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US 7,405,215 B2Granted
Indole acetic acids exhibiting CRTH2 receptor antagonism and uses thereof
AssigneeWyeth
InventorsYoussef L. Bennani, Lawrence Nathan Tumey, Elizabeth Ann Gleason, Michael Joseph Robarge
Life of this patent
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Abstract
The invention relates to indole acetic acid compounds which function as antagonists of the CRTH2 receptor. The invention also relates to the use of these compounds to inhibit the binding of prostaglandin D2 and its metabolites or certain thromboxane metabolites to the CRTH2 receptor and to treat disorders responsive to such inhibition.
Claims30
A compound having Formula I:
- or a pharmaceutically acceptable salt, ester or amide thereof, where said ester is derived from a C1-6 alcohol and said amide is derived from a C1-6 amine,
- wherein:
- the dotted lines are single or double bonds;
- X is C═O;
- Z is N;
- R1 is selected from H, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C1-10 alkylaryl, optionally substituted C1-10 alkylheteroaryl, optionally substituted —C1-10 alkyl-O—C1-10 alkyl, optionally substituted —C1-10 alkyl-O-aryl, optionally substituted —C1-10 alkyl-O-heteroaryl, optionally substituted aryl, and optionally substituted heteroaryl;
- R2, R2a, R3 and R3a are independently selected from H, halogen, and C1-10 alkyl, wherein R2a and R3a are present only when the carbons to which they are attached are saturated;
- or
- R2 and R3, taken together with the carbon atoms to which they are attached, form an optionally substituted saturated, unsaturated, or aromatic 5- or 6-membered ring;
- or
- R2 and R2a, taken together with the carbon atoms to which they are attached, form an optionally substituted saturated 3-6 membered ring;
- R4 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or halogen, wherein R4 is present only when the carbon to which it is attached is saturated;
- R5 is H, C1-10 alkyl, perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- R6 is one or more H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, CN, OR7, SR7, aryl or heteroaryl groups;
- and
- R7 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl wherein unless otherwise specified, optional substituents are selected from C1-10 alkyl, halogen, halo C1-10 alkyl, halo C1-10 alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy, carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino, acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partially unsaturated heterocyclylalkyl and partially unsaturated heterocyclylalkoxy, and where each optional substituent may be further substituted with one or more C1-6 alkyl, halogen, halo C1-10 alkyl, C1-10 alkoxy, haloalkoxy, aryl, or heteroaryl groups.
13 more elements
A compound, which is:
- [3-(3-benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-indol-1-yl]-acetic acid;
- [3-(3-benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-acetic acid;
- [3-(1-benzyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-acetic acid;
- {5-chloro-3-[3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-1-yl}-2-methyl-indol-1-yl}-acetic acid;
- {5-chloro-3-[3-(4-chloro-phenoxy)-4-oxo-3,4-dihydro-phthalazin-1-yl}-2-methyl-indol-1-yl}-acetic acid;
- [3-(3-benzothiazol-2-ylmethyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-acetic acid;
- {5-chloro-3-[3-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-oxo-3,4-dihydro-phthalazin-1-yl]-2-methyl-indol-1-yl}-acetic acid;
- [3-(3-butyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-acetic acid;
- [3-(3-benzyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-acetic acid;
- [2-methyl-3-(4-oxo-3-phenethyl-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-acetic acid;
- or
- [3-(1-benzyl-5,5-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-acetic acid, or
- a pharmaceutically acceptable salt, ester or amide thereof, where said ester is derived from a C1-6 alcohol and said amide is derived from a C1-6 amine.
10 more elements
A method of preparing a compound having formula XXIV, comprising
- a) condensing a compound having formula VIII with a 1,4-dihalo phthalazine compound to form a compound having formula XXI;
- b) condensing a compound having formula XXI with a halogenated acetic acid alkyl ester to form a compound having formula XXII;
- c) hydrolyzing a compound having formula XXII to form a compound having formula XXIII;
- and
- d) alkylating or arylating a compound having formula XXIII followed by deprotecting to form a compound having formula XXIV;
- wherein
- R1 is selected from H, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C1-10 alkylaryl, optionally substituted C1-10 alkylheteroaryl, optionally substituted —C1-10 alkyl-O—C1-10 alkyl, optionally substituted —C1-10 alkyl-O-aryl, optionally substituted —C1-10 alkyl-O-heteroaryl, optionally substituted aryl, and optionally substituted heteroaryl, where unless otherwise specified, optional substituents are selected from C1-10 alkyl, halogen, halo C1-10 alkyl, halo C1-10 alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy, carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino, acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partially unsaturated heterocyclylalkyl and partially unsaturated heterocyclylalkoxy, and where each optional substituent may be further substituted with one or more C1-6 alkyl, halogen, halo C1-10 alkyl, C1-10 alkoxy, haloalkoxy, aryl, or heteroaryl groups;
- R5 is H, C1-10 alkyl, perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- R6 is one or more H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, CN, OR7, SR7, aryl or heteroaryl groups;
- R7 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl;
- R8 is H, halo, C1-10 alkoxy, cyano, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, —C1-10 alkyl-O—C1-10 alkyl, —C1-10 alkyl-O-aryl, —C1-10 alkyl-O-heteroaryl, aryl, or heteroaryl;
- Q is a halogen;
- and
- Y is a protecting group.
11 more elements
A method of preparing a compound having formula XXIV, comprising alkylating or arylating a compound having formula XXIII followed by deprotecting to form a compound having formula XXIV;
- wherein
- R1 is selected from H, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C1-10 alkylaryl, optionally substituted C1-10 alkylheteroaryl, optionally substituted —C1-10 alkyl-O—C1-10 alkyl, optionally substituted —C1-10 alkyl-O-aryl, optionally substituted —C1-10 alkyl-O-heteroaryl, optionally substituted aryl, and optionally substituted heteroaryl, where unless otherwise specified, optional substituents are selected from C1-10 alkyl, halogen, halo C1-10 alkyl, halo C1-10 alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy, carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino, acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partially unsaturated heterocyclylalkyl and partially unsaturated heterocyclylalkoxy, and where each optional substituent may be further substituted with one or more C1-6 alkyl, halogen, halo C1-10 alkyl, C1-10 alkoxy, haloalkoxy, aryl, or heteroaryl groups;
- R5 is H, C1-10 alkyl, perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- R6 is one or more H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, CN, OR7, SR7, aryl or heteroaryl groups;
- R7 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl;
- R8 is H, halo, C1-10 alkoxy, cyano, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, —C1-10 alkyl-O—C1-10 alkyl, —C1-10 alkyl-O-aryl, —C1-10 alkyl-O-heteroaryl, aryl, or heteroaryl;
- and
- Y is a protecting group.
5 more elements
A method of preparing a compound having formula XLII, comprising
- a) acylating an indole compound having formula VIII with a compound having formula XXXIX to form a compound having formula XL;
- b) cyclizing a compound having formula XL with an alkylhydrazide to form a compound having formula XLI;
- and
- c) alkylating a compound having formula XLI with a halogenated acetic acid alkyl ester followed by deprotecting to form a compound having formula XLII;
- wherein
- R1 is selected from H, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C1-10 alkylaryl, optionally substituted C1-10 alkylheteroaryl, optionally substituted —C1-10 alkyl-O—C1-10 alkyl, optionally substituted —C1-10 alkyl-O-aryl, optionally substituted —C1-10 alkyl-O-heteroaryl, optionally substituted aryl, and optionally substituted heteroaryl, where unless otherwise specified, optional substituents are selected from C1-10 alkyl, halogen, halo C1-10 alkyl, halo C1-10 alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy, carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino, acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partially unsaturated heterocyclylalkyl and partially unsaturated heterocyclylalkoxy, and where each optional substituent may be further substituted with one or more C1-6 alkyl, halogen, halo C1-10 alkyl, C1-10 alkoxy, haloalkoxy, aryl, or heteroaryl groups;
- R2, R2a, and R3 are independently selected from H, halogen, and C1-10 alkyl, wherein R2a are present only when the carbons to which it is attached is saturated;
- or
- R2 and R3, taken together with the carbon atoms to which they are attached, form an optionally substituted saturated, unsaturated, or aromatic 5- or 6-membered ring, wherein optional substituents are selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- or
- R2 and R2a, taken together the carbon atoms to which they are attached, form an optionally substituted saturated 3-6 membered ring, wherein optional substituents are selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- R5 is H, C1-10 alkyl, perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- and
- R6 is one or more H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, CN, OR7, SR7, aryl or heteroaryl groups;
- and
- R7 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl.
13 more elements
A method of preparing a compound having formula XLII, comprising condensing a compound having formula XLI with a halogenated acetic acid alkyl ester followed by deprotecting to form a compound having formula XLII;
- wherein
- R1 is selected from H, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C1-10 alkylaryl, optionally substituted C1-10 alkylheteroaryl, optionally substituted —C1-10 alkyl-O—C1-10 alkyl, optionally substituted —C1-10 alkyl-O-aryl, optionally substituted —C1-10 alkyl-O-heteroaryl, optionally substituted aryl, and optionally substituted heteroaryl, where unless otherwise specified, optional substituents are selected from C1-10 alkyl, halogen, halo C1-10 alkyl, halo C1-10 alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy, carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino, acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partially unsaturated heterocyclylalkyl and partially unsaturated heterocyclylalkoxy, and where each optional substituent may be further substituted with one or more C1-6 alkyl, halogen, halo C1-10 alkyl, C1-10 alkoxy, haloalkoxy, aryl, or heteroaryl groups;
- R2, R2a, and R3 are independently selected from H, halogen, and C1-10 alkyl, wherein R2a are present only when the carbons to which it is attached is saturated;
- or
- R2 and R3, taken together with the carbon atoms to which they are attached, form an optionally substituted saturated, unsaturated, or aromatic 5- or 6-membered ring, wherein optional substituents are selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- or
- R2 and R2a, taken together with the carbon atoms to which they are attached, form an optionally substituted saturated 3-6 membered ring, wherein optional substituents are selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- R5 is H, C1-10 alkyl, perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylaryl, C1-10 alkylheteroaryl, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from C1-10 alkyl, halogen, C1-10 alkoxy, and CN;
- and
- R6 is one or more H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, CN, OR7, SR7, aryl or heteroaryl groups;
- and
- R7 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, or heteroaryl.
9 more elements
Dependencies are inferred from the claim text.