US 7,022,730 B2Granted

Bis-heteroaryl alkanes as therapeutic agents

AssigneeTransTech Pharma, Inc.

InventorsAdnan M. M. Mjalli, Kathy G. J. Shahbaz

Life of this patent

Estimating the term…

Abstract

This invention provides compounds which are useful as inhibitors of protein tyrosine phosphatases (PTPases). As inhibitors of PTPases the compounds of the invention are useful for the management, treatment, control and adjunct treatment of diseases in mammals mediated by PTPase activity. Such diseases include type I diabetes, type II diabetes, immune dysfunction, AIDS, autoimmunity, glucose intolerance, obesity, cancer, psoriasis, allergic diseases, infectious diseases, inflammatory diseases, diseases involving the modulated synthesis of growth hormone or the modulated synthesis of growth factors or cytokines which affect the production of growth hormone, or Alzheimer's disease.

Claims16

Dependent claims

A compound of Formula (I):

wherein
R1 and R2 are independently selected from the group consisting of
R3 is
(a) hydrogen;
(b) alkyl;
(c) alkenyl;
or
(d) alkynyl;
R4 in combination with R5 is:
5-carboxy -2-furyl;
5-hydroxymethylfuran-2-yl;
or 5-methoxycarbonylmethoxymethyl-2-furyl;
R6, R6′, R7, R7′, R8, and R8′ are independently selected from the group consisting of
(a) hydrogen;
(b) aryl;
(c) heteroaryl;
(d) heterocyclyl;
(e) cycloalkyl;
(f) halogen;
and
(g) -alkylene-Y-aryl;
-alkenylene-Y-aryl;
-alkynylene-Y-aryl;
-alkylene-Y-heteroaryl;
-alkenylene-Y-heteroaryl;
-alkynlene-Y-heteroaryl;
-alkylene-Y-cycloalkyl -alkenylene-Y-cycloalkyl;
-alkynlene-Y-cycloalkyl;
-alkylene-Y-heterocyclyl;
-alkenylene-Y-heterocyclyl;
-alkynlene-Y-heterocyclyl;
—Y-alkyl;
—Y-aryl;
—Y-alkylene-aryl;
—Y-alkylene-NR11R12;
—Y—O—Si-(alkyl)3;
and —Y—O—Si-(alkylene-aryl)3;
wherein
Y is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O2)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHS(O2)—, —S(O2)N(H)—, —C(O)—O—, —NHS(O2)NH—, or —O—CO—;
and
R11 and R12 are independently selected from the group consisting of:
hydrogen, aryl, alkyl, and alkylene-aryl;
or
R11 and R12 are taken together to form a ring having the formula —(CH2)q-Q-(CH2)r— bonded to the nitrogen atom to which R11 and R12 are attached, wherein q and r are, independently, 1, 2, 3, or 4;
Q is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —(O)CO—, —NHSO2NH—, —OC(O)—, —N(R13)—, —N(C(O)R13)—, —N(C(O)NHR13)—, —N(SO2NHR13)—, —N(SO2R13)—, or —N(C(O)OR13)—;
or
R11 and R12 are taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;
R9, R10, and R13 are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl;
A1 and A2 are N—R14, where R14 is
(a) alkyl;
or
(b) -alkylene-aryl
R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, and halogen;
Ar1 and Ar2 are phenyl;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

52 more elements

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the Formula:

wherein
R1 and R2 are independently selected from the group consisting of
R3 is
(a) hydrogen;
(b) alkyl;
(c) alkenyl;
or
(d) alkynyl;
R4 is heteroarylene;
wherein
R4 is optionally substituted with a substituent of the formula
wherein
L1 is a direct bond, alkylene, —O-alkylene-, alkylene-O—, —NH—C(O)—, —C(O)—NH—or —NH—CO—NH—;
L2 is alkyline, alkenyline, heteroaryline, aryline, or heterocyclyline;
L3 is —O—, —C(O)—N(R19)—, —C(O)—O—, —C(O)—, or —N(R19)—CO—N(R20)—;
L4 is H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, alkylene-aryl;
L5 is hydrogen, alkyl, alkenyl, alkynyl, -alkylene-aryl, -alkylene-heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH2, -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR9, -alkylene-C(O)—NR9R10, -alkylene-NR9R10, -alkylene-N(R9)—C(O)—R10, -alkylene-N(R9)—S(O2)—R10;
or
may be taken together to constitute a direct bond;
R5 is
(a) hydrogen;
(b) alkyl;
(c) alkenyl;
(d) alkynyl;
(e) aryl;
(f) heteroaryl;
(g) cycloalkyl;
(h) heterocyclyl;
(i) alkylene-OH;
(j) alkylene-COOH;
(k) alkylene-NH2;
(l) COOH;
(m) CONH2;
or
(n) NH2;
R6, R6′, R7, R7′, R8, and R8′ are independently selected from the group consisting of
(a) hydrogen;
(b) aryl;
(c) heteroaryl;
(d) heterocyclyl;
(e) cycloalkyl;
(f) halogen;
and
(g) -alkylene-Y-aryl;
-alkenylene-Y-aryl;
-alkynylene-Y-aryl;
-alkylene-Y-heteroaryl;
-alkenylene-Y-heteroaryl;
-alkynlene-Y-heteroaryl;
-alkylene-Y-cycloalkyl-alkenylene-Y-cycloalkyl;
-alkynlene-Y-cycloalkyl;
-alkylene-Y-heterocyclyl;
-alkenylene-Y-heterocyclyl;
-alkynlene-Y-heterocyclyl;
—Y-alkyl;
—Y-aryl;
—Y-alkylene-aryl;
—Y-alkylene-NR11R12;
—Y—O—Si-(alkyl)3;
and —Y—O—Si-(alkylene-aryl)3;
wherein
Y is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O2)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHS(O2)—, —S(O2)N(H)—, —C(O)—O—, —NHS(O2)NH—, or —O—CO—;
and
R1 and R12 are independently selected from the group consisting of:
hydrogen, aryl, alkyl, and alkylene-aryl;
or
R11 and R12 are taken together to form a ring having the formula —(OH2)q-Q-(CH2)r— bonded to the nitrogen atom to which R11 and R12 are attached, wherein q and r are, independently, 1, 2, 3, or 4;
Q is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —(O)CO—, —NHSO2NH—, —OC(O)—, —N(R13)—, —N(C(O)R13)—, —N(C(O)NHR13)—, —N(SO2NHR13)—, —N(SO2R13)—, or —N(C(O)OR13)—;
or
R11 and R12 are taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;
R9, R10, R13, R19, and R20 are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl;
A1 and A2 are N—R14, where R14 is
(a) alkyl;
or
(b) -alkylene-aryl;
R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, and halogen;
Ar1 and Ar2 are phenyl;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

75 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/273,795Filed 18 Oct 2002 · us provisional application
Priority: 19 Oct 2001
Published: US 2003/0130335 A110 Jul 2003
Granted: 4 Apr 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/348,187Us provisional application · filed 19 Oct 2001
US 2003/0130335 A1Pre-grant publication · published 10 Jul 2003
US 7,022,730 B2This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of Formula (I):

wherein
R1 and R2 are independently selected from the group consisting of
R3 is
(a) hydrogen;
(b) alkyl;
(c) alkenyl;
or
(d) alkynyl;
R4 in combination with R5 is:
5-carboxy -2-furyl;
5-hydroxymethylfuran-2-yl;
or 5-methoxycarbonylmethoxymethyl-2-furyl;
R6, R6′, R7, R7′, R8, and R8′ are independently selected from the group consisting of
(a) hydrogen;
(b) aryl;
(c) heteroaryl;
(d) heterocyclyl;
(e) cycloalkyl;
(f) halogen;
and
(g) -alkylene-Y-aryl;
-alkenylene-Y-aryl;
-alkynylene-Y-aryl;
-alkylene-Y-heteroaryl;
-alkenylene-Y-heteroaryl;
-alkynlene-Y-heteroaryl;
-alkylene-Y-cycloalkyl -alkenylene-Y-cycloalkyl;
-alkynlene-Y-cycloalkyl;
-alkylene-Y-heterocyclyl;
-alkenylene-Y-heterocyclyl;
-alkynlene-Y-heterocyclyl;
—Y-alkyl;
—Y-aryl;
—Y-alkylene-aryl;
—Y-alkylene-NR11R12;
—Y—O—Si-(alkyl)3;
and —Y—O—Si-(alkylene-aryl)3;
wherein
Y is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O2)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHS(O2)—, —S(O2)N(H)—, —C(O)—O—, —NHS(O2)NH—, or —O—CO—;
and
R11 and R12 are independently selected from the group consisting of:
hydrogen, aryl, alkyl, and alkylene-aryl;
or
R11 and R12 are taken together to form a ring having the formula —(CH2)q-Q-(CH2)r— bonded to the nitrogen atom to which R11 and R12 are attached, wherein q and r are, independently, 1, 2, 3, or 4;
Q is —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO2—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO2—, —SO2N(H)—, —(O)CO—, —NHSO2NH—, —OC(O)—, —N(R13)—, —N(C(O)R13)—, —N(C(O)NHR13)—, —N(SO2NHR13)—, —N(SO2R13)—, or —N(C(O)OR13)—;
or
R11 and R12 are taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;
R9, R10, and R13 are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl;
A1 and A2 are N—R14, where R14 is
(a) alkyl;
or
(b) -alkylene-aryl
R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, and halogen;
Ar1 and Ar2 are phenyl;
or a pharmaceutically acceptable salt, solvate or prodrug thereof.

52 more elements

Facts

Application

10/273,795Filed 18 Oct 2002 · us provisional application

Priority

19 Oct 2001

Published

US 2003/0130335 A110 Jul 2003

Granted

4 Apr 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics