US2015202185A1PendingUtilityA1
Compositions and methods for treating lysosomal disorders
Assignee: NEURALTUS PHARMACEUTICALS INCPriority: Nov 29, 2007Filed: Apr 1, 2015Published: Jul 23, 2015
Est. expiryNov 29, 2027(~1.4 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 7/06A61P 3/06A61P 39/02A61P 3/00A61P 25/00A61P 11/00A61P 17/00A61P 13/02A61K 31/41A61K 31/45A61K 31/445A61K 31/4164A61K 45/06A61K 31/4178A61K 31/4174Y02A50/30
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Claims
Abstract
The present invention provides compositions and methods for treating lysosomal disorders using a class of substituted imidazole derivatives or compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for treating a lipid storage disease in a subject comprising administering to said subject an effective amount of a compound of Formula 1
in the form of a free compound or its pharmaceutically acceptable pro-drug, metabolite, analogue, derivative, solvate or salt wherein the substituents R 1 , R 2 , R 3 , and R 4 are defined as described in A and B below:
(a) when R 1 is selected from the group consisting of:
(i) substituted C 1-11 alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 1-6 alkyloxy; or
(ii) mono-, di-, and tri-substituted aryl-C 0-11 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl wherein the substituents are selected from the group consisting of:
(a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, wherein the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C 1-4 alkyl and C 1-4 alkyloxy,
(b) substituted C 1-6 alkyl, substituted C 2-6 alkyloxy, substituted C 2-6 alkylthio, substituted C 2-6 alkoxycarbonyl, wherein the substituents are selected from the group consisting of C 1-6 alkoxy, and C 1-6 alkylthio; and
(c) C 1-11 CO 2 R 5 , C 1-11 CONHR 5 , trans-CH═CHCO 2 R 5 , or trans-CH═CHCONHR 5 wherein R 5 is C 1-11 alkyl, or phenyl C 1-11 alkyl, C 1-6 alkoxycarbonylmethyleneoxy;
then R 2 and R 3 are each independently selected from the group consisting of mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from:
(i) substituted C 1-6 alkyl,
(ii) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino,
(iv) C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino,
(v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
wherein the substituents are selected from the group consisting of:
(a) hydroxy, C 1-6 alkylalkoxy, C 1-6 alkylamino
(b) C 3-6 alkenyloxy, C3-6 alkenylamino, or
(c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
or R 2 and R 3 taken together forming an aryl group or substituted aryl, wherein the substituents are defined as above in (i)-(v);
and R 4 is selected from the group consisting of:
(i) hydrogen;
(ii) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, C 1-6 alkoxycarbonyl; or
(iii) substituted aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, thienyl in which the substituents are selected from A(a-c); or
(b) when R 1 is selected from the group consisting of:
Mono-, di-, and tri-substituted aryl-C 0-6 alkyl wherein aryl is selected from the group consisting of phenyl, thienyl, and the substituents are selected from the group consisting of:
(a) trans-2-substituted benzimidazolylethenyl, trans-2-substituted benzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in which the substituents are selected from the group consisting of hydrogen, hydroxy, halo, trihalomethyl, C 1-4 alkyl and C 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 alkenylamino, di(C 3-6 alkenyl)amino, C 1-4 alkyloxy-C 1-4 alkylamino, substituted C 1-4 alkyl and C 1-4 alkyloxy, substituted C 1-4 alkyloxycarbonyl, substituted C 1-4 alkylamino, di(substituted C 1-4 alkyl)amino, substituted C 3-6 alkenylamino, di(substituted C 3-6 alkenyl)amino, wherein the substituents are as defined above,
(b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonyl ethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which the substituents are defined above,
(c) C 1-6 CO 2 R 5 , trans-CH═CHCO 2 R 5 , C 1-6 CONHR 5 , or trans-CH═CHCONHR 5 , wherein R 5 is C 1-6 alkoxy C 2-6 alkyl, amino C 2-6 alkyl, C 1-6 alkylamino C 2-6 alkyl, di(C 1-6 alkyl)amino C 2-6 alkyl, C 1-6 alkylthio C 2-6 alkyl, substituted C 1-6 alkoxy C 2-6 alkyl, substituted C 1-6 alkylamino C 2-6 alkyl, di(substituted C 1-6 alkyl)amino C 2-6 alkyl, substituted C 1-6 alkylthio C 2-6 alkyl, in which the substituents are selected from the group consisting of pyrrolidino, piperidino morpholino, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,
(d) C 1-6 CONR 6 R 7 , or trans-CH═CHCONR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of C 1-6 alkyl, phenyl C 1-6 alkyl, C 1-6 alkoxycarbonylmethyleneoxy, hydroxy C 2-6 alkyl, C 1-6 alkyloxy C 2-6 alkyl, amino C 2-6 alkyl, C 1-6 alkylamino C 2-6 alkyl, di(C 1-6 alkyl)amino C 2-6 alkyl, C 1-6 alkylthio C 2-6 alkyl, substituted C 1-6 alkoxy C 2-6 alkyl, substituted C 1-6 alkylamino C 2-6 alkyl, di(substituted C 1-6 alkyl)amino C 2-6 alkyl, substituted C 1-6 alkylthio C 2-6 alkyl, wherein the substituents are selected from the group consisting of pyrrolidino, piperidino, morpholino, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,
(e) R 7 C(O) C 1-6 alkyl, R 7 C(O) C 2-6 alkenyl, in which R 7 is defined as above [ 2 (d)],
(f) HO—C 1-6 alkyl-C 2-6 alkenyl, R 7 —O—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 O—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 —C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, wherein R 6 and R 7 is defined as above [ 2 (d)],
(g) R 7 —O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 NH—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 6 R 7 N-C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 NH—C(O)—O—C 0-3 C 3-6 cycloalkan-1-yl, R 6 R 7 N-C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 O—C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 —C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 O—C(O)—Co-3 alkyl-C 3-6 cycloalkan-1-yl, wherein R 7 and is defined as above [B(d)];
then R 2 and R 3 are each independently selected from the group consisting of:
(1) hydrogen, halo, trihalomethyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 1-6 alkenyl, C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy, C 1-6 alkylamino, substituted C 1-6 alkylamino, C 3-6 alkenylamino, substituted C 3-6 alkenylamino,
(2) mono-, di-, and tri-substituted phenyl wherein the substituents are independently selected from:
(i) halo, trifluoromethyl, substituted C 1-6 alkyl,
(ii) C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) C 1-6 alkyl-amino, di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino, or
(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
wherein the substituents are selected from the group consisting of:
(a) hydrogen, hydroxy, halo, trifluoromethyl,
(b) C 1-6 alkylalkoxy, C 1-6 alkylamino, C 1-6 alkylthio,
(c) C 3-6 alkenyloxy, C 3-6 alkenylamino, C 3-6 alkenylthio, or
(d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino;
with the proviso that at least one of R 2 and R 3 group be selected from [B (2)] and the phenyl and the substituents be selected from (ii)-(v) above; or R 2 and R 3 taken together forming an aryl group such as phenyl, pyridyl, in which the aryl may be optionally substituted, wherein the substituents are defined as above in (i)-(iv);
and R 4 is selected from the group consisting of:
(a) hydrogen;
(b) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of:
(i) hydrogen, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, C 1-6 alkoxycarbonyl;
(ii) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino; and
(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, and 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino; and
(c) aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, thienyl.
2 . The method of claim 1 , wherein the compound of Formula 1 has the following formula (Formula 2):
in the form of a free compound or as its pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt.
3 . The method of claim 1 , wherein the disease is characterized by a defect in glycosphingolipid synthesis.
4 . The method of claim 3 , wherein the glycosphingolipid is a neutral glycosphingolipid.
5 . The method of claim 1 , wherein the disease is characterized by a defect in ceramide synthesis.
6 . The method of claim 1 , wherein the disease is Gaucher's disease or Fabry's disease.
7 . The method of claim 1 , wherein the disease is characterized by a defect in ganglioside synthesis in the subject.
8 . The method of claim 7 , wherein the ganglioside is a GM1 ganglioside or a GM2 ganglioside.
9 . The method of claim 8 , wherein the disease is Tay Sach's disease or Sandhoff's disease.
10 . The method of claim 7 , wherein the disease is cystic fibrosis.
11 . A method for treating a lipid storage disease in a subject comprising administering to the subject an effective amount of:
a first compound of Formula 1
in the form of a free compound or its pharmaceutically acceptable pro-drug, metabolite, analogue, derivative, solvate or salt wherein the substituents R 1 , R 2 , R 3 , and R 4 are defined as described in A and B below:
(a) when R 1 is selected from the group consisting of:
(i) substituted C 1-11 alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 1-6 alkyloxy; or
(ii) mono-, di-, and tri-substituted aryl-C 0-11 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl wherein the substituents are selected from the group consisting of:
(a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, wherein the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C 1-4 alkyl and C 1-4 alkyloxy,
(b) substituted C 1-6 alkyl, substituted C 2-6 alkyloxy, substituted C 2-6 alkylthio, substituted C 2-6 alkoxycarbonyl, wherein the substituents are selected from the group consisting of C 1-6 alkoxy, and C 1-6 alkylthio; and
(c) C 1-11 CO 2 R 5 , C 1-11 CONHR 5 , trans-CH═CHCO 2 R 5 , or trans-CH═CHCONHR 5 wherein R 5 is C 1-11 alkyl, or phenyl C 1-11 alkyl, C 1-6 alkoxycarbonylmethyleneoxy;
then R 2 and R 3 are each independently selected from the group consisting of mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from:
(i) substituted C 1-6 alkyl,
(ii) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino,
(iv) C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino,
(v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
wherein the substituents are selected from the group consisting of:
(a) hydroxy, C 1-6 alkylalkoxy, C 1-6 alkylamino
(b) C 3-6 alkenyloxy, C3-6 alkenylamino, or
(c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
or R 2 and R 3 taken together forming an aryl group or substituted aryl, wherein the substituents are defined as above in (i)-(v);
and R 4 is selected from the group consisting of:
(i) hydrogen;
(ii) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyloxy, C i-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, C 1-6 alkoxycarbonyl; or
(iii) substituted aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, thienyl in which the substituents are selected from A(a-c); or
(b) when R 1 is selected from the group consisting of:
Mono-, di-, and tri-substituted aryl-C 0-6 alkyl wherein aryl is selected from the group consisting of phenyl, thienyl, and the substituents are selected from the group consisting of:
(a) trans-2-substituted benzimidazolylethenyl, trans-2-substituted benzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in which the substituents are selected from the group consisting of hydrogen, hydroxy, halo, trihalomethyl, C 1-4 alkyl and C 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylamino, alkyl)amino, C 3-6 alkenylamino, di(C 3-6 alkenyl)amino, C 1-4 alkyloxy-C 1-4 alkylamino, substituted C 1-4 alkyl and C 1-4 alkyloxy, substituted C 1-4 alkyloxycarbonyl, substituted C 1-4 alkylamino, di(substituted C 1-4 alkyl)amino, substituted C 3-6 alkenylamino, di(substituted C 3-6 alkenyl)amino, wherein the substituents are as defined above,
(b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonyl ethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which the substituents are defined above,
(c) C 1-6 CO 2 R 5 , trans-CH═CHCO 2 R 5 , C 1-6 CONHR 5 , or trans-CH═CHCONHR 5 , wherein R 5 is C 1-6 alkoxy C 2-6 alkyl, amino C 2-6 alkyl, C 1-6 alkylamino C 2-6 alkyl, di(C 1-6 alkyl)amino C 2-6 alkyl, C 1-6 alkylthio C 2-6 alkyl, substituted C 1-6 alkoxy C 2-6 alkyl, substituted C 1-6 alkylamino C 2-6 alkyl, di(substituted C 1-6 alkyl)amino C 2-6 alkyl, substituted C 1-6 alkylthio C 2-6 alkyl, in which the substituents are selected from the group consisting of pyrrolidino, piperidino morpholino, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,
(d) C 1-6 CONR 6 R 7 , or trans-CH═CHCONR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of C 1-6 alkyl, phenyl C 1-6 alkyl, C 1-6 alkoxycarbonylmethyleneoxy, hydroxy C 2-6 alkyl, C 1-6 alkyloxy C 2-6 alkyl, amino C 2-6 alkyl, C 1-6 alkylamino C 2-6 alkyl, di(C 1-6 alkyl)amino C 2-6 alkyl, C 1-6 alkylthio C 2-6 alkyl, substituted C 1-6 alkoxy C 2-6 alkyl, substituted C 1-6 alkylamino C 2-6 alkyl, di(substituted C 1-6 alkyl)amino C 2-6 alkyl, substituted C 1-6 alkylthio C 2-6 alkyl, wherein the substituents are selected from the group consisting of pyrrolidino, piperidino, morpholino, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,
(e) R 7 C(O) C 1-6 alkyl, R 7 C(O) C 2-6 alkenyl, in which R 7 is defined as above [ 2 (d)],
(f) HO—C 1-6 alkyl-C 2-6 alkenyl, R 7 —O—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 O—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 —C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, wherein R 6 and R 7 is defined as above [ 2 (d)],
(g) R 7 —O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 NH—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 6 R 7 N-C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 NH—C(O)—O—C 0-3 C 3-6 cycloalkan-1-yl, R 6 R 7 N-C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 O—C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 —C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 O—C(O)—Co-3 alkyl-C 3-6 cycloalkan-1-yl, wherein R 7 and is defined as above [B(d)];
then R 2 and R 3 are each independently selected from the group consisting of:
(1) hydrogen, halo, trihalomethyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 1-6 alkenyl, C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy, C 1-6 alkylamino, substituted C 1-6 alkylamino, C 3-6 alkenylamino, substituted C 3-6 alkenylamino,
(2) mono-, di-, and tri-substituted phenyl wherein the substituents are independently selected from:
(i) halo, trifluoromethyl, substituted C 1-6 alkyl,
(ii) C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) C 1-6 alkyl-amino, di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino, or
(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
wherein the substituents are selected from the group consisting of:
(a) hydrogen, hydroxy, halo, trifluoromethyl,
(b) C 1-6 alkylalkoxy, C 1-6 alkylamino, C 1-6 alkylthio,
(c) C 3-6 alkenyloxy, C 3-6 alkenylamino, C 3-6 alkenylthio, or
(d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino;
with the proviso that at least one of R 2 and R 3 group be selected from [B (2)] and the phenyl and the substituents be selected from (ii)-(v) above; or R 2 and R 3 taken together forming an aryl group such as phenyl, pyridyl, in which the aryl may be optionally substituted, wherein the substituents are defined as above in (i)-(iv);
and R 4 is selected from the group consisting of:
(a) hydrogen;
(b) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of:
(i) hydrogen, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, C 1-6 alkoxycarbonyl;
(ii) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino; and
(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, and 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino; and
(c) aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, thienyl; and
a second compound effective to treat the lipid storage disease.
12 . The method of claim 11 , wherein the second compound is a glucosylceramide synthase inhibitor.
13 . The method of claim 12 , wherein the glucosylceramide synthase inhibitor is miglustat.
14 . The method of claim 11 , wherein the second compound is an enzyme administered as enzyme replacement therapy.
15 . The method of claim 11 , wherein the second compound is a pharmacological chaperone which binds to an enzyme and promotes trafficking of the enzyme from the endoplasmic reticulum to the lysosome.
16 . A composition comprising a glucosylceramide synthase inhibitor and a compound of Formula 1
in the form of a free compound or its pharmaceutically acceptable pro-drug, metabolite, analogue, derivative, solvate or salt wherein the substituents R 1 , R 2 , R 3 , and R 4 are defined as described in A and B below:
(a) when R 1 is selected from the group consisting of:
(i) substituted C 1-11 alkyl or substituted C 2-11 alkenyl, wherein the substituents are selected from the group consisting of hydroxy, C 1-6 alkyloxy; or
(ii) mono-, di-, and tri-substituted aryl-C 0-11 alkyl wherein aryl is selected from the group consisting of phenyl, furyl, thienyl wherein the substituents are selected from the group consisting of:
(a) phenyl, trans-2-phenylethenyl, 2-phenylethynyl, 2-phenylethyl, wherein the said phenyl group is mono- or disubstituted with a member selected from the group consisting of hydroxy, halo, C 1-4 alkyl and C 1-4 alkyloxy,
(b) substituted C 1-6 alkyl, substituted C 2-6 alkyloxy, substituted C 2-6 alkylthio, substituted C 2-6 alkoxycarbonyl, wherein the substituents are selected from the group consisting of C 1-6 alkoxy, and C 1-6 alkylthio; and
(c) C 1-11 CO 2 R 5 , C 1-11 CONHR 5 , trans-CH═CHCO 2 R 5 , or trans-CH═CHCONHR 5 wherein R 5 is C 1-11 alkyl, or phenyl C 1-11 alkyl, C 1-6 alkoxycarbonylmethyleneoxy;
then R 2 and R 3 are each independently selected from the group consisting of mono-, di, and tri-substituted phenyl wherein the substituents are independently selected from:
(i) substituted C 1-6 alkyl,
(ii) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino,
(iv) C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino,
(v) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
wherein the substituents are selected from the group consisting of:
(a) hydroxy, C 1-6 alkylalkoxy, C 1-6 alkylamino
(b) C 3-6 alkenyloxy, C3-6 alkenylamino, or
(c) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
or R 2 and R 3 taken together forming an aryl group or substituted aryl, wherein the substituents are defined as above in (i)-(v);
and R 4 is selected from the group consisting of:
(i) hydrogen;
(ii) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, C 1-6 alkoxycarbonyl; or
(iii) substituted aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, thienyl in which the substituents are selected from A(a-c); or
(b) when R 1 is selected from the group consisting of:
Mono-, di-, and tri-substituted aryl-C 0-6 alkyl wherein aryl is selected from the group consisting of phenyl, thienyl, and the substituents are selected from the group consisting of:
(a) trans-2-substituted benzimidazolylethenyl, trans-2-substituted benzoxazolylethenyl, trans-2-substituted benzthiazolylethenyl, in which the substituents are selected from the group consisting of hydrogen, hydroxy, halo, trihalomethyl, C 1-4 alkyl and C 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 alkenylamino, di(C 3-6 alkenyl)amino, C 1-4 alkyloxy-C 1-4 alkylamino, substituted C 1-4 alkyl and C 1-4 alkyloxy, substituted C 1-4 alkyloxycarbonyl, substituted C 1-4 alkylamino, di(substituted C 1-4 alkyl)amino, substituted C 3-6 alkenylamino, di(substituted C 3-6 alkenyl)amino, wherein the substituents are as defined above,
(b) trans-2-cyano ethenyl, trans-2-alkylsulfonyl ethenyl, trans-2-alkenylsulfonyl ethenyl, trans-2-substituted alkylsulfonyl ethenyl, trans-2-substituted alkenylsulfonyl ethenyl, in which the substituents are defined above,
(c) C 1-6 CO 2 R 5 , trans-CH═CHCO 2 R 5 , C 1-6 CONHR 5 , or trans-CH═CHCONHR 5 , wherein R 5 is C 1-6 alkoxy C 2-6 alkyl, amino C 2-6 alkyl, C 1-6 alkylamino C 2-6 alkyl, di(C 1-6 alkyl)amino C 2-6 alkyl, C 1-6 alkylthio C 2-6 alkyl, substituted C 1-6 alkoxy C 2-6 alkyl, substituted C 1-6 alkylamino C 2-6 alkyl, di(substituted C 1-6 alkyl)amino C 2-6 alkyl, substituted C 1-6 alkylthio C 2-6 alkyl, in which the substituents are selected from the group consisting of pyrrolidino, piperidino morpholino, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-C 1-6 alkylamino C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,
(d) C 1-6 CONR 6 R 7 , or trans-CH═CHCONR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of C 1-6 alkyl, phenyl C 1-6 alkyl, C 1-6 alkoxycarbonylmethyleneoxy, hydroxy C 2-6 alkyl, C 1-6 alkyloxy C 2-6 alkyl, amino C 2-6 alkyl, C 1-6 alkylamino C 2-6 alkyl, di(C 1-6 alkyl)amino C 2-6 alkyl, C 1-6 alkylthio C 2-6 alkyl, substituted C 1-6 alkoxy C 2-6 alkyl, substituted C 1-6 alkylamino C 2-6 alkyl, di(substituted C 1-6 alkyl)amino C 2-6 alkyl, substituted C 1-6 alkylthio C 2-6 alkyl, wherein the substituents are selected from the group consisting of pyrrolidino, piperidino, morpholino, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-C 1-6 alkylamino C 3-6 alkenyl)piperazino, imidazolyl, oxazolyl, thiazolyl,
(e) R 7 C(O) C 1-6 alkyl, R 7 C(O) C 2-6 alkenyl, in which R 7 is defined as above [2(d)],
(f) HO—C 1-6 alkyl-C 2-6 alkenyl, R 7 —O—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 O—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 —C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, wherein R 6 and R 7 is defined as above [2(d)],
(g) R 7 —O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 NH—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 6 R 7 N-C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 NH—C(O)—O—C 0-3 C 3-6 cycloalkan-1-yl, R 6 R 7 N-C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 O—C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 —C(O)—O—C 0-3 alkyl-C 3-6 cycloalkan-1-yl, R 7 O—C(O)—Co-3 alkyl-C 3-6 cycloalkan-1-yl, wherein R 7 and is defined as above [3(d)];
then R 2 and R 3 are each independently selected from the group consisting of:
(1) hydrogen, halo, trihalomethyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 1-6 alkenyl, C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy, C 1-6 alkylamino, substituted C 1-6 alkylamino, C 3-6 alkenylamino, substituted C 3-6 alkenylamino,
(2) mono-, di-, and tri-substituted phenyl wherein the substituents are independently selected from:
(i) halo, trifluoromethyl, substituted C 1-6 alkyl,
(ii) C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) C 1-6 alkyl-amino, di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino, or
(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino,
wherein the substituents are selected from the group consisting of:
(a) hydrogen, hydroxy, halo, trifluoromethyl,
(b) C 1-6 alkylalkoxy, C 1-6 alkylamino, C 1-6 alkylthio,
(c) C 3-6 alkenyloxy, C 3-6 alkenylamino, C 3-6 alkenylthio, or
(d) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino;
with the proviso that at least one of R 2 and R 3 group be selected from [B (2)] and the phenyl and the substituents be selected from (ii)-(v) above; or R 2 and R 3 taken together forming an aryl group such as phenyl, pyridyl, in which the aryl may be optionally substituted, wherein the substituents are defined as above in (i)-(iv);
and R 4 is selected from the group consisting of:
(a) hydrogen;
(b) substituted C 1-11 alkyl or C 2-11 alkenyl wherein the substituents are independently selected from the group consisting of:
(i) hydrogen, hydroxy, C 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkylamino, phenyl-C 1-6 alkylamino, C 1-6 alkoxycarbonyl;
(ii) substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, substituted C 3-6 alkenyloxy,
(iii) di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, di(substituted C 3-6 alkenyl)amino; and
(iv) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, and 4-N-(C 1-6 alkylamino C 3-6 alkenyl)piperazino; and
(c) aryl C 0-11 alkyl wherein the aryl group is selected from phenyl, imidazolyl, furyl, thienyl.
17 . The composition of claim 16 , wherein the glucosylceramide synthase inhibitor is miglustat.
18 . The method of claim 1 , wherein the compound of Formula 1 is a compound wherein R 1 is selected from the group consisting of mono-, di-, and tri-substituted aryl-C 0-6 alkyl wherein aryl is selected from the group consisting of phenyl and thienyl, and the substituents are selected from the group consisting of:
(a) C 1-6 CO 2 R 5 , trans-CH═CHCO 2 R 5 , C 1-6 CONHR 5 , or trans-CH═CHCONHR 5 ; (b) C 1-6 CONR 6 R 7 , or trans-CH═CHCONR 6 R 7 ; (c) R 7 C(O) C 1-6 alkyl or R 7 C(O) C 2-6 alkenyl; and (d) HO—C 1-6 alkyl-C 2-6 alkenyl, R 7 —O—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 O—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, or R 7 —C(O)—O—C 1-6 alkyl-C 2-6 alkenyl.
19 . The method of claim 1 , wherein R 2 and R 3 are each independently selected from the group consisting of: mono-, di-, and tri-substituted phenyl wherein the substituents are independently selected from the group consisting of:
(i) C 1-6 alkyloxy, substituted C 1-6 alkyloxy, C 3-6 alkenyloxy, or substituted C 3-6 alkenyloxy; (ii) C 1-6 alkyl-amino, di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, or di(substituted C 3-6 alkenyl)amino, and (iii) pyrrolidino, piperidino, morpholino, imidazolyl, substituted imidazolyl, piperazino, 4-N-C 1-6 alkylpiperazino, 4-N-C 3-6 alkenylpiperazino, 4-N-(C 1-6 alkoxy C 1-6 alkyl)piperazino, 4-N-(C 1-6 alkoxy C 3-6 alkenyl)piperazino, 4-N-(C 1-6 alkylamino C 1-6 alkyl)piperazino, or 4-N-C 1-6 alkylamino C 3-6 alkenyl)piperazino.
20 . The method of claim 1 , wherein the compound of Formula 1 is a compound of Formula 1b:
wherein each instance of R a is independently C 1-6 alkyl-amino, di(C 1-6 alkyl)amino, substituted C 1-6 alkyl-amino, di(substituted C 1-6 alkyl)amino, C 3-6 alkenyl-amino, di(C 3-6 alkenyl)amino, substituted C 3-6 alkenyl-amino, or di(substituted C 3-6 alkenyl)amino; and
R b is HO—C 1-6 alkyl-C 2-6 alkenyl, R 7 —O—C 1-6 alkyl-C 2-6 alkenyl, R 7 NH—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C 1-6 alkyl-C 2-6 alkenyl, R 7 NH'C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 6 R 7 N-C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, R 7 O—C(O)—O—C 1-6 alkyl-C 2-6 alkenyl, or R 7 —C(O)—O—C 1-6 alkyl-C 2-6 alkenyl.Join the waitlist — get patent alerts
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