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 kappa receptor agonist or pharmaceutically acceptable salts thereof. 
     
     
         2 . The method of  claim 1 , 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, β-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  R 2 , morpholinyl, thiomorpholinyl, (C)piperidinyl, piperazinyl, 4-mono- or 4,4-di-substituted piperazinyl or δ-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, ξ-(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-ornithine, ε-ornithine, γ-amino-butyric acid, δ-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, —CF 3 , —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. 
       
     
     
         3 . The method of  claim 2 , wherein the kappa receptor agonist is peripherally restricted. 
     
     
         4 . The method of  claim 3 , 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 δ-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, ξ-(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-β,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-ornithine, 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, —CF 3 , —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. 
       
     
     
         5 . The method of  claim 1 , wherein the subject is a menopausal or perimenopausal woman. 
     
     
         6 . The method of  claim 1 , wherein the subject has surgical or medically-induced VMS. 
     
     
         7 . The method of  claim 1 , 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, or intermittent hot flashes or chills/shivering in the subject. 
     
     
         8 . The method of  claim 1  wherein the kappa receptor agonist is pentazocine or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof. 
     
     
         9 . The method of  claim 8  wherein treating or limiting development of VMS comprises decreasing or limiting development of hot flashes in the subject. 
     
     
         10 . The method of  claim 9 , wherein the subject is a menopausal or perimenopausal woman.