Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-12
2003-06-03
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...
C546S118000
Reexamination Certificate
active
06573274
ABSTRACT:
This application is a 371 of PCT/JP99/06748 filed Dec. 1, 1999, now WO 00/34277 Jun. 15, 2000.
TECHNICAL FIELD
The present invention relates to novel sulfonamide compounds. More particularly, the present invention relates to novel sulfonamide compounds and salts thereof having hypoglycemic activity or PDE-V inhibitory activity. The present invention also relates to a method for producing the above-mentioned sulfonamide compound and salts thereof. Moreover, The present invention relates to pharmaceutical compositions comprising the above-mentioned sulfonamide compound or a salt thereof as an active ingredient.
DISCLOSURE OF THE INVENTION
The present invention aims at providing novel sulfonamide compounds, pharmaceutically acceptable salts thereof and pharmaceutical preparations comprising the above-mentioned sulfonamide compound or a pharmaceutically acceptable salt thereof as an active ingredient, which are used as an agent for the prophylaxis and treatment of impaired glucose tolerance disorder, diabetes (e.g., type II diabetes), gestational diabetes, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy and the like), insulin resistance syndrome (e.g., insulin receptor abnormality, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (e.g., stenocardia, cardiac failure and the like), hyperglycemia (e.g., those characterized by abnormal saccharometabolism such as eating disorders), pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases, and skin disorders related to an anomaly of differentiation of epidermic cells; and which, based on the cGMP-PDE (particularly PDE-V) inhibitory action, smooth muscle relaxing action, bronchodilating action, vasodilating action, smooth muscle cell inhibitory action, allergy suppressing action and the like, are used as prophylactic and therapeutic agents for angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis), tubulointerstitial disorders (e.g., kidney diseases induced by FK506, cyclosporin and the like), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), peripheral vascular diseases, cerebral apoplexy, chronic reversible obstructive impairment (e.g., bronchitis, asthma inclusive of chronic asthma and allergic asthma), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by impaired intestinal motility (e.g., irritable bowel syndrome), impotence (e.g., organic impotence, psychic impotence and the like), nephritis, cancer cachexia, restenosis after PTCA, cachexia (e.g., progressive weight loss due to lipolysis, myolysis, anemia, edema, anorexia and the like in chronic diseases such as cancer, tuberculosis, endocrine diseases and AIDS), and the like.
The sulfonamide compound, which is the novel compound of the present invention, is expressed by the formula (I):
wherein
R
1
is an aryl or heterocyclic group substituted by at least one substituent selected from the group consisting of (1) aryl, (2) a heterocyclic group optionally substituted by oxo or halogen, (3) halogen, (4) halo(lower)alkyl, (5) lower alkoxy optionally substituted by cyclo(lower)alkyl, (6) amino optionally substituted by at least one substituent selected from the group consisting of lower alkyl optionally substituted by cyclo(lower)alkyl, protected carboxy, acyl, lower alkylcarbamoyl, and lower alkanesulfonyl, (7) nitro and (8) lower alkynyl optionally substituted by aryl,
R
2
is a lower alkyl or lower alkoxy,
R
3
is a hydrogen or lower alkyl,
R
4
is a lower alkenyl optionally substituted by aryl or heterocyclic group, aryl optionally substituted by carboxy or protected carboxy, lower alkyl optionally substituted by acyloxy, amino optionally substituted by lower alkyl, or heterocyclic group optionally substituted by halogen, and
A is a lower alkylene
[hereinafter to be also referred to as the objective compound (I)].
Preferred salts of the objective compound (I) are conventional salts that are non-toxic and acceptable for use as pharmaceuticals. Examples thereof include salts with alkali metal such as sodium and potassium, salts with alkaline earth metal such as calcium and magnesium, salts with inorganic base such as ammonium salt, salts with organic amine such as triethylamine, pyridine, picoline, ethanolamine and triethanolamine, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, salts with organic carboxylic acid such as formic acid, acetic acid, trifluoroacetic acid, maleic acid and tartaric acid, addition salts with sulfonic acid such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and salts or acid addition salts with base such as basic or acidic amino acid such as arginine, aspartic acid and glutamic acid.
The objective compound (I) and a salt thereof of the present invention can be produced by the method shown by the following reaction formulas.
PRODUCTION METHOD 1
wherein each symbol in the formula is as defined above.
The objective compound (I) and a salt thereof of the present invention can be also produced by the method shown by the following reaction formulas.
PRODUCTION METHOD 2
wherein R
4a
is aryl substituted by at least one protected carboxy, R
4b
is aryl substituted by at least one carboxy, and other symbols are as defined above.
PRODUCTION METHOD 3
wherein R
1a
is aryl or heterocyclic group substituted by at least one amino substituted by at least one protected carboxy, R
1b
is aryl or heterocyclic group substituted by at least one unsubstituted or monosubstituted amino, and other symbols are as defined above.
PRODUCTION METHOD 4
wherein R
a
is hydrogen or lower alkyl optionally substituted by cyclo(lower)alkyl, R
1c
is aryl or heterocyclic group substituted by at least one amino substituted by at least one lower alkyl optionally substituted by cyclo(lower)alkyl, and other symbols are as defined above.
PRODUCTION METHOD 5
wherein R
1d
is aryl or heterocyclic group substituted by at least one halogen, R
b
and R
c
are each independently hydrogen, lower alkyl optionally substituted by cyclo(lower)alkyl, protected carboxy, acyl or lower alkanesulfonyl, R
1e
is aryl or heterocyclic group substituted by at least one amino optionally substituted by at least one substituent selected from the group consisting of lower alkyl optionally substituted by cyclo(lower)alkyl, protected carboxy, acyl and lower alkanesulfonyl, and other symbols are as defined above.
PRODUCTION METHOD 6
wherein R
1f
is aryl or heterocyclic group substituted by at least one amino substituted by at least one acyl, and other symbols are as defined above.
PRODUCTION METHOD 7
wherein each symbol in the formula is as defined above.
PRODUCTION METHOD 8
wherein R
1g
is aryl or heterocyclic group substituted by at least one amino substituted by at least one lower alkanesulfonyl, and other symbols are as defined above.
Various definitions included in the entire specification are explained in detail in the following.
“Lower” means 1 to 6 carbon atoms, unless otherwise specified.
“Alkyl” and “alkyl moiety” are preferably linear or branched alkyl. Specific examples include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, i-butyl, t-butyl, sec-butyl, 1-pentyl, i-pentyl, sec-pentyl, t-pentyl, methylbutyl, 1,1-dimethylpropyl, 1-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, 1-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4-ethylpentyl, 1,1-dimethylpentyl, 2,2-di
Abe Yoshito
Hamashima Hitoshi
Hiramura Takahiro
Imoto Takafumi
Ishibashi Naoki
Aulakh Charanjit S.
Fujisawa Pharmaceutical Co. Ltd.
Oku Tomohito
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