Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-16
2002-12-17
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S593000
Reexamination Certificate
active
06495542
ABSTRACT:
This application is a national-stage entry under 35 U.S.C. §371 of PCT/JP99/00072, filed Jan. 11, 1999.
The present invention relates to new benzamide derivatives and salts thereof which are useful as medicaments.
BACKGROUND ART
Some benzamide derivatives have been known as vasopressin antagonist, for example, in PCT International Publication Nos. WO 91/05549 and WO 95/29152, EP Publication No. 0620216, and Japanese Patent Unexamined Publication Nos. 154765/1992 and 221476/1997.
DISCLOSURE OF THE INVENTION
This invention relates to new benzamide derivatives and salts thereof.
More particularly, it relates to new benzamide derivatives and salts thereof which exhibit activities such as vasopressin antagonistic activity, to pharmaceutical compositions comprising the same and to methods for the treatment and/or prophylaxis of cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), depressant, anxiety and the like in human beings and animals.
One object of this invention is to provide new and useful benzamide derivatives and salts thereof which possess the aforesaid activities.
Another object of this invention is to provide processes for the preparation of said benzamide derivatives and salts thereof.
A further object of this invention is to provide pharmaceutical compositions comprising, as an active ingredient, said benzamide derivatives or pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide methods for the treatment and/or prophylaxis of the aforesaid diseases in human beings and animals, using said benzamide derivatives and pharmaceutically acceptable salts thereof.
The object benzamide derivatives of this invention are new and can be represented by the following formula (I):
wherein
A is an optionally substituted heterocyclic group;
R is a lower alkoxy;
Z is C═O or CH
2
; and
B is a saturated or unsaturated condensed ring group selected from the group consisting of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, each member being optionally substituted,
preferably, by the following formula (II):
wherein A, B, R and Z are each as defined above, or a salt thereof.
The object compound (I) of the present invention can be prepared according to the following reaction schemes.
(wherein B, Z, and R are each defined above.)
(wherein A
1
is a heterocyclic group substituted with an N-protective group, a protected amino or a substituent having protected amino, B
1
is any one of benzazepinyl, thienoazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with an N-protective group, a protected amino or a substituent having protected amino, A
2
is a heterocyclic group not substituted with an N-protective group or substituted with amino or a substituent having amino, B
2
is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pryridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is not substituted with an N-protective group or substituted with amino or a substituent having amino, and Z and R are each defined above.)
(wherin B
3
is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with =O, B
4
is any one of benzazepinyl, benzodiazepinyl, pyridoazepinyl, pyridodiazepinyl, thienoazepinyl, benzoxazepinyl, benzothiazepinyl, imidazobenzazepinyl, pyridobenzoxazepinyl and indolinyl, which is substituted with hydroxy, and A, Z and R are each as defined above.)
(wherein A
3
is a heterocyclic group substituted with phthaloylaminoalkyl, A
4
is a heterocyclic group substituted with aminoalkyl, and B, Z and R are each defined above.)
(wherein A
5
is a heterocyclic group substituted with amino or aminoalkyl, A
6
is a heterocyclic group substituted with (di)alkylamino or (di)alkylaminoalkyl, and B, Z and R are defined above.)
(wherein A
8
is a heterocyclic group substituted with protected hydroxyalkyl, A
9
is a heterocyclic group substituted with hydroxyalkyl, and B, Z and R are each as defined above.)
(wherein B
5
is saturated or unsaturated benzothiazenpinyl, B
6
is a saturated or unsaturated S-oxo-benzothiazepinyl, and A, Z and R are each as defined above.)
(wherein B
7
is a saturated or unsaturated S,S-dioxo-benzothiazepinyl, and A, Z, B
6
and R are each as defined above.)
Suitable salts of the object compound [I] are pharmaceutically acceptable, conventional non-toxic mono- or di-salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate), an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate) and a salt with an amino acid (e.g. arginine salt, aspartic acid salt, glutamic acid salt).
Suitable examples of the various definitions to be included within the scope of the invention, which are given in the description of the present specification, are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise provided.
Suitable “lower alkoxy” includes straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 2-ethylpropoxy and hexoxy, in which the preferred one is (C
1
-C
4
)alkoxy.
Suitable “heterocyclic group” defined for A of the formula (I) includes saturated or unsaturated, monocyclic or polycyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. 1H-azepinyl), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl), etc.;
saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl (e.g. perhydro-1H-azepinyl), pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (e.g. imidazo[4,5-c]pyridyl), tetrahydroimidazopyridyl (e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyridyl), etc.;
saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]-nonanyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl (e.g. 2-morpholinyl, 3-morpholinyl, 4-morpholino), sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containin
Ohkawa Takehiko
Oku Teruo
Oku Tomohito
Osoda Kazuhiko
Sawada Yuki
Coleman Brenda
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Oku Tomohito
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