Cyclic GMP-specific phosphodiesterase inhibitors

Details Cyclic GMP-specific phosphodiesterase inhibitors Cyclic GMP-specific phosphodiesterase inhibitors

1998-05-15

1999-11-09

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544343, C07D47114, A61K 31395

Patent

active

059815272

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a series of tetracyclic derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to tetracyclic derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Thus, according to a first aspect, the present invention provides compounds of formula (I) ##STR3## and solvates (e.g. hydrates) thereof, in which: R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl; ##STR4## which may be optionally substituted by one or more groups selected from halogen and C.sub.1-3 alkyl; and
The term "halogen" as used herein denotes bromine, chlorine, fluorine and iodine.
The terms "C.sub.1-3 alkyl" and "C.sub.1-6 alkyl" as used herein denote a straight or branched alkyl chain such as methyl, ethyl, i-propyl, n-butyl, pentyl,hexyl or the like.
A particularly preferred subgroup of compounds according to the present invention are.compounds wherein R.sup.0 represents hydrogen.
A further preferred subgroup includes compounds wherein R.sup.1 is selected from hydrogen, methyl and iso-propyl.
Preferably, R.sup.2 represents the unsubstituted bicyclic ring ##STR5##
A still further subgroup of compounds of formula (I), are compounds wherein R.sup.3 represents hydrogen or methyl.
It is to be understood that the present invention covers all appropriate combinations of particular and preferred groupings hereinabove.
The compounds of formula (I) may contain one or more asymmetric centres and thus can exist as enantiomers or diastereoisomers. It is to be understood that the invention includes both mixtures and separate individual isomers of the compounds of formula (I). Particularly preferred are 6R and 12aR isomers.
Particular individual compounds of the invention include: 1':6,1]pyrido[3,4-b]indole-1,4-dione; rido[3,4-b]indole-1,4-dione; 2',1':6,1]pyrido[3,4-b]indole-1,4-dione; ino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; 2',1':6,1]pyrido[3,4-b]indole-1,4-dione;
A most particular compound of the invention is 1':6,1]pyrido[3,4-b]indole-1,4-dione;
It has been shown that compounds of the present invention are potent and selective inhibitors of cGMP specific PDE. Thus, compounds of formula (I) are of interest for use in therapy, specifically for the treatment of a variety of conditions where inhibition of cGMP specific PDE is thought to be beneficial.
As a consequence of the selective PDE 5 inhibition exhibited by compounds of the present invention, cGMP levels are elevated, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natriuretic and diuretic activities as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and endothelium-dependent relaxing agents such as bradykinin, acetylcholine and 5-HT.sub.1. The compounds of formula (I) therefore have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction and diseases characterised by disorders of gut motility (e.g. irritable bowel syndrome).
It will be appreciated that references herein to treatment extend to prophylaxis as well as treatment of established conditions.
It will also be appreciated that `a compound of formula (I),` or a physiologically acceptable salt or solvate thereof ca

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.
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. Comm., (1990), 170(2), 843-850.
J. Krall et al., Bio. Reprod., (1988), 39, 913-922.
M. Wilkins et al., Proc. Natl. Acad. Sci., USA, (1990, Aug.), 87, 6465-6469.
M. Wilkins et al., J. Clin. Invest., (1990, Apr.), 85, 1274-1279.
J. Rajfer, N. Eng. J. Med., (1992, Jan.), 326(2), 90-94.
H. Knispel, Urol. Res., (1992), 20, 253-257.
G. Gwinup, Annals. of Internal Medicine, (1988, Jul.), 162-163.
A. Zorgniotti, J. Urol., (1992, Apr.), 147(4), 308A.
K. Azadozoi et al., J. Urol., (1992, Nov.), 148, 1587-1591.
K. Azadozoi et al., J. Urol., (1992, Jan.), 147, 220-225.
C. Sparwasser et al., J. Urol., (1994, Dec.), 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, 3331-3339.
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., Geriatics, (1993, Jan.), 48(1), 46-58.
M. Webster et al., Hematol. Oncol. Cl. of N. Am., (1990, Feb.), 4(1), 265-289.
F. Holmquist et al., Acta. Physiol. Scand., (1991), 141, 441-442.
J. Taher et al., J. Urol., (1993, Apr.), 149, 285A.
S. Uckert et al., J. Urology., 151(5 Suppl), p. 495A (1994).
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, (1993, May), 87 Supp. V, V-30-V-32.
R. Pickard et al., J. Urol., (1993, May) 149 (4 Supp.), 245A.
R. Pickard et al., Clin. Pharmacol., (1993, Jan.), 35(5), 536P-537P.
F. Trigo-Rocha et al., J. Urol., (1993, Apr.), 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., (1993, Feb.), 108(2), 562-568.
E. Kim et al., J. Urol., (1995), 153, 361-365.
S. Korenman et al., JAGS, (1993, Apr.), 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., (1986, Nov.), vol. IV, No. 4, 236-238.
J. Beavo et al., TiPS, (1990, Apr.), 11, 150-155.
S. Korenman et al., Clin. Res., (1988), 36, 123A.
D. Halsted et al., J. Urol., (1986, Jul.), 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, (1991, Jan.), 12, 19-27.
J. LeBlanc et al., Eur. J. Cardiothorac Surg., (1993), 7, 211-215.
C. Stief et al., J. Urol., (1992, Nov.), 148, 1437-1440.
C. Stief et al., World J. Urol., (1991), 9, 237-239.
C. Clyne et al., Br. J. Surg., (1987, Apr.), 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. Heaton et al., Urology, (Feb. 1995), 45(2), 200-206.
A. Bowman et al., Br. J. Pharmac., (1984), 81, 665-674.
F. Trigo-Rocha et al., Am. J. Physiol., (1993, Feb.), 164, H419-H422.
J. Reiser et al., Br. J. Dis. Chest, (1986), 80, 157-163.
P. Bush et al., J. Urol., (1992, Jun.), 147, 1650-1655.
F. H

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