US 6,486,141 B2Granted

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

AssigneeMerck Frosst Canada, Inc.

InventorsCheuk Kun Lau, Christopher Bayly, Jacques Yves Gauthier, Yves Leblanc, Chun Sing Li, Patrick Roy, Michel Therien, Zhaoyin Wang

Life of this patent

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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 diabetes-related conditions.

Claims28

Dependent claims

A compound represented by formula I:

or a pharmaceutically acceptable salt or prodrug 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, halogen, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl, OC1-10alkyl, C1-6alkyl, C1-6haloalkyl, OC1-10alkyleneCO2H, S(O)yC1-6alkyl, S(O)yNR3′R4′, and Het, wherein y is 0, 1, or 2;
Ar represents Aryl or Het, wherein said Aryl or Het is substituted with 1-5 substituents Rb, wherein optionally 2 Rb groups can join together to form a 5-7 membered ring fused to Ar, where the fused portion of the 5-7 membered ring may be saturated or may include 1-2 double bonds and may include 1-4 heteroatoms selected from N, S, O, and C(═O) in the fused portion of the ring, said ring optionally being substituted with 1-3 groups independently selected from Ra;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together 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;
Each y is 0, 1 or 2;
Each Rb is independently selected from the group consisting of:
OH, CN, halogen, C0-6alkyleneOC1-6alky](Ra)0-7, C0-6alkyleneOAryl(Ra)0-7, Het, C0-6alkyleneS(O)yC1-6alkyl(Ra)0-7, with y equal to 0-2, C0-6alkyleneS(O)3H, C1-10alkyl(Ra)0-7, N3, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl(Ra)0-7, C0-6alkyleneCO2C2-6 alkenyl(Ra)0-7, C0-6alkyleneC(O)C1-6alkyl(Ra)0-7, C(O)NR3′R4′, s(O)yNR3′R4′, NR3′R4′, PO(OR5)2, and CF2PO(OR5)2, wherein R3′ and R4′ are as defined above;
Each R5 is H;
Y1, Y2, Z1 and Z2 each independently represents —(CR3R4)a—X—(CR3R4)b— wherein a and b are each zero or an integer 1 or 2 such that the sum of a and b equals 0, 1, 2 or 3,
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, halogen, C1-10alkyl or C1-10haloalkyl;
R3′ is selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6 alkyl, C(O)Aryl, C(O)Het, C(O)C1-6 haloalkyl, Aryl and Het;
R4′ is selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, Aryl and Het;
Each W1 is independently selected from the group consisting of:
H, OH, CN, halogen, OC1-6alkyl(Ra)0-7, OAryl(Ra)0-7, S(O)yC1-6alkyl(Ra) with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-7, N3, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl(Ra)0-7, C0-6alkyleneCO2C2-6 alkenyl(Ra)0-7, C0-6alkyleneC(O)C1-6alkyl(Ra)0-7, C(O)NR3′R4′, S(O)yNR3′R4′, NR3′R4′, Aryl and Het, wherein R3′ and R4′ are as defined above;
or alternatively two W1 groups on adjacent atoms of the aromatic ring are joined together to form a fused phenyl ring, optionally substituted with 1-3 groups Rb.

19 more elements

A compound of Formula I as described in Examples 1-27, or a pharmaceutically acceptable salt or prodrug thereof:

Example 1:
{[4-(2-Benzotriazol-1-yl-3-biphenyl-4-yl-2-phenyl-propyl)-phenyl]difluoro-methyl}-phosphonic acid
Example 2:
({4-[2-Benzotriazol-1-yl-2-phenyl-3-(2′-sulfamoyl-biphenyl-4-yl)-propyl]-phenyl}-difluoro-methyl)-phosphonic acid
Example 3:
[(4-{2-Benzotriazol-1-yl-2-phenyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-propyl}-phenyl)-difluoro-methyl]-phosphonic acid
Example 4:
(4′-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl]-2-phenyl-propyl}-biphenyl-3-yl)-phosphonic acid diethyl ester
Example 5:
(4′-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl]-2-phenyl-propyl}-biphenyl-3-yl)-phosphonic acid
Example 6:
({4-[2-Benzotriazol-1-yl-3-(4′-methylsulfanyl-biphenyl-4-yl)-2-phenyl-propyl]-phenyl}-difluoro-methyl)-phosphonic acid
Example 7:
(4-{2-(1H-1,2,3-Benzotriazol-1-yl)-3-[4′(methylsulfanyl) (1,1′-biphenyl]yl]phenylpropyl}phenyl)(difluoro)methylphosphonic acid
Example 8:
{4-[2-(1H-1,2,3-Benzotriazol-1-yl)-3-(3′phenoxy(1,1′-biphenyl]-3-yl)-2-phenylpropyl)phenyl}-(difluoro)methylphosphonic acid.
Example 9:
3-(2-(1H-1,2,3-Benzotriazol-1-yl)-3-(4-[difluoro(phosphono)methyl]phenyl}-2-phenylpropyl)(1,1′-biphenyl)]-3-ylphosphonic acid
Example 10:
{4-[2-(1H-1,2,3-Benzotriazol-1-yl)-3-[(4-(2-carboxy-5-isopropoxyphenyl)benzyl)oxy]-3-oxo-2-phenylpropyl]phenyl}(difluoro)methylphosphonic acid
Example 11:
{4-[2-(1H-1,2,3-Benzotriazol-1-yl)-3-[(4-(4-carboxy-3-isopropoxyphenyl)benzyl)oxy]-3-oxo-2-phenylpropyl]phenyl}(difluoro)methylphosphonic acid
Example 12:
{4-[2-(1H-1,2,3-Benzotriazol-1-yl)-3-[(4-(3-t-butoxycarbonyl-5-isopropoxyphenyl)benzyl)oxy]-3-oxo-2-phenylpropyl]phenyl}(difluoro) methylphosphonic acid
Example 13:
{4-[2-(1H-1,2,3-Benzotriazol-1-yl)-3-[(4-(3-carboxy-5-isopropoxyphenyl)benzyl)oxy]-3-oxo-2-phenylpropyl]phenyl}(difluoro)methylphosphonic acid
Example 14:
(4-{2-(1H-1,2,3-Benzotriazol-1-yl)-3-[2′-(tert-butoxycarbonyl)-5′-isopropoxy(1,1′-biphenyl]-4-yl]-2-phenylpropyl}phenyl)(difluoro) methylphosphonic acid
Example 15:
(4′-(2-(1H-1,2,3-Benzotriazol-1-yl)-3-{4-[difluoro(phosphono)methyl]phenyl}-2-phenylpropyl)-5-isopropoxy[1,1′-biphenyl]-2-carboxylic acid
Example 16:
(4-{2-(1H-1,2,3-benzotriazol-1-yl)-3-[4′-(tert-butoxycarbonyl)-3′-isopropoxy[1,1′-biphenyl]-4-yl]-2-phenylpropyl}phenyl) (difluoro) methylphosphonic acid
Example 17:
(4-{2-Benzotriazol-1-yl-4-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethylsulfanyl]-2-phenyl-butyl}-phenyl)-difluoro-methyl-phosphonic acid
Example 18:
[6-(4-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl]-2-phenyl-propyl}-phenyl)-2-methyl-quinolin-8-yl]-phosphonic acid
Example 19:
[6-(4-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl] -2-phenyl-propyl}-phenyl)-2-(1-methoxy-3-methyl-butyl)-quinolin-8-yl]-phosphonic acid
Example 20:
[6-(4-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl]-2-phenyl-propyl}-phenyl)-2-(1-methoxymethoxy-3-methyl-butyl)-quinolin-8-yl]-phosphonic acid diethyl ester
Example 21:
[6-(4-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl]-2-phenyl-propyl}-phenyl)-2-(1-hydroxy-3-methyl-butyl)-quinolin-8-yl]-phosphonic acid
Example 22:
[(4-{2-Benzotriazol-1-yl-3-[4-(5-methoxycarbonyl-thieno[3,2-b-pyridin-3-yl)-phenyl]-2-phenyl-propyl}-phenyl)-difluoro-methyl]-phosphonic acid
Example 23 3-(4-{2-Benzotriazol-1-yl-3-[4-(difluoro-phosphono-methyl)-phenyl]-2-phenyl-propyl}-phenyl)-thieno[3,2-b]pyridine-5-carboxylic acid trisodium salt
Example 24:
[4-(1-Benzotriazol-1-yl-2-biphenyl-3-yl-2-hydroxy-1-phenylethyl)phenyl]difluoromethylphosphonic acid
Example 25:
4′(2-(1H-1,2,3-Benzotriazol-1-yl)-3-{4-[difluoro(phosphono)methyl]phenyl}-2-phenylpropyl)(1,1′-biphenyl]-3-carboxylic acid
Example 26:
4′-{2-Benzotriazol-1-yl-3-[4-(difluorophosphonomethy)phenyl]-2-phenylpropyl}-4-methoxybiphenyl-3-yl-phosphonic acid and
Example 27:
4′-{2-Benzotriazol-1-yl-3-[4-(difluorophosphonomethy)phenyl]-2-phenylpropyl}-4-(3-methylbutoxy)biphenyl-3-yl-phosphonic acid.

50 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/745,199Filed 21 Dec 2000 · us provisional application
Priority: 22 Dec 1999
Published: US 2002/0052346 A12 May 2002
Granted: 26 Nov 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
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

Family

Application60/171,376Us provisional application · filed 22 Dec 1999
US 2002/0052346 A1Pre-grant publication · published 2 May 2002
US 6,486,141 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 or prodrug 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, halogen, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl, OC1-10alkyl, C1-6alkyl, C1-6haloalkyl, OC1-10alkyleneCO2H, S(O)yC1-6alkyl, S(O)yNR3′R4′, and Het, wherein y is 0, 1, or 2;
Ar represents Aryl or Het, wherein said Aryl or Het is substituted with 1-5 substituents Rb, wherein optionally 2 Rb groups can join together to form a 5-7 membered ring fused to Ar, where the fused portion of the 5-7 membered ring may be saturated or may include 1-2 double bonds and may include 1-4 heteroatoms selected from N, S, O, and C(═O) in the fused portion of the ring, said ring optionally being substituted with 1-3 groups independently selected from Ra;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together 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;
Each y is 0, 1 or 2;
Each Rb is independently selected from the group consisting of:
OH, CN, halogen, C0-6alkyleneOC1-6alky](Ra)0-7, C0-6alkyleneOAryl(Ra)0-7, Het, C0-6alkyleneS(O)yC1-6alkyl(Ra)0-7, with y equal to 0-2, C0-6alkyleneS(O)3H, C1-10alkyl(Ra)0-7, N3, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl(Ra)0-7, C0-6alkyleneCO2C2-6 alkenyl(Ra)0-7, C0-6alkyleneC(O)C1-6alkyl(Ra)0-7, C(O)NR3′R4′, s(O)yNR3′R4′, NR3′R4′, PO(OR5)2, and CF2PO(OR5)2, wherein R3′ and R4′ are as defined above;
Each R5 is H;
Y1, Y2, Z1 and Z2 each independently represents —(CR3R4)a—X—(CR3R4)b— wherein a and b are each zero or an integer 1 or 2 such that the sum of a and b equals 0, 1, 2 or 3,
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, halogen, C1-10alkyl or C1-10haloalkyl;
R3′ is selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, OH, C(O)C1-6 alkyl, C(O)Aryl, C(O)Het, C(O)C1-6 haloalkyl, Aryl and Het;
R4′ is selected from the group consisting of:
H, C1-6alkyl, C1-6haloalkyl, Aryl and Het;
Each W1 is independently selected from the group consisting of:
H, OH, CN, halogen, OC1-6alkyl(Ra)0-7, OAryl(Ra)0-7, S(O)yC1-6alkyl(Ra) with y equal to 0-2, S(O)3H, C1-6alkyl(Ra)0-7, N3, C0-6alkyleneCO2H, C0-6alkyleneCO2C1-6alkyl(Ra)0-7, C0-6alkyleneCO2C2-6 alkenyl(Ra)0-7, C0-6alkyleneC(O)C1-6alkyl(Ra)0-7, C(O)NR3′R4′, S(O)yNR3′R4′, NR3′R4′, Aryl and Het, wherein R3′ and R4′ are as defined above;
or alternatively two W1 groups on adjacent atoms of the aromatic ring are joined together to form a fused phenyl ring, optionally substituted with 1-3 groups Rb.

19 more elements

Facts

Application

09/745,199Filed 21 Dec 2000 · us provisional application

Priority

22 Dec 1999

Published

US 2002/0052346 A12 May 2002

Granted

26 Nov 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
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