Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-09
2003-06-24
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S262000
Reexamination Certificate
active
06583147
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to pyrazolopyrimidinone derivatives of the following formula 1, their preparation method and pharmaceutical compositions containing the said derivatives. The compounds have efficacy on the treatment of impotence, one of male sexual dysfunctions with the side effects reduced.
Wherein,
R
1
represents hydrogen, alkyl group of C
1
-C
6
, fluoroalkyl group of C
1
-C
3
, or cycloalkyl group of C
3
-C
6
;
R
2
represents hydrogen, substituted or unsubstitutedalkyl group of C
2
-C
6
, fluoroalkyl group of C
1
-C
3
, or cycloalkyl group of C
3
-C
6
;
R
3
represents substituted or unsubstituted alkyl group of C
1
-C
6
, fluoroalkyl group of C
1
-C
6
, cycloalkyl group of C
3
-C
6
, alkenyl group of C
3
-C
6
, or alkynyl group of C
3
-C
6
; and
R
4
represents substituted or unsubstituted and linear or branched alkyl group of C
1
-C
10
, substituted or unsubstituted alkenyl group of C
1
-C
9
, substituted or unsubstituted cycloalkyl group of C
3
-C
6
, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
In case of R
2
, R
3
and R
4
being substituted, the substituent is alkyl group of C
1
-C
10
, cycloalkyl group of C
3
-C
6
, halogen, fluoroalkyl group of C
1
-C
6
, alkyloxy group of C
1
-C
10
, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
The compounds of formula 1 may exist in tautomeric equilibrium represented by the following reaction scheme 1.
The compounds of formula 1 may contain asymmetric centers and thus they can exist as enantiomers. The present invention includes both mixtures and separate individual isomers.
Male erectile dysfunction is one of the most common sexual dysfunctions in men. Although erectile dysfunction can be primarily psychogenic in origin, it often accompanies chronic illnesses, such as diabetes mellitus, heart disease, hypertension, and a variety of neurological diseases. Its prevalence is strongly related to age, with a estimated prevalence of 2% at age 40 years rising to 25-30% by age of 65. Although no data are available on the prevalence of erectile dysfunction in men aged over 75, it is probably over 50%.
Various treatment options for erectile dysfunction are available, such as counseling, hormonal therapy, self-injection or transurethral application of vasodilator agents, vacuum devices, prosthesis implantation, and venous/arterial surgery. However, these therapeutic options have several limitations such as side effects, high-cost and low efficacy. Therefore it has called for research efforts to develop new, high effective and simple to use treatment methods, potentially oral medication.
Recently, sildenafil has been developed as a therapeutic agent for male erectile dysfunction by oral administration. Sildenafil is the first in a new class of drugs known as inhibiting phosphodiesterase-5 enzyme distributed specifically in corpus cavernosal tissues and induces relaxation of the corpus cavernosal smooth muscle cells, so that blood flow to the penis is enhanced, leading to an erection. Sildenafil has shown a response rate of around 80% in men with erectile dysfunction of organic cause.
On the other hand, U.S. Pat. No. 3,939,161 discloses that 1,3-dimethyl-1H-pyrazolopyrimidinone derivatives exhibit anticonvulsant and sedative activiity, and also exhibit anti-inflammatory activity and gastric antisecretory activity; EP 201,188 discloses that 5-substituted pyrazolopyrimidinone derivatives have effects of antagonizing adenosine receptor and of inhibiting phosphodiesterase enzymes and can be used for the treatment of cardiovascular disorders such as heart failure or cardiac insufficiency; EP 463,756, EP 526,004, WO 93/6,104 and WO 93/7,149 disclose that pyrazolopyrimidinone derivatives which inhibit c-GMP phosphodiesterase more selectively than c-AMP phosphodiesterase have efficacy on cardiovascular disorders such as angina pectoris, hypertension, heart failure, atherosclerosis, chronic asthma, etc.; and WO 94/28,902, WO 96/16,644, WO 94/16,657 and WO 98/49,166 disclose that the known inhibitors of c-GMP phosphodiesterase including the pyrazolopyrimidinone derivatives of the above mentioned patents can be used for the treatment of male erectile dysfunction.
We, the inventors of the present invention, have investigated to develop the improved therapeutic agent for impotence and synthesized new pyrazolo pyrimidinone derivatives which have better potency for the treatment of impotence than that of sildenafil, based on the mechanism of inhibiting phosphodiesterase-5 enzyme. The selectivity over phosphodiesterase-6 distributed in retina and phosphodiesterase-3 distributed in heart, of the compounds of the present invention, is much more improved, to reduce the side effects. The solubility and the metabolism in the liver, which are very important factor affecting the rate of the absorption when administered orally, of the compounds of the present invention is much more improved.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide pyrazolopyrimidinone derivatives represented by formula 1 and their pharmaceutically acceptable salts.
It is another object of the present invention to provide preparation method of the said pyrazolopyrimidinone derivatives.
It is still another object of the present invention to provide pharmaceutical compositions for the treatment of impotence which contain the said pyrazolopyrimidinone derivatives and/or their pharmaceutically acceptable salts as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new pyrazolopyrimidinone derivatives of the following formula 1 and their pharmaceutically acceptable salts.
Wherein,
R
1
, represents hydrogen, alkyl group of C
1
-C
6
, fluoroalkyl group of C
1
-C
3
, or cycloalkyl group of C
3
-C
6
;
R
2
represents hydrogen, substituted or unsubstitutedalkyl group of C
2
-C
6
, fluoroalkyl group of C
1
-C
3
, or cycloalkyl group of C
3
-C
6
;
R
3
represents substituted or unsubstituted alkyl group of C
1
-C
6
, fluoroalkyl group of C
1
-C
6
, cycloalkyl group of C
3
-C
6
, alkenyl group of C
3
-C
6
, or alkynyl group of C
3
-C
6
; and
R
4
represents substituted or unsubstituted and linear or branched alkyl group of C
1
-C
10
, substituted or unsubstituted alkenyl group of C
1
-C
9
, substituted or unsubstituted cycloalkyl group of C
3
-C
6
, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
In case of R
2
, R
3
and R
4
being substituted, the substituent is alkyl group of C
1
-C
10
, cycloalkyl group of C
3
-C
6
, halogen, fluoroalkyl group of C
1
-C
6
, alkyloxy group of C
1
-C
10
, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
In the formula 1, preferably R
1
is alkyl group of C
1
-C
3
; R
2
is substituted or unsubstituted alkyl group of C
2
-C
6
; R
3
is substituted or unsubstituted alkyl group of C
2
-C
6
; and R
4
is substituted or unsubstituted alkyl group of C
1
-C
6
, substituted or unsubstituted cycloalkyl group of C
3
-C
6
, substituted or unsubstitutedbenzene, substituted or unsubstituted pyridine, or substituted or unsubstituted pyrrole. In case o
Ahn Byoung Ok
Chang Min Sun
Doh Hyounmie
Kang Kyung Koo
Kim Dong Goo
Bachman & LaPointe P.C.
Dong A Pharm Co., Ltd.
Liu Hong
Raymond Richard L.
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