Carboline derivatives
First Claim
Patent Images
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,NO2trifluoromethyl,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)ORa or C1-4 alkyl, C1-6 alkyl optionally substituted by --ORa, C1-3 alkoxy, C(═
O) Ra, O--C (═
O) Ra, C(═
O) ORa, C1-4 alkylene-C (═
O)ORa, O--C1-4 alkylene --C (═
O) ORa, C1-4 alkylene--O--C1-4 alkylene-C(═
O)ORa, C(═
O)NRa SO2 Rc, C(═
O)C1-4 alkylene-Het, C1-4 alkylene-NRa Rb, C2-6 alkenylene-NRa Rb, C(═
O)NRa Rb, C(═
O)NRa Rc, C(═
O)NRa C1-4 alkylene-ORb C(═
O)NRa C1-4 alkylene-Het, ORa OC2-4 alkylene-NRa Rb, OC1-4 alkylene-CH (ORa) CH2 NRa Rb, O--C1-4 alkylene-Het, O--C2-4 alkylene-ORa, O--C2-4 alkylene-NRa--C(═
O)--ORb, NRa Rb, NRa C1-4 alkylene-NRa Rb, NRa C(═
O)Rb, NRa C(═
O)NRa Rb, N(SO2 C1-4 alkyl)2, NRa (SO2 C1-4 alkyl), SO2 NRa Rb, and OSO2 trifluoromethyl;
R2 is selected from the group consisting of;
hydrogen,halogen,ORa,C1-6 alkyl,NO2, andNRa Rb,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,C1-6 alkyl, andC(═
O)ORa ;
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 C1-4 alkyl;
Ra and Rb can be the same or different, and are independently selected from hydrogen and C1-6 alkyl;
Rc represents phenyl or C4-6 cycloalkyl, wherein the phenyl or C4-6 cycloalkyl can be optionally substituted by one or more halogen atoms, one or more --C(═
O)ORa, or one or more --ORa ;
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.
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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.
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Citations
14 Claims
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1. A combination comprising:
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(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)ORa or C1-4 alkyl, C1-6 alkyl optionally substituted by --ORa, C1-3 alkoxy, C(═
O) Ra, O--C (═
O) Ra, C(═
O) ORa, C1-4 alkylene-C (═
O)ORa, O--C1-4 alkylene --C (═
O) ORa, C1-4 alkylene--O--C1-4 alkylene-C(═
O)ORa, C(═
O)NRa SO2 Rc, C(═
O)C1-4 alkylene-Het, C1-4 alkylene-NRa Rb, C2-6 alkenylene-NRa Rb, C(═
O)NRa Rb, C(═
O)NRa Rc, C(═
O)NRa C1-4 alkylene-ORb C(═
O)NRa C1-4 alkylene-Het, ORa OC2-4 alkylene-NRa Rb, OC1-4 alkylene-CH (ORa) CH2 NRa Rb, O--C1-4 alkylene-Het, O--C2-4 alkylene-ORa, O--C2-4 alkylene-NRa--C(═
O)--ORb, NRa Rb, NRa C1-4 alkylene-NRa Rb, NRa C(═
O)Rb, NRa C(═
O)NRa Rb, N(SO2 C1-4 alkyl)2, NRa (SO2 C1-4 alkyl), SO2 NRa Rb, and OSO2 trifluoromethyl;R2 is selected from the group consisting of; hydrogen, halogen, ORa, C1-6 alkyl, NO2, and NRa Rb, 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, C1-6 alkyl, and C(═
O)ORa ;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 C1-4 alkyl; Ra and Rb can be the same or different, and are independently selected from hydrogen and C1-6 alkyl; Rc represents phenyl or C4-6 cycloalkyl, wherein the phenyl or C4-6 cycloalkyl can be optionally substituted by one or more halogen atoms, one or more --C(═
O)ORa, or one or more --ORa ;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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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Specification