Method of treating c3 glomerulopathy

Abstract

Methods of treating a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a C5aR antagonist are provided.

1 . A method of treating a human suffering from or susceptible to complement 3 glomerulopathy comprising administering to the human an effective amount of a compound having the formula (Ie), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  is independently selected from the group consisting of
 halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a C(O)NR a R b , —NR a R b , —OR a , and —S(O) 2 NR a R b ; wherein each R a  and R b  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R a , R b  and R c  are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R 1  substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; 
 
 each R 2  is independently selected from the group consisting of
 halogen, —CN, —R f , —CO 2 R d , —CONR d R e , —C(O)R d , —OC(O)NR d R e , —NR e C(O)R d , —NR e C(O) 2 R f , —NR d C(O)NR d R e , —NR d C(O)NR d R e , —NR d R e , —OR d , and —S(O) 2 NR d R e ; wherein each R d  and R e  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R d , R e  and R f  are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; 
 
 each R 3  is independently selected from the group consisting of
 halogen, —CN, —R i , —CO 2 R g , —CONR g R h , —C(O)R g , —OC(O)NR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —S(O) 2 NR g R h , —X 4 —R j , —X 4 —NR g R h , —X 4 —CONR g R h , —X 4 —NR h C(O)R g , —NHR j  and —NHCH 2 R j , wherein X 4  is a C 1-4  alkylene; each R g  and R h  is independently selected from hydrogen, C 1-8  alkyl, C 3-6  cycloalkyl and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R i  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R j  is selected from the group consisting of C 3-6  cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of R g , R h , R i  and R j  are optionally further substituted with from one to three halogen, methyl, CF 3 , hydroxy, amino, alkylamino and dialkylamino groups; and 
 
 p is 0, 1 or 2. 
 
     
     
         2 . The method of  claim 1 , wherein
 each R 1  is independently selected from the group consisting of halogen, —CN, —R c , —NR a R b , and —OR a ; wherein each R a  and R b  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each R c  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl and wherein the aliphatic and cyclic portions of R a , R b  and R c  are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R 1  substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring;   each R 2  is independently selected from the group consisting of halogen, —R f , and —OR d ; wherein each R d  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, each R f  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl and heteroaryl, and wherein the aliphatic and cyclic portions of R d  and R f  are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups;   each R 3  is independently selected from the group consisting of halogen, —R i , —CO 2 R g , —CONR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g R h , —OR g , —X 4 —R j , —X 4 —NR g R h , —X 4 —CONR g R h , —X 4 —NR h C(O)R g , —NHR j  and —NHCH 2 R j , wherein X 4  is a C 1-4  alkylene; each R g  and R h  is independently selected from hydrogen, C 1-8  alkyl, C 3-6  cycloalkyl and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R i  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R j  is selected from the group consisting of C 3-6  cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of R g , R h , R i  and R j  are optionally further substituted with from one to three halogen, methyl, CF 3 , hydroxy, amino, alkylamino and dialkylamino groups; and   p is 1.   
     
     
         3 . The method of  claim 1 , wherein
 each R 1  is independently selected from the group consisting of C 1-8  alkyl and C 1-8  haloalkyl;   each R 2  is independently selected from the group consisting of halogen and C 1-8  alkyl;   each R 3  is —NR g R h  wherein each R g  and R h  is independently selected from hydrogen and C 3-6  cycloalkyl; and   p is 1.   
     
     
         4 . The method of  claim 1 , wherein
 each R 1  is independently selected from the group consisting of C 1-3  alkyl and C 1-3  haloalkyl;   each R 2  is independently selected from the group consisting of halogen and C 1-3  alkyl;   each R 3  is —NR g R h  wherein each RR and R h  is independently selected from hydrogen and C 4-6  cycloalkyl; and   p is 1.   
     
     
         5 . The method of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A method of slowing the rate of decline in Estimated Glomerular Filtration Rate (eGFR) in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A method of slowing the rate of decline in Estimated Glomerular Filtration Rate (eGFR) in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A method of reducing glomerular inflammation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A method of clearing glomerular endocapillary proliferation in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method of reducing glomerular inflammatory macrophages in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method of reducing proteinuria in a human suffering from or susceptible to C3 glomerulopathy comprising administering to the human an effective amount of a compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 1  wherein the human suffers from complement 3 glomerulonephritis. 
     
     
         15 . The method of  claim 1  wherein the human suffers from progressive complement 3 glomerulonephritis. 
     
     
         16 . The method of  claim 1  wherein the human suffers from recurrent complement 3 glomerulonephritis after a renal transplant. 
     
     
         17 . The method of  claim 1  wherein the human suffers from dense deposit disease. 
     
     
         18 . The method of  claim 1  wherein the complement 3 glomerulopathy is refractory to other treatment. 
     
     
         19 . The method of  claim 1  wherein the human has refractory disease to immunosuppressive drugs. 
     
     
         20 . The method of  claim 1  wherein the human has refractory disease to one or more of rituximab, cyclophosphamide, mycophenolate mofetil, tacrolimus, and steroids. 
     
     
         21 . The method of any one of  claims 1  to  20  wherein the human shows improved health-related quality of life. 
     
     
         22 . The method of  claim 21  wherein the health-related quality-of-life is based on Short Form-36 version 2 (SF-36 v2) or EuroQOL-5D-5L (EQ-5D-5L) assessment. 
     
     
         23 . The method of  claim 1  wherein the compound is administered twice daily. 
     
     
         24 . The method of  claim 1  wherein the compound is administered once a day. 
     
     
         25 . The method of  claim 1  wherein the compound is administered orally. 
     
     
         26 . The method of  claim 1  wherein the human receives 30 mg of the compound twice daily. 
     
     
         27 . The method of  claim 1  wherein the human receives 20 mg of the compound twice daily. 
     
     
         28 . The method of  claim 1  wherein the human receives 10 mg of the compound twice daily. 
     
     
         29 . The method of  claim 1  wherein the human has a Complement factor H related protein 5 (CFHR5) mutation. 
     
     
         30 . The method of  claim 1  wherein the human receives treatment for 12 weeks. 
     
     
         31 . The method of  claim 1  wherein the human receives treatment for 26 weeks. 
     
     
         32 . The method of  claim 1  wherein the human receives treatment for 52 weeks. 
     
     
         33 . The method of  claim 1  wherein the human receives chronic treatment. 
     
     
         34 . The method of  claim 1  further comprising administering to the human a therapeutically effective amount of one or more additional therapeutic agents. 
     
     
         35 . The method of  claim 34 , wherein the one or more additional therapeutic agents is selected from immunosuppressive drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type-1 receptor blockers (ARBs) and corticosteroids. 
     
     
         36 . The method of  claim 34 , wherein the one or more additional therapeutic agents is selected from the group consisting of cyclophosphamide, mycophenolate mofetil, rituximab, eculizumab, tacrolimus, belimumab, OMS721, ACH-4471, AMY-101, Acthar Gel, SAND-5, corticotropin, CDX-1135, ramipril, perindopril, lisinopril, perindopril arginine, captopril, spirapril, quinapril, enalapril, imidapril, fosinopril, zofenopril, benazepril, trandolapril, verapamil, benazepril, amlodipine, trandolapril, P-003, cilazapril, delapril, moexipril, quinapril, fosinopril, temocapril, losartan, candesartan, irbesartan, telmisartan, olmesartan, valsartan, azilsartan, telmisartan, fimasartan, EMA-401, azilsartan medoxomil potassium, sparsentan, candesartan cilexetil, olmesartan medoxomil, TRV-027, losartan potassium, YH-22189, azilsartan trimethylethanolamine, allisartan isoproxil, and eprosartan.