Anti-inflammatory compounds

• US 6,509,369 B2
• Filed: 01/08/2002
• Issued: 01/21/2003
• Est. Priority Date: 12/29/1997
• Status: Expired due to Term

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Pan, Kevin, Scott, Malcolm K., Fitzpatrick, Louis J. III, Cordova, Richard, Sanfilippo, Pauline J., Meschino, Joseph
• Primary Examiner(s): Huang, Evelyn Mei
• Application Number:
  US10/041,423
• Publication Number:
  US 20020103217A1
• Time in Patent Office: 378 Days
• Field of Search: 546/309, 548/483, 548/492, 549/57, 549/64, 549/72, 549/77, 549/441, 564/219, 564/182, 564/170, 514/352, 514/415, 514/438, 514/443, 514/447, 514/466, 514/630, 514/617, 514/448, 514/338
• US Class Current: 514/438
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07C 233/05 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/13 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 2603/32 Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
• CPC Class Codes: C07C 271/44 to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• 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
• CPC Class Codes: C07D 333/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/70 attached in position 2

Abstract

This invention relates to anti-inflammatory compounds, methods of making such compounds and methods of using such compounds having the following structure:

Claims

1. A compound having the formula:

wherein X is selected from the group consisting of a single bond, (CH₂)_n wherein n is an integer from 1 to 3 and —

HC═

CH—

;

R¹ is hydrogen or is from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

R² is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C₂-C₆), lower alkoxy, lower alkylenoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- and unsubstituted thiophene, furan, pyrrole, or pyridine;

Y is selected from the group consisting of —

CH₂— and

H, H;

R³ is selected from the group consisting of hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

Z is selected from the group consisting of carbonyl;

carboxy;

carbonylamino;

or sulfone; and

R⁴ is phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, benzothiophene, furan, pyrrole, pyridine, and a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole and pyridine; and

R⁵ is selected from the group consisting of;

hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, and nitrile;

phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile.

2. A compound according to claim 1 wherein R¹ is selected from the group consisting of hydrogen and halogen.

3. A compound according to claim 2 wherein R¹ is hydrogen.

4. A compound according to claim 2 wherein R¹ is halogen.

5. A compound according to claim 4 wherein R¹ is fluorine.

6. A compound according to claim 1 wherein R² is selected from the group consisting of phenyl and halophenyl.

7. A compound according to claim 6 wherein R² is phenyl.

8. A compound according to claim 6 wherein R² is halophenyl.

9. A compound according to claim 8 wherein R² is chlorophenyl.

10. A compound according to claim 1 wherein R³ is selected from the group consisting of hydrogen and lower alkyl.

11. A compound according to claim 10 wherein R³ is hydrogen.

12. A compound according to claim 1 wherein R⁴ is heteroaromatic lower alkyl.

13. A compound according to claim 12 wherein R⁴ is thiophene.

14. compound according to claim 1 wherein Z is carbonyl.

33. A method of treating inflammatory conditions comprising applying to the skin of a mammal in need thereof an anti-inflammatory amount of a compound of Formula (I) according to claim 1.

34. A compound according to claim 1, having the name N-(2-carbonyl-5-methylthiophene)-2-(9H-fluoreny-9-yl)-2-phenenylethylamine.

35. A compound according to claim 1, having the name N-(2-propyl) carbonyl-1,2,2-triphenylcydopropylmethylamine.

15. An antiinflammatory composition comprising a pharmaceutically acceptable carrier and an antiinflammatory-effective amount of a compound having the formula:

wherein X is selected from the group consisting of a single bond, (CH₂)_n wherein n is an integer from 1 to 3 and —

HC═

CH—

;

R¹ is hydrogen or is from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

R² is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C₂-C₆), lower alkoxy, lower alkylenoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, and pyridine;

Y is selected from the group consisting of —

CH₂— and

H, H;

R³ is chosen from the group consisting of hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

Z is selected from the group consisting of carbonyl;

carboxy;

carbonylamino; and

sulfone; and

R⁴ is straight- or branched-chain alkyl having from 2 to 12 carbon atoms;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, and a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole and pyridine; and

R⁵ is selected from the group consisting of;

hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, and nitrile;

phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile.

16. A composition according to claim 15 wherein R¹ is selected from the group consisting of hydrogen and halogen.

17. A composition according to claim 16 wherein R¹ is hydrogen.

18. A composition according to claim 16 wherein R¹ is halogen.

19. A composition according to claim 18 wherein R¹ is fluorine.

20. A composition according to claim 15 wherein R² is selected from the group consisting of phenyl and halophenyl.

21. A composition according to claim 20 wherein R² is phenyl.

22. A composition according to claim 20 wherein R² is halophenyl.

23. A composition according to claim 22 wherein R² is chlorophenyl.

24. A composition according to claim 15 wherein R³ is selected from the group consisting of hydrogen and lower alkyl.

25. A composition according to claim 24 wherein R³ is hydrogen.

26. A composition according to claim 15 wherein R⁴ is heteroaromatic lower alkyl.

27. A composition according to claim 26 wherein R⁴ is thiophene.

28. A composition according to claim 15 wherein Z is carbonyl.

29. A method of making a compound having the formula:

wherein X is selected from the group consisting of a single bond, (CH₂)_n wherein n is an integer from 1 to 3 and —

HC═

CH—

;

R¹ is hydrogen or is from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

R² is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;

Y is H, H;

R³ is chosen from the group consisting of hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrite;

Z is selected from the group consisting of carbonyl;

carboxy;

carbonylamino; and

sulfone; and

R⁴ is straight- or branched-chain alkyl having from 2 to 12 carbon atoms;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole and pyridine; and

R⁵ is selected from the group consisting of;

hydrogen;

alkyl;

cydoalkyl;

alkenyl;

alkynyl;

phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, and nitrile;

phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

comprising the steps of

(1) reacting R²CH₂CN with a compound having the formula (II) in the presence of n-butyl lithium;

to obtain a compound having the formula (III)

(2) reacting said compound of formula (III) with lithium aluminum hydride to form a compound of formula (IV);

and

(3) reacting said compound of formula (IV) with compound selected from the group consisting of;

(a) sodium acetate and R⁴COCl;

(b) CDI and R⁴CO₂H;

(c) EtN═

C═

N(CH₂)₃ NMe₂HCl and R⁴CO₂H; and

(d) ClCO₂R⁴;

(e) ClC═

O(NHR⁴); and

(f) R⁴SO₂Cl to obtain a compound of formula (I).

30. A method of making a compound having the formula:

wherein X is selected from the group consisting of a single bond, (CH₂)_n wherein n is an integer from 1 to 3 and —

HC═

CH—

;

R¹ is hydrogen or is from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

R² is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C₂-C₆), lower alkoxy, lower alkylenoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, and pyridine;

R³ is chosen from the group consisting of hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

Z is selected from the group consisting of carbonyl;

carboxy;

carbonylamino;

or sulfone; and

R⁴ is straight- or branched-chain alkyl having from 2 to 12 carbon atoms;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted- or unsubstituted thiophene, furan, pyrrole and pyridine; and

R⁵ is selected from the group consisting of;

hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile;

phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

comprising the steps of;

(1) reacting R²CH₂CN with a compound having the formula (II) in the presence of n-butyl lithium;

to obtain a compound having the formula (III)

(2) reacting said compound of formula (III) with CH₂CI₂ in the presence of KNH₂ and liquid NH₃ to obtain a compound having formula (V);

(3) reacting said compound of formula (V) with lithium aluminum hydride to form a compound of formula (VI);

and

(4) reacting said compound of formula (VI) with compound selected from the group consisting of;

(a) sodium acetate and R⁴COCl;

(b) CDl and R⁴CO₂H;

(c) EtN═

C═

N(CH₂)3 NMe2HCl and R⁴CO₂H;

(d) ClCO₂R⁴;

(e) ClC═

O(NHR⁴); and

(f) R⁴SO₂Cl to obtain a compound of formula (I).

31. A method of making a compound having the formula:

wherein X is selected from the group consisting of a single bond, (CH₂)_n wherein n is an integer from 1 to 3 and —

HC═

CH—

;

R¹ is hydrogen or is from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

R² is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C₂-C₆), lower alkoxy, lower alkylenoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, and pyridine;

Y is selected from the group consisting of —

CH₂— and

H, H;

R³ is hydrogen;

Z is selected from the group consisting of carbonyl;

carboxy;

carbonylamino; and

sulfone; and

R⁴ is straight- or branched-chain alkyl having from 2 to 12 carbon atoms;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;

a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted- or unsubstituted thiophene, furan, pyrrole and pyridine; and

R⁵ is selected from the group consisting of;

hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, and nitrile;

phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

comprising the steps of

(1) reacting diisobutylaluminum hydride with a compound having the formula (VII);

to obtain a compound having the formula (VIII)

(2) reacting said compound of formula (VIII) with Rink resin to give a resin-bound compound of formula (IX);

(3) reacting said compound of formula (IX) with sodium triacetoxyborohydride to form a compound of formula (X);

(4) reacting said compound of formula (X) with R⁴CO₂H in the presence of O—

(7-azabenzotriazol-1-yl)-N,N,N′

,N′

-tetramethyluronium hexafluorophasphate and diisopropyl ethylamine followed by treatment with TFA to form a compound of formula (I).

32. A method of making a compound having the formula:

wherein X is selected from the group consisting of a single bond, (CH₂)_n wherein n is an integer from 1 to 3 and —

HC═

CH—

;

R¹ is hydrogen or is from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

R² is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C₂-C₆), lower alkoxy, lower alkylenoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;

wherein Y is selected from the group consisting of —

CH₂— and

H, H;

R³ is hydrogen;

Z is selected from the group consisting of carbonyl;

carboxy;

carbonylamino; and

sulfone; and

R⁴ is straight- or branched-chain alkyl having from 2 to 12 carbon atoms;

phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted- or unsubstituted thiophene, furan, pyrrole and pyridine;

R⁵ is selected from the group consisting of;

hydrogen;

alkyl;

cycloalkyl;

alkenyl;

alkynyl;

phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C₂-C₆), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, and nitrile;

phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido and nitrile;

comprising the steps of

(1) reacting a compound of formula (XII) with Merrifield resin to form a compound of formula (XIII);

to obtain a compound of formula XIII

(2) reacting said compound of formula XIII with a compound of formula XIV and an appropriate acid R⁴CO₂H

to obtain a compound of formula (1).