AU650034B2 - Benzodiazepine derivatives - Google Patents

Description

OPI DATE 18/02/92 AOJP DATE 26/03/92 APPLN. InT 821.71 91 PCT NUMBER PCT/JP91/00952 INTERNATIuiNAL rrLiU/A IlIN rUaLlrtlanu uINutK inci rAn iIi uurr. aiuiN fREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/01683 C07D 403/06, 401/14, 403/14 Al C07D 243/20, A61K 31/55 (43) International Publication Date: 6 February 1992 (06.02.92) (21) International Application Number: PCT/JP91/00952 (74) Agent: SEKI, Hideo; Fujisawa Pharmaceutical Co., Ltd.

Osaka Factory, 1-6, Kashima 2-chome, Yodogawa-ku, (22) International Filing Date: 17 July 1991 (17.07.91) Osaka-shi, Osaka 532 (JP).

Priority data: (81) Designated States: AT (European patent), AU, BE (Euro- 9015879.1 19 July 1990 (19.07.90) GB pean patent), CA, CH (European patent), DE (European patent), DK (European patent), ES (European patent), FI, FR (European patent), GB (European patent), (71) Applicant (for all designated States except US): FUJISAWA GR (European patent), HU, IT (European patent), JP, PHARMACEUTICAL CO., LTD. [JP/JP]; 4-7, Dosh- KR, LU (European patent), NL (European patent), NO, omachi 3-chome, Chuo-ku, Osaka-shi, Osaka 541 SE (European patent), SU, US.

(72) Inventors; and Inventors/Applicants (for US only) SATO, Yoshinari [JP/ Published JP]; 1-9, Higashihagoromo 7-chome, Takaishi-shi, Osaka With international search report, 592 ITANI, Hiromichi [JP/JP]; 2-13-541, Kawasak- Before the expiration of the time limit for amending the icho, Akashi-shi, Hyogo 673 OGAHARA, Takato- claims and to be republished in the event of the receipt of mo [JP/JP]; 6-20, Misuzugaokamidori 3-chome, Saeki- amendments.

ku, Hiroshima-shi, Hiroshima 731-51 (JP).

65(54) Title: BENZODIAZEPINE DERIVATIVES (54) Title: BENZODIAZEPINE DERIVATIVES 1

A-R-

I

N

R~ /---NHCO-R 4 R (I) (57) Abstract Benzodiazepine derivatives of formula wherein R 1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R 2 is hydrogen or halogen, R 3 is aryl which may have one or more suitable substituent(s), R 4 is aryl which may have one or more suitable substituent(s), etc., and A is lower alkylene, and pharmaceutically acceptable salts thereof which are use'ul as a medicament.

WO 92/01683 PCY/JP91/00952 1

DESCRIPTION

BENZODIAZEPINE DERIVATIVES TECHNICAL FIELD This invention relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.

BACKGROUND ART Some benzodiazepine derivatives have been known as described, for example, in European Patent Application Publication No. 349949 and U.S. Patent 4,820,834.

DISCLOSURE OF INVENTION This invention relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof.

More particularly, it relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCK) antagonists and therefore useful as therapeutical and/or preventive agents for emesis, pancreatitis, disorders of appetite regulatory systems, pain, insulinoma, gastroparesis, carcinoma of pancreas, gallbladder disease acute cholecystitis, calculus, etc.), disorders associated with intenstinal smooth muscle hyperactivity irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia, dyspepsia, nausea, etc.

The benzodiazepine derivatives of this invention can be represented by the following formula WO 92/01683 PCT/JP91/00952 2 2 NNHCO-R 4

R

3 3 wherein R 1 is heterocyclic group which may have one or more suitable substituent(s), or cyano,

R

2 is hydrogen or halogen, R is aryl which may have one or more suitable substituent(s), R is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R 4 is indolyl, then R is tetrazolyl which may have one or more suitable substituent(s) and

R

3 is halophenyl or (ii) R 1 is imidazolyl which may have one or more suitable substituent(s), R is halophenyl and A is ethylene.

According to the present invention, the new benzodiazepine derivatives can be prepared by the processes which are illustrated in the following scheme.

WO 92/01683 WO 9201683PCT/3P91/00952 -3 Process I.

R2 N. N- N 2 or its reactive derivative at the am~no group, or a salt thereof 0 HO-C-R 4

(III)

or its reactive derivative, or a salt thereof

A-R

(1) or a salt thereof Process 2 or a salt thereof WO 92/01683 WO 9201683PCT/JIP91/00952 -411- I.Elimination reaction of the irnino protective group AR1 b 0 2_NHCO-R 4 (Ib) or a salt thereof Process 3 (Ic) or a salt thereof Reduction WO 52/01683 WO £201683PC1'/JP91 /00952 5 1 0

N

R 3 (Id) or a salt thereof Process 4 H 0 is R 2/NHCO-R 4 R 3 X-A-R

I

MV

or a salt thereof

(IV)

or a salt thereof or a salt thereof WO 92/01683PT/P9095 PCY/JP91/00952 Process A-CN0

-NHCO-R

4

N"

2 HN 3

(VI)

(Ie) or a salt thereof or a salt thereof

H

N-N

N

A 0 N NHCO-R4 or a salt thereof.L wherein R, R, R R and A are each as defined above, R i heterocyclic group having a protected imino gr:oap of the formula I (in which R 6is imino protective R 6 group0) in its hetero ring, which m~y have one or WO 92/01683 PCT/JP91/00952 more suitable substituent(s), R1 is heterocyclic group having an imino group of the formula

\N

H

in its hetero ring, which may have one or more suitable substituent(s),

R

4 is ar(lower)alkenyl having a nitro group, a4

R

b is ar(lower)alkenyl having an amino group and X is an acid residue.

The starting conounds (II) and (IV) can be prepared by the following processes.

Process A

A-R

1 24' R 7 N

(VII)

or a salt thereof Elimination reaction of the amino protective group

A-R

1 N

NH

2

R

3

(II)

salt thereof or a salt thereof WO 92/01683 PCT/JP91/00952 8 Piocess B

H

NH

0 I 4

HO-C-R

(VIII)

or its reactive derivative at the amino group, or a salt thereof

(III)

or its reactive derivative, or a salt thereof 0

-NHCO-R

%NHCO-R"

(IV)

or a salt thereof wherein R R R R and A are each as defined above, 25 and

R

7 is protected amino.

The starting compound (VII) or a salt thereof can be prepared by the methods disclosed in the Preparations 1-3, 6 and 7 described later or similar manners thereto.

With regard to the object compound in case that the compound has the group of the formula 9

NH

in R said group can also exist in the tautomeric form and such tautomeric equilibrium can be represented by the following scheme.

H

N

N

NH N

(B)

Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula Further, in case that the compound has the group of tne formula S 0

/N

N- N 30 in R said group can also exist in the tautomeric form and such tautomeric equilibrium can be represented by the following scheme.

WO 92/01683 PCr/JP91/009-52 10

H

N N N- N N NH

(D)

Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula Suitable pharmaceutically acceptable salts of the object compound are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g.

sodium salt, potassium salt, etc.) and an alkaline earth metal salt calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g.

arginine, aspartic acid, glutamic acid, etc.), and the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon WO 92/01683 PCr/JP91/00952 11 atom(s), unless otherwise indicated.

Suitable "heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.

1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl 4,5-dihydro-1,2,4triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl tetrazoloetc.), dihydrotriazolopyridazinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l1,2,5-oxadiazolyl, etc.) etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitroger atom(s), for example, morpholinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 WO 9)2/01683 PCr/J P91/0952 12 oxygen atom(s) and 1 to 3 nitrogen atom( for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazol-1l, thiazolinyl, thiadiazolyl 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like.

Suitable "substituent" in the terms "heterocyclic group which may have one or more suitable substituent(s)" and "heteromonocyclic group which may have one or more suitable substituent(s)" may include amino, protected amino as exemplified below, oxo, hydroxy, imino protective group as exemplified below, lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.) and the like.

Suitable "protected amino" may include acylairino and the like.

Suitable "imino protective group" may include acyl, mono(or di or tri)phcnyl(lower)alkyl trityl, etc.) tetrahydropyranyl and the like.

Suitable "acy!" and "acyl moiety" in the ter.

"acylamino" may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.

And, suitable examples of the said acyl may be lower WO 92/01683 PCr/JP9]/0952 13 alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl benzeneSulfonyl, tosyl, etc.); aroyl benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

The acyl moiety as stated above may have at least one suitable substituent(s) such as halogen chlorine, bromine, fluorine and iodine), a.nino, protected amino lower alkanoylamino, phenylthioureido, etc.), or the like.

Suitable "acid residue" may include halogen and the like.

Suitable "halogen" may include chlorine, bromine, fluorine and iodine.

Suitable "aryl" and "aryl moiety" in the terms "ar(lower)alkenyl" and "arylamino" may include phenyl, naphthyl and the like.

Suitable "substituent" in the terms "aryl which may have one or more suitable substituent(s)", ar(lower)alkenyl which may have one or more suitable substituent(s)" and "arylamino which may have one or more suitable substituent(s)" may include hydroxy, protected WO 92/01683 i3CY/JPF91 /00952- 14 hydroxy as exemplified below, nitro, lower alkoxy (e.g.

methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloy, t-pentyloxy, hexyloxy, etc.), amino, protected amino as exemplified above, lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.), halogen as exemplified above, and the like.

Suitable "lower alkenyl moiety" in the term "ar(lower)alkenyl" may include vinyl, allyl, 1-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.

Suitable 'heteromonocyclic group" may include saturated or unsaturated heteromonocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heteromonocyclic group may be heteromonocyclic group such as unsaturated 3to 8-membered heteromonocyclc group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.

1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl 4,5-dihydro-l,2,4triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadazolyl, etc.) etc.; saturated 3 to 8-membered heteromonocyclic group WO 92/01683 PCT/J P91 /00952 15 containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazoylyl, 1,2,3-thiadiazolyl, etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.; unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; and the like.

Suitable "lower alkylene" may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atom(s).

Preferable "heterocyclic group" in the terms "heterocyclic group having a protected imino group of the formula N 1 (in which R is imino protective group)

R

6 in its hetero ring" and "heterocyclic group having an imino group of the formula in its hetero ring"

H

may include unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrroly1, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyridaziny', tetrahydropyridazinyl, triazolyl 1,2,4-triazolyl, 1H-l,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl WO 92/01683 PC~/JP91/00952 16 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl 4,5-dihydro-l,2,4-triazinyl, 2,5-dihydro-l,2,4-triazinyl, etc.), etc.; saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; and the like.

The preferred embodiments of the object compound (I) are as follows.

R

1 is heterocyclic group (more preferably unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), most preferably tetrazolyl or imidazolyl) which may have one to three (more preferably one) suitable substituent(s) [more preferably tetrazolyl or imidazolyl, each of which may have an imino protective group; most preferably tetrazolyl or imidazolyl, each of which may have mono(or di or tri)phenyl(lower)alkyl], or cyano;

R

2 is hydrogen;

R

3 is aryl (more preferably phenyl) which may have one to three (more preferably one) suitable substicuent(s) [more preferably phenyl or halophenyl];

R

4 is aryl (more preferably phenyl or naphthyl) which may have one to three (more preferably one or two) suitable substituent(s) [more preferably phenyl or naphthyli each of which may have one or two substituent(s) selected from the group consisting of halogen and amino; most preferably naphthyl, dihalophenyl or phenyl having halogen and amino], ar(lower)alkenyl (more preferably phenyl(lower)alkenyl) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenyl(lower)alkenyl which may have amino or nitro; most preferably nitrophenyl(lower)alkenyl WO 92/01683 PCr/JP9]/00952 17 or aminophenyl(lower)alkenyl], arylamino (more preferably phenylamino) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenylamino which may have lower alkyl or halogen; most preferably lower alkylphenylamino or halophenylamino], heteromonocyclic group (more preferably pyridyl or tetrahydropyridazinyl) which may have one to three (more preferably one) suitable substituent(s) [more preferably pyridyl, or tetrahydropyidazinyl which may have an oxo group; most preferably pyridyl, or tetrahydropyridazinyl having an oxo group], quinolyl, isoquinolyl, cinnolinyl, indolyl or quinoxalinyl, and A is lower alkylene (more preferably C 1

-C

4 alkylene), with proviso that when R is indolyl, then

R

1 is tetrazolyl and

R

3 is halophenyl or (ii) R 1 is imidazolyl which may have mono(or di or tri)phenyl(lower)alkyl,

R

3 is halophenyl and A is ethylene.

The processes for preparing the object compound (I) and the starting compounds of the present invention are explained in detail in the following.

Process 1 The compound or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (II) or its reactive derivative or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with-a carbonyl compound such as WO 92/01683 PC/JP91/0952 18 aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as N,0-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene and the like.

Suitable salts of the compound (II) and (III) can be referred to the ones as exemplified for the compound Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, isocyanate and the like. The suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g.

methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.

pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.

cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2 ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound N,N-dimethylhydroxylamine, WO 92/01683 P(cr/J P9j/00952 19 l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6-chloro-lH-benzotriazole, etc.), isocyanate of the formula R5-N=C=O (in which R 5 is aryl which may have one or more suitable substituent(s)), and the like.

These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphsphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);-phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; hydroxide intra-molecular salt; l-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of WO 92/01683 PCr/JP91/009$2 20 N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like. The reaction temerrature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2 The compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the imino protective group.

Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.

For Hydrolysis The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and an organic base such as an alkali metal sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo[4.3.01- 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

Suitable acid may include an organic acid [e.g.

formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. The elimination using Lewis acid such as trihaloacetic acid trichloroacetic acid, trifluoroacetic acid, etc.) or WO 92/01683 PT/JP9]/00952 21 the like is preferably carried out in the presence of cation trapping agents anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, an alcohol methanol, ethanol, etc.], N,N-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

(ii) For reduction Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are a combination of a metal tin, zinc, iron, etc.) or metallic compound chromium chloride, chromium acetate, etc.) and an organic or inorganic acid formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g.

platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g.

reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g.

reduced iron, Raney iron, etc.), copper catalysts (e.g.

reduced copper, Raney copper, Ullman copper, etc.) and the like. The reduction is usually carried out in a conventional solvent which does not adversely influence WO 92/01683 Pr-/J P91 /00952 22 the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.

Process 3 The compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to reduction reaction. This reduction reaction can be referred to that of the aforementioned Process 2.

Process 4 The compound or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound or a salt thereof.

Suitable salts of the compounds (IV) and can be referred to 'the'ones as exemplified for the compound This reaction is usually carried out in the presence of base.

Suitable base may include an inorganic base such as alkali metal hydride sodium hydride, etc.), alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g.

magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g.

magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate sodium acetate, potassium acetate, etc.), alkaline earth metal WO 92/01683 1'1/J P9 1/00952 23 phosphate magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine or the like.

This reaction is usually carried out in a solvent such as alcohol methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process The compound (If) or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof with the compound (VI) or a salt thereof.

Suitable salts of the compounds (Ie) and (If) can be referred to the ones as exemplified for the compound Suitable salts of the compound (VI) may include an alkali metal salt sodium salt, potassium salt, etc.) and the like.

The reaction is usually carried out in a conventional solvent such as l-methyl-2-pyrrolidinone, N,N-dimethylformamide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out under warming to heating.

Process A The compound (II) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to elimination reaction of the amino protective group.

WO 92/01683 PCT/JP91/00952 24 Suitable salts of the compound (VII) can be referred to the ones as exemplified for the compound The elimination reaction is carried out in accordance with a conventional method such as hydrolysis; reduction; Edman's method (phenyl isothiocyanate method); or the like. The hydrolysis may include a method using an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliminated.

Among these methods, hydrolysis ti ng an acid is one of the most common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl, for example, tert-pentyloxycarbonyl, lower alkanoyl formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.

Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acids can be selected according to the kind of the protective group to be eliminated.

The elimination reaction reaction using trifluoroacetic acid may be carried out in the presence of anisole. The hydrolysis using hydrazine is commonly applied for eliminating a phthaloyl, succinyl type amino-protective group.

The elimination using base is used for elimini ig an acyl group such as trifluoroacetyl. Suitable base may WVO 92/01683 PCf/JP91t/00952 25 include an inorganic base and an organic base.

The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g.

benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc.

Suitable reduction may include, for example, reduction with an alkali metal borohydride sodium borohydride, etc.), reduction with a combination of a metal tin, zinc, iron, etc.) or the said metal together with a metal salt compound chromous.chloride, chromous acetate, etc.) and an organic or inorganic acid acetic acid, propionic acid, hydrochloric acid, etc.); and catalytic reduction. Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide, palladium on carbon and the like.

Among the protective groups, the acyl group can generally be eliminated by hydrolysis. Especially, halogen substituted-alkoxycarbonyl and 8-quinolyloxycarbonyl groups are usually eliminated by treating with a heavy metal such as copper, zinc, or the like.

The reaction is usually carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned above, and the reaction is usually carried out under a mild condition such as under cooling or at slightly elevated temperature. Among the protective groups, the acyl group derived from a-amino acid can be eliminated by Edman's method.

WO 92/01683 PCT/J 1,91/00952 26 Process B The compound (IV) or a salt thereof can be prepared by reacting the compound (VIII) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof.

The reaction is carried out by substantially the same method as that of Process 1, and therefore the reaction method and conditions are to be referred to said Process 1.

The object compound and pharmaceuzically acceptable salts thereof are. CCK antagonists and therefore useful as therapeutical agents for emesis, pancreatitis, etc.

Further, it is expected that the object compound (I) and pharmaceutically acceptable salts thereof have gastric antagonism and are useful as therapeutical and/or preventive agents for ulcers, excess gastric secretion, Zollinger-Ellison 'Syndrome, etc.

In order to show the utility of the object compound the pharmacological activity of the representative compound thereof is shown in the following.

II] Test Compound (3S)-l,3-Dihydro-l-(4-imidazolylmethyl)-3-[(E)-3-(2eminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one dihydrochloride [hereinafter referred to as test compound A] [II] Test CCK receptor antagonism in isolated fundic circular muscle from auinea Dia stomach Test Method The strip of circular muscle from guinea pig stomach was suspended in 25 ml organ bath containing Krebs' WO 92/01683 PCT/JPg!/o0952 27 bicarbonate solution (NaCl 118mM, KCl 4.8mM, KH 2

PO

4 1.2mM, MgSO 4 1.2mM, CaCl 2 2.5mM, NaHCO 3 25mM, glucose llmiV and bovine serum albumin maintained at 37°C and gassed with 95% 02 and 5% CO 2 The strip was placed under an initial tension of g and equilibrated for 60 minutes during which the bath volume was replaced every 15 minutes. Isometric contraction was measured using a force transducer. CCK-8 (3.2 x 10- 7 M) was added to the bathing solution and the contractile force was measured. After washing out CCK-8, it stood for about 15 minutes until contractile force became plateau. Then test compound A (1 x 10- 6 M) was added. 5 minutes later, CCK-8 was added and the contractile force was recorded. CCK antogonism was calculated by comparing the contractile force induced by CCK in the absence or presence of test compound A.

Test Result Inhibition 89.9 The object compound or pharmaceutically acceptable salts thereof can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection.

The pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate calcium carbonate, etc.), binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, WO 92/01683 PCT/P91/00952 28 gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent citric acid, mentol, glycine, orange powders, etc.), preservative (e.g.

sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer citric acid, sodium citrate, acetic acid, suspending agent methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent water), base wax cacao butter, polyethyleneglycol, white petrolatum, etc.).

The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.

The following Preparations and Examples are given only for the purpose of illustrating the present invention in more detail.

WO 92/01683 PC/JP91/00952 ?9 Preparation 1 To a solution of (3RS)-3-phthalimido-5-(2fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one (21.17 g) in N,N-dimethylformamide (400 ml) was added gradually sodium hydride (2.0 g, 60% suspension in mineral oil) under cooling in an ice-bath and nitrogen atmosphere.

The mixture was stirred under the same conditions for hour and at ambient temperature for 1 hour. The mixture was cooled in ice-bath and a solution of chloroacetonitrile (3.48 ml) in N,N-dimethylformamide ml) was added dropwise thereto. The mixture was stirred for 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture'was added acetic acid (3.5 g) under cooling and the resultant mixture was poured into a mixture of ethyl acetate and water under stirring. The mixture was adjusted to pH with aqueous sodium bicarbonate. The crystals were collected by filtration and washed with cold ethyl acetate to give (3Ra)-3-phthalimido-l-cyanomethyl-l,3-dihydro-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (20.9 g).

mp 260 0 C (dec.) IR (Nujol) 2160, 1776, 1725, 1700, 1604 cm-1 NMR (DMSO-d 6 6) 5.15 (2H, ABq, J=24.6Hz, 17.8Hz), 5.83 (1H, 7.2-8.1 (12H, m) Preparation 2 A mixture of (3RS)-3-phthalimido-l-cyanomethyl-l,3dihydro-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (20.0 sodium azide (8.43 g) and triethylamine hydrochloride (8.92 g) in N-methyl-2-pyrrolidone (350 ml) was heated at 145°C under stirring for 3.5 hours. After cooling to ambient temperature, the mixture was poured into 5% hydrochloric acid (500 ml) and ice. The resultant precipitates were collected by filtration, washed with cold water several times -and dried over phosphorus WO 92/01683 PCT/JP91/00952 30 pentoxide under reduced pressure to afford (3RS)-3phthalimido-l,3-dihydro-5-(2-fluorophenyl)-l-[(1Htetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (18.07 g).

-i IR (Nujol) 1778, 1720, 1693, 1610 cm 1 NMR (DMSO-d 6 6) :5.46 (2H, 5.85 (1H, s), 7.2-8.0 (13H, m) Preparation 3 To a solution of (3RS)-3-phthalimido-l,3-dihydro-5- (2-fluorophenyl)-l-[(IH-tetrazol-5-yl)methyl]-2H-1,4benzodiazepin-2-one (18.07 g) and trityl chloride (10.99 g) in N,N-dimethylformamide (330 ml) was dropwise added a solution of triethylamine (4.6 g) in N,N-dimethylformamide (10 ml) under stirring and cooling in an ice-bath. The mixture was stirred for 20 minutes under the same conditions and at ambient temperature overnight. The reaction mixture was poured into an ice-water (500 ml), and the resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to afford (3RS)-3-phthalimido-l,3-dihydro-5-(2-fluorophenyl)-1- [(l-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin- 2-one (33.41 g) as white powder.

-i IR (Nujol) :1778, 1723, 1695, 1610 cm NMR (DMSO-d 6 6) 5.56 (2H, ABq, J=16.0Hz, 52.6Hz), 5.80 (1H, 6.8-8.1 (27H, m) Preparation 4 To a suspension of (3RS)-3-phthalimido-l-[(l-trityl- 1H-tetrazol-5-yl)methyll-5-(2-fluorophenyl)-1,3-dihydro- 2H-1,4-benzodiazepin-2-one (33.4 g) in tetrahydrofuran (500 ml) was added hydrazine hydrate (1.90 g) under stirring at ambient temperature. The mixture was stirred for 2 hours at the same temperature and refluxed under WO 92/01683 WO 9201683PCT/JP91 /00952 stirring for 2 hours. The reaction mixture was cooled in an ice-bath and the resultant precipitates were filtered off. The filtrate and the washings were combined and evapoorated to afford a residue, which was stirred in ethyl acetate and filtered. The filtrate and washings were combined and evaporated to give white powder (14.43 g) of (3RS)-3-a-mino-l,3-dihydro-5-(2-fluorophenyl)-l-[ (1trityl-lH-tetrazol-5-yl)methyll-2H-l, 4-benzodiazepin-2one.

IR (Nujol) 3350, 1686, 1597, 760, 700 cm1 NNR (CDC 3 6) :2.93 '(2Hi, br 4.62 (1H1, 5.42 (2H1, ABg, J=19.GHz, 15.8Hz), 6.8-7.6 .(23H1, m) Preparation The following compound was obtained according to a similar manner to that of Preparation 4.

(3RS)-3-Amino-l,3-dihydro-5-phenyvl-l-[ (l-trityl-lHt-etrazol-5-yl)methylJ-2H-1,4-benzodiazerin-2-one mp :132-135'C IR (Nujol) 3375,*1680, 1595, 1575, 1560 cm- NIVR (CDCl 3 6) 2.72 (2H1, 4.55 (1H1, s), 5.46 (2H1, ABg, J=1611z, 51Hz), 6.90-6.70 (6H, in), 7.15-7.50 (18H, m) Preparation 6 ITo a solution of (3RS)-3-amino-l,3-dihydro-5-(2fluorophenyl)-'l-[ (l-trityl-lH-tetrazol-5-yl)methyl-2Hl,4-benzodiazepin-2-one (11.54 g) and N-t-butoxycarbonyl- L-phenylalanine (5.42 g) in N,N-dimethylformamide (200 ml) were added successively l-hydroxybenzotriazole (2.76 g), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.91 g) and triethylamine (2.36 g) u;.dcr stirring at ambient temperature. The mixture was stirred under the same conditions for 4.5 hours and then poured WO 92/01683 PCT/JP91/00952 32 into water (1.5 under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give a mixture (16.29 g) of (3R)-3-[((2S)-2-t-butoxycarbonylamino-3phenylpropanoyl)amino]-l,3-dihydro-5-(2-fluorophenyl)-l- [(1-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin- 2-one and (3S)-3-[((2S)-2-t-butoxycarbonylamino-3phenylpropanoyl)amino]-l,3-dihydro-5-(2-fluorophenyl)-l- [(l-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin- 2-one.

mp 108-114°C

-I

IR (Nujol) 3330, 1700, 1690, 1675, 1610 cm- 1 NMR (DMSO-d 6 6) 1.28 (9H, 2.65-2.9 (1H, m), 3.0-3.2 (1H, 4.40 (1H, 5.33-5.41 (2H, 5.39, 5.40 (1H, each d, J=8Hz), 5.58 (2H, ABq, J=16.8Hz, 82.2Hz), 6.8-7.95 (14H, m), 9.25, 9.37 (1H, each d, J=8Hz) Preparation 7 A mixture.of a mixture (16.2 g) of butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro- 5-(2-fluorophenyl)-l-[(l-trityl-lH-tetrazol-5-yl)methyl]- 2H-1,4-benzodiazepin-2-one and (3S)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-l,3-dihydro-5- 2H-1,4-benzodiazepin-2-one and 4N solution of hydrogen chloride in ethyl acetate (200 ml).was stirred at ambient temperature for 5 hours. The mixture was concentrated in vacuo to give a residue, which was dissolved in methanol (100 ml) and neutralized with a.n ethanolic ammonia. The mixture was concentrated in vacuo to dryness. The residue was subjected to column chromatography on silica gel with an eluent (CHC1 3 :CH3OH 10:1). The fractions containing WO 92/01683 PCT/JP91/00952 -33 the object compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3S)-3-[((2S)-2-amino-3-phenylpropanoyl)anino3-1,3dihydro-5-(2-fluorophenyl)-l-[ 2H-l,4-benzodiazepin-2-one (4.57 g).

NI4R (DMSO-d 616) :2.91 (1H, dd, J=14.0Hz, 8.4Hz), 3.20 (1H, dd, J=4Hz, 14.0Hz), 4.13 (1H, dd, J=4Hz, 8.4Hz), 5.26 (2H, ABq, J=15.4Hz, 31.6Hz), 5.39 (1K, d, J8S.OHz), 7.1-7.35 (10H, mn), 7.52-7.66 (4H, in), 7.96 (1H, d, J=8.4Hz), 9.77 (1H, d, J=8.O~z) The fractions containing the other object compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give ((2S)-2-amino-3-phenylpropanoyl)amino]-l,3-dihydro-5-(2-fluorophenyl)-l-[ (1Ktetrazol-5-y1)methyl]-2H-1,4-benzodiazepin-2-one (4.76 g).

NI4R (DMSO-d 6 6) :3.0-3.17 (1H, mn), 3.57-3.64 (1H, in), 3.0-4.1 (2H, broad), 4.21 (1H, t, J=4.2Hz), 5.19 (2K, ABg, J=15.6Hz, 70.1Hz), 5.38 (1H, d, J=8.3Hz), 7.16-7.4 (10H, in), 7.51-7.67 (4H, mn), 7.97 (1H, d, J=8.2Kz), 9.78 (1H, d, J=B3.3Hz) Preparation 8 To a solution of (3S)-3-[I((2S)-2-amino-3phenylpropanoyl) amino] 3-dihydro-5- (2-f luorophenyl) -1- [(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (4.57 and triethylamine (0.974 g) in dried tetrahydrofuran (45 ml) was added phenyl isothiocyanate (2.54 g) under stirring at ambient temperature.

The mixture was stirred for 2 hours at ambient temperature and for 1 hour at 50 0 C. To the reaction mixture was added lN-hydrochloric acid (9.64 ml) under ice cooling.

WO 92/01683 PCT/JP91/00952 34 The mixture was concentrated in vacuo to give a residue, which was extracted with ethyl acetate. The extract was washed with water twice and dried over magnesium sulfate.

Removal of the solvent in vacuo afforded an amorphous mass (7.23 which was powdered by stirring in diisopropyl ether for 3 hours. The resultant powder was collected by filtration and washed with diisopropyl ether to give (3S)-3-[[(2S)-2-{N'-(phenyl)thioureido}-3-phenylpropanoyl]amino]-l,3-dihydro-5-(2-fluorophenyl)-l-[(1Htetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (5.63 g).

The product obtained above was suspended in tetrahydrofuran (35 ml) and'4N-hydrogen chloride in ethyl acetate (33.5 ml) was added dropwise thereto under ice-cooling. Tbe mixture was stirred for 5 hours and then evaporated in vacuo to give a viscous oil, which was washed with ethyl acetate by stirring for 3 hours. The resultant powder was collected by filtration, and dried under reduced pressure to give (3S)-3-amino-l,3-dihydro- 5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4benzodiazepin-2-one hydrochloride (2.91 g).

30 =-36.360 (C=0.495, CH3OH) Preparation 9 The following compound was obtained according to a similar manner to that of Preparation 8.

(3R)-3-Amino-l,3-dihydro-5-(2-fluorophenyl)-1-[(1Htetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride 30 [a 30 33.460 (C=0.505, Preparation To a suspension of (3RS)-3-amino-l,3-dihydro-5-(2fluorophenyl)-2H-l,4-benzodiazepin-2-one (2.0 g) in methylene chloride (30 ml) was added dropwise WO 92/01683 PCT/JP91/00952 35 triethylamine (1.61 g) under stirring and cooling in an ice-bath. To the mixture was added 2-naphthoyl chloride (1.52 g) under the same conditions. The mixture was stirred for 2 hours at the same temperature. The resultant precipitate was collected by filtration and washed with methylene chloride and water successively.

The collected crystals were dried over phosphorus pentoxide under reduced pressure to give (3RS)-3-(2-naphthoylamino)-5-(2-fluorophenyl)-1,3dihydro-2H-1,4-benzodiazepin-2-one (2.33 g).

NMR (DMSO-d 6 6) 5.6D (1H, d, J=7.7Hz), 7.22-7.39 7.54-7.66 (5H, 7.99-8.11 (4H, m), 8.72 (1H, 9.74 (1H, d, J=7.7Hz), 11.05 (1H, m) MASS 423 (M Prenaration 11 The following compounds were obtained according to a similar manner to that of Preparation (3RS)-3-(3-Quinolylcarbonylamino)-5-(2-fl .orophenyl)- 1,3-dihydro-2H-l,4-benzodiazepin-2-one IR (Nujol) 3600, 1695, 1670, 1610, 1590, 1515 cm-1 NMR (DMSO-d 6 6) 5.59 (1H, d, J=7.6Hz), 7.23-7.40 (5H, 7.61-7.76 (4H, 7.67-7.94 (1H, m), 8.1-8.16 (2H, 9.09 (1H, 9.40 (1H, d, J=2.1Hz), 10.1 (1H, d, J=7.6Hz), 11.08 (1H, s) (3RS)-3-(3,4-Dichlorobenzoylamino)-5-(2fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one NMR (DMSO-d 6 6) 5.49 (1H, d, J=7.6Hz), 7.2-8.02 (11H, 8.21 (1H, 9.93 (1H, d, J=7.6Hz), 11.03 (1H, s) MASS 442 (M WO 92/01683 PCT/JP91/00952 36 Example 1 To a solution of (3S)-1,3-dihydro-5-(2-fluorophenyl)- 3-amino-l-[(l-tritylimidazol-4-yl)methyl]-2H-1,4benzodiazepin-2-one (1.0 g) in N,N-dimethylformamide ml) were added successively (E)-3-(2-nitrophenyl)propenoic acid (330 mg), l-hydroxybenzotriazole (230 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg) and triethylamine (170 mg) under stirring at ambient temperature. The mixture was stirred for 3 hours and allowed to stand overnight. The reaction mixture was poured into a mixture of ethyl acetate and water under stirring. The separated organic layer was washed with water twice and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3S)-l,3-dihydro-l-[(l-tritylimidazol-4-yl)methyl)-3- [(E)-3-(2-nitrophenyl)propenoylamino]-5-(2-fluorophenyl)- 2H-l,4-benzodiazepin-2-one (1.16 g).

NMR (CDC13, 6) :5.07 (2H, br 5.66-5.7 (1H, m), 6.49-8.14 (32H, m) Example 2 The following compounds were obtained according to a similar manner to that of Example 1.

(3S)-l,3-Dihydro-l-[(l-tritylimidazol-4-yl)methyl]- 3-[(2-amnino-4-chlorobenzoyl)amino]-5- (2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR (CDC13, 6) 5.06 (2H, d, J=3.7Hz), WO 92/01683 PCT/JP9]/00952 37- 5.62-5.68 (3H, mn), 6.63-8.04 (29H, mn) MASS (in/e) 502 (M +-243) (3RS)-1,3-Dihydro-1-t (l-trit~yliinidazol-4-y1)inethyl)- 3-[H2,3,4,5-tetrahydro-3-oxopyridazin-6-yl)- (2-f luorophenyl) 4benzodiazepin-2-one (3RS)-1,3-Dihydro-1-[ (l-trityliinidazol-4-yl)rnethyll- 3-(3,4-dichlorobenzoylanino)-5-(2--fluorophenyl)-2H- 1, 4-benzodiazepin-2-one- NMR (CDC1 3 1 6) :5.02 (1H, d, 5.12 (1H, d, J=15H-z), 5.67 (1H, d, J=7.8Hz), 6.85-8.04 (29H, in) (3RS)-1,3-Dihydro-l-t (l-trityiiidazol-4-yl)inethyl)- 3- (3-quinolylcarbonylanino) (2-f luorophenyl) -2H- 1, 4-benzodiazepin-2-one NMR (DMSO-d 6 6) 5.01-5.18 (2H, mi), 5.78 (1H, d, J=7.8Hz), 6.87-8.26 (30H, mn), 8.72 (1H, d, J=1.9Hz), 9.44 (1H, d, J=2.2Hz) MASS (in/e) :504 243), 424 (3RS)-1,3-Dihydro-1-E (1-trityliiniazoli-4-yl)inethyl3- 3- (2-quinoxalinylcarbonylanino) (2-f iuorc,,henyi) 2H-1, 4-benzodiazepin-2-one (3RS)-1,3-Dihydro-1-t (1-trityliinidazol-4-yl)methyl]- 3- (4-cinnolinylcarbonylanino) (2-f luorophenyl) 2H-1, 4-benzodiazepin-2-one NMR (CDC1 3 6) :5.09 (2H, 5.80 (1H, d,J=7.8Hz), 6.86-8.09 (28H, in), 8.49-8.66 (2H, in), 9.54 (1H,

S)

WO 92/01683 PCr/JP91/00952 38 3-(l-isoquinolylcarbonylaxrino)-5-(2-fluorophenyl)- 2H-1,4-benzodiazepin-2-one NMR (CDCl 3 6) 5.11 (2H, 5.78 (1H, d, 3=8.3Hz), 6.89-7.89 (28H, 8.05 (1h, d, 3=8.2Hz), 8.59 (1H, d, J=5.5Hz), 9.52-9.56 (1Hi 9.93 (Ih, d, 3=8.2Hz) (3RS)-1,3-Dhydro-l-[(l-tritylimidazol-4ylmtl) 3-nicotinoylamino-5-(2-fluorophenyl)-2H-l,4benzodiazeoin-2-one )UMR (CDCl 3 6) 4.99-.5.16 (4H, m), 5.71 (1H, d, 3=7.7Hz), 6.85-9.18 (28H, m) Example 3 To a solution of (3RS)-1,3-dihydro-l-[Hltritylimidazol-4-yl)methyll-3-amino-5-(2-f luoropDhenyl)-21- 1,4-benzodiazepin-2-one (1.0 g) in methylene chloride ml) were added successively triethylanine (340 mg) and 2-naphthoyl chloride (320 mg). The mixture was stirred for 1.5 hours. The reaction mixture was washed w.h water and dried. The solvent was removed under reduced Pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.

The fractions containing the desired product were combined and evaporated to afford on oil, which was dried under reduced pressure to give (3RS)-l,3-dihydro-l-[(ltrityliiidazol-4-yl)methylj-3-(2-naphthoylamino)-5-(2fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.21 g).

NMR (CDCl 3 6) 5.03 (2H, d, 3=15Hz), 5.15 (2H, d, 3=15Hz), 5.79 (1H, d, J=8Hz), 6.89-8.07 (291, 8.22 (1H, d, 3=8Hz), 8.47 (1H, s) ExamDle 4 To a solution of (3RS)-1,3-dihydro-l-[Hltritylimidazol-4-yl)methyll>3-amino-5-(2-fluorophenyl)-21- WO 92/01683 PCT"/JP91/00952 -39 1,4-benzodiazepin-2-one (1.5 g) in tetrahydrofuran (23 ml) was added m-tolyl isocyanate (0.35 g) under stirring at ambient temperature. The mixture was stirred for 2 hours under the same condition. From the reaction mixture, the solvent was removed in vacuo to give crude product, which was recrystallized from a mixture of ethyl acetate and tetrabydrofuran to afford pure (3RS)-1,3dihydro-l-[(i-tri.tylimidazol-4-yl)methyl]-3-[3-(3methylphenyl)ureido]-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one (1.47 g).

NMR (DMSO-d 6 6) 2.24 (3H, 4.85 (IH, d, J=14.8Hz), 5.24-5.33 (2H, 6.67-7.68 (29H, 7.91 (1H, d, J=8.2Hz), 8.97 (1H, s) Example 1 'uspended mixture of iron powder (1.1 g) and ammonium aloride (0.13 g) in a mixture of water (2.5 ml) and ethanol (7.5 ml) was added portionwise (3S)-1,3dihydro-l-[(l-tritylimidazol-4-yl)methyl]-3-[(E)-3-(2nitrophenyl)propenoylamino)-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one-(1.1 g) under stirring and refluxing.

After ethanol (7.5 ml) and water (2.5 ml) were added, the resultant mixture was refluxed under stirring for hours. The reaction mixture was filtered through celite and the filtered mass was washed with hot ethanol several times. From the filtrate and the washings, ethanol was removed under reduced pressure. To the residual mixture was added a saturated aqueous solution of sodium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml). After washing with water and drying over magnesium sulfate, the extract was evaporated to give an amorphous residue, which was pulverized with diisopropyl ether and collected by filtration to afford (3S)-l,3-dihydro-l-[(l-tritylimidazol-4-yl)methyl]-3- [(E)-3-(2-aminophenyl)propenoylaminol-5-(2-fluorophenyl)- WO 92/01683 PC/J P91/00952 40 2H-l,4-benzodiazepin-2-one (0.98 g).

NMR (CDC1 3 6) :3.71-4.07 (2H, br 5.06 (2H, s), 5.68 (1H, d, J=8Hz), 6.47-7.99 (32H, m) MASS 476 (M+-260) Example 6 To a solution of (3S)-l,3-dilydro-l-[(ltritylimidazol-4-yl)methyl]-3-[(E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-1,4-benzodiazepin- 2-one (0.49 g) in N,N-dimethylformamide (4.9 ml) was added 6N-hydrochloric acid (3.4 mll under stirring and cooling in an ice-bath. The mixture was warmed to 50°C and stirred for 1 hour. After cooling to room temperature, to the reaction mixture were added water and ethyl acetate under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was pulverized and stirred for several hours.in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3S)-l,3-dihydro-l-(4imidazolylmethyl)-3-[(E)-3-(2-aminophenyl)propenoylamino 5-(2-fluoropheny.)-2H-1,4-benzodie.zepin-2-one (350 mg).

To a solution of the product obtained above in chloroform ml) was added 20%-hydrogen chloride in ethanol (5 ml) under cooling.- The clear yellow solution was evaporated to dryness under reduced pressure. The residue was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave yellow powder (234 mg) of (3S)-l,3-dihydro-l-(4-imidazolylmethyl)-3- [(E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)- 2H-1,4-benzodiazepin-2-one dihydrochloride.

IR (Nujol) 3650-3050, 2700-2150, 1660, 1605 cm 1 WO 92/01683 PCf/IP91/00952 41 NMR (CDC1 3 6) 3.8-4.8 (2H, 5.15-5.56 (3H, m), 7.04-7.81 (18H, 9.03 (1H, 9.43 (1H, d, J=8Hz) MASS 494 476 Example 7 The following compounds were obtained according to a similar manner to that of Example 6.

(3S)-l,3-Dihydro-l-(4-imidazoly-methyl)-3-[(2-amino- 4-chlorobenzoyl)amino3-5-(2-fluorophenyl)-21,4benzodiazepin-2-one mp 180-220 0 C (dec.) IR (Nujol) 3500-3000, 1675, 1640 cm- NMR (CDC1 3 6) 4.93 (1H, d, J=15Hz), 5.20 (1H, d, J=ISHz), 5.25-5.69 (31, 6.62-6.67 (2H, m), 6.98-7.26 (6H, 7.40'7.69 (5H, 7.89-7.91 (2H, m) MASS 502 (M (3RS)-1,3-Dihydro-l-(4-imidazolylmnetlhyl)-3-[ 2,3,4,5tetrahydro-3-oxopyridazin-6-yl)carbonylarino]-5-(2fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride mp 230-240 0 C (dec.) IR (Nujol) 3650-3050, 2650, 2200, 1670, 1610, 1500 cm- NMR (DMSO-d 6 6) 2.41-2.88 (41, 5.20 (1H, d, J=l6Hz), 5.42 (1H, d, J=16Hz), 5.43 (1H, d, J=7.8Hz), 7.15-7.78 (9H, 8.58 (lH, d, J=7.8Hz), 9.02 (1H, 11.31 (l1, 14.67 (1H, br s) MASS 393 (M -153) (3RS)-1,3-Dihydro-l-(4-iiidazolylmethyl)-3-(3,4- WO 942/01683 PCr/J P91/00952 42 dichlorobenzoylanino)-5-C2-fluorophenyl)-2H-1,4benzodiazepin-2-one hydrochloride mp 212-2300C (dec.) IR (Nujol) 3650, 3150, 2650-2000, 1650, 1600, 1510 cm 1 NMR (DMSO-d 6 1 6) 5.20 (1H, d, 7=16Hz), 5.43 (1H, d, J=16Hz), 5.61 t1, d, J=7.3Hz), 7.19-7.82 (10H, 7.98 (1H, dd, J=2Hz, 8Hz), 8.30 (1H, d, J=2Hz), 9.02 (I1H, d, 3=1.2Hz), 10.0 (1H, d, J=9.4Hz), 14.64 (1H, br s) MASS 521 441 (3RS)-1i,3-Dihydro-i-(4-imidazolylmethyl)-3-(3quinoiylcarbonyla-mino)-5-(2-fiuorophenyl)-2H-1,4benzodiazepin-2-one dihydrochloride mp 230-233 0 C (dec.) IR (Nujol) 3600-3100, 2700-2100, 1670, 1610, 1510 cm1 NMR (DMSO-d 6 6) 5.24 (1H, d, J=l6Hz), 5.47 (iN, d, J=16.lHz), 5.71 (iH, d, J=7.2Hz), 7.2-8.39 (13H, 9.05 (1H, d, J=1.iHz), 9.48 (1Hi, d, J=1.8Nz), 9.60 (1H, d, J=2Hz), 10.36 (1H, d, J=7.2Hz), 14.72 (1H, br s) MASS 504 (M 424 (3RS)-1,3-Dihydro--(4-iidazolylmethyi)-3-(2quinoxalinylcarbonylamino)-5-(2-fluorophenyl)-21-1,4benzodiazepin-2-one hydrochloride mp 205-220 0 C (dec.) IR (Nujol) 3600-3050, 2700-2000, 1670, 1600 cm- NMR (DMSO-d 6 6) 5.25 (1H, d, J=16.1Hz), 5.48 (1H, d, J=16.lz), 5.68 (1N J=7.8z), 7.18-8.35 (13H, 9.04 (1H, s), 9.53-9.61 (2H, 14.63 (1H, m) MASS 505 (M 425 WO 92/01683 PCT/,IP91/00952 43- (3RS)-1,3-Dihydro-1-(4-inidazolylmethy)-3-(24cinnolinylcarbonylamino) (2-f luorophenyl) -2H-1, 4benzodiazepin-2-one dihydr-ochioride rnp :215-230'C (dec.) IP. (Nujol) :3600-3100, 2700-2100, 1660, 1610 cm 2 i NTMR (DMSO-d 6 6) :5.21-5.72 (3H, in), 7.18-8.61 (13H, mn), 9.01 (1K, 9.48 (1H, s), 10.46 (1H, d, 14.61 (1H, br s) MASS (rn/e) 505 (M 448 (3RS)-1,3-Dihydro-1-(4-inidazolylrnethyl)-3-(1isoauinolylcarbonylanino) (2-f luorophenyl) -2H-1, 4benzodiazepin-2-one dihydrochioride MD:209-220'C (dec.) IR (Nujol) :3600-3200, 2700-2100, 1670, 1610 cm 1 NMR (DMSO-d 6 f 6) 5.2-5.55 (2H, mn), 5.67 (1H, d, J=7.7Hz), 7.23-8.19 (13H, mn), 8.67 (1H, d, J=5.6Hz), 9.03 (1K, s), 9.19 (111, d, J=8.4Hz), 9.9 (1H, d, J=7.7Hz), 14.62 (1H, br s) MASS 504 73), 424 C 3RS)-1,3-Dihydro-1-( 4-iinidazolylinethyl)-3- (2-f luorophenyl) -2K-1, 4benzodiazepin-2-one dihydrochioride mp 220-235*C (dec.) NM~R (DMSO-d 6 6) :5.21 (1H, d, J=16.l~z), 5.45 (1K, d, J=16.l~z), 5.64 (1K, d, J=7.2Kz), 7.2-8.0 (1H, mn), 8.76-9.04 (2H, mn), 9.32 (1H, 10.32 (1H, d, J=7.2Hz), 14.67 (1K, br s) MASS (in/e) :454 (M +-73) (3RS)-1,3-Dihydro-1-(4-inidazolyiinethvl)-3-(2naphthoylaniino) -5-C 2-f luorophenyl) -2K-i,4- WO 92/01683 PCT/JP91/00952 44 benzodiazepin-2-one hydrochloride mp 220-230°C (dec.) IR (Nujol) 3600-3050, 2800-2000, 1690, 1660, 1610 cm-1 NMR (DMSO-d 6 6) 5.22 (1H, d, J=16Hz.), 5.45 (1H, d, J=16Hz), 5.70 (1H, d, J=7.4Hz), 7.19-8.1 (15H, 8.70 i.H, 9.03 (1I, s), 9.78 (1H, d, J=7.4Hz), 14.61 (IH, br s) MASS 503 (M 427 (3RS)-1,3-Dihydro-l-(4--imidazolylmethyl)-3-[3-(3methylphenyl)ureido]-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one hydrochloride mp 210-225°C (dec.) -1 IR (Nujol) 3600-3050, 1680, 1610, 1555 cm NMR (DMSO-d 6 6) 2.24 (3H, 5.06 (2H, s), 5.26 (1H, d, J=8.4Hz), 6.74 (1H, d, J=6.6Hz), 6.87 (1H, 7.07-7.71 (13H, 8.02 (1H, d, 8.99 (1H, s) Example 8 To a mixture of (3RS)-l,3-dihydro-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin- 2-one (850 mg) and l-trityl-4-(2-chloroethyl)imidazole monohydrochloride (900 mg) in N,N-dimethylformamide were added sodium hydride (60% suspension in mineral oil, 180 mg) and sodium iodide (3.98 g) under stirring and cooling at 0 C in an ice-salt bath in a stream of nitrogen. The mixture was stirred at room temperature for 1.5 hours and at 60-65°C for 6 hours. Acetic acid (2 ml) was added to the reaction mixture. The resultant mixture was poured into a mixture of ethyl acetate (200 ml) and water (200 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was WO 92/01683 PCT/JP91/00952 45 removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3RS)-l,3-dihydro-l-[2-(ltritylimidazol-4-yl)ethyl)-3-(3-quinolylcarbonylamino)-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (750 mg).

NMR (DMSO-d 6 6) 2.49-2.65 (2H, 3.8-4.6 (2H, 5.62 (1H, d, J=7.48Hz), 6.70 (1H, s), 7.00-8.1 (28H, m),.9.05 (1H, 9.35 (1H, d, J=2.2Hz), 10.0 (1H, d, J=7.64Hz) Example 9 To a solution of (3RS)-l,3-dihydro-3-(2-naphthoylamino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (1.25 g) in N,N-dimethylformamide (31 ml) was added sodium hydride (60% suspension in mineral oil, 130 mg) under stirring and cooling at 0 C in an ice-salt bath in a stream of nitrogen. After the mixture was stirred at room temperature for 45 minutes, a solution of chloroacetonitrile (270 mg) in N,N-dimethylformamide ml) was added to the mixture at 0°C under stirring. The resultant mixture was stirred overnight at room temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resultant mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was removed under reduced pressure to give amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressure WO 92/0183 IICT/3?91/0095*- 46 to give (3RS)-1,3-dihydro-l-cyanomethyl-3-(2-naphthoylamino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one (1.19 g).

NMR (DMSO-d 6 6) 5.08-5.32 (2H, in), 5.74 (1H, d, J=7.65Hz), 7.25-7.82 (14H, 8.71 (1H, s), 9.95 (lH, d, J=7.68z) Example The following compounds were obtained according to similar manners to those of Examples 8 and 9.

(3RS)-l,3-Dihydro-3-(3-uinolylcarbonylaino)-5-(2fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-21,4benzodiazepin-2-one mp 284-285'C IR (Nujol) 3400, 1695, 1650, 1600, 1525 cm 1 NMR (DMSO-d 6 6) 5.4-5.62 (2H, 5.76 (1H, d, J=7.74Hz), 7.23-7.39 (4H, 7.63-7.79 (4H, 7.86-7.93 8.09-8.32 (2H, 9.05 (1H, 9.37 (1n, d, J=2.36Hz), 10.12 (1H, d, J=7.78Hz), 15.2-16.0 (1H, br s) MASS 507 (M 424 (M -83) (3RS'-1,3-Dihydro-3-(3,4-dichlorobenzoylaino)-5-(2fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4benzodiazepin-2-one mp 260-265 0 C (dec.) IR (Nujol) 3600, 3050, 1650, 1600 cm- NMR (DMSO-d 6 6) 3.83 (1H, br 5.2-5.4 (2H, 5.63 (1H, d, J=7.8Hz), 7.14-7.33 7.55-7.67 (4H, 7.77 (1H, d. J=8.4Hz), 7.97 (2H, d, J=8.4Hz), 8.28 (1H, d, J=1.9-iz), 9.94 (li, d, j=7.83Hz) MASS (mle) 524 (M 368 (M+-156) WO 92/01683 Pr-r/JP91/00952 47 (3RS)-l,3-Dihydro-3-(2-indolylcarbonylamino)-5-(2fluorophenyl)--I(lH-tetrazol-5-yl)methylj-2H-1,4benzodiazepin-2-one mp 280-290*C (dec.) IR (Nujol) 3150, 1640, 1540 cm1 NM? (DMSO-d,, 6) 5.21-5.3 (2H, 5.69 (1H, d, J8.14Hz), 7.02-7.66 (13H, 7.97 (1H, d, J=8.26Hz), 9.52 (lH, d, J=8.18Hz), 11.67 (1H, s) MASS 351 (M -144), 332 (M+-162) (3RS)-1,3-Dihydro-l-[2-(4-imidazlyl)ethyl--3 guinolylcarbonylaino)-5-(2-fluorophenyl)-2W-1,4benzodiazepin-2-one mp 165-175 0 C (dec.) 1R (Nujol) 3600-3000, 1650, 1600 cm- (3S)-3-(2-Indolylcarbonylanino)-l,3-dihydro-5-(2fluorophenyl)-l-[(lH-tetrazol-5-yl)rethyl3-2H-l,4benzodiazepin-2-one NMR (DMSO-d 6 6) 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (1H, d, J=8.0Wz), 7.0-7.91 (14H, 9.60 (1H, d, J=8.Oz), 11.65 (lH,.s) Example 11 To a solution of (3RS)-1,3-dihydro-l-[2-l-trit-'limidazol-4-yl)ethyl]-3-(3-quinolylcarbonylamino)-5-(2fluorophenyl)-2H-1,4-benzodiazepin-2-one (740 mg) in N,N-direthylformamide (7.4 ml) was added 6N-hydrochloric acid (5.18 ml) under stirring and cooling in an ice-bath.

The mixture was warmed to 60-70*C and stirred for one hour. After cooling to room temperature, to the reaction mixture were added ice water and ethyl acetate under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried.

WO 92/01683 PCT/JP91/00952 48 The solvent was removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.

The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give (3RS)-l,3-dihydro-l-[2-(4-imidazolyl)ethyl]-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)- 2H-l,4-benzodiazepin-2-one (0.25 g).

mp 165-175°C (dec.) IR (Nujol) 3600-3000, 1650, 1600 cm 1 NMR (DMSO-d 6 6) 2.52-2.66 4.09-4.63 (2H, 5.65 (1H, d, J=7.6Hz), 6.77 (1H, s), 7.24-8.32 (13H, 9.07 (1H, d, J=1.92Hz), 9.39 (1H, d, J=2.2Hz), 10.11 (1H, d, J=7.6Hz), 11.82 (1H, br s) MASS 518 (M Example 12 To a mixture of (3RS)-l,3-dihydro-3-(3,4-dichlorobenzoylamino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2one (500 mg) and l-trityl-4-(2-chloroethyl)imidazole monohydrochloride (295 mg) in N,N-dimethylformamide ml) were added sodium hydride (60% suspension in mineral oil, 99.5 mg) and sodium iodide (2.25 g) under stirring and cooling at 0 C in an ice-salt bath in a stream of nitrogen. After the mixture was stirred at room temperature for 1.5 hours and at 60-65 0 C for 6 hours. To the reaction mixture were added acetic acid (1.1 ml) and 6N-hydrochloric acid (5 ml) and the mixture was stirred at 60-70°c for one hour. The resultant mixture was poured into a mixture of ethyl acetate (100 ml) a.;d water (100 ml) under stirring. The mixture was adjusted to pH 8 with WO 92/01683 PCf/JP91/00952 49 an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.

The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3RS)-1,3-dihydro-l-[2-(4-imidazolyl)ethyl]-3-{3,4dichlorobenzoylamino)-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one (0.18 g).

mp 149-159°C -1 IR (Nujol) 3600-3100, 1650, 1600 cm 1 NMR (DMSO-6 6 6) 2.5-2.59 (2H, 3.95-4.62 (2H, 5.5 (1H, d, J=7.52Hz), 6.77 (1H, br s), 7.23-8.32 (12H, 9.99 (1H, br 11.8 (1H, br s) MASS 386 (M+-150) Example 13 The following compounds were obtained according to a similar manner to that of Example 12.

(3RS)-1,3-Dihydro-l-[2-(4-imidazolyl)ethyl]-3-(2naphthoylamino)-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one mp 198-205°C (dec.) IR (Nujol) 3275, 1680, 1630, 1530 cm- NMR (DMSO-d 6 6) 2.5-2.8 (2H, 4.0-4.6 (2H, m), 5.65 (1H, d, J=7.67Hz), 6.81 (1H, br s), 7.24-8.09 (15H, 8.71 (1H, 9.78 (1H, d, J=7.71Hz), 11.8 (1H, br s) MASS 518 (M WO 92/01683 PCT/JP91/00952 50 (3RS)-l,3-Dihydro-l-[2-(4-imidazolyl)ethyl]-3-(2indolylcarbonylamino)-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2-one mp 188-205°C (dec.) -2.

IR (Nujol) 3550-3100, 1640, 1540 cm NMR (DMSO-d 6 6) 2.51-2.65 (2H, 4.01-4.08 (1H, 4.50-4.57 (1H, 5.63 (1H, d, J=7.9Hz), 6.56 (1H, 6.76-7.81 (14H, 9.60 (1H, d, J=7.9Hz), 11.64 (1H, 11.81 (1H, br s) Example 14 A mixture of (3RS)-1,3-dihydro-l-cyanomethyl-3-(2naphthoylamino)-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2one (1.15 sodium azide (480 mg) and triethylamine monohydrochloride (510 mg) in l-methyl-2-pyrrolidinone ml) was stirred at 145aC for 3.5 hours. The reaction mixture was poured into 5°C hydrochloric acid (100 ml) under stirring. The resultant precipitates were collected by filtration, washed with water and purified by column chromatography on silica gel with an eluent of chloroform.

The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3RS)-1,3-dihydro-3-(2-naphthoylamino)-5-(2-fluorophenyl)- 1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (540 mg).

mp 265-275C (dec.) -1 IR (Nujol) 3570-3100, 1650, 1490 cm NMR (DMSO-d 6 6) 5.33 5.73 (1H, d, J=7.98Hz), 7.18-8.09 (15H. 8.69 (1H, s), 9.72 (1H, d, J=8Hz) MASS 505 (M 1 WO 92/01683 PCT/JP91/00952 51 The following compound was obtained according to a similar manner to that of Example 14(1).

(3S)-3-(2-Indolylcarbonylamino)-l,3-dihydro-5-(2fluorophenyl)-l-[(1H-tetrazol-5-yl)methyl]-2H-1,4benzodiazepin-2-one NMR (DMSO-d 6 6) 5.49 (2H, ABq, 3=16.4Hz, 24.8Hz), 5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, 9.60 (1H, d, J=8Hz), 11.65 (1H, s) Example 4-Chlorophenyl isocyanate (0.14 g) was added to a solution of (3RS)-3-amino-l,3-dihydro-5-phenyl-l-[(1trityl-1H-tetrazol-5-yl)methyll-2H-1,4-benzodiazepin-2-one (0.50 g) in dry tetrahydrofuran (10 ml) at room temperature. After the mixture was stirred for 3 hours, 8.4N-ethanolic hydrogen chloride (1.5 ml) was added to the mixture at room temperature and then the mixture was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was suspended with a mixture of ethanol and ethyl acetate and the resultant precipitate was collected by filtration to give (3RS)-1,3dihydro-3-[3-(4-chlorophenyl)ureido]-5-phenyl-l-[(1Htetrazol-5-yl)methyll-2H-1,4-benzodiazepin-2-one monohydrochloride (0.40 g).

mp 205-208°C IR (Nujol) 3325, 3250, 3190, 2725, 1690, 1600,

-I

1545 cm 1 NMR (DMSO-d 6 6) :5.30-5.50 (1H, 5.46 (2H, ABg, J=17Hz, 24Hz), 7.20-7.85 (15H, 9.0-11.0 (1H, broad), 9.42 (1H, s) Example 16 The following compounds were obtained according to a similar manner to that of Example WO 92/01683 WO 9201683PCI/J P911?00952 52 (3RS)-1,3-Dihydro-3-113-(4-chlorophenyl)ureido]-5-(2- (fluorophenyl)-l--[ (1H-tetrazol-5-yl)methyl)-2i-1, 4benzodiazepin-2-one ronohydrochloride MD:203-2050 C 111 (Nujol) 3320, 3250, 3190, 2720, 1695, 1605, 1525 cm- NTMR (DMSO-d 6 6) :5.30-5.40 (1H1, mn), 5.48 (2H1, ABg, J=l7Hz, 21Hz), 7.20-7.80 (1311, mn), 8.0-10.5 (2H1, broad), 9.37 (1H1, s) (3RS)-1,3-Dihydro-3-[3-(3-inethylrpheny1}ureido3-5phenyl-1-[ (1H-tetrazol-5-yl)methyl]-211-1,4benzodiazepin-2-one ionohydrochloride mn 188-194*C (dec.) IR (Nujol) 3290, 2720, 2605, 1685, 1610, 1595, 1540 cm N1M. (DMSO-d 6 6) 2.24 5.30-5.48 (1H1, m), 5.46 (211, A~g, J=l7Hz, 25Hz), 6.70-6.80 (111, mn), 7.00-7.54 (12H1, nm), 7.70-7.60 (2H1, mn), 8.0-10.20 broad), 9.12 (1H1, s) (3RS)-1,3-Dihydro-5-(2-fluorophenyl)-3-13-(3methylphenyl)ureido]-1-[ (11-tetrazol-5-yl)inethyl]-2H- 1, 4-benzodiazepin-2-one inonohydrochioride mp :181-191'C (dec.) IR (Nujol) :3300, 2710, 2610, 1690, 1595, 1550 cm- 1 N1MR (DMSO-d 6 6) :2.24 (311, 5.35-5.45 111, mn), 5.48 (211, ABq, J=llHz, 22Hz), 6.70-6.78 (1H, in), 7.05-7.38 (711, mn), 7.50-7.81 (611, mn), 8.0-10.4 (2H1, broad), 9.11 (111, s) Exami~le 17 To a solution of (3S)-1,3-dihydro-1-[(1trityliinidazol-4-yl)inethyl)-3-(3,4-dichlorobenzoylanino) 5-(2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (20.34 g) in WO 92/01683 1P('1/JP191/00952 53 N,N-dimethylformamide (204 ml) was added 6N-hydrochloric acid (157 ml) under stirring and cooling in an ice-bath.

The mixture was warmed to 70-80 0 C and stirred for 1 hour.

After cooling to room temperature, to the reaction mixture were added ice water and ethyl acetate under stirring.

The mixture was adjusted to pH 8.0 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3S)-1,3-dihydro-l-(4imidazolylmethyl)-3-(3,4-dichlorobenzoylamino)-5-(2fluorophenyl)-2H-1,4-benzodiazepin-2-one. This was dissolved in chloroform (200 ml) and to the resultant solution was added 20%-hydrogen chloride in ethanol ml) under cooling. The clear yellow solution was evaporated to dryness under reduced pressure to give an amorphous mass, which was lyophirized to give (3S)-1,3dihydro-1-(4-imidazolylmethyl)-3-(3,4-dichlorobenzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride as yellow powder (12.97 g).

IR (CHC1 3 3000, 2900-2200, 1660, 1600, 1500 cm 1 NMR (DMSO-d 6 6) 5.19 (1H, d, J=16Hz), 5.43 (1H, d, J=16Hz), 5.61.(1H, d, J=7.3Hz), 7.19-7.39 7.56-7.82 (5H, 7.95-8.00 (1H, m), 8.30 (1H, d, J=1.9Hz), 9.01 (1H, 9.99 (1H, d, J=7.3Hz), 14.6 (1H, br s) MASS 521 (M -37) [a]0 24.750 (C=0.832, CH3OH) Example 18 To a suspension of 2-indolecarboxylic acid (161.2 mg) WO 92/01683 1101/31191/00952 -54in methylene chloride (3.25 ml) was added thionyl chloride (119.0 mg) and one drop of N,N-dimethylformamide under stirring at ambient temperature. The mixture was ref luxed for 1 hour with stirring. To a solution of (3S)-3-amino-l,3-dihydro-5-(2-fluorophenyl)-l-[(lHtetrazol-5-yl)methyl]--2H-1,4-benzodiazepin--2-one hydrochloride (387.8 mg) and triethylanine (506.0 mg) in methylene chloride (8 ml) was added dropwise the solution of 2-indolylcarbonyl chloride in methylene chloride obtained above under ice-'cooling and stirring. The mixture was stirred under the same conditions for 3 hours.

To '-he reaction mixture was added chloroform. The mixture was washed with diluted hydrochloric acid and water, successively and dried over magnesium sulfate. Removal of the solvent in vacuo afforded an amorphous mass, which was suspended with stirring in diisopropyl ether. The resultant powder was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give (3s)-3-(2-indolylcarbonylamino)-l,3-dihydro-5-(2fluorophenyl)-l-[ (lH-tetrazol-5-yl)methyl3-2H-l,4benzodiazepin-2-one.

mp :270-271'C (dec.) []28.5 =1~8.870 (C=0.62, tetrahydrofuran) ~aD NM?. (DMSO-d, 6) 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 d, J=8.OHz), 7.0-7.91 (14H, in), 9.60 (1H1, d, J=8.0Hz~, 11.65 (l1H, s) MASS 494 (M+ Example 19 the following compound was obtained according to a similar manner to that of Example 18.

(2-indolylcarbonylamino) 3-dihydro-5- (2fluorophenyl)-l-[ (lH-tetrazo1-5-yl)methyll-2H-1,4benzodiazepin-2-one I O 92/01683 PCrJ 1191/00952mp 270-271'C (dec.) 28 28.5 +18.72' (C=0.625, tetrahydrofuran) NMR (DMSO-d 6 5) 5.49 (2H, ABg, J=16.3Hz, 24.7Hz), 5.73 (1H, d, J=8.OHz), 7.0-7.91 (14H, 9.60 (1H, d, J=8.OHz), 11.65 (1H, s) MASS 494 (M Example The following compounds were obtained according to a similar manner to that of Example 1.

(3S)-1,3-Dihydro-l-[(l-tritylimidazol-4-yl)methyl]- 3-C3,4-dichlorobenzoylainno) -5-(2-fluorophenyl)-2H- 1,4-benzodiazepir-2-one NMR (CDC1 3 5.02 (1H, d, 5.11 (1H, d, Jl1SHz), 5.67 (1H, d, J=78Hz), 6.84-8.04 (29H, m) (3RS)-l,3-Dihydro-l-[2-(4-imidazolyl)ethyll-3-(3quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-l,4benzodiazepin-2 -one mp 165-175'C (dec.) IR (Nujol) 3600-3000, 1650, 1600 cm 1 Example 21 The following compound was obtained according to a similar manner to that of Example 11.

(3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-(2fluorophenyl)-l-[ (1H-tetrazol-5-yl)methyl)-2H-1, 4benzodiazepin-2-one NICR (DMSO-d 6 6) 5.49 (2H, ABq, j=l6.4Hz, 24.8Hz), 5.73 (1H, d, J=8.0Hz), 7.0-7.91 (14H, r (1ii, d, J=8.0Hz), 11.65 s) Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

*t.

940408,p:\operdab.82171-91.O98,5

Claims (12)

1. A compound of the formula A-PR 1 0 4 -NHCO-R N whereiin R 1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, 2 R is hydrogen or halogen, R is aryl which may have one or more suitable substituent(s), 4 R is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R 4 is indolyl, then R 1 is tetrazolyl which may have one or more suitable substituent(s) and R 3 is halophenyl or (ii) R 1 is imidazolyl which may have one or more suitable substituent(s), R 3 is halophenyl and 1 WO 92/01683 PCr/31)91/00952 57 A is ethylene, and a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein R 1 is tetrazolyl which may have an imino protective group, imidazolyl which may have an imino protective group, or cyano, R 3 is phenyl or halophenyl, R 4 is phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of halogen and amino; phenyl(lower)alkehyl which may have amino or nitro; phenylamino which may have lower alkyl or halogen; pyridyl; tetrahydropyridazinyl which may have an oxo group; quinolyl; isoquinolyl; cinnolinyl; indolyl; or quinoxalinyl.

3. A compound of claim 2, wherein R is tetrazolyl which may have mono(or di or tri)- phenyl(lower)alkyl, imidazolyl which may have mono(or di or tri)phenyl(lower)alkyl, or cyano, R is naphthyl; dihalophenyl; phenyl having halogen and amino; nitrophenyl(lower)alkenyl; aminophenyl(lower)alkenyl; lower alkylphenylamino; halophenylamino; pyridyl; tetrahydropyridazinyl having an oxo group; quinolyl; isoquinolyl; cinnolinyl; indolyl; or quinoxalinyl.

4. A compound of claim 3, wherein R 1 is tetrazolyl, R 2 is hydrogen, R 3 is halophenyl, R 4 is indolyl and A is C 1 -C 4 alkylene.

WO 92/01683 PCr/JP91/00952 58 A compound of claim 4, which is (3S)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-(2- fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-l,4- benzodiazepin-2-one

6. A process for preparing a compound of the formula A-R 1 R3 (I) wherein R 1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R 2 is hydrogen or halogen, R 3 is aryl which may have one or more suitable substituent(s), R 4 is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R 4 is indolyl, then R 1 is tetrazolyl which may have one or more suitable substituent(s) and R 3 is halophenyl or WO, 92/01683 I',;II/J 19'1/00952 59 (ii) R 1 is imidazolyl which may have one or more suitable substituent(s), R 3 is halophenyl and A is ethylene, or a salt thereof, which comprises reacting a compound of the formula A-R- wherein R, R 2 R and A are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula 0 4 HO-C-R wherein R 4 is as defined above, or its reactive derivative or a salt thereof to give a compound of the formula A-R 1 1 0 R 2 -NHCO-R 4 R 3 1 2 3 4 wherein R R R 4 and A are each as defined above, WO 92/01683 PCT/J P91/00952 60 or a salt thereof, or subjecting a compound of the formula wherein R 2 R R and A are each as defined above, and R is heterocyclic group having a a protected imino group of the formula (in which R is imino protective R 6 group) ir its hetero ring, which may have one or more suitable substituent(s), or a salt thereof to elimination reaction of the imino protective group to give a compound of the formula 2 3 4 wherein R R P4 and A are each as defined above, and Rb is heterocyclic group having an imino group of the formula WO 92/016833 PCI'/JP91/00952 61 in its hetero ring, which may have one or more suitable substituent(s), or a salt thereof, or subjecting a compound of the formula A-R wherein R R 2 R and A are each as defined above, and 4 R is ar(lower)alkenyl having a nitro a group, or a salt thereof to give a compound of the formula wherein R R2 R and A are each as defined above, and R 4 is ar(lower)alkenyl having an amino b group, or a salt thereof, or reacting a compound of the formula WO 92/01683 PC'/JP91/00952 62 wherein R 2 R 3 and R 4 are each as defined above, or a salt thereof with a compound of the formula X-A-R 1 wherein R 1 and A are each as defined above, and X is an acid residue, or a salt thereof to give a compound of the formula A-R 1 1 2 3 4 wherein R R R R and A are each as defined above, or a salt thereof, or reacting a compound of the formula A-CN WO 92/01683 PCI'/J P'91/00952 63 wherein R R and A are each as defined above, or a salt thereof with a compound of the formula HN 3 or a salt thereof to give a compound of the formula H N-N N N 2 -NHCO-R 4 R 3 2 3 4 wherein R 2 R R and A are each as defined above, or a salt thereof.

7. A compound of the formula wherein R 1 is tetrazolyl which may have one or more c suitable substituent(s), R 2 is hydrogen or halogen, R 3 is aryl which may have one or more Isuitableosubstituent(s), and WO 9 2/016833 PCT/JP91/00952 64 A is lower alkylene, and a salt thereof.

8. A process for preparing a compound of the formula A-R 1 1 C wherein R I is tetrazolyl which may have one or more suitable substituent(s), 2 R is hydrogen or halogen, R is aryl which may have one or more suitable substituent(s), and A is lower alkylene, or a salt thereof, which comprises subjecting a compound of the formula; A-R R 2 R R 3 wherein R R R and A are each as defined above, and R 7 is protected amino, or a salt thereof to elimination reaction of the amino protective group.

9. A pharmaceutical composition which comprises, as an active ingredient, a compound of ea3: or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.

A method for treating or preventing cholecystokinin- mediated diseases which comprises administering a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof to human or animals.

11. A process for preparing a pharmaceutical composition of claim 9 which comprises admixing a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

12. Compounds of formula or processes for their preparation, substantially as hereinbefore described with reference to the Examples. DATED this llthday of April 1994. FUJISAWA PHARMACEUTICAL CO., LTD. by its Patent Attorneys DAVIES COLLISON CAVE e*SS 940408,p:\oper\dab,8217191.098,65 INTERNATIONAL SEARCH REPORT International Application No PCT/JP 91/00952 I. CLASSIFICATION OF SrUBJECT MATTER (if several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC C 07 D 403/06, 401/14, 403/14, 243/20, A 61 K 31/55 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols C 07 D Documentation Searched other than Minimum Documentation to the Extent that such Documents are included in Fields Searched 8 Ill. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of Document, 11 with indication, where appropriate, of the relevant p.i'-ges 12 Relevant to Claim No.1 3 X EP, A2, 0349949 (FUJISAWA PHARMACEUTICAL CO., 1-9, LTD.) 10 January 1990, 12 see especially examples 33-41 A US, A, 4820834 (BEN E. EVANS ET AL.) 1 11 April 1989, see ccmpound 643 and claim 1 Special categories of cited documents: 0 later document published after the international filing date docurent defining the general state of the art which is not or priority date and not In conflict will, the application but A c en de n t beofp ral tae thecited to understand the principle or theory underlying the considered to be or particular relevance invention earlier document but published on or after the international d o p r filing date document of particular relevance, the claimed invention cannot be considered novel or cannot be tonsidered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another citation o other special reason (as specified) Y document of particular relevance, tle claimed invention cannot be considered to involve an inventive step when the 0 document refrring to an oral disclosure, use, exhibition or document is combined with ona or more other such docu- other means to an oral di ments, such combination being obvious to a person skilled in the art. "P document published prior to the international filing date but d m o t later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 1st October 1991 2 g .1 91 International Searching Authority Signatulre.n.AutPhrized Officer EUROPEAN PATENT OFFICE Form PCT/ISA/210 (second sheet) (January 1985) International Application No. PCT/JF' 91/00952 FURTHER INF~ORMATION CONTINUED FROM THE SECOND SHEET incompletely V.[K OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND JSEARC1ABLE'I This International search report has not been established in respect of certain claims under Article 17(2) for the following reasons: 1.Mi Claim numbers 2 l-becsuse they relate to subject matter not required to be searched by this Authority, namely: A method for treatment of the human or animal body by therapy, see rule 39. 2.M1 Claim numberi l boo .use f~?rltF part3 of the International application that do not comply with the prescribed require- ments to such an extent that no meaningful International search can be carried out. ewpecrttc-ally: The scope of claim 1 is so broadly formulated that a very wide range of structures arer-included. This claim has thus not been fully searched. Ciawintmbers.......because trey awe d aperrent claims and are not drafted in accordsnce with the second and third setsoe of PCT Rule 8.44.). VIf] OntSERVATION8 WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple Inventions In this Inlternational application as follows:. IQAs all req4uired additional search fees were timely paid by th. applicant, this International search report, covers all searchable claims of the International application. 2QAs only some of the required additional search foes were timely paid by the applicant, this International search report covers only those claims of the International application for which tees ware puld, specifIcally claims: LJNo required additional search fees were timely paid by the applicant. Consequently, this International search report 13 restricted to the Invention first miontioned In the claimst it Ia covered by clain numbers: 4MAs all searchable claims could be searched without effort justifying an additional Iee, the International Searching Authority did not Invite payment of any additional fee. Remark on Protest SThe additional search fees were accompanied by applicant's protest. No protest accompanied the payment of additional search tas. Form PCTIISAIT1O (supplemental sheet (January 1085) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/JP 91/00952 SA 49394 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 30/08/91 The European Patent office is in no way liable for theseparticulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date EP-A2- 0349949 10/01/90 AU-D- 3785989 11/01/90 US-A- 4820834 11/04/89 JP-A- AU-D- EP-A- .JP-A- US-A- ZA-A- AU-D- EP-A- 2056481 1313388 0284256 63238069 5004741 8801866 4415285 0167919 26/02/90 15/09/88 28/09/88 04/10/88 02/04/91 06/09/88 02/01/86 15/01/86 For more details about this annex: see Official Journal of the European patent Office, No. 12/82 EPO FORM P0479