Methods and Compositions for Treating Vasomotor Symptoms

Abstract

The present disclosure is generally directed to compositions and methods for treating or limiting development of vasomotor symptoms in a subject.

We claim: 
     
         1 . A method for treating or limiting development of vasomotor symptoms (VMS), comprising administering to a subject in need thereof an amount effective to treat or limit development of VMS of a compound that inhibits kisspeptin/neurokinin B/dynorphin (KNDy) neurons. 
     
     
         2 . The method of  claim 1 , wherein the compound is a kappa receptor agonist. 
     
     
         3 . The method of any one of  claims 1 - 2  wherein the compound comprises a neurokinin 3 receptor (NK3R) antagonist and/or a neurokinin 1 receptor (NK1R) antagonist. 
     
     
         4 . A method for treating or limiting development of VMS comprising administering to a subject in need thereof an amount effective to treat or limit development of VMS of a compound selected from the group consisting of a kappa agonist, an NK3R antagonist, an NK1R antagonist, combinations thereof, and pharmaceutically acceptable salts thereof. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the kappa receptor agonist is selected from the group consisting of dynorphin A, (−) U50,488, ICI 199.441, ICI 204,448, Asimadoline, Bremazocine, BRL 52537, ═-NNTA, Enadoline, FE 200665, Fedotozine, 6′ GNTI, GR89696, HZ-2, Ketocyclazocine, Levallorphan, LPK-26, Nalfurafine HCl, N-Methyl-N-(7-(1-pyrolidinyl)-1-oxaspiro(4,5)dec-8-yl)-4-benzofuranacetamide, N-MPPP Hydrochloride, (−) Pentazocine, (+) Pentazocine, Salvinorin, Salvinorin B, Tifluadom, Cara Therapeutics compound CR854, Spiradoline, U-69593, U62066, a peptide having the following general formula:
   H-Xaa1-Xaa2-Xaa3-Xaa4-substituted amide 
 
       wherein Xaa1 is (A)D-Phe, (C α Me)D-Phe, D-Tyr, D-Tic or D-Ala(cyclopentyl or thienyl), with A being H, NO 2 , F, Cl or CH 3 ; Xaa2 is (A′)D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, with A′ being A or 3,4Cl 2 ; Xaa3 is D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H or C α Me: Xaa4 is D-Arg, D-Har, D-nArg, D-Lys, D-Lys(Ipr), D-Arg(Et 2 ), D-Har(Et 2 ), D-Amf(G), D-Dbu, (B)D-Orn or D-Orn(Ipr), with G being H or amidino; and Q is NR 1 R2, morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazinyl, 4-mono- or 4,4-di-substituted piperazinyl or 6-ornithinyl, with R 1  being lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, aminocyclohexyl, 2-thiazolyl, 2-picolyl, 3-picolyl or 4-picolyl, R 2  being H or lower alkyl; and C being H, 4-hydroxy or 4-oxo; and
 a compound having the formula: 
 
       
         
           
           
               
               
           
         
         
           wherein each Xaa1 is independently chosen from (A)(A′)D-phenylalanine, (A)(A′)(α-Me)D-phenylalanine, D-tyrosine, D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid, D-phenylglycine, D-neopentylglycine, D-homophenylalanine, β-(E)D-Ala and D-tert-butyl-Gly, wherein (A) and (A′) are each phenyl ring substituents independently chosen from —H, —F, —Cl, —NO 2 , —CH 3 , —CF 3 , —CN, —CONH 2 , and wherein each (E) is independently chosen from tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and benzothienyl; 
           each Xaa2 is independently chosen from (A)(A′)D-phenylalanine, (A)(A′)(α-Me)D-phenyl-alanine, naphthyl-1-D-alanine, naphthyl-2-D-alanine, D-tyrosine, (E)D-alanine, and D-tryptophan; 
           each Xaa3 is independently chosen from D-norleucine, D-phenylalanine, (E)D-alanine, D-leucine, (α-Me)D-leucine, D-homoleucine, D-valine, and D-methionine; 
           each Xaa4 is independently chosen from (B)2D-arginine, (B)2D-norarginine, (B)2D-homoarginine, ζ-(B)D-homolysine, D-2,3-diaminopropionic acid, ε-(B)D-lysine, ε-(B)2-D-lysine, D-(NH2CH2-)phenylalanine, amidino-D-(NH2CH2-) phenylalanine, γ-(B)2D-diamino butyric acid, 5-(B)2α-(B′)D-ornithine, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidyl)propionic acid, D-α-amino-β-amidino-propionic acid, α-amino-4-piperidineacetic acid, cis-α,4-diaminocyclohexane acetic acid, trans-α,4-diaminocyclohexaneacetic acid, cis-α-amino-4-methyl-aminocyclo-hexane acetic acid, trans-α-amino-4-methylaminocyclohexane acetic acid, α-amino-1-amidino-4-piperidineacetic acid, cis-α-amino-4-guanidino-cyclohexane acetic acid, and trans-α-amino-4-guanidinocyclohexane acetic acid, wherein each (B) is independently chosen from —H and C1-C4 alkyl, and (B′) is —H or (α-Me); and p is zero or 1; 
           G is selected from one of the following three moieties: 
           (i) G is 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein p, q, r, s and t are each independently zero or 1, provided that at least one of s and t are 1; and L is a linker chosen from ε-D-lysine, ε-lysine, δ-D-omithine, ε-ornithine, γ-amino-butyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxa-octanoic acid, 4-amino-4-carboxylic piperidine and bis(D-Lys-Gly)Lactam; 
           
           (ii) G is 
         
       
       
         
           
           
               
               
           
         
         
           and p is 1; and the moiety 
         
       
       
         
           
           
               
               
           
         
         
           
             is an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein Y is C or N and Z is a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a sulfoxide group, or a sulfonyl group; provided that when such ring moiety is a 6-, 7- or 8-membered ring, Y and Z are separated by at least two ring atoms; and provided further that when such ring moiety is aromatic, then Y is a carbon atom; and 
           
           (iii) G is 
         
       
       
         
           
           
               
               
           
         
         
           wherein J is a 5-, 6-, or 7-membered heterocyclic ring moiety comprising 1, 2, or 3 heteroatoms in the ring, wherein R3 and R4 are each independently selected from H, C1-C3 alkyl, halo, —OH, —CF3, —NH 2 , —COOH and amidino; and R5 and R6 are each independently chosen from H, C1-C3 alkyl, oxo, halo, —OH, —CF 3 , —NH 2 , —COOH and amidino; wherein W′ is chosen from: the moiety —NH—(CH 2 ) b — with b equal to zero, 1, 2, 3, 4, 5, or 6; and the moiety —NH—(CH 2 ) c —O— with c equal to 2 or 3, 
         
         and stereoisomers, mixture of stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, N-oxides and isomorphic crystalline forms thereof. 
       
     
     
         6 . The method of any one of  claims 2 - 5 , wherein the kappa receptor agonist is peripherally restricted. 
     
     
         7 . The method of  claim 6 , wherein the peripherally restricted kappa receptor agonist is selected from the group consisting of ICI-204,448, CR845, Asimadoline, FE 200665, and Fedotozine, a peptide having the following general formula:
   H-Xaa1-Xaa2-Xaa3-Xaa4-substituted amide   
       wherein Xaa1 is (A)D-Phe, (C α Me)D-Phe, D-Tyr, D-Tic or D-Ala(cyclopentyl or thienyl), with A being H, NO 2 , F, Cl or CH 3 ; Xaa2 is (A′)D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, with A′ being A or 3,4Cl 2 ; Xaa3 is D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala(cyclopentyl) with B being H or C α Me; Xaa4 is D-Arg, D-Har, D-nArg, D-Lys, D-Lys(Ipr), D-Arg(Et 2 ), D-Har(Et 2 ), D-Amf(G), D-Dbu, (B)D-Orn or D-Orn(Ipr), with G being H or amidino; and Q is NR 1 R 2 , morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazinyl, 4-mono- or 4,4-di-substituted piperazinyl or S-ornithinyl, with R 1  being lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, aminocyclohexyl, 2-thiazolyl, 2-picolyl, 3-picolyl or 4-picolyl, R 2  being H or lower alkyl; and C being H, 4-hydroxy or 4-oxo; and
 a compound having the formula: 
 
       
         
           
           
               
               
           
         
         
           wherein each Xaa1 is independently chosen from (A)(A′)D-phenylalanine, (A)(A′)(α-Me)D-phenylalanine, D-tyrosine, D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid, D-phenylglycine, D-neopentylglycine, D-homophenylalanine, β-(E)D-Ala and D-tert-butyl-Gly, wherein (A) and (A′) are each phenyl ring substituents independently chosen from —H, —F, —Cl, —NO 2 , —CH 3 , —CF 3 , —CN, —CONH 2 , and wherein each (E) is independently chosen from tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and benzothienyl; 
           each Xaa2 is independently chosen from (A)(A′)D-phenylalanine, (A)(A′)(α-Me)D-phenyl-alanine, naphthyl-1-D-alanine, naphthyl-2-D-alanine, D-tyrosine, (E)D-alanine, and D-tryptophan; 
           each Xaa3 is independently chosen from D-norleucine, D-phenylalanine, (E)D-alanine, D-leucine, (α-Me)D-leucine, D-homoleucine, D-valine, and D-methionine; 
           each Xaa4 is independently chosen from (B)2D-arginine, (B)2D-norarginine, (B)2D-homoarginine, ζ-(B)D-homolysine, D-2,3-diaminopropionic acid, ε-(B)D-lysine, ε-(B)2-D-lysine, D-(NH2CH2-)phenylalanine, amidino-D-(NH2CH2-) phenylalanine, γ-(B)2D-diamino butyric acid, δ-(B)2α-(B′)D-ornithine, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidyl)propionic acid, D-α-amino-β-amidino-propionic acid, α-amino-4-piperidineacetic acid, cis-α,4-diaminocyclohexane acetic acid, trans-α,4-diaminocyclohexaneacetic acid, cis-α-amino-4-methyl-aminocyclo-hexane acetic acid, trans-α-amino-4-methylaminocyclohexane acetic acid, α-amino-1-amidino-4-piperidineacetic acid, cis-α-amino-4-guanidino-cyclohexane acetic acid, and trans-α-amino-4-guanidinocyclohexane acetic acid, wherein each (B) is independently chosen from —H and C1-C4 alkyl, and (B′) is —H or (α-Me); and p is zero or 1; 
           G is selected from one of the following three moieties: 
           (i) G is 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein p, q, r, s and t are each independently zero or 1, provided that at least one of s and t are 1; and L is a linker chosen from ε-D-lysine, ε-lysine, δ-D-ointhine, ε-ornithine, γ-amino-butyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxa-octanoic acid, 4-amino-4-carboxylic piperidine and bis(D-Lys-Gly)Lactam; 
           
           (ii) G is 
         
       
       
         
           
           
               
               
           
         
         
           and p is 1; and the moiety 
         
       
       
         
           
           
               
               
           
         
         
           
             is an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein Y is C or N and Z is a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, a sulfoxide group, or a sulfonyl group; provided that when such ring moiety is a 6-, 7- or 8-membered ring, Y and Z are separated by at least two ring atoms; and provided further that when such ring moiety is aromatic, then Y is a carbon atom; and 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein J is a 5-, 6-, or 7-membered heterocyclic ring moiety comprising 1, 2, or 3 heteroatoms in the ring, wherein R3 and R4 are each independently selected from H, C1-C3 alkyl, halo, —OH, —CF3, —NH 2 , —COOH and amidino; and R5 and R6 are each independently chosen from H, C1-C3 alkyl, oxo, halo, —OH, —CF 3 , —NH 2 , —COOH and amidino; wherein W′ is chosen from: the moiety —NH—(CH) b — with b equal to zero, 1, 2, 3, 4, 5, or 6; and the moiety —NH—(CH 2 ) c —O— with c equal to 2 or 3, 
           
         
         and stereoisomers, mixture of stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, N-oxides and isomorphic crystalline forms thereof. 
       
     
     
         8 . The method of any one of  claims 1 - 7  wherein the compound comprises a neurokinin type 3 receptor (NK3R) antagonist. 
     
     
         9 . The method of  claim 8 , wherein the NK3R antagonist is selected from the group consisting of SB222200, SR 142801, SB 218795, SSR 146977 HCl, AZD2624, Talnetant, and stereoisomers, mixture of stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, N-oxides and isomorphic crystalline forms thereof. 
     
     
         10 . The method of any one of  claims 1 - 9  wherein the compound comprises a neurokinin type 1 receptor (NK1R) antagonist. 
     
     
         11 . The method of  claim 10 , wherein the NKR1 antagonist is selected from the group consisting of SR140333, L-733,060 hydrochloride, CP 96345, Aprepitant, RP 67580, RPR-100893, CP-122721, CJ-11974; L-754,274; GR-203040, GR-205171, LY-303870, CP 99994, FK 888, GR 82334, L 760735, L-732,138; SDZ NKT 343; Spantide I, and stereoisomers, mixture of stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, N-oxides and isomorphic crystalline forms thereof. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein the subject is a menopausal or perimenopausal woman. 
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the subject has surgical or medically-induced VMS. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein treating or limiting development of VMS comprises decreasing or limiting development of one or more of flushing of the skin, sweating, palpitations, racing heart rate, shivering, intermittent feeling of being too hot (hot flashes) or too cold (chills/shivering), irritability, anxiety, mood disorders, and depression, in the subject. 
     
     
         15 . A pharmaceutical composition, comprising:
 (1) two or more of a kappa agonist, an NK3R antagonist, an NK1R antagonist, or salts thereof; and   (2) a pharmaceutically acceptable carrier.   
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the composition comprises a kappa agonist, and wherein the kappa agonist is a peripherally restricted kappa agonist. 
     
     
         17 . The pharmaceutical composition of  claim 15  or  16 , wherein the composition comprises a kappa agonist, and wherein the kappa agonist is a kappa agonist as recited in any one of  claims 5 - 7 . 
     
     
         18 . The pharmaceutical composition of any one of  claims 15 - 17 , wherein the composition comprises a NK3R antagonist, and wherein the NK3R antagonist is an NK3R antagonist as recited in  claim 9 . 
     
     
         19 . The pharmaceutical composition of any one of  claims 15 - 18 , wherein the composition comprises a NK1R antagonist, and wherein the NK1R antagonist is an NK1R antagonist as recited in  claim 11 .