Benzimidazole derivatives

Details Benzimidazole derivatives Benzimidazole derivatives

2000-03-24

2002-07-16

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S304700, C548S309700

Reexamination Certificate

active

06420409

ABSTRACT:

This is a 371 of PCT/JP98/02885, filed Jun. 26, 1998.
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 gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, 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.), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia (e.g., abnormal saccharometabolism such as feeding disorders, etc.), hypertension, stenocardia, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g., renopathy induced by FK506, cyclosporin, etc.), renal failure, atherosclerosis aiiostenosis (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chrci reversible obstructions (e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.), autoimmune disease, allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), nephritis, cachexia (e.g., progressive weight loss due to the lipolysis, myolysis, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc.), pancreatitis, or restenosis after PTCA.
The present inventors provide a novel benzimidazole derivative represented by the following formula (I) and its pharmaceutically acceptable salt, and a pharmaceutical composition comprising said compound or its pharmaceutically acceptable salt as an effective ingredient, which is usable for preventing and treating impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, 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.), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.), hyperglycemia(e.g., abnormal saccharometabolism such as feeding disorders, etc.), hypertension, stenocardia, 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.), autoimmune disease, allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders (e.g., hypersensitive enteropathy syndrome, etc.), impotence (e.g., organic impotence, psychic impotence, etc.), and nephritis, cachexia (e.g., progressive weight loss due to the lipolysis, myolysis, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc.), pancreatitis, or restenosis after PTCA.
wherein R
1
represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a lower alkylthio group;
R
2
represents an aromatic lower alkyl group, which may be substituted with one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, a nitro group, a lower alkoxycarbonyl group, an aromatic group, an aromatic lower alkyloxy group, a lower cycloalkyloxy-lower alkyl group, an aromatic lower alkyl group, an aromatic lower alkenyl group, an aromatic lower alkynyl group, an aromatic oxy lower alkyl group, a lower cycloalkyl-lower alkyloxy group, an alkenyl group, a lower alkoxy group, a lower alkylthio group, a lower alkanesulfinyl group, a lower alkanesulfonyl group, and a lower alkanesulfonylcarbamoyl group;
R
3
represents an alkyl group, a hydroxy lower alkyl group, an alkenyl group, an aromatic group, a halogenated aromatic group, a lower alkyl aromatic group, a lower alkenyl aromatic group, an aromatic lower alkyl group, or an aromatic lower alkenyl group; and —X— is a cross-linking group represented by any one of the following formulas (II) to (VI):
In the above formula (I), R
1
is preferably a lower alkyl group, and X is a cross-linking group represented by the above formula (V).
The benzimidazole derivatives provided by the present invention can be prepared according to the following reaction formulae (a) to (m).
wherein R
1
, R
2
, and R
3
have the same meanings as described above, R is a protecting group for a carboxyl group, and Z is a halogen atom.
Compound (1) can be converted to Compound (2) by hydrolyzing it with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. (Reaction formula (a)). Compound (3) can be obtained by treating Compound (2) with a carboxylic acid activator represented by N,N′-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a salt thereof, dicyclohexylcarbodiimide, isobutyloxycarbonyl chloride, isobutyloyl chloride, pivaloyl chloride, isobutyl chloroformate, diphenylphosphoryl azide, or diethyl cyanophosphate followed by reacting with the corresponding sulfonamide in the presence of a base represented by diazabicycloundecene, triethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, pyridine, N-methylmorpholine, N-ethylpiperidine, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, sodium methoxide, or sodium ethoxide (Reaction formula (b)) The compound obtained by the reaction between Compound (2) and the carboxylic acid activator may or may not be isolated.
Compound (6) can be obtained by reacting Compound (2) with an aminosulfonamide in the presence of carbonyldiimidazole, etc. (Reaction formula (g)).
Compound (7) can be obtained by reacting Compound (2) with hydrazine with one of the amino groups thereof protected in the presence of carbonyldiimidazole, etc. and treating the resulting product under the acidic conditions (Reaction formula (h)). Compound (7) can be converted to Compound (8) by reacting it with sulfonyl chloride or the like in the presence of a base such as triethylamine, etc. (Reaction formula (i)).
Compound (2) can be converted to Compound (9) by reacting it with diphenylphosphoryl azide and an alcohol in the presence of a base such as triethylamine, etc. (Reaction formula (j)). Compound (9) can be converted to Compound (10) by treating it under acidic conditions (Reaction formula (k)). Compound (10) can be converted to Compound (11) by reacting it with sulfonyl isocyanate (Reaction formula (1)), and to Compound (12) with isocyanate (Reaction formula (m)), respectively.
The terms “sulfonamides,”

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