Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-28
2002-03-05
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S094000, C514S238800, C514S255030, C514S307000, C514S314000, C514S359000, C514S363000, C514S381000, C514S382000, C514S383000, C514S394000, C544S062000, C544S110000, C544S133000, C544S139000, C544S360000, C544S366000, C546S148000, C546S152000, C546S176000, C546S199000, C546S273400, C548S559000, C548S112000, C548S127000, C548S139000, C548S253000, C548S265400, C548S304400, C548S305100, C548S306400, C548S309400, C548S310400
Reexamination Certificate
active
06352985
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel benzimidazole derivatives, and, more precisely, to novel benzimidazole derivatives and their pharmaceutically acceptable salts having blood sugar level-depressing activity or PDE5-inhibiting activity. The present invention also relates to pharmaceutical compositions comprising, as an active ingredient, such benzimidazole derivatives or their salts.
DISCLOSURE OF THE INVENTION
The subject matter of the present invention is to provide novel benzimidazole derivatives and their pharmaceutically acceptable salts, and also pharmaceutical compositions which comprise, as an active ingredient, such benzimidazole derivatives or their pharmaceutically acceptable salts, and which are useful for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), or hypertension; or stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerous cachexia, or restenosis after PTCA.
The present inventors provide pharmaceutical compositions comprising, as an active ingredient, any of benzimidazole derivatives of the following formulae (I) to (IV) and (VIII) to (XIV), and their pharmaceutically acceptable salts, which is usable for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications such as diabetic nephropathy, diabetic neuropathy and diabetic retinopathy, syndrome of insulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), or hypertension; or stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerous cachexia, or restenosis after PTCA.
In formula (I);
R
1
represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyl group, an aryl-lower alkyloxy group, a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group;
R
2
represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a chlorocarbonyl group, an aryl group, or a heterocyclic group;
R
3
represents a carboxyl group, an esterified carboxyl group, an amidated carboxyl group, an amino group, an amido group, or a sulfonyl group; said amino group and said amido group may be substituted by an acyl group or a sulfonyl group; and a halogen atom, an amino group, or an acylamino group is bonded to said sulfonyl group; or R
3
may be bonded to the skeleton via a lower alkylene or alkenylene group;
R
4
represents a neutral substituent; and
n means an integer from 0 to 3.
In formula (II);
R
6
represents an aryl-lower alkyl group or an aryl-lower alkyl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, a cyanoaryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyl group, and a heterocyclic group;
R
7
represents a lower alkyl group or a lower cycloalkyl group;
R
8
represents a carbamoyl group, which may be substituted by a lower alkyl group, a lower alkyl group substituted by a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, an aryl group, a heterocyclic group, or a group of:
in which R
9
represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, an aryl-lower alkyl group, a hydroxy-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, a heterocyclic group, or an aryl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;
or R
8
may be bonded to the skeleton via a lower alkylene or alkenylene group;
R
4
′ represents a hydrocarbon group or a halogenated hydrocarbon group; and
n means an integer from 0 to 3.
In formula (III);
R
6
represents an aryl-lower alkyl group or an aryl-lower alkyl group substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, a haloaryl group, a cyanoaryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyl group, and a heterocyclic group;
R
7
represents a lower alkyl group or a lower cycloalkyl group;
R
11
represents a substitutent of a formula:
in which R
12
represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, an aryl-lower alkyl group, a hydroxy-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, a heterocyclic group, or an aryl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;
or R
11
may be bonded to the skeleton via a lower alkylene or alkenylene group;
R
4
′ represents a hydrocarbon group or a halogenated hydrocarbon g
Hiramura Takahiro
Imoto Takafumi
Murai Yoshiyuki
Oku Teruo
Sawada Kouzou
Fish & Richardson PC
Fujisawa Pharmaceutical Co. Ltd.
Higel Floyd D.
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