US2006106061A1PendingUtilityA1
PGD2 receptor antagonists for the treatment of inflammatory diseases
Est. expiryOct 4, 2022(expired)· nominal 20-yr term from priority
A61P 5/14A61P 37/06A61P 9/00A61P 43/00A61P 37/02A61P 35/00A61P 3/10A61P 9/10A61P 37/08A61P 25/00A61P 29/00A61P 27/16A61P 1/04A61P 21/00C07D 405/06A61P 11/06C07D 401/12A61P 13/12A61P 19/02A61P 19/08A61P 15/00C07D 401/10C07D 215/44A61P 1/18A61P 11/00C07D 215/42C07D 491/04C07D 401/06C07D 409/06Y02P20/582C07D 471/04A61P 17/04C07D 495/04A61P 15/02A61K 31/47A61P 17/00A61P 19/04A61P 21/04C07D 413/06A61P 17/02A61K 31/4353A61P 11/02A61P 1/16A61P 17/10A61P 17/06C07D 413/10C07D 417/06C07D 215/50
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Claims
Abstract
Disclosed herein are compounds represented by Structural Formula (I): (I), wherein the variables are defined herein. Also disclosed is the use of such compounds for inhibiting the G-protein coupled receptor referred to as chemoattractant receptor-homologous molecule expressed on Th2 (“CRTH2”) for the treatment of inflammatory disorders.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting CRTH2 in a subject in need of CRTH2 inhibition, comprising administering to the subject an effective amount of a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted monocyclic aromatic ring;
R is —X 1 —R 1 ;
R x is —X 2 —R 4 , and R 3 is an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; or —NR x R 3 , taken together, is an optionally substituted non-aromatic nitrogen containing heterocyclic group;
X is —C(O)— or —C(R 2 ) 2 —;
X 1 and X 2 are each independently a bond, S(O), S(O) 2 , C(O) or C(O)NH;
R 1 is H or an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
provided that when X 1 is a bond, SO or SO 2 , then R 1 is not H;
each R 2 is independently H, —X 4 —R 8 or an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
R 4 is H, —X 6 —R 10 or an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
provided that when X 2 is a bond, SO or SO 2 , then R 4 is not H;
X 4 and X 6 are each independently a straight or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, —OH, ═O, C 1 -C 3 alkoxy, nitro and cyano;
R 5 and R 6 are each independently H or C 1 -C 3 alkyl; and
R 8 and R 10 are each independently H, —C(O)OR′ or an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
where,
the optional substituents on the aliphatic group, the cycloaliphatic group or the non-aromatic heterocyclic group are one to three groups each independently selected from the group consisting of halo, R 11 , ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl) and ═NR*;
the optional substituents on unsaturated carbon atoms of the aromatic group is R 1 ;
the optional substituents on a nitrogen atom of the aromatic group or the nitrogen atom of the non-aromatic nitrogen containing heterocyclic group are one to three groups each independently selected from the group consisting of R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R + ) 2 , —C(═NH)—N(R + ) 2 and —NR + SO 2 R + ;
R 11 is one to four substituents each independently selected from the group consisting of halo, R o , —OH, —OR o , —SH, —SR o , 1,2-methylenedioxy, 1,2-ethylenedioxy, protected —OH, phenyl, [R 12 ]-phenyl, —O(phenyl), —O([R 12 ]-phenyl), —CH 2 (phenyl), —CH 2 ([R 12 ]-phenyl), —CH 2 CH 2 (phenyl), —CH 2 CH 2 ([R 12 ]-phenyl), —NO 2 , —CN, —N(R′) 2 , —NR′CO 2 R o , —NR′C(O)R o , —NR′NR′C(O)R o , —N(R′)C(O)N(R′) 2 , —NR′NR′C(O)N(R′) 2 , —NR′NR′CO 2 R o , —C(O)C(O)R o , —C(O)CH 2 C(O)R′, —CO 2 R′, —C(O)R o , —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —S(O) 2 R o , —SO 2 N(R′) 2 , —S(O)R′, —NR′SO 2 N(R′) 2 , —NR′SO 2 R o , —C(═S)N(R′) 2 , —(CH 2 ) y N(R′) 2 , —C(═NH)—N(R′) 2 , —(CH 2 ) y C(O)N(R′) 2 , —(CH 2 ) y NHC(O)R′ or —(CH 2 ) y NHC(O)CH(V-R′)(R′);
R′ is H, R o , —CO 2 R o , —SO 2 R o or —C(O)R o ;
y is 0-6;
V is C 1 -C 6 alkylene;
each R* is independently H, an aliphatic group or an aliphatic group substituted with R 12 ;
R + is H, phenyl, [R 12 ]-phenyl, —O(phenyl), —O([R 12 ]-phenyl), —CH 2 (phenyl), —CH 2 ([R 12 ]-phenyl), a heteroaryl group, a non-aromatic heterocyclic group, an aliphatic group or an aliphatic group substituted with R 12 ;
R o is an aliphatic group, a cycloaliphatic group, an aromatic group, an aralkyl group or a non-aromatic heterocyclic group, each group being optionally substituted with R 12 ;
R 12 is one to four substituents each independently selected from the group consisting of halo, C 1 -C 6 alkyl, (halo) r C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (halo) r C 3 -C 8 cycloalkyl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OR′, —OR 13 C(O)R′, —C(O)OR′, —C(O)N(R 16 ) 2 , —N(R 16 ) 2 , —NO 2 , —NR 16 C(O)R′, —NR 16 C(O)OR′, —NR 16 C(O)N(R 16 ) 2 , —NR 16 SO 2 R 17 , —S(O) q R 17 , —R 13 NR 16 C(O)R′, —R 13 C(O)R′, —R 13 NR 16 C(O)OR′, tetrazolyl, imidazolyl or oxadiazolyl;
R 13 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
each R 16 is independently R′ or benzyl;
R 17 is R 13 or —CF 3 ;
q is 0-2; and
r is 1-3.
2 . The method of claim 1 wherein:
Ring A is phenyl or [R 11 ]-phenyl; X is —CHR 2 —; R x is —X 2 —R 4 ; R 1 and R 3 are each independently an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R 2 is H or an optionally substituted, C 1 -C 4 alkyl group, C 1 -C 4 alkyl alkoxymethylene group or C 3 -C 6 cycloalkyl group; R 4 is an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; and R 5 and R 6 are each H.
3 . The method of claim 2 wherein R 3 is an optionally substituted aromatic group.
4 . The method of claim 3 wherein the compound is represented by the following structural formula:
where Ring A, R 1 , R 2 and R 4 are each independently defined in claim 2 .
5 . The method of claim 4 wherein:
R 1 is H or an optionally substituted, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R 3 is phenyl or [R 11 ]-phenyl; R 4 is H, —CH 2 C(O)R 14 , —CH 2 R 15 , —CH 2 OR 14 or an optionally substituted, C 1 -C 3 alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R 14 is H or an optionally substituted, alkyl group, aromatic group, cycloalkyl group or non-aromatic heterocyclic group; and R 15 is an optionally substituted, aromatic group, cycloalkyl group or non-aromatic heterocyclic group; where R 11 and the optional substituents are each independently defined in claim 1 .
6 . The method of claim 1 wherein Ring A is thiophene, furan, pyridine, pyrazole, pyrrole, [2,3]pyrimidine, [3,4]pyrimidine, [4,5]pyrimidine, [5,6]pyrimidine, oxazole, isoxazole or 1,2,3-triazole, each group being optionally substituted with R 11 .
7 . The method of claim 6 wherein:
X is —CHR 2 —; R x is —X 2 —R 4 ; R 1 and R 3 are each independently an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R 2 is H or an optionally substituted, C 1 -C 4 alkyl group, C 1 -C 4 alkyl alkoxymethylene group or C 3 -C 6 cycloalkyl group; R 4 is an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; and R 5 and R 6 are each H.
8 . A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted monocyclic aromatic ring;
R is —X 1 —R 1 ;
R x is —X 2 —R 4 , and R 3 is an optionally substituted aromatic group; or —NR x R 3 , taken together, is an optionally substituted non-aromatic nitrogen containing heterocyclic group;
X is —C(O)— or —C(R 2 ) 2 —;
X 1 and X 2 are each independently a bond, S(O), S(O) 2 , C(O) or C(O)NH;
R 1 is H or an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
provided that when X 1 is a bond, SO or SO 2 , then R 1 is not H;
each R 2 is independently H, —X 4 —R 8 or an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
R 4 is H, —X 6 —R 10 or an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
provided that when X 2 is a bond, SO or SO 2 , then R 4 is not H;
X 4 and X 6 are each independently a straight or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, —OH, ═O, C 1 -C 3 alkoxy, nitro and cyano;
R 5 and R 6 are each independently H or C 1 -C 3 alkyl; and
R 8 and R 10 are each independently H, —C(O)OR′ or an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
where,
the optional substituents on the aliphatic group, the cycloaliphatic group or the non-aromatic heterocyclic group are one to three groups each independently selected from the group consisting of halo, R 11 , ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl) and ═NR*;
the optional substituents on unsaturated carbon atoms of the aromatic group is R 11 ;
the optional substituents on a nitrogen atom of the aromatic group or the nitrogen atom of the non-aromatic nitrogen containing heterocyclic group are one to three groups each independently selected from the group consisting of R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R + ) 2 , —C(═NH)—N(R + ) 2 and —NR + SO 2 R + ;
R 11 is one to four substituents each independently selected from the group consisting of halo, R o , —OH, —OR o , —SH, —SR o , 1,2-methylenedioxy, 1,2-ethylenedioxy, protected —OH, phenyl, [R 12 ]-phenyl, —O(phenyl), —O([R 12 ]-phenyl), —CH 2 (phenyl), —CH 2 ([R 12 ]-phenyl), —CH 2 CH 2 (phenyl), —CH 2 CH 2 ([R 12 ]-phenyl), —NO 2 , —CN, —N(R′) 2 , —NR′CO 2 R o , —NR′C(O)R o , —NR′NR′C(O)R o , —N(R′)C(O)N(R′) 2 , —NR′NR′C(O)N(R′) 2 , —NR′NR′CO 2 R o , —C(O)C(O)R o , —C(O)CH 2 C(O)R′, —CO 2 R′, —C(O)R o , —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —S(O) 2 R o , —SO 2 N(R′) 2 , —S(O)R′, —NR′SO 2 N(R′) 2 , —NR′SO 2 R o , —C(═S)N(R′) 2 , —(CH 2 ) y N(R′) 2 , —C(═NH)—N(R′) 2 , —(CH 2 ) y C(O)N(R′) 2 , —(CH 2 ) y NHC(O)R′ or —(CH 2 ) y NHC(O)CH(V-R′)(R′);
R′ is H, R o , —CO 2 R o , —SO 2 R o or —C(O)R o ;
y is 0-6;
V is C 1 -C 6 alkylene;
each R* is independently H, an aliphatic group or an aliphatic group substituted with R 12 ;
R + is H, phenyl, [R 12 ]-phenyl, —O(phenyl), —O([R 12 ]-phenyl), —CH 2 (phenyl), —CH 2 ([R 12 ]-phenyl), a heteroaryl group, a non-aromatic heterocyclic group, an aliphatic group or an aliphatic group substituted with R 12 ;
R o is an aliphatic group, a cycloaliphatic group, an aromatic group, an aralkyl group or a non-aromatic heterocyclic group, each group being optionally substituted with R 12 ;
R 12 is one to four substituents each independently selected from the group consisting of halo, C 1 -C 6 alkyl, (halo) r C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (halo) r C 3 -C 8 cycloalkyl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OR′, —OR 13 C(O)R′, —C(O)OR′, —C(O)N(R 16 ) 2 , —N(R 16 ) 2 , —NO 2 , —NR 16 C(O)R′, —NR 16 C(O)OR′, —NR 16 C(O)N(R 16 ) 2 , —NR 16 SO 2 R 17 , —S(O) q R 17 , —R 13 NR 16 C(O)R′, —R 13 C(O)R′, —R 13 NR 16 C(O)OR′, tetrazolyl, imidazolyl or oxadiazolyl;
R 13 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
each R 16 is independently R′ or benzyl;
R 17 is R 13 or —CF 3 ;
q is 0-2; and
r is 1-3;
provided that the compound is not 2-methyl-N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(2-methyl-1-oxobutyl)-4-quinolinyl]-butamide; N-(1-Acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-heptamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxo-3-phenylpropyl)-4-quinolinyl]-benzenepropanamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(3-nitrobenzoyl)-4-quinolinyl]-hexanamide; N-[1,1′-biphenyl]-3-yl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(4-nitrophenyl)-heptanamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(4-methoxyphenyl)-2-methyl-propanamide; N-[1-(4-fluorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-butanamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-pentanamide; 2-ethyl-N-[1-(2-ethyl-1-oxobutyl)-1,2,3,4-tetrahydro-2,8-dimethyl-4-quinolinyl]-N-(2-methylphenyl)-butanamide; N-[1-[(4-fluorophenyl)acetyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-propanamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(4-nitrobenzoyl)-4-quinolinyl]-octanamide; N-cyclohexyl-4-[(cyclohexylamino)carbonyl]phenylamino]-3,4-dihydro-2-methyl-1(2H)-quinolinecarboxamide; N-[1-(4-ethylbenzoyl)-1,2,3,4-tetrahydro-2,8-dimethyl-4-quinolinyl]-N-(2-methylphenyl)-3-(4-nitrophenyl)-2-propenamide; 3-(4-methoxyphenyl)-N-phenyl-N-[1,2,3,4-tetrahydro-1-[3-(4-methoxyphenyl)-1-oxo-2-propenyl]-2-methyl-4-quinolinyl]-2-propenamide; 4-[(ethoxyoxoacetyl)phenylamino]-3,4-dihydro-2-methyl-∀-oxo-ethyl ester-1(2H)-quinolineacetic acid; N-[1-(3-cyclohexyl-1-oxopropyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-cyclohexanepropanamide; 4-(acetylphenylamino)-3,4-dihydro-2-methyl-gamma-oxo-1(2H)-quinolinepentanoic acid; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-2,2-dimethyl-N-phenyl-propanamide; N-(1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-pentanamide; N-[1-(2-furanylcarbonyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; 2-methyl-N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-propanamide; N-[1-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)acetyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; 2,2,2-trifluoro-N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide; 2-ethyl-N-[1-(2-ethyl-1-oxobutyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-butanamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(3-methoxyphenyl)-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxohexyl)-4-quinolinyl]-acetamide; N-(1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-2-thiophenecarboxamide; N-[1-(2-fluorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-hexanamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-hexanamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-hexanamide; N-[1-(cyclopropylcarbonyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-cyclopropanecarboxamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-(4-methylphenyl)-acetamide; 2-methyl-N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(2-methyl-1-oxopropyl)-4-quinolinyl]-propanamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-2-thiophenecarboxamide; 1-(3,5-dinitrobenzoyl)-N-formyl-1,2,3,4-tetrahydro-2-methyl-N-phenyl-4-quinolinamine; N-[1-(4-chloro-3-nitrobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(3-nitrobenzoyl)-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-hexanamide; N-[1-(2-furanylcarbonyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-2-furancarboxamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxopropyl)-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-[3-(4-methoxyphenyl)-1-oxo-2-propenyl]-2-methyl-4-quinolinyl]-acetamide; 3-(2-furanyl)-N-[1-[3-(2-furanyl)-1-oxo-2-propenyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-2-propenamide; N-[1-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-octanamide; N-[1-(3-chlorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; Relative stereochemistry N-phenyl-N-[(2R,4S)-1,2,3,4-tetrahydro-2-methyl-1-(1-oxopropyl)-4-quinolinyl]-acetamide; Relative stereochemistry N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2-methyl-N-phenyl-propanamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-hexanamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-propanamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-heptanamide; Relative stereochemistry N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2,2-dimethyl-N-phenyl-propanamide; N-[1-(3-fluorobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; N-[1-[4-(1,1-dimethylethyl)benzoyl]-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; N-(1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-2-methyl-N-phenyl-propanamide; 2,2,2-trifluoro-N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(trifluoroacetyl)-4-quinolinyl]-acetamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-2,2-dimethyl-N-phenyl-propanamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-butanamide; Relative stereochemistry N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; Relative stereochemistry N-phenyl-N-[(2R,4S)-1,2,3,4-tetrahydro-2-methyl-1-(1-oxoheptyl)-4-quinolinyl]-acetamide; Relative stereochemistry N-phenyl-N-[(2R,4S)-1,2,3,4-tetrahydro-2-methyl-1-(1-oxohexyl)-4-quinolinyl]-acetamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-pentanamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxo-3-phenyl-2-propenyl)-4-quinolinyl]-acetamide; Relative stereochemistry N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-heptanamide; Relative stereochemistry N-[(2R,4S)-1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; Relative stereochemistry N-[(2R,4S)-1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-pentanamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(tricyclo[3.3.1.13.7]dec-1-ylcarbonyl)-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxopropyl)-4-quinolinyl]-propanamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(2-thienylcarbonyl)-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-2-furancarboxamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(4-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide; N-[1-(3,5-dinitrobenzoyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]-N-phenyl-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(4-nitrobenzoyl)-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(2-iodobenzoyl)-2-methyl-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(2-methyl-1-oxopropyl)-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-[(4-methylphenyl)sulfonyl]-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-[(4-nitrophenyl)methyl]-4-quinolinyl]-acetamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-methoxybenzoyl)-2-methyl-4-quinolinyl]-acetamide; N-(1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-butanamide; N-phenyl-N-[1,2,3,4-tetrahydro-2-methyl-1-(1-oxobutyl)-4-quinolinyl]-acetamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-hexanamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-pentanamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-propanamide; 1-benzoyl-1,2,3,4-tetrahydro-4-(N-phenylacetamido)quinaldine; N-(1-acetyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-acetamide; N-(1-acetyl-1,2,3,4-tetrahydro-2-methyl-6-nitro-4-quinolyl)-acetanilide; N-(1-acetyl-6-chloro-1,2,3,4-tetrahydro-2-methyl-4-quinolyl)-acetanilide; N-(1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-acetamide; N-(1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-acetamide; N-(1-benzoyl-6-chloro-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-acetamide; N-(1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-butanamide; N-phenyl-N-[1,2,3,4-tetrahydro-1-(3-fluorobenzoyl)-2-methyl-4-quinolinyl]-hexanamide; N-[1-(3-chloro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide; N-[1-(4-fluoro-benzoyl)-2-methyl-6-nitro-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide; pentanoic acid (1-benzoyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-phenyl-amide; N-(1-benzoyl-6-chloro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-phenyl-acetamide; N-[6-chloro-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide; N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide; N-(1-benzoyl-6-nitro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-phenyl-acetamide; N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-phenyl-butyramide; N-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-2,2-dimethyl-N-phenyl-propionamide.
9 . The compound of claim 8 wherein:
X is —CHR 2 —; R 2 is H, methyl or ethyl; R 3 is an optionally substituted aromatic group; and R 5 and R 6 are each H.
10 . The compound of claim 9 wherein the compound is represented by the following structural formula:
where Ring A, R 1 and R 4 are each independently defined in claim 8 .
11 . The compound of claim 10 wherein:
R 1 is H or an optionally substituted, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R 3 is phenyl or [R 11 ]-phenyl; R 4 is H, —CH 2 C(O)R 14 , —CH 2 R 15 , —CH 2 OR 14 or an optionally substituted, C 1 -C 3 alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R 14 is H or an optionally substituted, alkyl group, aromatic group, cycloalkyl group or non-aromatic heterocyclic group; and R 15 is an optionally substituted, aromatic group, cycloalkyl group or non-aromatic heterocyclic group; where R 11 and the optional substituents are each independently defined in claim 8 .
12 . The compound of claim 10 wherein:
Ring A is phenyl or [R 11 ]-phenyl, where R 11 is at the five, six, seven and/or eight position; R 1 is R 18 ; and R 4 is R 18 , C 1 -C 4 alkyl, —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 or —CH 2 CH 2 OCH 2 CH 3 ; and R 18 is an optionally substituted, phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, thiazolyl, benzyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, benzomorpholinyl, benzopyrazolyl, indolyl, —CH 2 —(N-pyridyl), —CH 2 -furanyl, —CH 2 -thiophienyl, —CH 2 -isoxazolyl, —CH 2 -imidazolyl, —CH 2 -pyrazolyl, —CH 2 -pyrollyl, —CH 2 -benzofuranyl, —CH 2 -tetrazolyl, —CH 2 -thiazolyl, —CH 2 -tetrazolyl, —CH 2 -benzothiazolyl, —CH 2 -benzimidazolyl, —CH 2 —O-phenyl, —CH 2 C(O)-phenyl, naphthalimidyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or cyclopropyl group; where R 11 and the optional substituents are each independently defined in claim 8 .
13 . The compound of claim 12 wherein:
Ring A is phenyl or [R 11 ]-phenyl, where R 11 is at the six and/or seven position; R 1 is phenyl, thiophenyl, furanyl, pyridyl, pyrmidinyl, oxazolyl, isoxazolyl, benzotriazolyl or benzomorpholinyl, each group being optionally substituted with R 11 ; R 3 is [R 11 ]-phenyl; and R 4 is methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, —CH 2 OCH 3 or —CH 2 OCH 2 CH 3 ; where R 11 is defined in claim 8 .
14 . The compound of claim 12 wherein:
R 1 is thiophenyl, [R 11 ]-thiophenyl, isoxazolyl, [R 11 ]-isoxazolyl, pyridinyl, [R 11 ]-pyridinyl, benzotriazolyl, [R 11 ]-benzotriazolyl, benzomorpholinyl or [R 11 ]-benzomorpholinyl, where R 11 is defined in claim 8; or R 1 is phenyl or [R 11 ]-phenyl, where R 11 is halo, —OR o , —N(R′) 2 , oxazolyl or R 3 is [R 11 ]-phenyl, where R 11 is Br, Cl, —CH 3 , —N(R′) 2 , —NHC(O)OR′, —S(O) 2 CH 3 , —S(O) 2 N(R′) 2 or —(CH 2 ) y C(O)N(R′) 2 ; and R 4 is methyl, ethyl or —CH 2 OCH 3 ; where R o and R′ are each independently defined in claim 8 .
15 . The compound of claim 14 wherein R 3 is [R 11 ]-phenyl, where R 11 is one substituent at the para position.
16 . The compound of claim 8 wherein:
X is —CHR 2 ; and R 2 and NR x R 3 are in a cis configuration relative to one another; where R 2 , R x and R 3 are each independently defined in claim 8 .
17 . The compound of claim 16 where the cis configuration is 2S,4R or 2R,4S:
18 . The compound of claim 8 which is represented by a structural formula selected from the group consisting of:
Structure
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable diluent, excipient or carrier.
20 . A method of inhibiting CRTH2 in a subject in need of CRTH2 inhibition, comprising administering to the subject an effective amount of the compound or pharmaceutical salt of claim 8 .
21 . A method of inhibiting DP in a subject in need of DP inhibition, comprising administering to the subject an effective amount of the compound or pharmaceutical salt of claim 8 .
22 . A method of treating an inflammatory disease, disorder or symptom in a subject in need of the treatment, comprising administering to the subject an effective amount of the compound or pharmaceutical salt of claim 8 .
23 . The method of claim 22 , where the inflammatory disease, disorder or symptom is allergic rhinitis, allergic asthma, atopic dermatitis, chronic obstructive pulmonary disorder, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease or a skin disorder.
24 . The method of claim 23 , where the inflammatory disease, disorder or symptom is allergic rhinitis or allergic asthma.Cited by (0)
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