Compositions and methods for inhibition of the JAK pathway

Patent metadata

Field	Value
Publication number	US-9248190-B2
Application number	US-201414315073-A
Country	US
Kind code	B2
Filing date	Jun 25, 2014
Priority date	Jun 8, 2005
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

Abstract

The invention encompasses compounds having formula I-V and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, may be therapeutically useful.

First claim

What is claimed is:

1. A method of inhibiting a signal transduction cascade in which JAK3 kinase plays a role, comprising contacting a cell expressing a receptor involved in such a signaling cascade with a compound having formula II, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the signal transduction cascade

wherein:
X is fluoro or methyl;
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;
ring A is phenyl;
Y is selected from the group consisting of a bond, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O), —NR 7 C(O)O—, —OC(O)NR 7 —, —NR 7 C(O)NR 7 —, oxygen and sulfur, where R 7 is independently hydrogen, alkyl or substituted alkyl;
alk is methylene, ethylene, or n-propylene;
R 1 is selected from the group consisting of cyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester, carboxyl ester oxy, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and aminocarbonylamino; or
R 1 -alk-Y— is R 10 —C(O)—S-alk-C(O)—, wherein alk is as defined herein and R 10 is alkyl or substituted alkyl; or
R 1 -alk-Y— is R 11 R 12 NS(O) 2 —, wherein R 11 and R 12 independently are alkyl or substituted alkyl;

p is 0, 1, 2 or 3;
each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, nitro, and halo;
Z 1 , Z 2 , and Z 3 are carbon;
q is 1, 2 or 3;
each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;
R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl and M + , wherein M + is a metal counterion selected from the group consisting of K + , Na + , Li + , or + N(R 6 ) 4 , wherein R 6 is hydrogen or alkyl, and the nitrogen of SO 2 NR 4 W is N − , a divalent counterion selected from the group consisting of Ca 2+ , Mg 2 +, and Ba 2+ , and the nitrogen of SO 2 NR 4 W is N − ; and
W is selected from the group consisting of C 1 -C 3 alkylene, substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene and substituted C 2 -C 3 alkenylene wherein one or more of the carbon atoms have been replaced with a moiety selected from oxygen, sulfur, S(O), S(O) 2 , C(O), or NR 8 where R 8 is selected from the group consisting of hydrogen and alkyl or is a bond participating in a —N═C< site of unsaturation.

2. A pharmaceutical formulation, comprising:
a compound having formula II, or a pharmaceutically acceptable salt thereof,

wherein:
X is fluoro or methyl;
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;
ring A is phenyl;
Y is selected from the group consisting of a bond, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O), —NR 7 C(O)O—, —OC(O)NR 7 —, —NR 7 C(O)NR 7 —, oxygen and sulfur, where R 7 is independently hydrogen, alkyl or substituted alkyl;
alk is methylene, ethylene or n-propylene;
R 1 is selected from the group consisting of cyano, acylamino, aminoacyl, aryl, substituted aryl, carboxyl, carboxyl ester, carboxyl ester oxy, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acyl, aminoacyloxy, and aminocarbonylamino; or
R 1 -alk-Y— is R 10 —C(O)—S-alk-C(O)—, wherein alk is as defined herein and R 10 is alkyl or substituted alkyl; or
R 1 -alk-Y— is R 11 R 12 NS(O) 2 —, wherein R 11 and R 12 independently are alkyl or substituted alkyl;

p is 0, 1, 2 or 3;
each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, nitro, and halo;
Z 1 , Z 2 , and Z 3 are carbon;
q is 1, 2 or 3;
each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;
R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl and M + , wherein M + is a metal counterion selected from the group consisting of K + , Na + , Li + , or + N(R 6 ) 4 , wherein R 6 is hydrogen or alkyl, and the nitrogen of SO 2 NR 4 W is N − , a divalent counterion selected from the group consisting of Ca 2+ , Mg 2 +, and Ba 2+ , and the nitrogen of SO 2 NR 4 W is N 31 ; and
W is selected from the group consisting of C 1 -C 3 alkylene, substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene and substituted C 2 -C 3 alkenylene wherein one or more of the carbon atoms have been replaced with a moiety selected from oxygen, sulfur, S(O), S(O) 2 , C(O), or NR 8 where R 8 is selected from the group consisting of hydrogen and alkyl or is a bond participating in a —N═C< site of unsaturation; and
at least one pharmaceutically acceptable excipient, diluent, preservative, or stabilizer, or mixtures thereof.

3. The method of claim 1 in which the compound is administered in combination with, or adjunctively to, a second compound that inhibits JAK3 kinase.

4. The method of claim 1 wherein the compound has a formula IIA:

5. The method of claim 4 , wherein R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and acyl.

6. The pharmaceutical formulation of claim 2 wherein the compound has a formula IIA

7. The pharmaceutical formulation of claim 6 , wherein R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and acyl.

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Li Hui
• Thota Sambaiah
• Carroll David
• Argade Ankush
• Tso Kin
• Sran Arvinder
• Clough Jeffrey
• Keim Holger
• Bhamidipati Somasekhar
• Taylor Vanessa
• Cooper Robin
• Singh Rajinder
• Wong Brian

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title