Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-10
2000-10-31
Moezie, Minna
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3150, A61K 31495
Patent
active
061403296
DESCRIPTION:
BRIEF SUMMARY
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 intracavernosally (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.sub.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): ##STR1## and salts and solvates (e.g. hydrates) thereof, in which:
R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl;
R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, haloC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkylC.sub.1-3 alkyl, arylC.sub.1-3 alkyl or heteroarylC.sub.1-3 alkyl;
R.sup.2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR2## attached to the rest of the molecule via one of the benzene ring 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.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 and R.sup.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: l)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; 6,1]pyrido[3,4-b]indole-1,4-dione; pyrido[3,4-b]indole-1,4-dione; -pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; l)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; razino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione
REFERENCES:
patent: 3644384 (1972-02-01), Schulenberg
patent: 3717638 (1973-02-01), Schulenberg
patent: 3917599 (1975-11-01), Saxena et al.
patent: 4188390 (1980-02-01), Campbell
patent: 4686228 (1987-08-01), Campbell et al.
patent: 5145852 (1992-09-01), Virag
patent: 5270323 (1993-12-01), Milne, Jr. et al.
A. Bowman et al., Br. J. Pharmac., (1984), 81, 665-674.
F. Trigo-Rocha et al., Am. J. Physiol., (Feb. 1993), 264, H419-H422.
J. Reiser et al., Br. J. Dis. Chest, (1986), 80, 157-163.
P. Bush et al., J. Urol., (Jun. 1992), 147, 1650-1655.
F. Holmquist et al., J. Urol. (Oct. 1993), 150, 1310-1315.
R. Rudd et al., Br. J. Dis. Chest, (1983), 77, 78-86.
E. McMahon et al., J. Pharmacol. Exp. Thera., (1989), 251, 1000-1005.
F. Holmquist et al., Acta Physiol. Scand., (1991), 143, 299-304.
G. Barbanti, Urol. Res., (1988), 16, 299-302.
L. Ignarro et al., Biochem. and Biophys. Res. Commun., (1990), 170(2), 843-850.
J. Krall et al., Bio. Reprod., (1988), 39, 913-922.
M. Wilkins et al., Proc. Natl. Acad. Sci., USA, Aug. 1990), 87, 6465-6469.
M. Wilkins et al., J. Clin. Invest., (Apr. 1990), 85, 1274-1279.
J. Raifer, N. Eng. J. Med., (Jan. 1992), 326(2), 90-94.
H. Knispel, Urol. Res., (1992), 20, 253-257.
G. Gwinup, Annals. of Internal Medicine, (Jul. 1988), 162-163.
A. Zorgniotti, J. Urol., (Apr. 1992), 147(4), 308A.
K. Azadzoi et al., J. Urol., (Nov. 1992), 148, 1587-1591.
K. Azadzoi et al., J. Urol., (Jan. 1992), 147, 220-225.
C. Sparwasser et al., J. Urol., (Dec. 1994), 152, 2159-2163.
T. Lue, "Campbell's Urology," 6th Ed., Chap. 16, P. Walsh et al., Eds., W.B. Saunders Co., 709-728 (1991).
N. Kim et al., J. Clin. Invest., (1991), 88, 112-118.
S. Francis et al., in J. Beavo et al. eds. "Cyclic Nucleotide PDEs," Ch. 5 (1990) 117-140.
R. Weishaar et al., J. Med. Chem., (1985), 28:5, 537-542.
H. Ahn et al., Biochem. Pharmacol., (1989), 39:19, 331-3339.
C. Lugnier et al., Biochem. Pharmacol., (1986), 35:10, 1743-1751.
J. Doremieux et al., Ann. Urol. Paris, (1987), 21(6), 429-434.
D. Green et al., Geriatrics, (Jan. 1993), 48(1), 46-58.
M. Webster et al., Hematol. Oncol. Cl. of N. Am., (Feb. 1990), 4(1), 265-289.
F. Holmquist et al., Acta. Physiol. Scand., (1991), 141, 441-442.
J. Taher et al., J. Urol., (Apr. 1993), 149, 285A.
S. Uckert et al., , 495A.
W. Aronson et al., J. Urol., (1991), 145 (4 Supp.), 341A.
P. Bush et al., Fed. Am. Soc. Exp. Biol., (1991), 5(4), 175.
P. Bush et al., Fed. Am. Soc. Exp. Biol., (1992), 6(4), 2092.
W. Aronson et al., J. Urol., (1992), 147 (4 Supp.), 454A.
P. Bush et al., Circulation, (May 1993), 87 Supp. V, V-30-V-32.
R. Pickard et al., J. Urol., (May 1993) 149 (4 Supp.), 245A.
R. Pickard et al., Clin. Pharmacol., (Jan. 1993), 35(5), 536P-537P.
F. Trigo-Rocha et al., J. Urol., (Apr. 1993), 149, 872-877.
M. Krupp et al., J. Cardiovas. Pharmacol., (1989), 13 (Supp. 2), S11-S19.
"Physicians' Desk Reference," (1992), 683,1099-1100, 1344, 1941-1943.
R. Morales et al., World J. Urol., (1990), 8, 80-83.
J. Cortijo, Br. J. Pharmacol., (Feb. 1993), 108(2), 562-568.
E. Kim et al., J. Urol., (1995), 153, 361-365.
S. Korenman et al., JAGS, (Apr. 1993), 41(4), 363-366.
K. Allenby et al., Angiology, (1991), 42, 418-420.
H. Hamilton et al., J. Med. Chem., (1987), 30, 91-96.
H. Padma-Nathan et al., Sem. in Urol., (Nov. 1986), vol. IV, No. 4, 236-238.
J. Beavo et al., TiPS, (Apr. 1990), 11, 150-155.
S. Korenman et al., Clin. Res., (1988), 36, 123A.
D. Halsted et al., J. Urol., (Jul. 1986), 136, 109-110.
W. Thompson, Pharmac. Ther., (1991), 51, 13-33.
M. Giembycz et al., Clin. and Exper. Allergy, (1992), 22, 337-344.
C. Nicholson et al., TIPS, (Jan. 1991), 12, 19-27.
J. LeBlanc et al., Eur. J. Cardiothorac Surg., (1993), 7, 211-215.
C. Stief et al., J. Urol., (Nov. 1992), 148, 1437-1440.
C. Stief et al., World J. Urol., (1991), 9, 237-239.
C. Clyne et al., Br. J. Surg., (Apr. 1987), 74, 246-248.
V. Mirone et al., Acta. Urol. Ltd., (1992), Suppl. 4, 11-12.
P. Bush, Ph.D. Thesis (1992), pp. 159-160.
T. Lincoln, Pharmac. Ther., (1989), 41, 479-502.
J. Heato
ICOS Corporation
Moezie Minna
LandOfFree
Use of cGMP-phosphodiesterase inhibitors in methods and composit does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of cGMP-phosphodiesterase inhibitors in methods and composit, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of cGMP-phosphodiesterase inhibitors in methods and composit will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2052048