US 2009/0156560 A1Published application

Tissue non-specific alkaline phosphatase inhibitors and uses thereof for treating vascular calcification

AssigneeSanford-Burnham Medical Research Institute

InventorsJOSE LUIS MILLAN, EDUARD SERGIENKO

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Abstract

Disclosed herein are compounds that are tissue-nonspecific alkaline phosphatase inhibitors. The disclosed compounds are used to treat, prevent, or abate vascular calcification, arterial calcification and other cardiovascular diseases.

Claims15

Dependent claims

A method of treating or preventing vascular calcifcication in a subject, comprising administering to the subject one or more compounds having the formula:

wherein R is chosen from:
i) hydrogen;
ii) C1-C12 substituted or unsubstituted linear, branched, or cyclic alkyl;
iii) C2-C12 substituted or unsubstituted linear or branched alkenyl;
iv) C2-C12 substituted or unsubstituted linear or branched alkynyl;
v) substituted or unsubstituted aryl;
vi) substituted or unsubstituted heteroaryl;
vii) substituted or unsubstituted heterocyclic;
viii) —NHC(O)CH3;
ix) —C(O)OCH3;
or
x) —C(O)OH;
R1 is chosen from:
i) hydrogen;
ii) C1-C12 substituted or unsubstituted linear, branched, or cyclic alkyl;
iii) C2-C12 substituted or unsubstituted linear or branched alkenyl;
iv) C2-C12 substituted or unsubstituted linear or branched alkynyl;
v) substituted or unsubstituted aryl;
vi) substituted or unsubstituted heteroaryl;
vii) substituted or unsubstituted heterocyclic;
viii) —NHC(O)CH3;
ix) —C(O)OCH3;
x) —C(O)OH;
xi) —OH;
or
xii) —NH2;
R2 is:
i) hydrogen;
ii) halogen;
or
iii) R and R2 or R1 and R2 can be taken together to form ring A comprising one or more 5-member or 6-member substituted or unsubstituted cycloalkyl fused rings, substituted or unsubstituted aryl fused rings, 5-member or 6-member heteroaryl fused rings having one or more atoms chosen from nitrogen, oxygen, and sulfur, or substituted or unsubstituted 5-member, 6-member, or 7-member heterocyclic fused rings having one or more atoms chosen from nitrogen, oxygen, and sulfur;
L is a linking unit having the formula:
—[R5]z[C(R3aR3b)]x[R5]z[C(R4aR4b)]y[R5]z—
each R3a, R3b, R4a, and R4b are each independently chosen from:
i) hydrogen;
ii) C1-C4 linear or branched alkyl;
iii) phenyl;
iv) hydroxyl;
or
v) cyano;
vi) or two adjacent R3a units or two adjacent R3b units can be taken together to form a double bond;
R5 is chosen from:
i) —NR6—;
ii) —NR6C(O)—;
iii) —C(O)NR6—;
iv) —C(O)—;
v) —OC(O)—;
vi) —C(O)O—;
vii) —NHC(O)NH—;
viii) —NH(═NR6)NH—;
ix) —O—;
x) —S—;
or
xi) —CR6═CR6—;
R6 is chosen from hydrogen or methyl;
the index x is from 0 to 6;
the index y from 0 to 6;
each index z is 0 or 1;
L1 is a linking unit having the formula:
—[R9]r[C(R7aR7b)]p[R9]r[C(R8aR8b)]q[R9]r—
each R7a, R7b, R8a, and R8b are each independently chosen from:
i) hydrogen;
ii) C1-C4 linear or branched alkyl;
iii) phenyl;
iv) hydroxyl;
or
v) cyano;
each R9 is chosen from:
i) —NR10—;
ii) —NR10C(O)—;
iii) —C(O)NR10—;
iv) —C(O)—;
v) —OC(O)—;
vi) —C(O)O—;
vii) —NHC(O)NH—;
viii) —C(O)NHC(O)NH—;
ix) —NH(═NR10)NH—;
x) —O—;
xi) —S—;
or
xii) —CR10═CR10—;
each R10 is chosen from hydrogen or methyl;
the index p is from 0 to 6;
the index q from 0 to 6;
and
each index r is 0 or 1.

83 more elements

A method of treating or preventing vascular calcifcication in a subject, comprising administering one or more compounds chosen from:

3-(2-chlorophenyl)-1H-pyrazole-5-carboxylic acid;
methyl 3-(1H-indol-3-yl)-1H-pyrazole-5-carboxylate;
3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid;
methyl 3-phenyl-1H-pyrazole-5-carboxylate;
3-(napthalen-1-yl)-1H-pyrazol-5-ol;
3-(4-bromophenyl)-4-chloro-1-H-pyrazol-5-amine;
3-(1-methyl-1H-pyrrol-2-yl)-1H-pyrazole-5-carboxylate;
methyl 3-(4-bromophenyl)-1H-pyrazole-5-carboxylate;
3-butyl-6,6-dimethyl-6,7-dihydro-2H-indazol-4(5H)-one;
6,6-dimethyl-3-(thiophen-2-yl)-6,7-dihydro-2H-indazol-4(5H)-one;
3-benzyl-6,6-dimethyl-6,7-dihydro-2H-indazol-4(5H)-one;
4-methyl-3-phenylpyrano[2,3-c]pyrazol-6-ol;
3-(4-methoxyphenyl)-4-methylpyrano[2,3-c]pyrazol-6-ol;
6-amino-4-(4-hydroxy-3,5-dimethoxyphenyl)-3-(methoxymethyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile;
3-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole;
2-(5-methylisoxazol-3-ylamino)-2-oxoethyl 2H-indazole-3-carboxylate;
7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid;
2,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid;
3-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole;
N2-phenyl-6-[(5-phenyl-1H-1,2,4-triazol-3-ylthio)methyl]-1,3,5-triazine-2,4-diamine;
2-((5-(2-methoxyphenyl)-4H-1,2,4-triazol-3-ylthio)methyl)pyridine;
ethyl 4-cyano-5-{2-[5-(2-methoxyphenyl)-4H-1,2,4-triazol-3-ylthio]acetamide}-3-methylthiophene-2-carboxylate;
2-[5-(2-bromophenyl)-4H-1,2,4-triazol-3-ylthio]-N-(furan-2-ylmethylcarbamoyl)acetamide;
N-(furan-2-ylmethylcarbamoyl)-2-(5-phenyl-4H-1,2,4-triazol-3-ylthio)acetamide;
N2-phenyl-6-[(5-phenyl-1H-1,2,4-triazol-3-ylthio)methyl]-1,3,5-triazine-2,4-diamine;
2-((5-(2-methoxyphenyl)-4H-1,2,4-triazol-3-ylthio)methyl)pyridine;
6-(1-methyl-1H-imidazol-2-ylthio)-N2,N4-diphenyl-1,3,5-triazine-2,4-diamine;
2-(5-benzyl-4H-1,2,4-triazol-3-yl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione;
N-(5-(propylthio)-4H-1,2,4-triazol-3-yl)acetamide;
(Z)-4-(5-(2-bromophenyl)-4H-1,2,4-triazol-3-ylthio)-3-hydroxy-2-(1-iminoethyl)but-2-enenitrile;
N-(5-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)acetamide;
3,3′-(2,5-dimethoxy-1,4-phenylene)-bis(methylene)bis(sulfanediyl)bis(4H-1,2,4-triazole);
3,4,5-trimethoxy-N-(3-phenyl-1H-pyrazol-5-yl)benzamide;
3-(2-chlorophenyl)-5-phenyl-1H-1,2,4-triazole;
5-(furan-2-yl)-2-(4-methoxyphenyl)-5H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7(6H)-one;
5-(allylthio)-3-(4-methoxyphenyl)-1H-1,2,4-triazole;
2-(4H-imidazo[4,5-b]pyridin-2-ylthio)-1-(2,5-dimethoxyphenyl)ethanone;
5-chloro-1-phenyl-1H-benzo[d]imidazol-2-ol;
3-(2-chlorophenyl)-7-methyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine;
2-(4H-imidazo[4,5-b]pyridin-2-ylthio)-1-(4-fluorophenyl)ethanone;
3-((2,6-dimethylphenoxy)methyl)-7-methyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine;
7-(3,4-dimethylphenyl)-3-methyl-7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine;
5-(2-(3,4-dihydroxyphenyl)-2-oxoethylthio)-2-isopropylimidazo[1,2-c]quinazolin-3(2H)-one;
(Z)-5-((3-methylthiophen-2-yl)methylene)thiazolo[3,2-b][1,2,4]triazol-6(5H)-one;
7-(3,4-dimethylphenyl)-2-methyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine;
7-methyl-2-phenethyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine;
2-dimethoxy-N-(quinolin-3-yl)benzene-sulfonamide;
2-methoxy-5-methyl-N-(pyridine-3-yl)benzenesulfonamide;
2-ethoxy-5-methyl-N-(pyridine-3-yl)benzenesulfonamide;
N-[3-1H-1,2,4,-triazol-3-ylthio)-4-hydroxyphenyl)-2,5-dimethyoxybenzenesulfonamide;
2,2′-[2,2′-oxybis(ethane-2,1-diyl)bis(oxy)]bis(2,1-phenylene)diphosphonic acid;
2,2′-(pentane-1,5-diylbis(oxy))bis(2,1-phenylene)diphosphonic acid;
4-{2-[2-(3,4-dihydroxyphenyl)-2-oxoethylthio]-4-oxoquinazolin-3(4H)-yl}-N-[(tetrahydrofuran-2-yl)methyl]butanamide;
and
(E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)acrylamide.

52 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/117,570Filed 8 May 2008
Priority: 8 May 2007
Published: 18 Jun 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/416
1,2-Diazoles: condensed with carbocyclic ring systems, e.g. indazole
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles

Family

Application60/928,400Us provisional application · filed 8 May 2007
US 8,119,693 B2Related patent
US 2009/0156560 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method of treating or preventing vascular calcifcication in a subject, comprising administering to the subject one or more compounds having the formula:

wherein R is chosen from:
i) hydrogen;
ii) C1-C12 substituted or unsubstituted linear, branched, or cyclic alkyl;
iii) C2-C12 substituted or unsubstituted linear or branched alkenyl;
iv) C2-C12 substituted or unsubstituted linear or branched alkynyl;
v) substituted or unsubstituted aryl;
vi) substituted or unsubstituted heteroaryl;
vii) substituted or unsubstituted heterocyclic;
viii) —NHC(O)CH3;
ix) —C(O)OCH3;
or
x) —C(O)OH;
R1 is chosen from:
i) hydrogen;
ii) C1-C12 substituted or unsubstituted linear, branched, or cyclic alkyl;
iii) C2-C12 substituted or unsubstituted linear or branched alkenyl;
iv) C2-C12 substituted or unsubstituted linear or branched alkynyl;
v) substituted or unsubstituted aryl;
vi) substituted or unsubstituted heteroaryl;
vii) substituted or unsubstituted heterocyclic;
viii) —NHC(O)CH3;
ix) —C(O)OCH3;
x) —C(O)OH;
xi) —OH;
or
xii) —NH2;
R2 is:
i) hydrogen;
ii) halogen;
or
iii) R and R2 or R1 and R2 can be taken together to form ring A comprising one or more 5-member or 6-member substituted or unsubstituted cycloalkyl fused rings, substituted or unsubstituted aryl fused rings, 5-member or 6-member heteroaryl fused rings having one or more atoms chosen from nitrogen, oxygen, and sulfur, or substituted or unsubstituted 5-member, 6-member, or 7-member heterocyclic fused rings having one or more atoms chosen from nitrogen, oxygen, and sulfur;
L is a linking unit having the formula:
—[R5]z[C(R3aR3b)]x[R5]z[C(R4aR4b)]y[R5]z—
each R3a, R3b, R4a, and R4b are each independently chosen from:
i) hydrogen;
ii) C1-C4 linear or branched alkyl;
iii) phenyl;
iv) hydroxyl;
or
v) cyano;
vi) or two adjacent R3a units or two adjacent R3b units can be taken together to form a double bond;
R5 is chosen from:
i) —NR6—;
ii) —NR6C(O)—;
iii) —C(O)NR6—;
iv) —C(O)—;
v) —OC(O)—;
vi) —C(O)O—;
vii) —NHC(O)NH—;
viii) —NH(═NR6)NH—;
ix) —O—;
x) —S—;
or
xi) —CR6═CR6—;
R6 is chosen from hydrogen or methyl;
the index x is from 0 to 6;
the index y from 0 to 6;
each index z is 0 or 1;
L1 is a linking unit having the formula:
—[R9]r[C(R7aR7b)]p[R9]r[C(R8aR8b)]q[R9]r—
each R7a, R7b, R8a, and R8b are each independently chosen from:
i) hydrogen;
ii) C1-C4 linear or branched alkyl;
iii) phenyl;
iv) hydroxyl;
or
v) cyano;
each R9 is chosen from:
i) —NR10—;
ii) —NR10C(O)—;
iii) —C(O)NR10—;
iv) —C(O)—;
v) —OC(O)—;
vi) —C(O)O—;
vii) —NHC(O)NH—;
viii) —C(O)NHC(O)NH—;
ix) —NH(═NR10)NH—;
x) —O—;
xi) —S—;
or
xii) —CR10═CR10—;
each R10 is chosen from hydrogen or methyl;
the index p is from 0 to 6;
the index q from 0 to 6;
and
each index r is 0 or 1.

83 more elements

Facts

Application

12/117,570Filed 8 May 2008

Priority

8 May 2007

Published

18 Jun 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/416
1,2-Diazoles: condensed with carbocyclic ring systems, e.g. indazole
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles