Compounds for treating pulmonary hypertension

1. A method for treating or managing pulmonary hypertension in a subject in need thereof comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or diastereoisomeric form of said compound,

wherein said formula I is:

wherein

R 3 is H or lower alkyl;

R 6 is independently selected from the group consisting of

H;

alkyl;

cycloalkyl;

lower alkyl-N(R 3 ) 2 ; and

lower alkyl-OH;

R 4 is H, halogen, or lower alkyl;

p is 0, 1, or 2;

X is selected from the group consisting of O, S, and NR 3 ;

Y is selected from the group consisting of

—CH 2 —O—;

—CH 2 —NH—;

—O—;

—NH—; and

—O—CH 2 —;

q is 0, 1, or 2;

G 3 is a monovalent or bivalent moiety selected from the group consisting of:

lower alkyl;

—OR 6 ;

—COR 6 ;

—CH 2 OR 3 ;

—CON(R 6 ) 2 ; and

bivalent bridge of structure T 2 =T 2 −T 3

wherein

each T 2 independently represents N, CH, or CG 3′ ; and

T 3 represents S, O, CR 4 G 3′ , C(R 4 ) 2 , or NR 3 ; wherein

 G 3′ represents any of the above-defined moieties G 3 which are monovalent; and

the terminal T 2 is bound to L, and T 3 is bound to D, forming a 5-membered fused ring;

A and D independently represent N or CH;

B and E independently represent N or CH;

L represents N or CH; and

with the provisos that

a) the total number of N atoms in the ring containing A, B, D, E, and L is 0, 1, 2, or 3; and

b) when L represents CH and any G 3 is a monovalent substituent, at least one of A and D is an N atom; and

c) when L represents CH and a G 3 is a bivalent bridge of structure T 2 =T 2 −T 3 , then A, B, D, and E are also CH;

J is a ring selected from the group consisting of

aryl;

pyridyl; and

cycloalkyl;

q′ represents the number of substituents G 4 on ring J and is 0, 1, 2, 3, 4, or 5, and

G 4 is a monovalent or bivalent moiety selected from the group consisting of

—N(R 6 ) 2 ;

—NR 3 COR 6 ;

halogen;

alkyl;

cycloalkyl;

halogen-substituted alkyl;

—OR 6 ;

halogenated lower alkoxy;

heterocyclyl; and

fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures:

wherein

each T 2 independently represents N, CH, or CG 4′ ;

T 3 represents S, O, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein

 G4′ represents any of the above-defined moieties G 4 which are monovalent; and

binding to ring J is achieved via terminal atoms T 2 and T 3 ;

wherein

each T 2 independently represents N, CH, or CG 4′ ; wherein

 G4′ represents any of the above-defined moieties G 4 which are monovalent; and

with the proviso that a maximum of two bridge atoms T 2 may be N; and

binding to ring J is achieved via terminal atoms T 2 ; and

wherein

each T 4 , T 5 , and T 6 independently represents O, S, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein

G4′ represents any of the above-defined moieties G 4 which are monovalent; and

binding to ring J is achieved via terminal atoms T 4 or T 5 ;

with the provisos that:

i) when one T 4 is O, S, or NR 3 , the other T 4 is CR 4 G 4′ or C(R 4 ) 2 ;

ii) a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N; and

iii) in a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom;

when G 4 is an alkyl group located on ring J adjacent to the linkage —(CR 4 2 ) p —, and X is NR 3 wherein R 3 is an alkyl substituent, then G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure —(CH 2 ) p′ — wherein p′ is 2, 3, or 4, with the proviso that the sum of p and p′ is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members;

and with the further proviso that:

in G 3 and G 4 , when two groups R 3 or R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N-containing heterocycle of 5-7 ring atoms.

2. A method for treating or managing pulmonary hypertension in a subject in need thereof comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or diastereoisomeric form of said compound,

wherein said formula I is:

wherein

R 3 is H or lower alkyl;

R 6 is independently selected from the group consisting of

H;

alkyl;

cycloalkyl;

lower alkyl-N(R 3 ) 2 ; and

lower alkyl-OH;

R 4 is H, halogen, or lower alkyl;

p is 0, 1, or 2;

X is selected from the group consisting of O, S, and NR 3 ;

Y is selected from the group consisting of

—CH 2 —O—;

—CH 2 —NH—;

—O—;

—NH—; and

—O—CH 2 —;

q is 1 or 2;

G 3 is a monovalent or bivalent moiety selected from the group consisting of

lower alkyl;

—OR 6 ;

—CH 2 OR 3 ;

—CON(R 6 ) 2 ; and

bivalent bridge of structure T 2 =T 2 −T 3 :

wherein

each T 2 independently represents N, CH, or CG 3′ ; and

T 3 represents S, O, CR 4 G 3′ , C(R 4 ) 2 , or NR 3 ; wherein

G 3′ represents any of the above-defined moieties G3 which are monovalent; and

the terminal T 2 is bound to L, and T 3 is bound to D, forming a 5-membered fused ring;

A and D are CH;

B and E are CH;

L is CH;

with the proviso that the resulting phenyl ring bears as a G 3 substituent said bivalent bridge of structure T 2 =T 2 −T 3 ;

J is a ring selected from the group consisting of

aryl;

pyridyl; and

cycloalkyl;

q′ represents the number of substituents G 4 on ring J and is 0, 1, 2, 3, 4, or 5, and

G 4 is a monovalent or bivalent moiety selected from the group consisting of

—N(R 6 ) 2

—NR 3 COR 6 ;

halogen;

alkyl;

cycloalkyl;

halogen-substituted alkyl;

—OR 6 ;

halogenated lower alkoxy;

heterocyclyl; and

fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures:

wherein

each T 2 independently represents N, CH, or CG 4′ ;

T 3 represents S, O, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein

G 4′ represents any of the above-defined moieties G 4 which are monovalent; and

binding to ring J is achieved via terminal atoms T 2 and T 3 ;

wherein

each T 2 independently represents N, CH, or CG 4′ ; wherein

G4′ represents any of the above-defined moieties G 4 which are monovalent; and

with the proviso that a maximum of two bridge atoms T 2 may be N; and

binding to ring J is achieved via terminal atoms T 2 ; and

wherein

each T 4 , T 5 , and T 6 independently represents O, S, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein

G4′ represents any of the above-identified moieties G4 which are monovalent; and

binding to ring J is achieved via terminal atoms T 4 or T 5 ;

with the provisos that:

i) when one T 4 is O, S, or NR 3 , the other T 4 is CR 4 G 4′ or C(R 4 )2;

ii) a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N; and

iii) in a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom;

when G 4 is an alkyl group located on ring J adjacent to the linkage —(CR 4 2 ) p —, and X is NR 3 wherein R 3 is an alkyl substituent, then G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure —(CH 2 ) p —, wherein p′ is 2, 3, or 4, with the proviso that the sum of p and p′ is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members;

and with the further proviso that:

in G 3 and G 4 , when two groups R 3 or R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N-containing heterocycle of 5-7 ring atoms.

3. The method of claim 2 wherein, in the ring comprising A, B, D, E, and L and a bivalent bridge of structure T 2 =T 2 −T 3 , the terminal T 2 represents N and the T 3 unit of said bridge represents S, O, CR 4 2 , or NR 3 .

4. A method for treating or managing pulmonary hypertension in a subject in need thereof comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or diastereoisomeric form of said compound,

wherein said formula I is:

wherein

R 3 is H or lower alkyl;

R 6 is independently selected from the group consisting of

H;

alkyl;

cycloalkyl;

lower alkyl-N(R 3 ) 2 ; and

lower alkyl-OH;

R 4 is H, halogen, or lower alkyl;

p is 0, 1, or 2;

X is selected from the group consisting of O, S, and NR 3 ;

Y is selected from the group consisting of

—CH 2 —O—;

—CH 2 —NH—;

—O—;

—NH—; and

—O—CH 2 —;

q is 1 or 2;

G 3 is a monovalent or bivalent moiety selected from the group consisting of

—OR 6 ;

—COR 6 ;

—CH 2 OR 3 ;

—CON(R 6 ) 2 ; and

bivalent bridge of structure T 2 =T 2 −T 3

wherein

each T 2 independently represents N, CH, or CG 3′ ; and

T 3 represents S, O, CR 4 G 3′ , C(R 4 ) 2 , or NR 3 ; wherein

G 3′ represents any of the above-defined moieties G 3 which are monovalent; and

the terminal T 2 is bound to L, and T 3 is bound to D, forming a 5-membered fused ring;

A and D independently represent N or CH;

B and E independently represent N or CH;

L represents N or CH;

with the provisos that

a) the total number of N atoms in the ring containing A, B, D, E, and L is 0, 1, 2, or 3; and

b) when L represents CH and any G 3 is a monovalent substituent, at least one of A and D is an N atom; and

c) when L represents CH and a G 3 is a bivalent bridge of structure T 2 =T 2 −T 3 , then A, B, D, and E are also CH;

J is a ring selected from the group consisting of

aryl;

pyridyl; and

cycloalkyl;

q′ represents the number of substituents G 4 on ring J and is 0, 1, 2, 3, 4, or 5, and

G 4 is a monovalent or bivalent moiety selected from the group consisting of

—N(R 6 ) 2 ;

—NR 3 COR 6 ;

halogen;

alkyl;

cycloalkyl;

halogen-substituted alkyl;

—OR 6 ;

halogenated lower alkoxy;

heteroaryl;

fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures:

wherein

each T 2 independently represents N, CH, or CG 4′ ;

T 3 represents S, O, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein

G4′ represents any of the above-defined moieties G4 which are monovalent; and

binding to ring J is achieved via terminal atoms T 2 and T 3 ;

wherein

each T 2 independently represents N, CH, or CG 4′ ; wherein

G4′ represents any of the above-defined moieties G4 which are monovalent; and

with the proviso that a maximum of two bridge atoms T 2 may be N; and

binding to ring J is achieved via terminal atoms T 2 ; and

wherein

each T 4 , T 5 , and T 6 independently represents O, S, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein

G4′ represents any of the above-defined moieties G4 which are monovalent; and

binding to ring J is achieved via terminal atoms T 4 or T 5 ;

with the provisos that:

i) when one T 4 is O, S, or NR 3 , the other T 4 is CR 4 G 4′ or C(R 4 ) 2 ;

ii) a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N; and

iii) in a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom;

when G 4 is an alkyl group located on ring J adjacent to the linkage —(CR 4 2 ) p —, and X is NR 3 wherein R 3 is an alkyl substituent, then G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure —(CH 2 ) p′ — wherein p′ is 2, 3, or 4, with the proviso that the sum of p and p′ is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members;

and with the further proviso that:

in G 3 and G 4 , when two groups R 3 or R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N-containing heterocycle of 5-7 ring atoms.

5. The method of claim 4 wherein R 4 is H.

6. The method of claim 1 , wherein the compound of formula I is 4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine or a pharmaceutically acceptable salt or diastereoisomeric form thereof.

7. The method of claim 1 , further comprising administering a therapeutically effective amount of at least one elastase inhibitor and/or one kinase inhibitor.

8. The method of claim of 7 , wherein the kinase inhibitor is glivec.

9. The method of claim 1 , further comprising administering a therapeutically effective amount of at least one therapeutic agent selected from the group consisting of anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogues, endothelium antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors and other therapeutics known to reduce pulmonary artery pressure.

10. The method of claim 9 wherein the further therapeutic agent is a phosphodiesterase V inhibitor, endothelin antagonist or prostacyclin analogue.

11. The method of claim 9 wherein the further therapeutic agent is tadalafil, sildenafil, vardenafil, bosentan, sitaxentan, ilomedin, treprostinil or epoprostenol.

12. The method of claim 1 further comprising administering a therapeutically effective amount of at least one NO-independent and heme-dependent guanylyl cyclase stimulator or activator.

13. The method of claim 12 wherein the NO-independent and heme-dependent guanylyl cyclase stimulator is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl) carbamate or 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate.

14. The method of claim 12 wherein the NO-independent and heme-dependent guanylyl cyclase activator is 4-[((4-Carboxybutyl)-{2-[(4-phenetylbenzyl)oxy]phenethyl}amino)-methyl]benzoic acid.

15. The method of claim 1 , wherein X is NR 3 .

16. The method of claim 1 , wherein Y is —O—CH 2 —.

17. The method of claim 1 , wherein q′ is 1 or 2.

18. The method of claim 1 , wherein

X is NR 3 ;

Y is —O—CH 2 —; and

q′ is 1 or 2.