US 2012/0059055 A1Published application

N,n-disubstituted aminoalkylbiphenyl antagonists of prostaglandin d2 receptors

AssigneePanmira Pharmaceuticals, LLC

InventorsJohn Howard HUTCHINSON, Brian Andrew Stearns, Jill Melissa Scott, Yen Pham Truong, Jeffrey Roger Roppe, Nicholas Simon Stock, Jeannie M. Arruda, Thomas Jon Seiders, Bowei Wang

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Abstract

Described herein are compounds that are antagonists of PGD2 receptors. Also described are pharmaceutical compositions that include the compounds described herein, and methods of using such antagonists of PGD2 receptors, alone or in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.

Claims20

Dependent claims

A compound having the structure of Formula (I) or pharmaceutically acceptable salt thereof:

wherein,
R4 is H, halogen, —CN, —OH, C1-C4alkyl, C1-C4alkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, or C1-C4heteroalkyl;
R5 is H, halogen, —CN, —NO2, —OH, —S(═O)2R12, —NHS(═O)2R12, —C(═O)R12, —OC(═O)R12, —CO2R13, —N(R13)2—C(═O)N(R13)2, —NHC(═O)R12, —C(OH)(R13)2, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4alkoxy, C1-C4heteroalkyl, or —S—R12;
R20 is C1-C4alkyl, C3-C6cycloalkyl, —CH2—O—C1-alkyl, —CH2O—(substituted or unsubstituted phenyl), —CH(CH3)-O-(substituted or unsubstituted phenyl), —C(CH3)2—O—(substituted or unsubstituted phenyl), —CH2OCH2—(substituted or unsubstituted phenyl), —OC1-C4alkyl, —O—CH2—(substituted or unsubstituted phenyl), —O—CH(CH3)-(substituted or unsubstituted phenyl), —NR16C1-C4alkyl, —NR16—CH2—(substituted or unsubstituted phenyl), or —NR16—CH(CH3)-(substituted or unsubstituted phenyl), wherein if the phenyl of R20 is substituted, then the phenyl is substituted with 0, 1, or 2 R21 groups;
each R21 is independently selected from halogen, —OH, —OCH3, C1-C4alkyl, and —CF3;
R16 is H or C1-C4alkyl;
R11 is —CH3, —CH2CH3, —CF3, —CH2CF3, cyclopropyl, cyclobutyl, or cyclopentyl R12 is C1-C4alkyl, C1-C4heteroalkyl, or C1-C4fluoroalkyl;
each R13 is independently selected from H, C1-C4alkyl, C1-C4heteroalkyl, and C1-C4fluoroalkyl.

5 more elements

A compound selected from among:

{2′-[(Acetyl-methyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-1);
{2′-[(Acetyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-2);
(2′-{[Acetyl-(2,2-dimethyl-propyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-3);
(2′-{[Acetyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-4);
{2′-[(Acetyl-ethyl-amino)-methyl]-6-fluoro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-10);
(2′-{[Acetyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-6-fluoro-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-11);
{2′-[(Acetyl-cyclopropyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-12);
{2′-[(Ethyl-methoxycarbonyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-23);
{2′-[(Benzyloxycarbonyl-methyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-27);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-28);
{2′-[(Benzyloxycarbonyl-methyl-amino)-methyl]-6-fluoro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-29);
{2′-[(Acetyl-cyclobutyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-30);
{2′-[(Acetyl-cyclopentyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-31);
(2′-{[Ethyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-32);
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-33);
{2′-[(Benzyloxycarbonyl-cyclobutyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-34);
{2′-[(Benzyloxycarbonyl-cyclopentyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-35);
{2′-[(Benzyloxycarbonyl-cyclopropyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-36);
2-{[Acetyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-5′-carboxymethyl-2′-methoxy-biphenyl-4-carboxylic acid (Compound 1-37);
(2′-{[(3,5-Dichloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-38);
(2′-{[(2-Chloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-39);
(2′-{[(3,5-Difluoro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-40);
(2′-{[Ethyl-(4-fluoro-benzyloxycarbonyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-41);
(2′-{[(4-Chloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-42);
(2′-{[(3-Chloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-43);
[2′-({[1-(4-Chloro-phenyl)-ethoxycarbonyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-44);
(2′-{[Ethyl-(2-phenoxy-propionyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-45);
(2′-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-46);
(2′-{[Ethyl-(2-phenoxy-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-48);
(2′-{[Benzyloxycarbonyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-6-fluoro-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-49);
{2′-[(Acetyl-ethyl-amino)-methyl]-4′-bromo-6- methoxy-biphenyl-3-yl}-acetic acid (Compound 1-50);
{4′-Acetylamino-2′-[(acetyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-51);
{2′-[(Acetyl-ethyl-amino)-methyl]-6-methyl-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-56);
{2′-[(Acetyl-methyl-amino)-methyl]-6-fluoro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-58);
{2′-[(Acetyl-methyl-amino)-methyl]-6-methyl-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-59);
{2′-[(Acetyl-ethyl-amino)-methyl]-6-cyclopropyl-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-60);
{2′-[(Acetyl-ethyl-amino)-methyl]-6,4′-bis-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-61);
{2′-[(Acetyl-methyl-amino)-methyl]-4′-bromo-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-63);
{4′-Acetylamino-2′-[(acetyl-methyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-64);
{2′-[(Acetyl-ethyl-amino)-methyl]-6-methoxy-4′-methoxycarbonylamino-biphenyl-3-yl}-acetic acid (Compound 1-65);
{2′-[(Acetyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-66);
{2′-[(Acetyl-ethyl-amino)-methyl]-4′-methanesulfonyl-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-67);
{2′-[(Cyclopropoxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-75);
[2′-(1-Ethyl-3-methyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-76);
{2′-[(Cyclopropanecarbonyl-methyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-77);
{2′-[(Cyclopentanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-78);
{2′-[(Acetyl-ethyl-amino)-methyl]-6-chloro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-79);
(2′-{[(2-Benzyloxy-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-92);
[2′-({[2-(4-Chloro-phenoxy)-acetyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-93);
[2′-(3-Benzyl-1,3-diethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-94);
[2′-(3 -Benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-96);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-chloro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-110);
[2′-({[2-(4-Chloro-phenoxy)-2-methyl-propionyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-118);
{6-Benzyloxy-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-128);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-ethoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-129);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-3 -yl}-acetic acid (Compound 1-130);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-143);
{2′[3-(3,4-Dichloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-152);
{4′-Acetylamino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-153);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-155);
{2′-[3-(3,5-Dichloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-165);
{2′-[1-Ethyl-3-(4-fluoro-benzyl)-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-176);
{2′-[3-(3-Chloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-177);
{2′-[3-(3,5-Difluoro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-178);
(2′-{3-[(R)-1-(4-Chloro-phenyl)-ethyl]-1-ethyl-ureidomethyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-179);
(2′-{3-[(S)-1-(4-Chloro-phenyl)-ethyl]-1-ethyl-ureidomethyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-180);
[2′-(1,3-Diethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-181);
[2′-(3-Cyclopropyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-182);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-183);
{2′-[(Acetyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-184);
{2′-[3-(4-Chloro-benzyl)-1-ethyl-ureidomethyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-185);
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-186);
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-4′-fluoro-6-methoxy-biphenyl-3-yl]-acetic acid (Compound 1-187);
{2′-[(Cyclobutanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-206);
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonyl-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-215);
[2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-(1-hydroxy-1-methyl-ethyl)-6-methoxy-biphenyl-3-yl]-acetic acid (Compound 1-216);
[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-hydroxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-220);
2-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-5′-carboxymethyl-2′-methoxy-biphenyl-4-carboxylic acid (Compound 1-226);
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-methylsulfanyl-biphenyl-3-yl}-acetic acid (Compound 1-241);
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-244);
(2′-{[(2,2-Dimethyl-propionyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-245);
{2′-[(Ethyl-isobutyryl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-246);
{4′-Bromo-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-247);
{2′-[1-Ethyl-3-(4-hydroxy-benzyl)-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-252);
{2′-[1-Ethyl-3 -(2-hydroxy-benzyl)-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-253);
and {2′-[1-Ethyl-3-(3-hydroxy-benzyl)-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-257).

83 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/297,160Filed 15 Nov 2011
Priority: 1 Feb 2008
Published: 8 Mar 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification54 codes

A61K 31/5375
Having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines: 1,4-Oxazines, e.g. morpholine
A61K 31/17
Amides, e.g. hydroxamic acids: having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine
A61K 31/27
Esters, e.g. nitroglycerine, selenocyanates: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
A61K 31/277
Nitriles; Isonitriles: having a ring, e.g. verapamil

Family

Application61/025,597Us provisional application · filed 1 Feb 2008
Application61/110,496Us provisional application · filed 31 Oct 2008
Application12/362,439Continuation · filed 29 Jan 2009
Application13/297,160Continuation
US 2009/0197959 A1Published application
US 8,168,678 B2Related patent
US 8,338,484 B2Related patent
US 2012/0059055 A1This patent

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

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Abstract

Facts

Application

13/297,160Filed 15 Nov 2011

Priority

1 Feb 2008

Published

8 Mar 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification54 codes

A61K 31/5375
Having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines: 1,4-Oxazines, e.g. morpholine
A61K 31/17
Amides, e.g. hydroxamic acids: having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine
A61K 31/27
Esters, e.g. nitroglycerine, selenocyanates: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
A61K 31/277
Nitriles; Isonitriles: having a ring, e.g. verapamil

Family

Application61/025,597Us provisional application · filed 1 Feb 2008

Application61/110,496Us provisional application · filed 31 Oct 2008

Application12/362,439Continuation · filed 29 Jan 2009

Application13/297,160Continuation

US 2009/0197959 A1Published application

US 8,168,678 B2Related patent

US 8,338,484 B2Related patent

US 2012/0059055 A1This patent

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