US 6,486,142 B2Granted

Phosphonic acid derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B)

AssigneeMerck Frosst Canada, Inc.

InventorsYves Leblanc, Claude Dufresne, Jacques Yves Gauthier, Cheuk Kun Lau, Chun Sing Li, Patrick Roy, Michel Therien, John Scheigetz, Zhaoyin Wang

Life of this patent

Estimating the term…

Abstract

The invention encompasses the novel class of compounds represented by formula I, which are inhibitors of the PTP-1B enzyme. The invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and conditions related to diabetes.

Claims29

Dependent claims

A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are selected from the group consisting of:
C1-10alkyl(Ra)0-7, C2-10alkenyl(Ra)0-7, Aryl(Ra)0-3 and Het(Ra)0-3;
wherein, each Ra independently represents a member selected from the group consisting of. Aryl, OH, CN, halogen, CO2H, CO2C1-6alkyl, OC1-6alkyl, C1-6alkyl, OC1-10alkyleneCO2H, OAryl, C0-6alkyleneSO3H, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl, C0-6alkyleneCO2C2-6alkenyl, C0-6alkyleneC(O)C1-6alkyl, C(O)NR3′R4′, NR3′R4′, C1-6haloalkyl, OC1-6haloalkyl, S(O)yC1-6alkyl, S(O)yNR3′R4′, and Het, wherein y is 0, 1, or 2, wherein Het, Aryl, alkyl, and alkenyl in Ra are optionally substituted with 1-3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-10alkyl, OH, Het and Aryl, where said Het and Aryl are optionally substituted with 1-2 substituents independently selected from halogen, C1-3alkyl, OC1-3alkyl, CF3, and OCF3;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together so that adjacent rings share a common side when there is more than one aromatic ring;
Het represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)y wherein y is 0-2, and 0-2 carbonyl groups;
y, Z1 and Z2 each independently represents —(CR3R4)a—X—(CR3R4)b—wherein a and b are either 0 or 1, such that the sum of a and b equals 0, 1 or 2;
X represents a bond, O, S(O)y, NR3′, C(O), OC(O), C(O)O, C(O)NR3′, NR3′C(O) or —CH═CH—, where y is as previously defined;
R3 and R4 are independently H, halo, C1-3alkyl, or C1-3haloalkyl;
each R3′ is independently selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6alkyl, C(O)Aryl, C(O)Het, C(O)C1-6 haloalkyl, Aryl and Het;
each R4′ is independently selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, Aryl and Het;
and
each W1 is independently selected from the group consisting of:
H, OH, CN, halogen, OC1-6alkyl(Ra)0-3, S(O)yC1-6alkyl(Ra)0-3, with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-3, C1-6haloalkyl(Ra)0-3, CO2H, CO2C1-6alkyl(Ra)0-3, CO2C1-6haloalkyl(Ra)0-3, CO2C2-6alkenyl(Ra)0-3, C(O)C1-6alkyl(Ra)0-3, C(O)NR3′R4′, S(O)yNR3′R4′, NR3′R4′, Aryl and Het, wherein R3′ and R4′ are as defined above, and wherein Aryl and Het may be unsubstituted or are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-6alkyl, OC1-6haloalkyl, and OH;
or the two W1 groups are on adjacent positions of the aromatic ring and are taken in combination to represent a fused phenyl ring.

14 more elements

A compound having formula I, wherein R1 and R2 are each independently selected from the group consisting of

(a) (CH2)0-3phenyl, which is optionally mono, di-, or trisubstituted, wherein the substituents are selected from the group consisting of:
(1) halo,
(2) C1-6alkoxy,
(3) C1-6alkylthio,
(4) C1-6alkyl,
(5) C1-6fluoroalkyl,
(6) —CO2H,
(7) —CO2—C1-4alkyl,
(8) —CO2C1-4fluoroalkyl,
(9) heteroaryl, which is optionally mono, di-, or trisubstituted, wherein the substituents are independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-C6fluoroalkyl, C1-6alkyl, —CO2H, —CO2C1-4alkyl, —CO2C1-4fluoroalkyl, phenyl, and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this claim, and
(10) phenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-6alkyl, C1-6fluoroalkyl, —CO2H, —CO2C1-4alkyl, —CO2C1-4fluoroalkyl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this claim, and
(b) heteroaryl, which is optionally mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of:
(1) halo,
(2) C1-6alkoxy,
(3) C1-6alkylthio,
(4) C1-6fluoroalkyl,
(5) C1-6alkyl,
(6) —CO2H,
(7) —CO2—C1-4alkyl,
(8) —CO2C1-4fluoroalkyl,
(9) phenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-6alkyl, C1-6fluoroalkyl, CO2H, —CO2C1-4alkyl, —CO2C1-4fluoroalkyl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this claim, and
(10) heteroaryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C1-6alkoxy, C1-6alkylthio, C1-6alkyl, C1-6fluoroalkyl, phenyl and heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1-2 groups independently selected from the groups listed in (a)(1)-(a)(8) of this claim,
wherein each W1 is independently selected from the group consisting of:
halogen, C1-6alkyl, and C1-6fluoroalkyl;
Y is —CH2—;
and
Z1, and Z2 are independently selected from the group consisting of CH2, CH2CH2, C(O), C(O)CH2, CH2C(O)—, —OC(O)—, C(O)O, and a direct bond.

24 more elements

A compound as named below, or a pharmaceutically acceptable salt or prodrug thereof:

Example 1:
[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonic acid;
Example 2:
Difluoro(4-(3-oxo-2,3-diphenylpropyl)phenyl]methylphosphonic acid;
Example 3:
4-[2-(Benzyloxy)-1-(methoxycarbonyl)-2-oxoethyl]phenyl(difluoro) methylphosphonic acid;
Example 4:
2-Bromo-4-[2-phenyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl) ethyl] phenyl (difluoro)methylphosphonic acid;
Example 5:
2-Bromo-4-[2-phenyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)ethyl]phenyl (difluoro)methylphosphonic acid;
Example 6:
[4-(2-Benzotriazol-1-yl-2-m-tolylethyl)-phenyl]difluoromethylphosphonic acid;
Example 7:
{4-[2-Benzotriazol-1-yl-2-(4-fluorophenyl)-ethyl]-2-bromophenyl} difluoromethyl phosphonic acid;
Example 8:
{4-[2-Benzotriazol-1-yl-2-(4-trifluoromethylphenyl)-ethyl] phenyl} difluoromethylphosphonic acid disodium salt;
Example 9:
(4-2-(1H-1,2,3-Benzotriazol-1-yl)-2-[4-(methyloxycarbonyl)phenyl] ethylphenyl)(difluoro)methylphosphonic acid;
Example 10:
{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-(4-fluorophenyl)ethyl]phenyl} (difluoro)methylphosphonic acid;
Example 11:
{4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro) methylphosphonic acid;
Example 12:
{[(2,2-dimethylpropanoyl)oxy]methyl} hydrogen [2-bromo-4-(3-oxo -2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 13:
Bis{[(2,2-dimethylpropanoyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl) phenyl](difluoro)methylphosphonate;
Example 14:
1-{[[[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl)(difluoro)methyl] (hydroxy)phosphoryl]oxy}-2-methylpropyl propionate;
Example 15:
[1-(isobutyryloxy)ethyl] hydrogen[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl] (difluoro)methylphosphonate;
Example 16:
Bis[(isobutyryloxy)methyl] [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl] (difluoro)methylphosphonate;
Example 17:
[(isobutyryloxy)methyl] hydrogen [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl] (difluoro)methylphosphonate;
Example 18:
Bis{[(isopropoxycarbonyl)oxy]methyl}[2-bromo-4-(3-oxo-2,3-diphenylpropyl) phenyl](difluoro)methylphosphonate;
Example 19:
[(isopropoxycarbonyl)oxy]methyl hydrogen [2-bromo-4-(3-oxo-2,3-diphenyl)phenyl] (difluoro) methylphosphate;
Example 20:
Dibenzyl[2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro)methylphosphonate;
Example 21:
Benzyl hydrogen [2-bromo-4-(3-oxo-2,3-diphenylpropyl)phenyl](difluoro) methylphosphonate;
Example 22:
[2-bromo-4-(3-oxo-2-phenylbutyl)phenyl](difluoro)methylphosphonic acid;
Example 23:
{2-bromo-4-[3-oxo-2-phenyl-3-(1,3-thiazol-2-yl)propyl]phenyl}(difluoro) methylphosphonic acid;
and
Example 24:
{2-bromo-4-[2-(4-methoxy-1,3-thiazol-2-yl)-3-oxo-3-phenylpropyl)phenyl}(difluoro) methylphosphonic acid.

46 more elements

A compound having formula Ia, or a pharmaceutically acceptable salt thereof,

wherein one group —OG is optionally—OH, and wherein one or both groups —OG are groups that are converted to —OH under physiological conditions during or after administration to a mammalian patient, thereby yielding a phosphonic acid group, or a salt thereof,
R1 and R2 are each independently selected from Aryl(Ra)0-3 and Het(Ra)0-3;
wherein, each Ra independently represents a member selected from the group consisting of:
Aryl, OH, CN, halogen, CO2H, CO2C1-6alkyl, OC1-6alkyl, C1-6alkyl, OC1-10alkyleneCO2H, OAryl, C0-6alkyleneSO3H, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl, C0-6alkyleneCO2C2-6alkenyl, C0-6alkyleneC(O)C1-6alkyl, C(O)NR3′R4′, NR3′R4′, C1-6haloalkyl, OC1-6haloalkyl, S(O)yC1-6alkyl, S(O)yNR3′R4′, and Het, wherein y is 0, 1, or 2, wherein Het, Aryl, alkyl, and alkenyl in Ra are optionally substituted with 1-3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-10alkyl, OH, Het and Aryl, where said Het and Aryl are optionally substituted with 1-2 substituents independently selected from halogen, C1-3alkyl, OC1-3alkyl, CF3, and OCF3;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together so that adjacent rings share a common side when there is more than one aromatic ring;
Het represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)y wherein y is 0-2, and 0-2 carbonyl groups;
y, Z1 and Z2 each independently represents —(CR3R4)a—X—(CR3R4)b—wherein a and b are either 0 or 1, such that the sum of a and b equals 0, 1 or 2;
X represents a bond, O, S(O)y, NR3′, C(O), OC(O), C(O)O, C(O)NR3′, NR3′C(O) or —CH═CH—, where y is as previously defined;
R3 and R4 are independently H, halo, C1-3alkyl, or C1-3haloalkyl;
each R3′ is independently selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6alkyl, C(O)Aryl, C(O)Het, C(O)C1-6 haloalkyl, Aryl and Het;
each R4′ is independently selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, Aryl and Het;
and
each W1 is independently selected from the group consisting of:
H, OH, CN, halogen, OC1-6alkyl(Ra)0-3, S(O)yC1-6alkyl(Ra)0-3, with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-3, C1-6haloalkyl(Ra)0-3, CO2H, CO2C1-6alkyl(R0-2, a)0-3, CO2C1-6haloalkyl(Ra)0-3, CO2C2-6alkenyl(Ra)0-3, C(O)C1-6alkyl(Ra)0-3, C(O)NR3′R4′, S(O)yNR3′R4′, NR3′R4′, Aryl and Het, wherein R3′ and R4′ are as defined above, and wherein Aryl and Het may be unsubstituted or are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-6alkyl, OC1-6haloalkyl, and OH;
or the two W1 groups are on adjacent positions of the aromatic ring and are taken in combination to represent a fused phenyl ring.

14 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/745,211Filed 21 Dec 2000 · us provisional application
Priority: 22 Dec 1999
Published: US 2002/0058644 A116 May 2002
Granted: 26 Nov 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07F 9/6539
Having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms: five-membered rings
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics

Family

Application60/171,520Us provisional application · filed 22 Dec 1999
US 2002/0058644 A1Pre-grant publication · published 16 May 2002
US 6,486,142 B2This patent

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

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Abstract

A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are selected from the group consisting of:
C1-10alkyl(Ra)0-7, C2-10alkenyl(Ra)0-7, Aryl(Ra)0-3 and Het(Ra)0-3;
wherein, each Ra independently represents a member selected from the group consisting of. Aryl, OH, CN, halogen, CO2H, CO2C1-6alkyl, OC1-6alkyl, C1-6alkyl, OC1-10alkyleneCO2H, OAryl, C0-6alkyleneSO3H, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl, C0-6alkyleneCO2C2-6alkenyl, C0-6alkyleneC(O)C1-6alkyl, C(O)NR3′R4′, NR3′R4′, C1-6haloalkyl, OC1-6haloalkyl, S(O)yC1-6alkyl, S(O)yNR3′R4′, and Het, wherein y is 0, 1, or 2, wherein Het, Aryl, alkyl, and alkenyl in Ra are optionally substituted with 1-3 substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-10alkyl, OH, Het and Aryl, where said Het and Aryl are optionally substituted with 1-2 substituents independently selected from halogen, C1-3alkyl, OC1-3alkyl, CF3, and OCF3;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together so that adjacent rings share a common side when there is more than one aromatic ring;
Het represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)y wherein y is 0-2, and 0-2 carbonyl groups;
y, Z1 and Z2 each independently represents —(CR3R4)a—X—(CR3R4)b—wherein a and b are either 0 or 1, such that the sum of a and b equals 0, 1 or 2;
X represents a bond, O, S(O)y, NR3′, C(O), OC(O), C(O)O, C(O)NR3′, NR3′C(O) or —CH═CH—, where y is as previously defined;
R3 and R4 are independently H, halo, C1-3alkyl, or C1-3haloalkyl;
each R3′ is independently selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6alkyl, C(O)Aryl, C(O)Het, C(O)C1-6 haloalkyl, Aryl and Het;
each R4′ is independently selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, Aryl and Het;
and
each W1 is independently selected from the group consisting of:
H, OH, CN, halogen, OC1-6alkyl(Ra)0-3, S(O)yC1-6alkyl(Ra)0-3, with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-3, C1-6haloalkyl(Ra)0-3, CO2H, CO2C1-6alkyl(Ra)0-3, CO2C1-6haloalkyl(Ra)0-3, CO2C2-6alkenyl(Ra)0-3, C(O)C1-6alkyl(Ra)0-3, C(O)NR3′R4′, S(O)yNR3′R4′, NR3′R4′, Aryl and Het, wherein R3′ and R4′ are as defined above, and wherein Aryl and Het may be unsubstituted or are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, CO2H, CO2C1-6alkyl, OC1-6alkyl, OC1-6haloalkyl, and OH;
or the two W1 groups are on adjacent positions of the aromatic ring and are taken in combination to represent a fused phenyl ring.

14 more elements

Facts

Application

09/745,211Filed 21 Dec 2000 · us provisional application

Priority

22 Dec 1999

Published

US 2002/0058644 A116 May 2002

Granted

26 Nov 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07F 9/6539
Having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms: five-membered rings
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics