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US 6,271,241 B1Granted
Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors
AssigneeNeurogen Corporation
InventorsRobert W. DeSimone, Alan Hutchison
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein X, R1, R2, R3, R4, R5, R6, R7, A, B, C, and D are variables defined herein. Such compounds useful in treatment of obesity and diabetes. The invention also provides labeled probes for the localization of cellular receptors that are involved in the modulation of blood glucose levels.
Claims51
A compound of the formula:
- or pharmaceutically acceptable non-toxic salts thereof wherein:
- R7 represents H, or C1-C6 alkyl;
- when R7 is H, R1 is not 3-fluorobenzyl and R1 represents 2-, 3-, or 4-picolyl or benzyl, each of which is optionally mono-, di-, or trisubstituted independently with
- halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy, or C1-C6 alkyl;
- amino, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or di (C1-C6)alkylamino(C1-C6)alkoxy;
- —O(CH2)nCO2R8 where n is 1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms a 5-, 6- or 7-membered heterocycloalkyl ring;
- SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is as defined above;
- O(CH2)n-G where n=1,2,3,4 and G represents SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, where R8 is as defined above;
- or
- tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;
- and
- when R7 represents C1-C6 alkyl, R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
- and
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C5-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- or
- R4 can represent methyl when R1 and R7 are lower alkyl;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6)alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms or NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
- toms or NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
- X represents a bond, CH2O, or CH═CH;
- and
- A, B, C, and D are the same or different and represent CH or N with the proviso that not more than two of A, B, C and D represent N.
27 more elements
A compound of the formula
- where
- R7 is C1-C6 alkyl;
- R1 represents benzyl optionally mono-, di-, or trisubstituted independently with
- halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy, or C1-C6 alkyl;
- or
- amino, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or di (C1-C6)alkylamino(C1-C6)alkoxy;
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C5-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- and
- X represents a bond or CH2O.
15 more elements
A compound of the formula:
- wherein:
- R7 represents C1-C6 alkyl;
- R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C5-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- or
- R4 can represent methyl when R1 and R7 are lower alkyl;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms or NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
- X represents a bond or CH2O.
14 more elements
A compound of the formula:
- wherein:
- R7 represents C1-C6 alkyl;
- R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C5-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- or
- R4 can represent methyl when R1 and R7 are lower alkyl;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms or NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
- X represents a bond or CH2O.
14 more elements
A compound of the formula
- where
- R1 represents benzyl optionally mono-, di-, or trisubstituted independently with
- halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy, or C1-C6 alkyl;
- or
- amino, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkoxy;
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C5-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- and
- X represents a bond or CH2O.
14 more elements
A compound of the formula:
- or pharmaceutically acceptable non-toxic salts thereof wherein:
- R7 represents H, or C1-C6 alkyl;
- when R7 is H, R1 is not 3-fluorobenzyl and R1 represents 2-, 3-, or 4-picolyl or benzyl, each of which is optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy, or C1-C6 alkyl;
- amino, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkoxy;
- —O(CH2)nCO2R8 where n is 1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms a 5-, 6- or 7-membered heterocycloalkyl ring;
- SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8 where R8 is as defined above;
- O(CH2)n—G where n=1,2,3,4 and G represents SO2R8, NHSO2R8, SO2NHR8, SO2NHCOR8, CONHSO2R8, where R8 is as defined above;
- or
- tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;
- when R7 represents C1-C6 alkyl, R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
- or
- R1 represents benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy, or C1-C6 alkyl;
- or amino, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkoxy;
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C5-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl;
- or
- NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- or
- R4 represents methyl when R1 and R7 are lower alkyl;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6)alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms;
- NR8R9 forms a 5-, 6- or 7-membered heterocyclic ring;
- X represents a bond, CH2O, or CH═CH;
- and
- A, B, C, and D are the same or different and represent CH or N with the proviso that not more than two of A, B, C and D represent N.
29 more elements
A compound of the formula
- where
- R7 is hydrogen C1-C6 alkyl;
- R1 represents benzyl optionally mono-, di-, or trisubstituted independently with
- halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy, or C1-C6 alkyl;
- or
- amino, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkoxy;
- R2 represents
- hydrogen or hydroxy;
- C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted with amino or mono- or di(C1-C6)alkylamino, C5-C7 cycloalkylamino or C1-C7 cycloalkoxy;
- or
- O(CH2)nCO2R8 where n=1,2,3,4, NR8COR9, COR8, CONR8R9 or CO2R8 where R8 and R9 are the same or different and represent hydrogen or C1-C6 alkyl or NR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
- R3 represents C1-C6 alkyl;
- R4 represents C1-C6 alkoxy;
- R5 and R6 are the same or different and represent
- hydrogen or halogen;
- or
- C1-C6 alkyl or C1-C6 alkoxy, the alkyl portion of each being optionally substituted with amino, mono- or di(C1-C6) alkylamino, or a C5-C7 heterocycloalkyl group where the heteroatom is nitrogen and the nitrogen is attached to the parent alkyl portion;
- and
- X represents a bond or CH2O.
16 more elements
Dependencies are inferred from the claim text.