US2005107412A1PendingUtilityA1
Pharmaceutically active compounds
Est. expiryMar 16, 2021(expired)· nominal 20-yr term from priority
C07D 487/14C07D 471/14C07D 471/04C07D 213/80C07D 487/04
50
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Claims
Abstract
The present invention provides a compound of formula (I): where Q is a group of formula: These compounds inhibit cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds are potent and selective inhibitors of the type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases and have utility therefore in a variety of therapeutic areas. In particular, the present compounds are of value for the curative or prophylactic treatment of mammalian sexual disorders.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
where Q is a group of formula:
or a pharmaceutically acceptable salt thereof, wherein
A represents SO 2 , C(O) or CH(OH);
V represents O or NR 5 ;
W represents CHR, CH 2 , —(CH 2 ) m —CH(R)-, —C(O)—N(R a )-, —(CH 2 ) m —O, —(CH 2 ) m —N(R a )-, —(CH 2 ) m C(O)NH— or —(CH 2 ) m NHC(O)—;
X represents CH or N;
m equals 1, 2 or 3;
n equals 1, 2, 3, 4 or 5 with the proviso that the ring containing W contains 5, 6, 7 or 8 atoms only;
R is hydrogen; halo; cyano; nitro; C 1 to C 6 alkyl; C 3 to C 6 cycloalkyl; C 2 to C 6 alkenyl; C 1 to C 6 alkylhet; C 1 to C 6 alkylaryl; aryl; het; OR b ; OC(O)R b ; C(O)R b ; C(O)OR b ; NR b C(O)NR c R d ; NR b C(O)OR b ; OC(O)NR c R d ; C(O)NR c R d ; NR c R d ; SO 2 NR c R d ;
R a represents hydrogen, C 1 to C 6 alkyl; C 3 to C 6 cycloalkyl; C 2 to C 6 alkenyl; C 1 to C 6 alkylhet; C 1 to C 6 alkylaryl; aryl; het; C(O)OR b ; C(O)R b ; SO 2 NR c R d ; or SO 2 R b ;
wherein R b , R c and R d independently represent hydrogen or C 1 to C 6 alkyl or C 3 to C 6 cycloalkyl or C 2 to C 6 alkenyl optionally substituted by halo; or R c and R d together with the nitrogen atom to which they are attached form a heterocyclic ring;
R 1 and R 2 are bonded to a carbon atom in the ring and independently represent hydrogen; halo; cyano; nitro; C 1 to C 6 alkyl; C 3 to C 6 cycloalkyl; C 2 to C 6 alkenyl; C 1 to C 6 alkylhet; C 1 to C 6 alkylaryl; aryl; het; OR b ; OC(O)R b ; C(O)R b ; C(O)OR b ; NR b C(O)NR c R d ; NR b C(O)OR b ; OC(O)NR c R d ; C(O)NR e R f ; NR e R f ; SO 2 NR e R f ; or SO 2 R b ;
wherein when R 1 or R 2 is C 1 to C 6 alkyl; C 3 to C 6 cycloalkyl; C 2 to C 6 alkenyl; C 1 to C 6 alkylhet; C 1 to C 6 alkylaryl; aryl; or het each such group may be optionally substituted and/or terminated with one or more substituents selected from the group comprising: halo; cyano; nitro; OR b ; OC(O)R b ; C(O)R b ; C(O)OR b ; NR b C(O)NR c R d ; NR b C(O)OR b ; OC(O)NR c R d ; C(O)NR e R f ; NR e R f ; SO 2 NR e R f ; or SO 2 R b ;
wherein R e and R f independently represent H, C(O)R 12 , SO 2 R 17 or C 1 -C 6 alkyl; or R e and R f together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R 3 , R 4 and R 5 independently represent H, C 1 -C 6 alkyl, C 3 to C 6 cycloalkyl, Het, C 1 -C 6 alkylHet, aryl or C 1 -C 6 alkylaryl (which latter six groups may all be optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 6 , OC(O)R 6 , C(O)R 6 , C(O)OR 6 , NR 6 C(O)NR 7 R 8 , NR 6 C(O)OR 6 , OC(O)NR 7 R 8 , C(O)NR 9 R 10 , NR 9 R 10 , SO 2 NR 9 R 10 , SO 2 R 11 , C 1 -C 6 alkyl, C 3 to C 6 cycloalkyl, Het, C 1 -C 6 alkylHet, aryl or C 1 -C 6 alkylaryl wherein said latter six substituent and/or terminal groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 ); or R 3 and R 5 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 ; with the proviso that when A represents SO 2 , R 4 does not represent hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylhet, C 1 -C 6 alkylaryl, aryl or a C-linked Het;
R 6 represents H, C 1 -C 6 alkyl, C 3 to C 6 cycloalkyl, C 2 -C 6 alkenyl, Het, C 1 -C 6 alkylHet, aryl or C 1 -C 6 alkylaryl (which latter seven groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 );
R 7 and R 8 independently represent H, C 1 -C 6 alkyl, Het, C 1 -C 6 alkylHet, aryl or C 1 -C 6 alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 ); or R 7 and R 8 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R 9 and R 10 independently represent H, C(O)R 6 , SO 2 R 11 , C 1 -C 6 alkyl, Het, C 1 -C 6 alkylHet, aryl or C 1 -C 6 alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 ); or R 9 and R 10 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R 11 represents a C 1 -C 6 alkyl, Het, C 1 -C 6 alkylHet, aryl or C 1 -C 6 alkylaryl group which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 ;
R 12 represents H or C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl,;
R 13 and R 14 independently represent H or C 1 -C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R 15 and R 16 independently represent H, C(O)R 12 , SO 2 R 17 or C 1 -C 6 alkyl; or R 15 and R 16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
wherein when R 7 and R 8 , or R 9 and R 10 together with the nitrogen atom to which they are bound form a heterocyclic ring, said heterocyclic ring optionally also includes an oxygen atom, and/or wherein said heterocyclic ring is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 , NR 15 RR 16 , SO 2 NR 15 R 16 , SO 2 R 17 ;
R 17 represents C 1 -C 6 alkyl; and
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof, and wherein said heterocyclic ring is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR 12 , OC(O)R 12 , C(O)R 12 , C(O)OR 12 , NR 12 C(O)NR 13 R 14 , NR 12 C(O)OR 12 , OC(O)NR 13 R 14 , C(O)NR 15 R 16 ,NR 15 R 16 , SO 2 NR 15 R 16 , SO 2 R 17 .
2 . A compound as claimed in claim 1 , wherein A represents SO 2 or C(O).
3 . A compound as claimed in claim 1 , wherein V represents O.
4 . A compound as claimed in claim 1 , wherein W represents CHR, CH 2 , —(CH 2 ) m —CH(R)-, or —C(O)—N(R a )-.
5 . A compound as claimed in claim 4 , wherein R is hydrogen, methyl or ethyl.
6 . A compound as claimed in claim 1 , wherein X represents N.
7 . A compound as claimed in claim 1 , wherein n equals 2, 3 or 4.
8 . A compound as claimed in claim 7 , wherein n is 2 or 3.
9 . A compound as claimed in claim 1 , wherein m equals 1.
10 . A compound as claimed in claim 1 , wherein R 1 represents hydrogen or C 1 to C 6 alkyl.
11 . A compound as claimed in claim 1 , wherein R 2 represents hydrogen or C 1 to C 6 alkyl.
12 . A compound as claimed in claim 1 , wherein R 3 represents H or C 1 -C 6 alkyl optionally substituted by C 1 -C 6 alkoxy.
13 . A compound as claimed in claim 12 , wherein R 3 is ethyl, n-propyl, n-butyl, i-butyl, or 2-methoxyethoxy.
14 . A compound as claimed in claim 1 or 2 , wherein when A represents SO 2 , R 4 represents N-linked Het which is substituted by C 1 -C 6 alkyl.
15 . A compound as claimed in claim 14 , wherein R 4 is 4-ethylpiperazinyl, or 4-methylpiperazinyl.
16 . A compound as claimed in claim 1 or 2 , wherein when A is C(O), and R 4 represents C 1 -C 6 alkyl.
17 . A compound as claimed in claim 16 , wherein R 4 is methyl.
18 . A compound of Formula Iaa, having the formula:
wherein
A represents SO 2 or C(O) and more preferably A represents SO 2 ;
X represents CH or N;
Y represents W and is CH 2 , —(CH 2 ) m C(O)NH— or —(CH 2 ) m NHC(O)—;
n equals 0, 1, 2, 3, 4 or 5;
m equals 0, 1, 2, 3 or 4;
Het 1 represents a piperazin-1-yl group having a substituent R 6 at the 4-position of the piperazinyl group wherein said piperazinyl group is optionally substituted with one or two C 1 to C 4 alkyl groups and is optionally in the form of its 4-N-oxide;
R 1 and R 2 independently represent hydrogen; C 1 to C 6 alkyl; C 1 to C 6 alkoxy; C 3 to C 6 cycloalkyl; C 3 to C 6 alkenyl; phenyl; heterocyclyl containing one or more atoms from N, S or O, wherein each of the aforementioned substituents may be further substituted with a group selected from —CN, —NO 2 , -R 6 , —S(O) 2 R 6 ; —NR 4 R 5 , —OR 6 ; —OC(O)(C 1 to C 4 alkyl); halo;
R 3 represents C 1 to C 6 alkyl optionally substituted with one or two substituents selected from C 3 to C 5 cycloalkyl, hydroxy, C 1 to C 4 alkoxy, benzyloxy, NR 4 R 5 , phenyl, Het 2 , Het 3 , Het 4 or Het 5 wherein the C 1 to C 6 alkyl and C 1 to C 4 alkoxy groups may be optionally terminated by a haloalkyl group such as CF 3 and wherein the C 3 -C 5 cycloalkyl group may be optionally substituted by C 1 -C 4 alkyl, hydroxy or halo; C 3 to C 6 cycloalkyl; Het 2 , Het 3 , Het 4 or Het 5 ;
R 4 and R 5 each independently represents hydrogen; C 1 to C 4 alkyl optionally substituted with C 3 to C 5 cycloalkyl or C 1 to C 4 alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;
R 6 represents hydrogen; C 1 to C 4 alkyl optionally substituted with one or two substituents selected from halo, hydroxy, NR 4 R 5 , CONR 4 R 5 , phenyl optionally substituted with C 1 to C 4 alkyl or C 1 to C 4 alkoxy; C 3 to C 6 alkenyl; C 1 to C 4 haloalkoxy; or Het 5 ;
Het 2 represents an N-linked 4-, 5- or 6-membered nitrogen-containing heterocylic group optionally containing one or more further heteroatoms selected from S, N or O;
Het 3 represents a C-linked 5-membered heterocyclic group containing an O, S or N heteroatom optionally containing one or more further heteroatoms selected from N, O or S;
Het 4 represents a C-linked 6-membered heterocyclic group containing an O or S heteroatom optionally containing one or more further heteroatoms selected from O, S or N or Het 3 is a C-linked 6-membered heterocyclic group containing three N heteroatoms;
Het 5 represents a C-linked 4-, 5- or 6-membered heterocyclic group containing one, two or three heteroatoms selected from S, O or N; and
wherein any of said heterocyclic Het 2 , Het 3 , Het 4 or Het 5 may be saturated, partially unsaturated or aromatic and wherein any of said heterocyclic groups may be optionally substituted with one or more substituents selected from C 1 to C 4 alkyl, C 3 to C 4 alkenyl, C 1 to C 4 alkoxy, halo , CF 3 , CO 2 R 6 , COR 6 , SO 2 R 6 , NHR 6 or NHCOR 6 and/or wherein any of said heterocyclic groups is benzo-fused.
19 . A compound as claimed in claim 18 , wherein, Y, m and n are independently selected to form a 5 to 7 membered ring, more preferably a 6 membered ring.
20 . A compound as claimed in claim 19 , wherein Y represents CH 2 and n equals 3.
21 . A compound as claimed in claim 18 , 19 or 20 , wherein R 1 and R 2 each independently represent hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
22 . A compound as claimed in claim 21 , wherein R 1 and R 2 each independently represent hydrogen or C 1 -C 6 alkyl.
23 . A compound as claimed in claim 18 , wherein Het 1 represents a 4-R 6 -piperazin-1-yl group where R 6 has the meaning defined in claim 18 .
24 . A compound as claimed in claim 18 , wherein R 6 represents a C 1 to C 4 alkyl group.
25 . A compound as claimed in claim 18 , wherein R 3 represents C 1 to C 6 alkyl optionally substituted by C 1 to C 4 alkoxy.
26 . A compound selected from the group consisting of:
2-{2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulphonyl]-3-pyridinyl}-3,7,8,9-tetrahydro-4H-pyrrolo [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4-one; 2-{2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-9-ethyl-8,9-dihydropyrazino [2′,1′:5,1]pyrazolo[4,3-d]pyrimidine-4,10(3H,7 H)-dione; 2-[5-[(4-Ethyl-1-piperazinyl)sulfonyl-2-(2-methoxyethoxy)-3-pyridinyl]-3,7,8,9,10,11-hexahydro-4H-pyrimido [5′,4′:3,4]pyrazolo[1,5-a]azepin-4- one; 2-[5-[(4-Ethyl-1-piperazinyl)sulfonyl]-2-(2-methoxyethoxy)-3-pyridinyl]-11-methyl-3,7,8,9,10,11-hexahydro-4H-primido[5′,4′:3,4]pyrazolo[1,5-a]azepin-4-one; 2-{5-[(4-Ethyl-1-piperazinyl)sulfonyl]-2-n-propoxy-3-pyridinyl}-9-ethyl-8,9-dihydropyrazino [2′,1′:5,1]pyrazolo[4,3-d]pyrimidine-4,10(3H,7H)-dione; 2-{2-n-Butoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-9-ethyl-8,9-dihydropyrazino [2′,1′:5,1]pyrazolo[4,3-d]pyrimidine-4,10(3H,7H)-dione; 2-{2-n-Butoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-8,9-dihydropyrazino [2′,1′:5,1]pyrazolo[4,3-d]pyrimidine-4,10(3H,7H)-dione; (−)-2-{2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; (+)-2-{2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; 2-{5-[(4-Ethyl-1-piperazinyl)sulfonyl]-2-n-propoxy-3-pyridinyl}-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; 2-{5-[(4-Ethyl-1-piperazinyl)sullenly]-2-n-propoxy-3-pyridinyl}-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; (−)-2-{5-[(4-Ethyl-1-piperazinyl)sulfonyl]-2-(2-methoxyethoxy)-3-pyridinyl}-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; (+)-2-{5-[(4-Ethyl-1-piperazinyl)sulfonyl]-2-(2-methoxyethoxy)-3-pyridinyl}-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; 2-(5-Acetyl-2-ethoxy-3-pyridinyl)-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one; 2-(5-Acetyl-2-isobutoxy-3-pyridinyl)-10-methyl-7,8,9,10-tetrahydropyrido [2′,1′:5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one or pharmaceutically acceptably salts, solvates and polymorphs thereof.
27 . A pharmaceutical composition including a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.
28 - 29 . (canceled)
30 . A method for the curative or prophylactic treatment of a medical condition for which inhibition of cGMP PDE5 is desired or required.
31 . A method as recited in claim 30 . wherein the medical condition is selected from the group comprising: mammalian sexual dysfunctions including male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder, female orgasmic dysfunction (FSOD) as well as sexual dysfunction due to spinal cord injury; and non sexual medical disorders including premature labour, dysmenrrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, artherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, nitrate induced tolerance, bronchitis, allergic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS), pre-eclampsia, Kawasaki's syndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy, peripheral diabetic neuropathy, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxic vasoconstriction, diabetes, type 2 diabetes mellitus, the insulin resistance syndrome, insulin resistance or impaired glucose tolerance.
32 . The method claimed in claim 31 , wherein the medical condition is selected from: MED and FSD.
33 - 35 . (canceled)
36 . A compound of formula (IXA), (IXB) or (IXC):
wherein A, R 3 , R 4 , R 5 , Q, X, and X′ are as defined in claim 1 .
37 . A compound of formula (VII):
wherein Q are as defined in claim 1 .
38 . A compound of formula (XA), (XB) or (XC):
wherein A, R 3 , R 4 , R 5 , Q, X, and X′ are as defined in claim 1.Join the waitlist — get patent alerts
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