Carboline derivatives

• US 6,043,252 A
• Filed: 09/16/1998
• Issued: 03/28/2000
• Est. Priority Date: 05/05/1997
• Status: Expired due to Fees

• Current Assignee: ICOS Corporation (Eli Lilly and Company)
• Original Assignee: ICOS Corporation (Eli Lilly and Company)
• Inventors: Bombrun, Agnes
• Primary Examiner(s): Jones, Dwayne C.
• Assistant Examiner(s): Delacroix-Muirheid, C.
• Application Number:
  US09/154,052
• Time in Patent Office: 559 Days
• Field of Search: 514/292, 546/85
• US Class Current: 514/292
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Carboline derivatives of formula (I) ##STR1## are potent and selective inhibitors of cyclic guanosine 3'"'"',5'"'"'-monophosphate specific phosphodiesterase (cGMP-specific PDE) and have utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders and erectile dysfunction.

Claims

1. A combination comprising:

(a) a compound of formula ##STR12## wherein R⁰ represents hydrogen or halogen;

R¹ is selected from the group consisting of;

hydrogen,

NO²

trifluoromethyl,

trifluoromethoxy,

halogen,

cyano,

a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur, and is optionally substituted by --C(═

O)OR^a or C_1-4 alkyl, C_1-6 alkyl optionally substituted by --OR^a, C_1-3 alkoxy, C(═

O) R^a, O--C (═

O) R^a, C(═

O) OR^a, C_1-4 alkylene-C (═

O)OR^a, O--C_1-4 alkylene --C (═

O) OR^a, C_1-4 alkylene--O--C_1-4 alkylene-C(═

O)OR^a, C(═

O)NR^a SO₂ R^c, C(═

O)C_1-4 alkylene-Het, C_1-4 alkylene-NR^a R^b, C_2-6 alkenylene-NR^a R^b, C(═

O)NR^a R^b, C(═

O)NR^a R^c, C(═

O)NR^a C_1-4 alkylene-OR^b C(═

O)NR^a C_1-4 alkylene-Het, OR^a OC_2-4 alkylene-NR^a R^b, OC_1-4 alkylene-CH (OR^a) CH₂ NR^a R^b, O--C_1-4 alkylene-Het, O--C_2-4 alkylene-OR^a, O--C_2-4 alkylene-NRa--C(═

O)--OR^b, NR^a R^b, NR^a C_1-4 alkylene-NR^a R^b, NR^a C(═

O)R^b, NR^a C(═

O)NR^a R^b, N(SO₂ C_1-4 alkyl)₂, NR^a (SO₂ C_1-4 alkyl), SO₂ NR^a R^b, and OSO₂ trifluoromethyl;

R² is selected from the group consisting of;

hydrogen,

halogen,

OR^a,

C_1-6 alkyl,

NO₂, and

NR^a R^b,

or R¹ and R² are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and suflur;

R³ is selected from the group consisting of;

hydrogen,

halogen,

NO₂,

trifluoromethoxy,

C_1-6 alkyl, and

C(═

O)OR^a ;

R⁴ is hydrogen,

or R³ and R⁴ are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;

Het represents a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and is optionally substituted with C_1-4 alkyl;

R^a and R^b can be the same or different, and are independently selected from hydrogen and C_1-6 alkyl;

R^c represents phenyl or C_4-6 cycloalkyl, wherein the phenyl or C_4-6 cycloalkyl can be optionally substituted by one or more halogen atoms, one or more --C(═

O)OR^a, or one or more --OR^a ;

n is an integer selected from 1, 2 and 3;

m is an integer selected from 1 and 2;

and pharmaceutically acceptable salts and solvates thereof; and

(b) a second therapeutically active agent,

for simultaneous, separate, or sequential use in the treatment of a condition where inhibition of a cGMP-specific PDE is of a therapeutic benefit.

2. A pharmaceutical formulation comprising a combination according to claim 1, together with a pharmaceutically acceptable diluent or carrier.

3. The combination of claim 1 wherein the condition is stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, malignant hypertension, pheochromocytoma, congestive heart failure, acute respiratory distress syndrome, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, carotid angioplasty, myocardial infarction, post-bypass surgery graft stenosis, a peripheral vascular disease, a vascular disorder, Raynaud'"'"'s disease, thrombocythemia, an inflammatory disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, osteoporosis, preterm labor, benign prostatic hypertrophy, a gut motility disorder, or irritable bowel syndrome.

4. The combination of claim 1 wherein the condition is erectile dysfunction in a male or female animal.

5. The combination of claim 1 wherein the second therapeutically active agent comprises a vasodilator, prostaglandin E1, prostacyclin, α

-adrenergic blocker, a mixed, α

,β

-blocker, an α

₂ -adrenergic blocker, an ACE inhibitor, an NEP inhibitor, a centrally acting dopaminergic agent, a vasoactive intestinal peptide, a calcium channel blocker, a thiazide, or a mixture thereof.

6. The combination of claim 5 wherein the vasodilator is selected from the group consisting of an organic nitrate, an organic nitrite, a thionitrite, a thionitrate, an S-nitrosothiol, a nitrosoprotein, a substituted furoxane, a substituted sydnonimine, a nitrosyl complex compound, nitric oxide, and mixtures thereof.

7. The combination of claim 5 wherein the vasodilator agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate, pentaerythrityl tetranitrate, isosorbide-5-mono-nitrate, propatyl nitrate, trolnitrate, nicroandil, mannitol hexanitrate, inositol hexanitrate, N-[3-nitratopivaloyl]-6-cysteine ethyl ester, isoamyl nitrite, S-nitroso-N-acetyl-D,L-pencillamine, 1,2,5-oxadiazole-2-oxide, furazan-N-oxide, molsidomine, mesocarb, an iron nitrosyl compound, sodium nitroprusside, nitric oxide, and mixtures thereof.

8. The combination of claim 1 wherein the second therapeutically active compound is selected from the group consisting of prostaglandin E1, prostacyclin, apomorphine, yohimibine, phentolamine, prazocin, carvedilol, and mixtures thereof.

9. A method of treating a condition where inhibition of a cGMP-specific PDE is of therapeutic benefit, in a human or a nonhuman animal body, comprising administering to said body a therapeutically effective amount of a combination of claim 1.

10. The method of claim 9 wherein the cGMP-specific PDE is PDE5.

11. The method of claim 9 wherein the human animal is a human male or female.

12. The method of claim 9 wherein the treatment is an oral treatment.

13. A method of treating stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, chronic obstructive pulmonary disease, malignant hypertension, pheochromacytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, thrombocythemia, an inflammatory disease, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, a gut motility disorder, pospercutaneous transluminal coronary angioplasty, carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, or irritable bowel syndrome, in a human or nonhuman animal body, said method comprising administering to said body a therapeutically effective amount of a combination of claim 1.

14. The method of claim 13 wherein the compound is administered orally.