomorpholine (0.90 ml) at 23° under nitrogen. After 2 hours, the mixture was poured into water (75 ml) and extracted with EA (3x75 ml). The combined organic extracts are washed with saturated brine, dried and evaporated in vacuo. The crude product was purified by liquid chromatography eluting with EA to give, after trituration with EA-hexane, the title compound as a white solid (458 mg), m.p. 165°.

T.I.c. Et3N deactivated SiO2 (EA) Rf 0.52.

I.r. 3267; 2229; 1687; 1557; 1450; 1382; 1221 cm-1.

Example 5

1-(3-cyano-phenyl)-3-{1-[2-(cis-2,5-dimethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-5-morpholin-4-ylmethyl-2 -oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl} urea

NaH (80% in oil, 23 mg) was added to a suspension of Intermediate 9 (253 mg) in dry DMF (3 mL) at 0° under nitrogen. After 30 minutes, the resulting solution was treated with a solution of 2-(cis-2,5-dimethylpyrrolidin-1-yl)-2-oxo-ethyl bromide (145 mg) in dry DMF (0.5 ml) and stirring was continued at 0° through 2:25 a.m. and at 23° during 20 hours. The dark solution is poured into water (20 ml) and extracted with EA (2x30 ml), then the combined extracts are washed with water (20 ml), saturated brine (40 ml), dried and evaporated. Trituration of the residue with EA-DE gave the title compound (196 mg) as a white solid, m.p. 234-5°, dec.

T.I.c. (95:5 DCM-MeOH) Rf 0.26.

I.r. 3263; 2224: 1685: 1650; I590; 1557; 1449; 1378; 1115; 1001 cm-1.

Example 6

2-{3-[3-(3-cyano-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2.3-dihydro-benzo[e][1,4]diazepin-1-yl} -N-(4-fluoro-phenyl)-N-methyl-acetamide

NaH (80% in oil; 23 mg) was added to a suspension of Intermediate 9 (250 mg) in dry DMF (3 mL) at 0° under nitrogen. After 40 min, a solution of 2-bromo-N-(4-fluorophenyl)-N-methyl-acetamide (162 mg) in dry DMF (0.5 ml) was added to the resulting solution and stirring was continued at 23° for 22 h. The yellow solution is then poured into water (20 ml) and extracted with EA (2x30 ml). The combined extracts are washed with water (20 ml) and saturated brine (40 ml), dried and evaporated. A solution of the residue in MeOH was preadsorbed onto silica gel and chromatographed with 0 to 1 to 2 to 3 to 4% MeOH in DCM as eluent to give the title compound (260 mg) as an orange solid, m.p. 182-4° disp.

T.I.c. (95:5 DCM-MeOH) Rf 0.19.

I.r. 3341; 2229; 1674; 1510; 1223; 1116 cm-1.

Example 7

2-{3-[3-(3-cyano-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1- yl}-N-ethyl-N-phenyl-acetamide

NaH (80% in oil; 23 mg) was added to a solution of Intermediate 9 (250 mg) in dry DMF (3 mL) at 0° under nitrogen. After 40 minutes, a solution of 2-bromo-N-ethyl-N-phenyl acetamide (160 mg) in dry DMF (0.5 ml) was added to the resulting solution and stirring was continued at 23° for 22 hours. The orange solution was then poured into water (20 ml) and extracted with EA (2 x 30 ml). The combined extracts are washed with water (20 ml) and saturated brine (30 ml), dried and evaporated. Trituration of the residue with EA-DE gave the title compound (239 mg) as a white solid, m.p. 211-2° exp.

T.I.c. (95:5 DCM-MeOH) Rf 0.26.

I.r.3294; 2225; 1684; 1666; 1456; 1203; 777 cm-1.

Example 8

1 -(3-cyano-phenyl)-3-[1-(3,3-dimethyl 2-oxo-butyl)-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-1H-benzo[ e][1,4]diazepin-3-yl]-urea

Morpholine (62 μl) was added to a suspension of Intermediate 11 (72 mg) in dry DCM (2 ml) at 23° under nitrogen. After 1 hour, the mixture is poured into water (20 ml) and extracted with EA (20+15 ml). The combined extracts are washed with saturated brine (20 ml) and evaporated. The residue was triturated with EA-DE, filtered and dried in vacuo to give the title compound (53 mg) as a white solid, m.p. 168-9° disp.

T.I.c. (95:5 DCM-MeOH) Rf 0.26

I.r. 3279; 2229; 1688; 1455 cm-1

Example 9

2-{3-[3-(3-methoxy-phenyl)ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl }-N-methyl-N-phenyl-acetamide

3-Methoxyphenyl isocyanate (53 mg) was added to a solution of Intermediate 14 (150 mg) in DCM (5 mL) under nitrogen. The solution is stirred at 23° for 3 hours. The solvent is evaporated in vacuo and the residue is purified by chromatography. Elution with MeOH-DCM (1:20) gave the title compound as a straw-colored solid (176 mg), m.p. 164-6° disp.

T.I.c. (1:20 MeOH-DCM) Rf 0.25

I.r. (solution in CHCl3) 3431; 1670; 1599; 1495; 1454; 1425; 1392; 1289; 1158; 1116 cm-1.

Example 10

N-methyl-2-[5-morpholin-4-ylmethyl-2-oxo-3-(3-phenyl-ureido)-2,3-dihydro-benzo[e][1,4]diazepin-1-yl] -N-phenylacetamide

Phenyl isocyanate (42 mg) was added to a solution of Intermediate 14 (150 mg) in MeCN (5 mL) under nitrogen and the mixture was stirred at 23° for 2 hours. DE was added and the mixture was filtered to give the title compound as a white solid (160 mg), m.p. 157-8° disp.

T.I.c. (1:20 MeOH-DCM) Rf 0.33

I.r. (Solution in CHCl3) 3430; 1670; 1599; 1498; 1452; 1392; 1311; 1292; 1116; 1002 cm-1.

Example 11

N-methyl-2-{5-morpholin-4-ylmethyl-2-oxo-3-[3-(3-trifluoromethyl-phenyl)ureido]-2,3-dihydro benzo[e][1,4]diazepine- 1-yl}-N-phenylacetamide

3-Trifluoromethylphenyl isocyanate (103 μl) was added dropwise with stirring to a solution of Intermediate 14 (300 g) in dry DCM (3 ml). The mixture was stirred at room temperature under nitrogen for 18 hours. Purification by column chromatography eluting with DCM-MeOH-880 ammonia (94.4:5:0.5) gave the title compound (87 mg) as a white solid, m.p. 190° dist.

T.I.c. (94.5:5:0.5 DCM-MeOH-880 ammonia) Rf 0.22

I.r. 2924; 2854; 1688; 1671; 1450; 1339; 1116 cm-1.

Example 12

tert-butyl ester (3-{3-[1-fmethyl-phenyl-carbamoylmethyl)-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepine -3-yl]-ureido}phenyl)-carbamic acid

Carbonyl diimidazole (97 mg) was added to a solution of Intermediate 14 (230 mg) in THF (10 mL) under nitrogen and the mixture was stirred at 23° for 1 h. t-Butyl ester (3-amino-phenyl)-carbamic acid is added and the mixture is heated under reflux for 18 hours. The mixture was then cooled to 23° and partitioned between water and EA. The organic phase is dried (Na2SO4) and the solvent is evaporated in vacuo to give a residue which is purified by chromatography. Elution with MeOH-DCM (1:20) gave the title compound as a straw colored solid (78 mg).

T.I.c. (1:20 MeOH-DCM) Rf 0.32

Mass spectrum of MH+ (observed) 656

Example 13

2-{3-[3-(3-amino-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1- yl}-N-methyl-N-phenyl-acetamide

A solution of Example 12 (70 mg) in DCM (5 ml) was treated with trifluoroacetic acid (0.3 ml) and stirred for 1 h. EA is added, the mixture is washed with 2N sodium carbonate solution, dried (Na2SO4) and evaporated in vacuo. The residue was triturated with DE to give the title compound as a beige solid (31 mg), m.p. 158-60°.

T.I.c. (1:20 MeOH-DCM) Rf 0.22

I.r. 3353; 1667; 1613; 1596; 1556; 1496; 1321; 1204; 1115; 773 cm-1.

Example 14

(+)-2-{3-[3-(3-methoxy-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4] diazepin-1-yl}-N-methyl-N-phenyl-acetamide

3-Methoxyphenyl isocyanate (106 mg) was added with stirring to a solution of Intermediate 14 (300 mg) in DCM (10 ml) under nitrogen and the mixture was stirred at 23° for 2 h. The solvent is evaporated in vacuo and the residue is purified by chromatography. Elution with MeOH-DCM (1:20) gave a straw colored solid (205 mg), a portion (75 mg) of which was further purified by chiral h.p.l.c. to give the title compound as a white solid (26 mg), m.p. 169-70° disp.

T.I.c. (1:20 MeOH-DCM) Rf 0.25.

I.r. (solution in CHCl3) 3431; 1670; 1600; 1496; 1454; 1427; 1289; 1158; 1116; 1002 cm-1.

[image]

Example 15

(+)2-{3-[3-(3-methoxy-phenyn-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepine- 1-yl}-N-methyl-N-phenyl-acetamide

A solution of Intermediate 18 (189 mg) in chloroform (8 ml) and DE (3 ml) under nitrogen was treated with 5,5-dibromobarbituric acid (56 mg) and the mixture was stirred at 23° in the dark for 18 h. Morpholine (68 mg) was added and the mixture was stirred for 2 h at 23°. The mixture was partitioned between EA and phosphate buffer (pH 6.5). The organic phase is dried (Na2SO4) and the solvent is evaporated in vacuo to give a residue which is purified by chromatography. Elution with EA then MeOH-DCM (1:20) gave the title compound as a white solid (147 mg), m.p. 164-6° disp.

T.I.c. (1:20 MeOH-DCM) Rf 0.35

I.r. 3339; 1668; 1598; 1549; 1290; 1203; 1156; 1115; 771; 703 cm-1.

Example 16

2-{3-[3-(3-cyano-phenyl)-ureido]-5-(4-methyl-piperazin-1-ylmethine)-2-oxo-2,3-dihydro-benzo[e][1, 4]diazepin-1-yl}-N-methyl-N-phenyl-acetamide

A solution of Intermediate 19 (352 mg) in EtOH (20 ml) was hydrided at 23° and 1 atm pressure using 10% palladium on charcoal (80 mg) as a catalyst. After 7 hours, the mixture was filtered through hiflo and evaporated to give the crude amine as an orange-red oil. It was dissolved in dry MeCN (3ml) and treated with 3-cyanophenyl isocyanate (85 mg) at 23° under nitrogen. After 2 hours the mixture was evaporated in vacuo to give a red oil which was purified by liquid chromatography on silica gel (Merck 9385-Et 3 N deactivated) eluting with 2 to 5 to 10% MeOH in DCM. Trituration with DE-hexane gave the title compound as a cream solid (171 mg), m.p. 152-155°.

T.I.c. SiO2-Et3N deactivated (5% MeOH-DCM) Rf 0.20.

I.r. 3338; 2228; 1671; 1594; 1557; 1496; 1455 cm-1.

Example 17

2-{3-[3-(3-methoxy-phenyl)-ureido]-5-(2-dimethylamino-ethyl)-2-oxo-2,3-dihydro-benzo[e][1,4]diazepine- 1-yl}-N-methyl-N-phenyl-acetamide

A mixture of Intermediate 20 (100 mg) and Eschenmoser's salt (46 mg) in dimethoxyethane (5 ml) was heated at reflux for 4 hours, then poured into EA (50 ml) and extracted with 2N HCl (25 ml x 2). The combined aqueous extracts are basified to pH 8 with 2N Na2CO3 solution and then extracted with EA (30ml x 2). The combined organic extracts are dried and evaporated in vacuo. The crude product was purified by liquid chromatography on silica gel (Merck 9385-Et3N deactivated) eluting with 2 to 3 to 4 to 5% MeOH in DCM to afford the title compound as a cream solid (31 mg), m.p. 134°.

T.I.c. SiO2-Et3N deactivated (5% MeOH-DCM) Rf 0.13

I.r. (Solution in CHCl3) 2954; 1670; 1600; 1495; 1455; 1158 cm-1.

Example 18

2-{3-[3-(3-cyano-thenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1- yl)-N-methyl-N-phenyl-acetamide

A solution of Intermediate 14 (113 mg) in DCM (5 ml) was treated with 3-cyanophenyl isocyanate (39 mg) and the mixture was stirred at 23° under nitrogen for 18 h. The solvent was removed in vacuo and the residue chromatographed with EA-EtOH (10:0.5) as eluent to afford the title compound (64 mg) as a white solid, m.p. 165-7°.

T.I.c. (10:0.5 EA-EtOH) Rf 0.24

I.r. 3264; 2225; 1677; 1460; 1378 cm-1.

Example 19

1-[5-morpholin-4-yl-methyl)-2-oxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-benzo[e][1 ,4]diazepin-3-yl]-3-(3-oxazol-5-yl-phenyl)-urea

A solution of 3-(oxazol-5-yl)phenylamine (250 mg) in THF (6 ml) was treated under nitrogen at 0° with Et 3 N (79 mg) followed by triphosgene (77 mg). A solution of Intermediate 25 (125 mg) in THF (5 ml) was added and the mixture was stirred at 23° for 2 h. Phosphate buffer (pH 6.5; 30 ml) was added and the mixture was extracted with EA (30 ml). The organic phase is dried (Na2SO4) and the solvent is evaporated in vacuo. The residue is chromatographed. Elution with MeOH-EA (0.5:10) followed by MeOH-DCM (0.5:10) gave the title compound as a straw-colored solid (199 mg), m.p. 208-9°.

T.I.c. (9:1 DCM-MeOH) Rf 0.42

I.r. 3284; 1683; 1663; 1551; 1499; 1324; 1205; 1116; 1003; 774 cm-1.

Example 20

1-[5-(morpholin-4-yl-methyl)-2-oxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-benzo[e][ 1,4]diazepin-3-yl]-3-[3-(1,2,4-oxadiazol-3-yl)-phenyl)]-urea

A solution of Intermediate 31 (100 mg) in THF (6 ml) was treated with Et 3 N (63 mg) at 0° under nitrogen. Triphosgene and more Et3N (62 mg) are then added. The mixture is stirred at 0° for 0.5 hours. A solution of Intermediate 25 (200 mg) in THF (5 ml) was added and the mixture was stirred at 23° for 2 h. Then phosphate buffer (pH 6.5; 30 ml) is added and the mixture is extracted with DCM (30 ml). The organic phase was dried (Na 2 SO 4 ) and the solvent was evaporated in vacuo to give a residue which was chromatographed with MeOH-DCM (0.5:10 to 1:10) as eluent to give the title compound (97 mg) as a straw colored solid, m.p. 197-9° exp. T.I.c. (10:0.5 DCM-MeOH) Rf 0.27. I.r. (Solution in DMSO) 1684; 1656; 1615; 1599; 1568; 1540; 1510; 1347; 1204 cm-1

Example 21

N-ethyl-N-(4-fluoro-phenyl)-2-{3-[3-(4-fluoro-phenyl)-ureido]-5-(morpholin-4-yl-methyl)-2-oxo-2 ,3-dihydro-benzo[e][1,4]diazepin-1-yl}-acetamide

4-Fluorophenyl isocyanate (49 mg) in dry MeCN (0.5 ml) was added to a solution of Intermediate 30 (150 mg) in dry MeCN (1 ml) at 23° under nitrogen. After 1 h, DE (3 ml) was added and the precipitate was filtered off and dried in vacuo to give the title compound (100 mg) as a white solid, m.p. 197° decl.

T.I.c. (9:1 DCM-MeOH) Rf 0.51

I.r. 3340; 2926; 1672; 1509; 1461; 1378 cm-1.

Example 22

(+)-2-{3-[3-(3-methoxy-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4] diazepin-1-yl}-N-methyl-N-phenyl-acetamide hydrochloride salt

Solution of (+)-2-{3-[3-(3-methoxy-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4 ]diazepin-1-yl}-N-methyl-N-phenyl-acetamide (200 mg) in dry DCM (20 ml) under nitrogen is treated with 1M hydrogen chloride in diethyl ether (0.77 ml) while stirring the solution for 5 min. The solvent was removed in vacuo and the residue azeotroped with toluene (2x10 mL) to give the title compound (215 mg) as a straw-colored solid, m.p. 160-170° approx.

Pharmaceutical examples

[image]

The active ingredient, microcrystalline cellulose, lactose and pregelatinized starch are sifted through a 500 micron sieve and mixed in a suitable mixer. Magnesium stearate is sieved through a 250 micron sieve and mixed with the active mixture. The mixture is compressed into tablets using appropriate molds

[image]

The active ingredient, lactose and pregelatinized starch are mixed together and granulated with water. The wet mass is dried and ground. Magnesium stearate and Crospovidone are sieved through a 250 micron sieve and mixed with the granules. The resulting mixture is compressed using appropriate tablet molds.

[image]

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

[image] The active ingredient and lactose are mixed together and granulated with a Povidone solution. The wet mass is dried and ground. Magnesium stearate and Crospovidone are sieved through a 250 micron sieve and mixed with the granules. The resulting mixture is filled into hard gelatin capsules of the appropriate size.

The preferred active ingredient for use in pharmaceutical examples is the compound according to example 14.

CCK-B receptor binding

The binding affinity of the compounds of the invention for the CCK-B receptor (guinea pig cortex experiment) was determined using the method of G Dal Forno et al., J. Pharmacol. Exp. & Ther. 261 - 1056-1063. pKi values determined with representative compounds according to the invention are as follows:

[image]

The compounds according to the invention are essentially non-toxic and therapeutically useful doses. Thus, for example, no adverse effects were observed when the compound of Example 14 was administered to rats and dogs at doses in which the compound exhibits CCK-B antagonist activity.

Claims (15)

1. Compounds of general formula (I) [image] and their pharmaceutically acceptable salts; characterized in that R1 represents CH2CONR5R6 or CH2COR7; R2 represents a phenyl group optionally substituted with 1 or 2 substituents selected as halogen, alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, substituted amino, hydroxy, alkoxy, methylenedioxy, alkoxycarbonyl, oxazolyl or oxadiazolyl; A represents a C1-4 straight or branched alkylene chain; R3 and R4 independently represent hydrogen or C1-4 alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a saturated 5-7 membered heterocyclic ring, which ring may contain an additional heteroatom selected from oxygen, sulfur and nitrogen; R5 represents hydrogen or C1-4 alkyl; R 6 represents alkyl or phenyl, optionally substituted with halogen; or R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5- to 7-membered heterocyclic ring, which can optionally be substituted with 1 or 2 methyl groups or connected to a benzene ring; R7 represents a group selected from C1-4 alkyl, or optionally substituted phenyl; R8 represents hydrogen or a halogen atom; n is zero, 1 or 2. 2. Compounds according to Claim 1, characterized in that R1 is CH2CONR5R6 and R5 represents methyl or ethyl and R6 represents phenyl optionally substituted by halogen, or NR5R6 represents a saturated heterocyclic ring selected from pyrrolidino, 2,5-dimethylpyrrolidino, 3,3-dimethylpyrrolidino, piperidino, 3,3-dimethylpiperidino or 1-tetrahydroquinoline. 3. Compounds according to Claims 1 and 2, characterized in that R2 is phenyl or phenyl substituted by one or two groups selected from halogen, alkyl, alkoxy, amino, cyano, hydroxy, trifluoromethyl, oxazolyl or 1,2,4-oxadiazol-3- or groups. 4. Compounds according to one of Claims 1 to 3, characterized in that R2 is a phenyl substituent with a fluorine, oxazol-5-yl or methoxy group. 5. Compounds according to one of Claims 1 to 4, characterized in that A is a methylene chain. 6. Compounds according to one of Claims 1 to 5, characterized in that NR3R4 represents a pyrrolidino, piperidino, hexamethylene-imino, morpholino, thiomorpholino or N-methylpiperazine group. 7. Compounds according to one of claims 1 to 6, characterized in that NR3R4 is morpholino. 8. Compounds according to one of Claims 1 to 7, characterized in that R8 is hydrogen. 9. A compound characterized by the fact that 2-{3-[3-(3-methoxy-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1 ,4]diazepin-1-yl}-N-methyl-N-phenyl-acetamide, its (+) enantiomer or a pharmaceutically acceptable salt thereof. 10. A compound characterized by being selected as: N-methyl-2-[5-morpholin-4-ylmethyl-2-oxo-3-(3-phenyl-ureido)-2,3-dihydrobenzo[e][1,4]diazepin-1-yl]-N -phenylacetamide; N-methyl-2-{5-morpholin-4-ylmethyl-2-oxo-3-[3-(3-trifluoromethyl-phenyl)-ureido]-2,3-dihydrobenzo[e][1,4]diazepine- 1-yl}-N-phenylacetamide; 2-{3-[3-(3-cyano-phenyl)-ureido]-5-morpholin-4-ylmethyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1 - yl}-N-methyl-N-phenyl-acetamide; 1-[5-morpholin-4-yl-methyl)-2-oxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1 H-benzo[e][ 1,4]diazepin-3-yl]-3-(3-oxazol-5-yl-phenyl)-urea; N-ethyl-N-(4-fluoro-phenyl)-2-{3-[3-(4-fluorophenyl)-ureido]-5-(morpholin-4-yl-methyl)2-oxo.2,3- dihydro-benzo[e][1,4]diazepin-1-yl}-acetamide; their enantiomers, and their physiologically acceptable salts. 11. Process for the preparation of the compounds defined in Claim 1, characterized in that it includes: a) reacting compounds of formula (II), where R1, A, R3, R4 and R8 have the meaning defined as in formula (I), and R9 represents a group that is eliminated [image] with amine R 2 NH 2 , where R 2 has the meaning defined in formula (I); b) reacting the compound of formula (III) where R1, R3, R4, R8 and A have the meaning defined in formula (I) [image] with isocyanate R 2 NCO or carbamoyl chloride R 2 HNCOCl (where R 2 has the meaning defined in formula (I); c) reacting the compound of formula (XII), where R1, R2 and R8 have the meaning defined in formula (I) [image] with amine R3R4NH, where R3 and R4 have the meaning defined in formula (I); and thereafter, if desired or necessary, subjecting the resulting compound, either before or after separation into stereochemical isomers, to one or more of the following reactions. 1) conversion of one compound of formula (I) into another compound of formula (I). 2) converting the compound of formula (I) into its acid addition salt. 12. Pharmaceutical preparations, characterized in that they contain a compound as defined in one of Claims 1 to 10 together with one or more physiologically acceptable carriers or excipients. 13. Compounds as defined in any of Claims 1 to 10, characterized in that they are used in therapy. 14. Use of a compound as defined in any one of Claims 1 to 10, characterized in that they are used in the production of medicaments for the treatment of conditions in which modification of the effect of gastrin and/or CCK is of therapeutic benefit. 15. A method of treating a mammal, including a human, for use in a condition where modification of the effects of gastrin and/or CCK is of therapeutic benefit and comprising administering an effective amount of a compound as defined in any one of claims 1 to 10.