Polycyclic guanine phosphodiesterase V inhibitors
View Patent ↗A polycyclic guanine phosphodiesterase V inhibitor having the formula (I.1) or (II.1), with the variables defined herein, which is useful for treating sexual dysfunction and other physiological disorders: A representative example is:
1. A compound having the formula (I.1) or (II.1):
or a pharmaceutically acceptable salt thereof
where,
q=0 or 1;
R 1 is H, cycloalkyl, alkyl, R 23 -alkyl- or R 26 ;
R a , R b and R c are, independently of one another, each H, alkyl, cyoloalkyl, aryl, R 22 -aryl- or R 24 -alkyl-; or
R a and R b , together with the carbon to which they are both attached, form a 4- to 7-membered ring, and R c is H or alkyl; or
R a and R c , together with the respective carbons to which they are attached, form a 4- to 7-membered ring, and R b is H or alkyl;
(i) X is a bond;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is monohaloalkyl, polyhaloalkyl, provided that it is not trifluoromethyl, azido, cyano, oximino, cycloalkenyl, heteroaryl, R 22 -heteroaryl- or R 27 -alkyl-;
(ii) X is a bond;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is H, halo, —CONHR 6 , —CONR 6 R 7 , —CO 2 R 6 , monohaloalkyl, polyhaloalkyl, azido, cyano, —C═N—OR 6 , cycloalkyl, cycloalkylalkyl, R 26 , aminosulfonyl, alkyl or R 23 -alkyl-;
(iii) X is —O— or —S—;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is R 26 , cycloalkyl cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R 26 -alkyl-;
(iv) X is —O— or —S—;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is alkyl, R 26 , cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R 28 -alkyl-;
(v) X is —SO— or —SO 2 —;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is alkyl, R 26 , cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R 28 -alkyl-;
(vi) X is —NR 8 —;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is (R 29 ) p -alkyl-, cycloalkyl, (R 30 ) p -cycloalkyl-, cycloalkenyl, (R 30 ) p -cycloalkenyl-, heterocycloalkyl or (R 30 ) p -heterocycloalkyl-:
(vii) X is —NR 8 —;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is alkyl, R 26 , cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R 31 -alkyl-; or
(viii) X is —C≡C—;
Y is aryl-alkyl or R 22 -aryl-alkyl-; and
R 2 is alkyl, R 26 , cycloalkyl, cycloalkylalkyl or R 23 -alkyl-;
where,
R 6 is H or R 7 ;
R 7 is alkyl, cycloalkyl or cycloalkylalkyl;
R 8 is heterocycloalkyl or R 6 ;
R 21 is 1-6 substituents each independently selected from the group consisting of halo, hydroxy, alkoxy, phenoxy, phenyl, nitro, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, cyoloalkyl, cycloalkylalkyl, amino, alkylamino, acylamino, carboxyl, —C(O)OR 34 , carboxamido, —OCF 3 and acyloxy;
R 22 is 1-6 substituents each independently selected from the group consisting of alkyl and R 21 ;
R 23 is cycloalkoxy aryloxy, alkylthio, arylthio, cycloalkyl or R 28 ;
R 24 is cycloalkyl or R 26 ;
R 25 is hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or R 26 ;
R 26 is aryl, R 22 -aryl-, heteroaryl or R 22 -heteroaryl-;
R 27 is cycloalkoxy, aryloxy, alkylthio, arylthio, heteroaryl, R 22 -heteroaryl-, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkylamino or heterocycloalkylamino;
R 28 is cycloalkylamino, heterocycloalkylamino or R 25 ;
R 29 is alkoxy, cycloalkylamino, heterocycloalkylamino or R 26 ;
R 30 is halo, hydroxy, alkoxy, amino, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, alkyl, cyoloalkyl, cycloalkylalkyl or acyloxy;
R 31 is cycloalkyl or R 28 ;
R 34 is alkyl, aryl, aralkyl and heteroaryl; and
p is 1 to 4.
2. The compound or pharmaceutically acceptable salt according to claim 1 , where R 1 is aryl, R 22 -aryl-, alkyl or R 23 -alkyl-, where R 22 and R 23 are each independently defined in claim 1 .
3. The compound or pharmaceutically acceptable salt according to claim 1 , where in sections (i) through (viii), respectively, R 2 is (i) R 27 -alkyl-, (ii) R 23 -alkyl-, (iii) R 28 -alkyl-, (iv) alkyl or R 28 -alkyl-, (v) alkyl or R 28 -alkyl-, (vi) (R 29 ) p -alkyl-, (vii) alkyl or R 31 -alkyl- or (viii) alkyl or R 23 -alkyl-, where R 23 , R 27 , R 28 , R 29 , R 31 and p are each independently defined in claim 1 .
4. The compound or pharmaceutically acceptable salt according to claim 1 , which is
5. The compound or pharmaceutically acceptable salt according to claim 1 , which is
6. The compound or pharmaceutically acceptable salt according to claim 1 , which is
7. The compound or pharmaceutically acceptable salt according to claim 1 , which is
8. The compound or pharmaceutically acceptable salt according to claim 1 , which is
9. The compound or pharmaceutically acceptable salt according to claim 1 , which is
10. The compound or pharmaceutically acceptable salt according to claim 1 , which is
11. The compound or pharmaceutically acceptable salt according to claim 1 , where the compound has the formula (I.1):
where the substituents are defined in claim 1 .
12. The compound or pharmaceutically acceptable salt according to claim 1 , where X is —NH—, and R 2 is:
where R 80 is H or hydroxy.
13. The compound or pharmaceutically acceptable salt according to claim 1 , where X is —O—, Y is defined in section (ii) of claim 1 , and R 2 is alkyl or aralkyl.
14. The compound or pharmaceutically acceptable salt according to claim 1 , where X is —C≡C—, and R 2 is alkyl or R 25 , where R 26 is defined in claim 1 .
15. The compound or pharmaceutically acceptable salt according to claim 1 , where X is a bond, Y is defined in section (ii) of claim 1 , and R 2 is halo, —CONHR 6 , —CONR 6 R 7 , —CO 2 R 6 or —C═N—OR 6 , where R 6 and R 7 are each independently defined in claim 1 .
16. The compound or pharmaceutically acceptable salt according to claim 1 , where;
(a) R a is alkyl or R 24 -alkyl-, and R b and R c are each H, where R 24 is defined in claim 1 ; or
(b) R a and R b , together with the carbon to which they are both attached, form a 5- or 6-membered ring, and R c is H; or
(c) R a and R c , together with the respective carbons to which they are attached, form a 5-membered ring, and R b is H; or
(d) R a , R b and R c are each H.
17. The compound or pharmaceutically acceptable salt according to claim 1 , where X is —NR 8 —, Y is defined in section (i) of claim 1 , and R 2 is a group defined by the formula (III.1):
where,
R 8 is H or alkyl;
R 8 , R 10 and R 11 , independently of one another, are selected from the group consisting of H, cycloalkyl, heterocycloalkyl, carboxyl, carboxamido, alkoxycarbonyl, aryloxycarbonyl, oximino, alkyl, R 32 -alkyl- and R 26 , where
R 32 is cycloalkyl, heterocycloalkyl, carboxamido, alkoxycarbonyl, aryloxycarbonyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or R 26 , and
R 26 is defined in claim 1 ; or
R 9 and R 10 , together with the carbon, carbons and/or heteroatom of the ring to which they are attached, form a linearly-fused or bridged bicyclic ring of 7 to 12 members, and R 11 is defined above; or
R 10 and R 11 are, independently of one another, selected from the group consisting of hydroxy, alkoxy, aryloxy, acyloxy, —C(O)OR 34 , where R 34 is defined in claim 1 , amino, alkylamino, dialkylamino, acylamino and alkylsulfonylamino, and R 9 is defined above; or
R 10 and R 11 , together with the carbon, carbons and/or heteroatom of the ring to which they are attached, form a linearly-fused, spiro-fused or bridged bicyclic ring of 7 to 12 members, and R 9 is defined above;
l and m are, independently of one another, each 1 to 3; and
A is —O—, —S—, —C(R 4 R 16 )—, —SO—, —SO 2 — or —NR 12 —, where
R 4 and R 16 are, independently of one another, each selected from the group consisting of H, cycloalkyl heterocycloalkyl, carboxyl, carboxamido, alkoxycarbonyl, aryloxycarbonyl, oximino, alkyl, R 32 -alkyl- and R 26 , where R 32 is defined above and R 26 is defined in claim 1 ; and
R 12 is heterocycloalkyl, R 7 , R 26 , —COR 13 , —SO 2 R 14 , —CO 2 R 14 , —CONR 13 R 15 or —SO 2 NR 13 R 15 , where
R 7 is defined in claim 1 ;
R 14 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or R 26 , where R 26 is defined in claim 1 ; and
R 13 and R 15 are, independently of one another, each selected from the group consisting of H and R 14 ; or
R 13 and R 15 , together with the nitrogen to which they are both attached, form a 4- to 8-membered ring.
18. The compound or pharmaceutically acceptable salt according to claim 17 , where R 9 , R 10 and R 11 are each H.
19. The compound or pharmaceutically acceptable salt according to claim 1 , where R a is R 24 -alkyl-, and R b and R c are each H, where R 24 is defined in claim 1 .
20. The compound or pharmaceutically acceptable salt according to claim 1 , where the compound has a PDE V IC 50 of between <0 nM and about 5 nM.
21. The compound or pharmaceutically acceptable salt according to claim 1 , where the compound has a ratio of PDE VI IC 50 /PDE V IC 50 of >about 140.
22. The compound or pharmaceutically acceptable salt according to claim 1 , where the compound has a PDE V IC 50 of between >0 nM and about 5 nM and a ratio of PDE VI IC 50 /PDE V IC 50 of > about 140.
23. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable excipient or carrier.
24. A method for treating a physiological disorder, symptom or disease in a patient in need of the treatment, comprising administering to the patient an effective amount of at least one of the compound or pharmaceutically acceptable salt according to claim 1 , wherein the physiological disorder, symptom or disease is male erectile dysfunction.
25. A method for elevating a cGMP level in a patient, comprising administering to the patient an effective amount of at least one of the compound or pharmaceutically acceptable salt according to claim 1 .
26. A method for treating an erectile dysfunction in a patient in need of the treatment, comprising administering to the patient a combination therapy, comprising an effective amount of at least one of the compound or pharmaceutically acceptable salt according to claim 1 and at least one compound selected from the group consisting of: a prostanoid, α-adrenergic receptor, dopamine receptor agonist, melanocortin receptor agonist, endothelin receptor antagonist, endothelin converting enzyme inhibitor, angiotensin II receptor antagonist, angiotensin converting enzyme inhibitor, neutral metalloendopeptidase inhibitor, renin inhibitor, serotonin 5-HT 2c receptor agonist, nociceptin receptor agonist, rho kinase inhibitor, potassium channel modulator and multidrug resistance protein 5 inhibitor.