Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-18
2003-08-19
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S249000, C514S292000, C514S408000, C514S410000
Reexamination Certificate
active
06608065
ABSTRACT:
This invention relates to the use of tetracyclic derivatives which are potent and selective inhibitors of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase (cGMP specific PDE) in the treatment of impotence.
Impotence can be defined as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse. Its prevalence is claimed to be between 2 and 7% of the human male population, increasing with age, up to 50 years, and between 18 and 75% between 55 and 80 years of age.
Reports of well-controlled clinical trials in man are few and the efficacy of orally administered drugs is low. Although many different drugs have been shown to induce penile erection, they are only effective after direct injection into the penis, e.g. intraurethrally or intracavemosally (i.c.), and are not approved for erectile dysfunction. Current medical treatment is based on the i.c. injection of vasoactive substances and good results have been claimed with phenoxybenzamine, phentolamine, papaverine and prostaglandin E
1
, either alone or in combination; however, pain, priapism and fibrosis of the penis are associated with the i.c. administration of some of these agents. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also been shown to be active i.c., but cost and stability issues could limit development of the latter. An alternative to the i.c. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.
As a general alternative to pharmacological intervention, a variety of penile prostheses has been used to assist achievement of an erection. The short term success rate is good, but problems with infection and ischaemia, especially in diabetic men, make this type of treatment a final option rather than first-line therapy.
The compounds of the invention are potent inhibitors of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs). GB 9514464.8, which is the priority document for the present application describes the syntheses of the compounds of the invention and their utility in impotence. WO95/19978, which was unpublished at the priority date of the present application, also describes the syntheses of the compounds of the invention and their utility in other diseases associated with inhibition of cGMP PDEs. The compounds may be represented by the following general formula (I):
and salts and solvates (e.g. hydrates) thereof, in which:
R
0
represents hydrogen, halogen or C
1-6
alkyl;
R
1
represents hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, haloC
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkylC
1-3
alkyl, arylC
1-3
alkyl or heteroarylC
1-3
alkyl;
R
2
represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic
attached to the rest of the molecule via one of the benzene carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and
R
3
represents hydrogen or C
1-3
alkyl, or R
1
and R
3
together represent a 3- or 4- membered alkyl or alkenyl chain. Suitable individual compounds of the invention for use in the treatment of erectile dysfunction include:
Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione;
Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole -1,4-dione;
Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo2-thienyl)-2-methyl-pyrazino[2′, 1′:6,1 ]pyrido[3,4-b]indole -1,4-dione;
Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2′, 1′:6,1 ]pyrido[3,4-b]indole-1,4-dione;
(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1 ]pyrido[3,4-b]indole-1,4-dione;
(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione;
(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione;
(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione;
(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione;
(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido [3,4-b]indole-1,4dione;
(5aR, 12R, 14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5-1,4-dione;
Cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;
(3S, 6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione;
and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
The specific compounds of the invention are:
(6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl6-(3,4methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione (Compound A); and
(3S, 6R, 12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′, 1′:6,1]pyrido[3,4-b]indole-1,4-dione (Compound B);
and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
Unexpectedly, it has now been found that compounds of formula (I), and in particular compounds A and B, are useful in the treatment of erectile dysfunction. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration. Thus the present invention concerns the use of compounds of formula (I), and in particular compounds A and B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.
The pharmaceutically acceptable salts of the compounds of formula (I), and in particular compounds A and B which contain a basic centre are acid addition salts formed with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. Compounds of formula (I), and in particular compounds A and B can also provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases. Examples include the sodium and potassium salts.
It has been shown that compounds of the present invention are potent and selective inhibitors of cGMP specific PDE. It has now been surprisingly found that human corpus cavemosum contains three distinct PDE enzymes. The predominant PDE has further surprisingly been found to be cGMP PDE. As a consequence of the selective PDE V inhibition exhibited by compounds of the present invention, the subject compounds can elevate cGMP levels, which in turn can mediate relaxation of the corpus cavemosum tissue and consequent penile er
ICOS Corporation
Jiang S.
Marshall Gerstein & Borun
Padmanabhan Sreeni
LandOfFree
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