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US 6,509,369 B2Granted
Anti-inflammatory compounds
AssigneeOrtho-McNeil Pharmaceutical, Inc.
InventorsMalcolm K. Scott, Pauline J. Sanfilippo, Louis J. Fitzpatrick, III, Richard Cordova, Kevin Pan, Joseph Meschino
Life of this patent
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Abstract
This invention relates to anti-inflammatory compounds, methods of making such compounds and methods of using such compounds having the following structure:
Claims35
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.
24 more elements
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.
25 more elements
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).
37 more elements
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).
36 more elements
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).
25 more elements
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).
23 more elements
Dependencies are inferred from the claim text.