Novel pharmaceuticals

Abstract

This invention relates to compounds of formula (I)

1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is a cyclic group selected from R A , R B , R C  and R D , each of which is optionally substituted with one or more R 7  groups;  
 R 2  is hydrogen or C 1 -C 2  alkyl;  
 R 3  and R 4  are each independently C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl or C 3 -C 10  cycloalkyl, each of which is optionally substituted with one or more R 8  groups, or R E , which is optionally substituted with one or more R 9  groups, or hydrogen;  
 or —NR 3 R 4  forms R F , which is optionally substituted with one or more R 10  groups;  
 R 5  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 7  cycloalkyl, each of which is optionally substituted by one or more groups selected from hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 3 -C 7  cycloalkyl and C 3 -C 7  cycloalkoxy, or hydrogen;  
 R 6 , which may be attached at N 1  or N 2 , is R 6A  or hydrogen;  
 R 6A  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted by C 1 -C 6  alkoxy, (C 3 -C 6  cycloalkyl)C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy or a cyclic group selected from R J , R K , R L  and R M , or R 6A  is R N , C 3 -C 7  cycloalkyl or C 3 -C 7  halocycloalkyl, each of which is optionally substituted by C 1 -C 6  alkoxy or C 1 -C 6  haloalkoxy;  
 R 7  is halo, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, C 3 -C 10  halocycloalkyl, oxo, phenyl, OR 12 , OC(O)R 12 , NO 2 , NR 12 R 13 , NR 12 C(O)R 13 , NR 12 CO 2 R 14 , C(O)R 12 , CO 2 R 12 , CONR 12 R 13  or CN;  
 R 8  is halo, phenyl, C 1 -C 6  alkoxyphenyl, OR 12 , OC(O)R 12 , NO 2 , NR 12 R 13 , NR 12 C(O)R 13 , NR 12 CO 2 R 14 , C(O)R 12 , CO 2 R 12 , CONR 12 R 13 , CN, C 3 -C 6  cycloalkyl, R G  or R H , the last two of which are optionally substituted with one or more R 9  groups;  
 R 9  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl or CO 2 R 12 ;  
 R 10  is halo, C 3 -C 10  cycloalkyl, C 3 -C 10  halocycloalkyl, phenyl, OR 12 , OC(O)R 12 , NO 2 , NR 12 R 13 , NR 12 C(O)R 13 , NR 12 CO 2 R 14 , C(O)R 12 , CO 2 R 13 , CONR 12 R 13 , CN, oxo, C 1 -C 6  alkyl or C 1 -C 6  haloalkyl, the last two of which are optionally substituted by R 11 ;  
 R 11  is OH, phenyl, NR 12 R 13  or NR 12 CO 2 R 14 ;  
 R 12  and R 13  are each independently hydrogen, C 1 -C 6  alkyl or C 1 -C 6  haloalkyl;  
 R 14  is C 1 -C 6 alkyl or C 1 -C 6  haloalkyl;  
 R A  and R J  are each independently a C 3 -C 10  cycloalkyl or C 3 -C 10  cycloalkenyl group, each of which may be either monocyclic or, when there are an appropriate number of ring atoms, polycyclic and which may be fused to either 
 (a) a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, or  
 (b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;  
 
 R B  and R K  are each independently a phenyl or naphthyl group, each of which may be fused to 
 (a) a C 1 -C 7  cycloalkyl or C 5 -C 7  cycloalkenyl ring,  
 (b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, or  
 (c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;  
 
 R C , R L  and R N  are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated or partly unsaturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which ring may be fused to a C 5 -C 7  cycloalkyl or C 5 -C 7  cycloalkenyl group or a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;  
 R D  and R M  are each independently a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur, which ring may further be fused to 
 (a) a second 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;  
 (b) C 5 -C 7  cycloalkyl or C 5 -C 7  cycloalkenyl ring;  
 (c) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur; or  
 (d) a benzene ring;  
 
 R E , R F  and R G  are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;  
 and  
 R H  is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur;  
 a tautomer thereof or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer.  
 
   
   
       2 . A compound according to  claim 1  wherein R 6  is R 6A .  
   
   
       3 . A compound according to either  claim 1  or  claim 2  wherein R 1  is R D , which is optionally substituted with one or more R 7  groups.  
   
   
       4 . A compound according to  claim 3  wherein R D  is a 5-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulphur and optionally up to two further nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1, 2 or 3 nitrogen atoms.  
   
   
       5 . A compound according to  claim 4  wherein R D  is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl.  
   
   
       6 . A compound according to  claim 1  wherein R 7  is fluoro, methyl, ethyl, hydroxy, methoxy, propoxy, trifluoromethyl, oxo or CONHMe.  
   
   
       7 . A compound according to  claim 1  wherein R 2  is hydrogen.  
   
   
       8 . A compound according to  claim 1  wherein R 3  is hydrogen, C 1 -C 6  alkyl, which is optionally substituted with one or more R 8  groups, or R E , which is optionally substituted with one or more R 9  groups; and wherein R E  is a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.  
   
   
       9 . A compound according to  claim 1  wherein R 4  is hydrogen, methyl or ethyl.  
   
   
       10 . A compound according to  claim 1  wherein —NR 3 R 4  forms R F , which is optionally substituted with one or more R 10  groups and R F  is a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms containing one or two nitrogen atoms and optionally one other atom selected from oxygen and sulphur.  
   
   
       11 . A compound according to  claim 1  wherein R 5  is methyl, ethyl or propyl, each of which is optionally substituted by hydroxy, methoxy or ethoxy.  
   
   
       12 . A compound according to  claim 1  wherein R 6  is attached at N 1  of the pyrazolo[4,3-d]pyrimidine ring system.  
   
   
       13 . A compound according to  claim 1  wherein R 6A  is C 1 -C 4  alkyl or C 1 -C 4  haloalkyl, each of which is optionally substituted by C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, (C 3 -C 6  cycloalkyl)methoxy, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl or pyridinyl, or R 6A  is tetrahydropyranyl.  
   
   
       14 . A compound according to  claim 1  selected from: 
 1-(2-ethoxyethyl)-3-methyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    1-(2-ethoxyethyl)-3-ethyl-N 5 -methyl-N 5 -(1-methylpiperidin-4-yl)-N 7 -pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    3-methyl-5-[(3R)-3-methylpiperazin-1-yl]-1-(2-n-propoxyethyl)-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    5-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    5-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    1-(2-ethoxyethyl)-N 5 ,3-dimethyl-N 7 -(4-methylpyridin-2-yl)-N 5 -[(3S)-1-methylpyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    1-(2-ethoxyethyl)-3-ethyl-N 5 -methyl-N 7 -(4-methylpyridin-2-yl)-N 5 -[(3S)-1-methylpyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    1-(2-ethoxyethyl)-3-(methoxymethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    1-(2-ethoxyethyl)-3-(methoxymethyl)-N 5 ,N 5 -dimethyl-N 7 -(4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    {1-(2-ethoxyethyl)-5-[N-ethyl-N-methylamino]-7-[(4-methylpyridin-2-yl)amino]-1H-pyrazolo[4,3-d]pyrimidin-3-yl}methanol,    1-(2-isopropoxyethyl)-3-methyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    1-(2-ethoxyethyl)-N 5 ,3-dimethyl-N 5 -[(3S)-1-methylpyrrolidin-3-yl]-N 7 -pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    1-(2-ethoxyethyl)-3-ethyl-N 5 -methyl-N 7 -(5-methylpyridin-2-yl)-N 5 -[(3S)-1-methylpyrrolidin-3-yl]-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    1-methyl-5-[(3R)-3-methylpiperazin-1-yl]-3-propyl-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine,    N-[5-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpyridin-2-ylamine,    N-[5-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpyridin-2-ylamine,    N-{1-(2-ethoxyethyl)-3-methoxymethyl-5-[(3R)-3-methylpiperazin-1-yl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-methylpyridin-2-ylamine,    N-{3-methyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}pyrimidin-4-ylamine,    N-{5-(3,8-diazabicyclo[3.2.1]oct-3-yl)-3-methyl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-methylpyridin-2-ylamine,    N-{3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}pyrimidin-4-ylamine,    N-{3-methyl-5-(piperazin-1-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-methylpyridin-2-ylamine,    1-{3-methyl-7-(6-methylpyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine-4-carboxylic acid,    N-{3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}pyridazin-4-ylamine,    N-{3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-2-methylpyrimidin-4-ylamine,    3-ethyl-N 5 -methyl-N 5 -(1-methylpiperidin-4-yl)-N 7 -(6-methylpyrimidin-4-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine,    N-{3-methoxymethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-methylpyridin-2-ylamine,    N-{3-ethoxymethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-methylpyridin-2-ylamine,    N-{3-methoxymethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-4-methylpyridin-2-ylamine,    1-{3-methyl-7-(4-methylpyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine-4-carboxylic acid,    N-{3-ethoxymethyl-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-4-methylpyridin-2-ylamine,    1-{3-ethyl-7-(6-methylpyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine-4-carboxylic acid, and    3,N 5 -dimethyl-N 5 -(1-methylpiperidin-4-yl)-N 7 -(6-methylpyrimidin-4-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine    and tautomers thereof and pharmaceutically acceptable salts, solvates and polymorphs of said compound or tautomer.    
   
   
       15 . A pharmaceutical composition comprising a compound of formula (I) as claimed in claims  1  or  14 , or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier.  
   
   
       16 . A compound of formula (I) as claimed in claims  1  or  14 , or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament.  
   
   
       17 . A method of treatment of a disorder or condition where inhibition of PDE-5 is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as claimed in claims  1  or  14 , or a pharmaceutically acceptable salt, solvate or polymorph thereof.  
   
   
       18 . Use of a compound of formula (I) as claimed in claims  1  or  14 , or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament for the treatment of a disorder or condition where inhibition of PDE-5 is known, or can be shown, to produce a beneficial effect.  
   
   
       19 . A pharmaceutical composition comprising a compound of formula (I) as claimed in claims  1  or  14 , or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a second pharmaceutically active agent selected from aspirin, angiotensin II receptor antagonists (such as losartan, candesartan, telmisartan, valsartan, irbesartan and eprosartan), calcium channel blockers (such as amlodipine), beta-blockers (i.e. beta-adrenergic receptor antagonists such as sotalol, propranolol, timolol, atenolol, carvedilol and metoprolol), CI027, CCR5 receptor antagonists, imidazolines, soluble guanylate cyclase activators, diuretics (such as hydrochlorothiazide, torsemide, chlorothiazide, chlorthalidone and amiloride), alpha adrenergic antagonists (such as doxazosin), ACE (angiotensin converting enzyme) inhibitors (such as quinapril, enalapril, ramipril and lisinopril), aldosterone receptor antagonists (such as eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (such as insulin, sulfonylureas (such as glyburide, glipizide and glimepiride), glitazones (such as rosiglitazone and pioglitazone) and metformin), cholesterol lowering agents (such as atorvastatin, pravastatin, lovastatin, simvastatin, clofibrate and rosuvastatin), and alpha-2-delta ligands (such as gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-(aminomethyl)cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (1α,3α,5α)-(3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid).  
   
   
       20 . Use of a compound of formula (I) as claimed in claims  1  or  14 , or a pharmaceutically acceptable salt, solvate or polymorph thereof, in the preparation of a medicament combined with a second pharmaceutically active agent selected from aspirin, angiotensin II receptor antagonists (such as losartan, candesartan, telmisartan, valsartan, irbesartan and eprosartan), calcium channel blockers (such as amlodipine), beta-blockers (i.e. beta-adrenergic receptor antagonists such as sotalol, propranolol, timolol, atenolol, carvedilol and metoprolol), CI1027, CCR5 receptor antagonists, imidazolines, soluble guanylate cyclase activators, diuretics (such as hydrochlorothiazide, torsemide, chlorothiazide, chlorthalidone and amiloride), alpha adrenergic antagonists (such as doxazosin), ACE (angiotensin converting enzyme) inhibitors (such as quinapril, enalapril, ramipril and lisinopril), aldosterone receptor antagonists (such as eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (such as insulin, sulfonylureas (such as glyburide, glipizide and glimepiride), glitazones (such as rosiglitazone and pioglitazone) and metformin), cholesterol lowering agents (such as atorvastatin, pravastatin, lovastatin, simvastatin, clofibrate and rosuvastatin), and alpha-2-delta ligands (such as gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-(aminomethyl)cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (1α,3α,5α)-(3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid and (3S,5R)-3-amino-5-methyloctanoic acid), for the treatment of a disease or condition where inhibition of PDE-5 is known, or can be shown, to produce a beneficial effect.  
   
   
       21 . A compound of formula (VII)  
     
       
         
         
             
             
         
       
     
     wherein R 5  and R 6  are as defined in  claim 1 .  
   
   
       22 . A compound of formula (VIII)  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 5  and R 6  are as defined in  claim 1 .  
   
   
       23 . A process for the preparation of a compound of formula (I) as defined in  claim 1  comprising the step of treating a compound of formula (VII) as defined in  claim 22  with a compound HNR 3 R 4 , where R 3  and R 4  are as defined in  claim 1.