Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-30
2001-09-18
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S509000
Reexamination Certificate
active
06291452
ABSTRACT:
TECHNICAL FIELD
This invention relates to new benzodiazepine derivatives or a 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 International Publication No. WO 96/04254.
DISCLOSURE OF INVENTION
This invention relates to new benzodiazepine derivatives or pharmaceutically acceptable salts thereof.
More particularly, it relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are selective cholecystokinin-B (CCK-B) antagonists or cholecystokinin-A and B (CCK-A/B) antagonists and therefore useful as therapeutical and/or preventive agents for disorders of appetite regulatory systems (e.g., anorexia, etc.), disorders associated with intestinal smooth muscle hyperactivity (e.g., irritable bowel syndrome, sphineter spasm, etc.), panic disorder, psychosis (e.g., schizophrenia, etc.), pancreatitis, etc. and also useful as analgesics.
The benzodiazepine derivatives of this invention can be represented by the following formula (I):
Wherein
R
1
is
(1) lower alkyl;
(2) hydroxy(lower)alkyl;
(3) protected hydroxy(lower)alkyl;
(4) heterocyclic(lower)alkyl which may have one or more suitable substituent(s);
(5) aryl(lower)alkyl which may have one or more suitable substituent(s);
(6) carboxy(lower)alkyl;
(7) protected carboxy(lower)alkyl; or
[wherein
A is lower alkylene and
R
5
is
(a) lower alkyl,
(b) C
3
-C
8
cycloalkyl,
(c) adamantyl,
(d) aryl which may have one or more suitable substituent (s),
(e) amino which may have one or two suitable substituent(s),
(f) azabicyclo[3.2.2]nonyl, or
(g) saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s)],
R
2
is
(1) lower alkyl,
(2) C
3
-C
8
cycloalkyl,
(3) lower alkoxy(lower)alkyl,
(4) C
3
-C
8
cycloalkyl(lower)alkyl,
(5) N,N-di(lower)alkylamino(lower)alkyl,
(6) lower alkylpiperazinyl(lower)alkyl,
(7) lower alkylthio(lower)alkyl,
(8) hydroxy(lower)alkyl,
(9) protected hydroxy(lower)alkyl,
(10) azabicyclo[3.2.2]nonyl(lower)alkyl,
(11) aryl which may have one or more suitable substituent(s),
(12) cyano,
(13) lower alkanoyl,
(14) carboxy(lower)alkenyl, or
(15) protected carboxy(lower)alkenyl,
R
3
is indolyl or -NH-R
6
[wherein R
6
is
(1) aryl which may have one or more suitable substituent(s),
(2) pyridyl which may have one or more suitable substituent(s), or
(3)C
3
-C
8
cycloalkyl], and
R
4
is
(1) hydrogen,
(2) lower alkyl,
(3) halogen, or
(4) di(lower)alkylamino,
with proviso that when R
4
is hydrogen, then R
2
is lower alkyl or C
3
-C
8
cycloalkyl(lower)alkyl,
or a pharmaceutically acceptable salt thereof.
According to the present invention, the new benzodiazepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme.
wherein
R
1
, R
2
, R
3
, R
4
, and A are each as defined above,
is saturated heteromonocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s),
X is halogen,
R
7
is hydrogen, lower alkyl or hydroxy(lower)alkyl,
R
8
is lower alkyl, hydroxy(lower)alkyl, aryl(lower)alkyl or pyridyl.
The starting compounds (II), (IV) and (VI) can be prepared by the following processes.
wherein
R
1
, R
2
R
3
, R
4
, X,
and A are each as defined above,
R
9
is protected amino, and
R
10
is protected carboxy.
With regard to the object compound (I), in case that the compound (I) has the group of the formula:
in R
1
, said group can also exist in the tautomeric form and such tautomeric equilibrium can be represented by the following scheme.
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 (A).
Further, in case that the compound (I) has the group of the formula:
in R
6
, said group can also exist in the tautomeric from and such tautomeric equilibrium can be represented by the following scheme.
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 (C).
BEST MODE FOR CARRYING OUT THE INVENTION
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salts such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylene diamine salt, etc.), an organic acid salt (e.g., acetate, maleate, lartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g., 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 atom(s), unless otherwise indicated.
Suitable “lower alkyl” may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, 3-methylbutyl, pentyl, t-pentyl, hexyl and the like.
Suitable “hydroxy protective group” in “protected hydroxy(lower)alkyl” may include acyl, which includes aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.
And, suitable examples of the said acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
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 helerocyclic 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, pyperidyl, pyrimidinyl, pyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, azacycloheptyl, azacyclooetyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.,), dihydrotriazolopyridazinyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group contai
Katsumi Ikuyo
Mitsui Hitoshi
Sato Yoshinari
Tabuchi Seiichiro
Yamamoto Naoko
Fujisawa Pharmacetical Co., Ltd.
Kifle Bruck
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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