Treatment of insulin resistance syndrome and type 2 diabetes with PDE9 inhibitors

Abstract

This invention is directed to a method of treating insulin resistance syndrome (IRS), hypertension and/or type 2 diabetes in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor or a pharmaceutical composition thereof. This invention is also directed to such methods wherein said cGMP PDE9 inhibitor is used in combination with other agents to treat IRS, hypertension and/or type 2 diabetes.

1 - 4 . (cancel).  
     
     
         5 . A method of treating type 2 diabetes in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor, or salt or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt.  
     
     
         6 . A method of  claim 5  wherein said cGMP PDE9 inhibitor is a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, thereof, or a solvate of said compound or said salt, wherein: 
 R 1  is H or (C 1 -C 6 )alkyl;  
 R 2  is (C 1 -C 6 )alkyl, straight chain or branched chain, (C 3 -C 7 )cycloalkyl or heteroaryl;  
 R 3  is (C 1 -C 6 )alkyl, straight chain or branched chain, optionally substituted by 1-2 groups each independently selected from Ar, (C 3 -C 7 )cycloalkyl, OAr, SAr, NC(O)(C 1 -C 6 )alkyl, heteroaryl, xanthene, and naphthalene;  
 Ar is a group of formula  
                     
 wherein R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, said alkyl optionally substituted by a heteroaryl group or by a phenyl group, wherein said phenyl group is optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a (C 2 -C 3 )alkyl link, wherein said link may optionally incorporate a heteroatom selected from O, S and N; and  
 heteroaryl is aromatic 5-6 membered heterocycle containing 1-3 heteroatoms, each independently selected from O, S and N, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 )alkyl, halo and phenyl, said phenyl optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 )alkyl;  
 with the proviso that when R 1  is —CH 3 , R 2  cannot be —CH 2 CH 2 CH 3 .  
 
     
     
         7 . A method of  claim 6  wherein R 1  is H or CH 3 ; R 2  is (C 3 -C 4 )alkyl, cyclopentyl or pyridinyl; R 3  is (C 1 -C 3 )alkyl, optionally substituted by 1-2 groups selected from Ar, (C 3 -C 7 )cycloalkyl and heteroaryl; R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl; said alkyl in the definition of R 4 , R 5  and R 6  is optionally substituted by a heteroaryl group or by a phenyl group optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a C 2  alkyl link, said link incorporating an O atom; and heteroaryl is an aromatic 5-6 membered heterocycle containing at least 2 nitrogen atoms, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 ) alkyl, halo and phenyl, said phenyl in the definition of heterocycle optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 ) alkyl.  
     
     
         8 . A method of  claim 5  comprising administering to said mammal 5-(3-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A method of treating dyslipidemia in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt.  
     
     
         10 . A method of  claim 9  wherein said cGMP PDE9 inhibitor is a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, thereof, or a solvate of said compound or said salt,  
       wherein: 
 R 1  is H or (C 1 -C 6 )alkyl;  
 R 2  is (C 1 -C 6 )alkyl, straight chain or branched chain, (C 3 -C 7 )cycloalkyl or heteroaryl;  
 R 3  is (C 1 -C 6 )alkyl, straight chain or branched chain, optionally substituted by 1-2 groups each independently selected from Ar, (C 3 -C 7 )cycloalkyl, OAr, SAr, NC(O)(C 1 -C 6 )alkyl, heteroaryl, xanthene, and naphthalene;  
 Ar is a group of formula  
                     
 wherein R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, said alkyl optionally substituted by a heteroaryl group or by a phenyl group, wherein said phenyl group is optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a (C 2 -C 3 )alkyl link, wherein said link may optionally incorporate a heteroatom selected from O, S and N; and  
 heteroaryl is aromatic 5-6 membered heterocycle containing 1-3 heteroatoms, each independently selected from O, S and N, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 )alkyl, halo and phenyl, said phenyl optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 )alkyl;  
 with the proviso that when R 1  is —CH 3 , R 2  cannot be —CH 2 CH 2 CH 3 .  
 
     
     
         11 . A method of  claim 10  wherein R 1  is H or CH 3 ; R 2  is (C 3 -C 4 )alkyl, cyclopentyl or pyridinyl; R 3  is (C 1 -C 3 )alkyl, optionally substituted by 1-2 groups selected from Ar, (C 3 -C 7 )cycloalkyl and heteroaryl; R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl; said alkyl in the definition of R 4 , R 5  and R 6  is optionally substituted by a heteroaryl group or by a phenyl group optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a C 2  alkyl link, said link incorporating an O atom; and heteroaryl is an aromatic 5-6 membered heterocycle containing at least 2 nitrogen atoms, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 ) alkyl, halo and phenyl, said phenyl in the definition of heterocycle optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 ) alkyl.  
     
     
         12 . A method of  claim 9  wherein said dyslipidemia is hypertriglyceridemia.  
     
     
         13 . A method of  claim 9  comprising administering to said mammal 5-(3-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.  
     
     
         14 . A method of treating impaired glucose tolerance in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor, a or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt.  
     
     
         15 . A method of  claim 14  wherein said cGMP PDE9 inhibitor is a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, thereof, or a solvate of said compound or said salt,  
       wherein: 
 R 1  is H or (C 1 -C 6 )alkyl;  
 R 2  is (C 1 -C 6 )alkyl, straight chain or branched chain, (C 3 -C 7 )cycloalkyl or heteroaryl;  
 R 3  is (C 1 -C 6 )alkyl, straight chain or branched chain, optionally substituted by 1-2 groups each independently selected from Ar, (C 3 -C 7 )cycloalkyl, OAr, SAr, NC(O)(C 1 -C 6 )alkyl, heteroaryl, xanthene, and naphthalene;  
 Ar is a group of formula  
                     
 wherein R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, said alkyl optionally substituted by a heteroaryl group or by a phenyl group, wherein said phenyl group is optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a (C 2 -C 3 )alkyl link, wherein said link may optionally incorporate a heteroatom selected from O, S and N; and  
 heteroaryl is aromatic 5-6 membered heterocycle containing 1-3 heteroatoms, each independently selected from O, S and N, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 )alkyl, halo and phenyl, said phenyl optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 )alkyl;  
 with the proviso that when R 1  is —CH 3 , R 2  cannot be —CH 2 CH 2 CH 3 .  
 
     
     
         16 . A method of  claim 15  wherein R 1  is H or CH 3 ; R 2  is (C 3 -C 4 )alkyl, cyclopentyl or pyridinyl; R 3  is (C 1 -C 3 )alkyl, optionally substituted by 1-2 groups selected from Ar, (C 3 -C 7 )cycloalkyl and heteroaryl; R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl; said alkyl in the definition of R 4 , R 5  and R 6  is optionally substituted by a heteroaryl group or by a phenyl group optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a C 2  alkyl link, said link incorporating an O atom; and heteroaryl is an aromatic 5-6 membered heterocycle containing at least 2 nitrogen atoms, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 ) alkyl, halo and phenyl, said phenyl in the definition of heterocycle optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 ) alkyl.  
     
     
         17 . A method of  claim 14  comprising administering to said mammal 5-(3-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof or of said prodrug.  
     
     
         18 . A method of treating polycystic ovary syndrome in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor, a or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt.  
     
     
         19 . A method of  claim 18  wherein said cGMP PDE9 inhibitor is a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, thereof, or a solvate of said compound or said salt, wherein: 
 R 1  is H or (C 1 -C 6 )alkyl;  
 R 2  is (C 1 -C 6 )alkyl, straight chain or branched chain, (C 3 -C 7 )cycloalkyl or heteroaryl;  
 R 3  is (C 1 -C 6 )alkyl, straight chain or branched chain, optionally substituted by 1-2 groups each independently selected from Ar, (C 3 -C 7 )cycloalkyl, OAr, SAr, NC(O)(C 1 -C 6 )alkyl, heteroaryl, xanthene, and naphthalene;  
 Ar is a group of formula  
                     
 wherein R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, said alkyl optionally substituted by a heteroaryl group or by a phenyl group, wherein said phenyl group is optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a (C 2 -C 3 )alkyl link, wherein said link may optionally incorporate a heteroatom selected from O, S and N; and  
 heteroaryl is aromatic 5-6 membered heterocycle containing 1-3 heteroatoms, each independently selected from O, S and N, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 )alkyl, halo and phenyl, said phenyl optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 )alkyl;  
 with the proviso that when R 1  is —CH 3 , R 2  cannot be —CH 2 CH 2 CH 3 .  
 
     
     
         20 . A method of  claim 19  wherein R 1  is H or CH 3 ; R 2  is (C 3 -C 4 )alkyl, cyclopentyl or pyridinyl; R 3  is (C 1 -C 3 )alkyl, optionally substituted by 1-2 groups selected from Ar, (C 3 -C 7 )cycloalkyl and heteroaryl; R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl; said alkyl in the definition of R 4 , R 5  and R 6  is optionally substituted by a heteroaryl group or by a phenyl group optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a C 2  alkyl link, said link incorporating an O atom; and heteroaryl is an aromatic 5-6 membered heterocycle containing at least 2 nitrogen atoms, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 ) alkyl, halo and phenyl, said phenyl in the definition of heterocycle optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 ) alkyl.  
     
     
         21 . A method of  claim 18  comprising administering to said mammal 5-(3-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.  
     
     
         22 . A combination comprising a cGMP PDE9 inhibitor and one or more of a protein kinase inhibitor; an AMP-activated protein kinase; a weight loss agent; insulin; a PPAR-γ agonist; a PPAR-γ antagonist; a PPAR-α agonist; a dual PPAR-γ/PPAR-α agonist; a sorbitol dehydrogenase inhibitor; a glycogen phosphorylase inhibitor; a biguanide; an HMG-CoA reductase inhibitor; an aldose reductase inhibitor; or a PDE5 inhibitor.  
     
     
         23 . A combination of  claim 22  wherein said cGMP PDE9 inhibitor is a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, thereof, or a solvate of said compound or said salt, wherein: 
 R 1  is H or (C 1 -C 6 )alkyl;  
 R 2  is (C 1 -C 6 )alkyl, straight chain or branched chain, (C 3 -C 7 )cycloalkyl or heteroaryl;  
 R 3  is (C 1 -C 6 )alkyl, straight chain or branched chain, optionally substituted by 1-2 groups each independently selected from Ar, (C 3 -C 7 )cycloalkyl, OAr, SAr, NC(O)(C 1 -C 6 )alkyl, heteroaryl, xanthene, and naphthalene;  
 Ar is a group of formula  
                     
 wherein R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, said alkyl optionally substituted by a heteroaryl group or by a phenyl group, wherein said phenyl group is optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a (C 2 -C 3 )alkyl link, wherein said link may optionally incorporate a heteroatom selected from O, S and N; and  
 heteroaryl is aromatic 5-6 membered heterocycle containing 1-3 heteroatoms, each independently selected from O, S and N, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 )alkyl, halo and phenyl, said phenyl optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 )alkyl;  
 with the proviso that when R 1  is —CH 3 , R 2  cannot be —CH 2 CH 2 CH 3 .  
 
     
     
         24 . A combination of  claim 23  wherein R 1  is H or CH 3 ; R 2  is (C 3 -C 4 )alkyl, cyclopentyl or pyridinyl; R 3  is (C 1 -C 3 )alkyl, optionally substituted by 1-2 groups selected from Ar, (C 3 -C 7 )cycloalkyl and heteroaryl; R 4 , R 5  and R 6  are each independently selected from H, halo, phenoxy, phenyl, CF 3 , OCF 3 , S(C 1 -C 6 )alkyl, (C 1 -C 6 ) alkyl, O(C 1 -C 6 )alkyl; said alkyl in the definition of R 4 , R 5  and R 6  is optionally substituted by a heteroaryl group or by a phenyl group optionally substituted by 1-3 groups selected from halo, CF 3 , OCF 3  and (C 1 -C 6 )alkyl; or wherein R 4  and R 5  may combine to form a C 2  alkyl link, said link incorporating an O atom; and heteroaryl is an aromatic 5-6 membered heterocycle containing at least 2 nitrogen atoms, said heterocycle optionally substituted by 1-3 substituents, each independently selected from (C 1 -C 6 ) alkyl, halo and phenyl, said phenyl in the definition of heterocycle optionally substituted by 1-3 groups selected from halo and (C 1 -C 6 ) alkyl.  
     
     
         25 . A combination of  claim 22  wherein said cGMP PDE9 inhibitor is 5-(3-chloro-benzyl)-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, carrier or diluent.  
     
     
         26 . A kit comprising: 
 a) a first unit dosage form comprising a cGMP PDE9 inhibitor, a or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt and a pharmaceutically acceptable carrier, vehicle or diluent;    b) a second unit dosage form comprising: 
 a protein kinase inhibitor;  
 an AMP-activated protein kinase;  
 a weight loss agent;  
 insulin;  
 a PPAR-γ agonist;  
 a PPAR-γ antagonist;  
 a PPAR-α agonist;  
 a dual PPAR-γ/PPAR-α agonist;  
 a sorbitol dehydrogenase inhibitor;  
 a glycogen phosphorylase inhibitor;  
 a biguanide;  
 an HMG-CoA reductase inhibitor;  
 an aldose reductase inhibitor; or  
 a PDE5 inhibitor;  
   or solvate of said protein kinase inhibitor, AMP-activated protein, weight loss agent, insulin, PPAR-γ agonist, PPAR-γ antagonist, PPAR-α agonist, dual PPAR-γ/PPAR-α agonist, sorbitol dehydrogenase inhibitor, glycogen phosphorylase inhibitor, biguanide, vastatin, aldose reductase inhibitor or PDE5 inhibitor; or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt and a pharmaceutically acceptable carrier, vehicle or diluent; and    c) a container.    
     
     
         27 . A kit comprising: 
 a) a first unit dosage form comprising a cGMP PDE9 inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt and a pharmaceutically acceptable carrier, vehicle or diluent;    b) a second unit dosage form comprising a cGMP PDE5 inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt and a pharmaceutically acceptable carrier, vehicle or diluent;    c) a third unit dosage form comprising a cGMP PDE11 inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate of said inhibitor or said salt and a pharmaceutically acceptable carrier, vehicle or diluent; and    d) a container.    
     
     
         28 . A method of treating type 2 diabetes in a mammal comprising administering to said mammal a compound that increases intracellular cGMP in said mammal.  
     
     
         29 . A method of treating insulin resistance syndrome in a mammal comprising administering to said mammal a compound that increases intracellular cGMP in said mammal.  
     
     
         30 . A method of treating polycystic ovary syndrome in a mammal comprising administering to said mammal a compound that increases intracellular cGMP in said mammal.  
     
     
         31 . A method of treating dyslipidemia in a mammal comprising administering to said mammal a compound that increases intracellular cGMP in said mammal.  
     
     
         32 . A method of treating impaired glucose tolerance in a mammal comprising administering to said mammal a compound that increases intracellular cGMP in said mammal.