Treatment of osteoarthritis pain

Abstract

This invention discloses a method of treatment of osteoarthritis pain by administration of a histamine H 3 receptor antagonist, described herein, a salt thereof, or a composition comprising such compound or salt.

1 . A method of treatment of osteoarthritis pain comprising administration of a histamine H 3  receptor antagonist, a salt thereof, or a composition comprising such histamine H 3  receptor antagonist or salt, to a mammal in need of treatment thereof. 
     
     
         2 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 m is 0 or 1; 
 one of R A-1  and R A-2  is hydrogen, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR A-A R A-B , (NR A-A R A-B )carbonyl, —SO 2 N(R A-14a )(R A-14b ), N(R A - 14a )SO 2 (R A-14b ), a group of the formula -L A-2 -R A-6 , or a group of the formula -L A-3 a-R A-6a -L A-3b -R A-6b ; 
 the other of R 1  and R 2  is selected from hydrogen, cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy, alkylthio, —SO 2 N(R A-14a )(R A-14b ), and —N(R A-14a )SO 2 (R A-14b ); 
 R A-3a  and R A-3b  are each independently selected from hydrogen, cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy, alkylthio, —SO 2 N(R A-14a )(R A-14b ), and —N(R A-14a )SO 2 (R A-14b ); 
 R A-4  and R A-5  are each independently selected from alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl; or R A-4  and R A-5  taken together with the nitrogen atom to which each is attached form a non-aromatic ring; 
 R A-6  is selected from aryl, heterocycle, and heterocyclealkyl; 
 R A 6a  is selected from aryl and heterocycle; 
 RA-6b is selected from aryl and heterocycle; 
 L is a bond or alkylene; 
 L 2  is selected from a bond, —O—, alkylene, —C(═O)—, —S—, —SO 2 N(R A-14a )—, —N(R A-14a )SO 2 —, —C(O)N(R A-14a )—, —N(R A-14a )C(O)—, —N(R A-15 )—; 
 L 3a  and L 3b  are each independently selected from a bond, —O—, alkylene, —C(═O)—, —S—, —SO 2 N(R A-14a )—, —N(R A-14a )SO 2 —, —C(O)N(R A-14a )—, —N(R A-14a )C(O)—, and —N(R A 15 )—; 
 R A-10  is selected from hydrogen, cyano, fluoro, hydroxy, and alkyl; 
 R A-14a  and R A-14b  are each independently selected at each occurrence from hydrogen, alkyl, and cycloalkyl; 
 R A-15  is selected from hydrogen, alkyl, acyl, alkoxycarbonyl and (R A-14a )(R A-14b )NC(O)—; and 
 R A-A  and R A-B  are independently selected from hydrogen, alkyl, acyl, haloalkyl, alkoxycarbonyl, cycloalkyl, and formyl. 
 
     
     
         3 . The method of  claim 2 , wherein the histamine H 3  receptor antagonist is (S)-3-hydroxy-1-[2-(3-piperidin-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrrolidin-2-one; trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one; or cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one. 
     
     
         4 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 one of R B-1  and R B-2  is a group of the formula -L B-2 -R B-6a -L B-3 -R B-6b ; 
 the other of R B-1  and R B-2  is selected from hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy; 
 R B-3 , R B-3a , and R B-3b  are each independently selected from the group consisting of hydrogen, alkyl, trifluoroalkyl, trifluoroalkoxy, alkoxy, halogen, cyano, and thioalkoxy; 
 R B-4  and R B-5  are each independently selected from alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl, or R B-4  and R B-5  taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula: 
 
       
         
           
           
               
               
           
         
         R B-7 , R B-8 , R B-9 , and R B-10  at each occurrence are each independently selected from hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; 
         R B-11 , R B-12 , R B-13 , and R B-14  are each independently selected from hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; 
         R B-6a  is selected from a 5- to 6-membered heteroaryl ring, cyanophenyl, an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to 12-membered heterocyclic ring; 
         R B-6b  is selected from hydrogen, a 5- to 6-membered heteroaryl ring, an aryl ring, an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to 12-membered heterocyclic ring; 
         Q is selected from O and S; 
         L B  is —[C(R B-16 )(R B-17 )] k ; 
         L B-2  is selected from a bond, alkylene, —O—, —C(═O)—, —S—, —NH—, —N(R B-16 )C(═O)—, —C(═O)N(R B-16 ), and —N(alkyl)-; 
         L B-3  is selected from a bond, alkylene, —O—, —C(═O)—, —S—, —N(R B-16 )C(═O)—, —C(═O)N(R B-16 ), and —N(R B-15 )—; 
         R B-15  is selected from hydrogen, alkyl, acyl, alkoxycarbonyl, amido, and formyl; 
         R B-16  and R B-17  at each occurrence are independently selected from hydrogen and alkyl; 
         R B-x  and R B-y  at each occurrence are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; 
         k is 1, 2, or 3; and 
         m2 is an integer from 1 to 5. 
       
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, wherein
 A is selected from the group consisting of carbonyl and a covalent bond; 
 D is selected from the group consisting of O and S; 
 Lc is selected from the group consisting of lower alkylene, fluoroalkylene, and hydroxyalkylene; 
 Pc and Qc taken together form a covalent bond or are both hydrogen; 
 R C-1  and R C-2  are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, alkenyl, and alkynyl; or 
 R C-1  and R C-2  taken together with the nitrogen atom to which they are attached, together form a heterocycle; 
 R C-3  is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfmyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, —NR C-A RC— B , (NR C - A R C—B )alkyl, (NR C-A R C—B )carbonyl, and (NR c-A R c-B )sulfonyl; 
 R C-4 , R C-5 , R C-6  and R C-7  are each independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, —NR C-A R C—B , (NR C-A R C—B )alkyl, (NR C-A R C—B )carbonyl, (NR C-A R C—B )sulfonyl, -L C-2 R C-20 , and —R C21 L C-3 R C-22 ; 
 L C-2  is selected from the group consisting of alkylene, alkenylene, O, S, S(O), S(O) 2 , C(═O), C═(NOR C-21 ), and N(R C-A ); 
 L C-3 is selected from the group consisting of a covalent bond, alkylene, alkenylene, O, S, C(═O), N(═OR C-21 ), and N(R C-A ); 
 R C-20  is selected from the group consisting of aryl, heterocycle, and cycloalkyl; 
 R C-21 is selected from the group consisting of hydrogen and alkyl; 
 R C-22  is selected from the group consisting of aryl, heterocycle, and cycloalkyl; 
 R C-A  and R C—B  are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and formyl; 
 provided that at least one of R C-4 , R C-5 , R C-6 , or R C-7 is aryl, heterocycle, cycloalkyl, -L C-2 R C-20  or —R C-20 L C-3 R C-22 . 
 
     
     
         7 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein X D  is CH or N, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 7 , wherein the histamine H 3  receptor antagonist is (6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nicotinamide) or GSK-189254. 
     
     
         9 . The method of  claim 7 , wherein the histamine H3 receptor antagonist is (5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpyrazine-2-carboxamide) or GSK-207040. 
     
     
         10 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound having structure: 
       
         
           
           
               
               
           
         
       
       (E) or 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound structure: 
       
         
           
           
               
               
           
         
       
       (F) or GSK-334429 or (4-isopropyl-1,4-diazepan-1-yl)(1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-4-yl)methanone, or a pharmaceutically acceptable salt, thereof. 
     
     
         12 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein Ar is a divalent group formed by eliminating two hydrogen atoms from benzene, pyrimidine, pyridine, thiazole, oxazole, pyrazole, thiadiazole or thiophene (this divalent group may be further substituted by a halogen atom, lower alkoxy (this lower alkoxy group may be further substituted by halogen), hydroxy or lower alkyl); X 1  is a nitrogen atom, sulfur atom or oxygen atom; R G-1  is a 5- or 6-membered heteroaryl group having 1 to 4 heteroatoms selected from among nitrogen, sulfur and oxygen, heteroarylalkyl group (heteroaryl in this group has the same meaning as the above), straight chain or branched lower alkyl (this lower alkyl group may be further substituted by hydroxy, halogen, alkoxy, allyloxy or aralkyloxy), phenyl, aralkyl, alkoxy, alkylthio or lower alkylamino; Ring A is a 5- or 6-membered heteroaryl ring having 1 or 2 nitrogen atoms or sulfur atoms in the ring, or a benzene ring; R 2  and R3 may be the same or different, and each represents hydrogen, amino, alkylamino, dialkylamino, nitro, cyano, hydroxy, lower alkylsulfonyl, halogen, lower alkyl (this lower alkyl group may be further substituted by halogen), lower cycloalkyl (this lower cycloalkyl group may be further substituted by halogen), lower alkoxy (this lower alkoxy group may be further substituted by halogen or hydroxy), lower cycloalkoxy (this lower cycloalkoxy group may be further substituted by halogen), aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, aryl, heteroaryl, arylcarbamoyl, heteroarylcarbamoyl, arylalkylcarbamoyl, heteroarylalkylcarbamoyl, mono-lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkylcarboxamide, arylcarboxamide, heteroarylcarboxamide, arylalkylcarboxamide, heteroarylalkylcarboxamide, alkanoyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminosulfonyl, arylaminosulfonyl, aralkyl, alkanoylamino or alkanoylalkylamino; Y is CH or a nitrogen atom; —X 2  is a group represented by —(CH 2 ) Π —NRG-4RG-5, n is an integer of 2 to 4, where RG-4 and R G - 5  taken together with a nitrogen atom together form a 5- to 8-membered monocyclic ring (this monocyclic ring may be substituted by a halogen atom, an oxo group, or a lower alkyl group of 1-3 carbon atoms which itself may be substituted by halogen, or where —X 2  is a group represented by 
       
         
           
           
               
               
           
         
       
       where m is an integer from 0 to 4, and R G - 6  is a lower alkyl or cycloalkyl group), or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is 2-methyl-3-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5-(trifluoromethyl)quinazolin-4(3H)-one or 3-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-2-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one. 
     
     
         14 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of structure: 
       
         
           
           
               
               
           
         
       
       (H) or 6-(2-(1-isopropylpiperidin-4-yloxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of structure: 
       
         
           
           
               
               
           
         
       
       (I) or N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobutanecarboxamide, and stereoisomeric forms (1r,3r)-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobutanecarboxamide and trans-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is C 1-10 alkyl, C 3-8  alkenyl, C 3-8  cycloalkyl, (C 3-8  cycloalkyl)C 1-6  alkyl, (C 3-8  cycloalkyl)C 3-8  alkenyl, or (C 1-8  alkylcarbonyl)C 1-8  alkyl; 
 n is 1 or 2; 
 X J  is O or S; 
 one of R 2 , R 3  and R 4  is G and the other two independently are hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C 1-3  alkoxy; 
 G is LQ; 
 L is unbranched —(CH 2 ) m ,— wherein m is an integer from 1 to 7; 
 Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-6  alkyl, C 3-6  alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9 membered heterocyclyl)C 1-6  alkylene, and (phenyl)C 1-6  alkylene; and 
 R 9  is independently selected from C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-membered heteroyclyl)C 1-6  alkylene, and (phenyl) C 1 - 6  alkylene; or 
 Q is a saturated 3-12 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-12 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and NH; wherein Q is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, carboxamide, C 1-6  alkyl, 5-9 membered or 6-9 membered heterocyclyl, —N(C 1-6  alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 membered heterocyclyl), -0(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C 1-3  alkylene, C 1-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O—, where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C 1-3  alkyl; provided however that when R 1  is methyl, G is not piperidin-1-ylmethyl; and 
 wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents independently selected from trifluoromethyl, methoxy, halo, amino, nitro, hydroxy, and C 1-3  alkyl. 
 
     
     
         17 . The method of  claim 16 , wherein the histamine H 3  receptor antagonist is ((4-isopropylpiperazin-1-yl)(4-(piperidin-1-ylmethyl)phenyl)methanone), or (5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpyrazine-2-carboxamide). 
     
     
         18 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of structure: 
       
         
           
           
               
               
           
         
       
       or (1-((2-amino-6-methylpyridin-4-yl)methyl)-4-fluoropiperidin-4-yl)(4-(2-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is a compound of structure: 
       
         
           
           
               
               
           
         
       
       or 1-(1-methylethyl)-4-{[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]carbonyl}piperazine, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is BF2649 (1-{3-[3-(4-chloro-phenyl)-propoxy]-propyl}-piperidine), 6-{4-[3-(r-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2h-pyridazin-3-one, GSK- 239512, PF-3654746, MK-0249, JNJ- 17216498, CEP-26401, SCH-497079, ATH-90879, SAR-110894, APD916, S-38093, MK-3134, or JNJ-3100174. 
     
     
         21 . The method of  claim 1 , wherein the histamine H 3  receptor antagonist is administered in a therapeutically effective amount with an effective amount of ibuprofen, celecoxib, or rofecoxib. 
     
     
         22 . (canceled)