1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders

• US 7,202,247 B2
• Filed: 12/19/2002
• Issued: 04/10/2007
• Est. Priority Date: 12/19/2001
• Status: Expired due to Fees

• Current Assignee: Salutria Pharmaceuticals, LLC
• Original Assignee: Atherogenics, Inc.
• Inventors: Meng, Charles Q., Sikorski, James A., Weingarten, M. David
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US10/325,087
• Publication Number:
  US 20030232877A1
• Time in Patent Office: 1,573 Days
• Field of Search: 549/78, 549/80, 549/406, 549/498, 548/146, 548/215, 548/300.1, 546/184, 546/312, 544/224, 544/242, 544/335, 514/252.01, 514/252.1, 514/256, 514/438, 514/461, 514/465, 514/338
• US Class Current: 514/252.01
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 333/22 Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula

or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application.

Claims

1. A compound of Formula I:

20. The compound of claim 1 wherein the compound is selected from the group consisting of 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid methyl ester,

4-[3-{2,4-Dimethoxy-5-(thiophen-2-yl)-phenyl}propynoyl]-benzoic acid,

{4-[3-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester, and

{4-[3-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 together with one or more pharmaceutically acceptable carrier.

22. A method for the treatment of an inflammatory disorder mediated by VCAM-1, comprising administering amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the disorder is arthritis.

23. A method for the treatment of an inflammatory disorder mediated by VCAM-1, comprising administering an effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the disorder is rheumatoid arthritis.

24. A method for the treatment of an inflammatory disorder mediated by VCAM-1, comprising administering an effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the disorder is asthma.

25. A method for the treatment of an inflammatory disorder mediated by VCAM-1, comprising administering an effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein the disorder is allergic rhinitis.

2. A compound of the Formula I:

3. A compound of the Formula I:

4. A compound of the Formula I:

5. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, carboxyalkoxy, heteroaryl, heterocycle, alkoxy, lower alkoxy, alkylamino, amino, dialkylamino, halogen, and —

NHSO₂R², all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkyl, hydroxyalkyl, aminoalkyl, amino, and halo;

R¹ is selected from the group consisting of lower alkyl, and aryl, wherein all may be substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocycle or heteroaryl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of carboxy, and carboxymethoxy.

6. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkyl, hydroxyalkyl, aminoalkyl, amino, acyl, carboxyalkoxy, alkoxycarbonyl, and halo;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, heteroaryl, heterocycle, lower alkoxy, dialkylamino, acyl, alkoxycarbonyl, carboxyalkoxy, and halogen, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkyl, hydroxyalkyl, aminoalkyl, amino, and halo;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocycle or heteroaryl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy or carboxymethoxy.

7. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, lower alkoxy, carboxyalkoxy, and halogen;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, methyl, hydroxymethyl, aminomethyl, amino, acyl, alkoxycarbonyl, and halo;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocycle or heteroaryl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy or carboxymethoxy.

8. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, lower alkoxy, carboxyalkoxy, and halogen;

R^2β

, R^3β

, R<sup>4β

2</sup>, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy or carboxymethoxy.

9. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, lower alkoxy, carboxyalkoxy, and halogen;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocycle selected from the group consisting of pyrrolidinyl, pyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, and piperazinyl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy or carboxymethoxy.

10. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, methyl, carboxy, carboxyalkoxy, methoxy, chloro and fluoro;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, methyl, furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, isoquinolinyl, methoxy, dimethylamino, chloro and fluoro;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl;

with the proviso that at least one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

must be carboxy or carboxymethoxy.

11. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen, methyl, carboxy, carboxyalkoxy, methoxy, chloro and fluoro;

R^2β

, R^3β

, R^4β

, and R^6β

are independently selected from the group consisting of hydrogen, methyl, methoxy, dimethylamino, chloro and fluoro;

R^5β

is a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl;

with the proviso that at least one of R^2β

, R^3β

, or R^4α

must be carboxy or carboxymethoxy.

12. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^5α

, R^6α

R^3β

, and R^6β

are hydrogen;

R^4α

is carboxy;

R^2β

and R^4β

are methoxy; and

R^5β

is a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl.

13. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^5α

, R^6α

, R^3β

, and R^6β

are hydrogen;

R^4α

is carboxy;

R^2β

and R^4β

are methoxy; and

R^5β

is 5-(benzothien-2-yl).

14. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^5α

, R^6α

, R^3β

, and R^6β

are hydrogen;

R^4α

is carboxy;

R^2β

and R^4β

are methoxy; and

R^5β

is thienyl.

15. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^5α

, R^6α

, R^3β

, and R^6β

are hydrogen;

R^4α

is carboxy;

R^2β

and R^4β

are methoxy; and

R^5β

is indolyl.

16. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^6α

, R^3β

and R^6β

are hydrogen;

R^4α

is carboxymethoxy;

R^3α

, R^5α

, R^2β

and R^4β

are methoxy; and

R^5β

is a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl.

17. The compound of claim 16 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^6α

, R^3β

and R^6β

are hydrogen;

R^4α

is carboxymethoxy;

R^3α

, R^5α

, R^2β

and R^4β

are methoxy; and

R^5β

is 5-(benzothien-2-yl).

18. The compound of claim 16 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^6α

, R^3β

and R^6β

are hydrogen;

R^4α

is carboxymethoxy;

R^3α

, R^5α

, R^2β

and R^4β

are methoxy; and

R^5β

is thienyl.

19. The compound of claim 16 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^6α

, R^3β

and R^6β

are hydrogen;

R^4α

is carboxymethoxy;

R^3α

, R^5α

, R^2β

and R^4β

are methoxy; and

R^5β

is indolyl.