Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-21
2001-06-05
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S338500, C548S338100, C548S335100, C548S315100, C514S399000, C514S397000
Reexamination Certificate
active
06242474
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel aromatic ring derivatives and specifically to novel aromatic ring 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 such an aromatic ring derivative or its salt as an active ingredient.
DISCLOSURE OF THE INVENTION
An objective of the present invention is to provide novel aromatic ring derivatives and their pharmaceutically acceptable salts, and also pharmaceutical compositions comprising such an aromatic ring derivative or its pharmaceutically acceptable salt as an active ingredient, 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., those characterized by 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 diseases, 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 lipolysis, myolysis, anemia, edema, anorexia etc., in chronic diseases including cancer, tuberculosis, endocrinopathy, AIDS, etc.), pancreatitis, or restenosis after PTCA.
The present inventors provide novel aromatic ring derivatives represented by any one of formulae (I) and (III) to (VI) below and their pharmaceutically acceptable salts, and also provide pharmaceutical compositions comprising the compound as an active ingredient, 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., those characterized by 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 diseases, 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 lipolysis, myolysis, anemia, edema, anorexia etc., in chronic diseases including cancer, tuberculosis, endocrinopathy, AIDS, etc.), pancreatitis, or restenosis after PTCA.
wherein X indicates a substituent represented by formula (II):
wherein R
2
represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo-lower alkyl group, an aromatic group, or a heterocyclic group, each of which may have one or more substituents; ch
1
and ch
2
each represents a saturated or unsaturated cross-linking group, which may be branched; ch
1
may have one or more substituents selected from the group consisting of a lower alkyl group, a lower cycloalkyl group, an aromatic group, a heterocyclic group, a lower alkyl-lower cycloalkyl group, an aromatic-lower alkyl group, and a heterocyclic-lower alkyl group; Nu represents a 5- or 6-membered aromatic group; X and Nu may be bonded directly to each other; R
1
represents a hydrogen atom, a halogen atom, a lower alkyl group, an amino group, an acylamino group, a lower alkenyl group, a lower alkynyl group, a halo-lower alkyl group, a lower cycloalkyl group, a nitro group, a lower alkylamino group, a carboxyl group, an esterified carboxyl group, an amidated carboxyl group, a lower alkanesulfonyl group, an aromatic-sulfonyl group, a hydroxyl group, or a lower alkoxyl group; n is a natural number of 2 or less; and A is an aromatic ring that may have one or more substituents.
wherein R
3
represents a hydrogen atom or a lower alkyl group; R
4
represents a hydrogen atom or an acyl group; X and A are as defined above.
wherein A is as defined above.
wherein R
5
represents a hydrogen atom or a lower alkyl group; R
6
represents a hydrogen atom, a halogen atom, or a phenyl group; and X and A are as defined above.
wherein A, R
5
, and R
6
are as defined above.
The aromatic ring derivatives of the present invention in which Nu is a benzene ring can be synthesized through the reaction scheme represented by formulae (a) to (h) below.
In formulae (a) to (c), Z represents a halogen atom; R
1
has the same definition as CH
2
A described above; R
a
represents a hydrogen atom or an alkyl group; R
2
is a alkyl group, a lower alkenyl group, a lower alkynyl group, a cyclo-lower alkyl group, an aromatic group, or a heterocyclic group, which may have one or more substituents.
In formula (d), R
1
and R
2
are as defined above, and R
a
and R
b
represent a hydrogen atom or an alkyl group.
In formulae (e) to (h), R
1
and R
2
are as defined above, and R
a
represents a hydrogen atom or an alkyl group.
In formula (a) the compound of formula (2) can be synthesized from the compound of formula (1) and R
1
NHR
a
, wherein R
a
and R
1
are as defined above. In formula (b), the compound of formula (3) can be obtained by reacting the compound of formula (2) with a carboxylic acid-activating agent, such as N,N′-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its salts, dicyclohexylcarbodiimide, isobutyloxycarbonyl chloride, isobutyloyl chloride, pivaloyl chloride, isobutylchloroformate, diphenylphosphoryl azide, or diethyl cyanophosphate, and then reacting the reaction product with the corresponding sulfonamides in the presence of a base, such as diazabicycloundecene, triethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, pyridine, N-methylmorpholine, N-ethylpiperidine, potassium hydroxide, sodium hydroxide, potassium phosphate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, sodium methoxide, or sodium ethoxide.
In formula (c), the compound of formula (4) can be obtained by reducing the nitro group of the compound of formula (3) with a hydrogenation catalyst such as palladium-carbon in a hydrogen atmosphere. The nitro group can also be reduced with 1) reduced iron or zinc, 2) sodium hydrosulfite, 3) formic acid or ammonium formate in the presence of a transition metal catalyst
Abe Yoshito
Hamashima Hitoshi
Hiramura Takahiro
Imoto Takafumi
Kayakiri Hiroshi
Aulakh Charanjit S.
Foley & Lardner
Fujisawa Pharmaceutical Co. Ltd.
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