Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors
First Claim
Patent Images
1. A compound of the formula:
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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.
1 Assignment
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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.
63 Citations
51 Claims
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1. A compound of the formula:
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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;
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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;
ortetrazole, 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;
orO(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;
orR4 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. - View Dependent Claims (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)
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2. 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;
oramino, 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;
orO(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. - View Dependent Claims (3, 4, 5, 6, 7, 8)
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9. A compound of the formula:
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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;
orO(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;
orR4 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. - View Dependent Claims (10, 11, 12, 13, 14, 15, 16)
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17. A compound of the formula:
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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;
orO(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;
orR4 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. - View Dependent Claims (18, 19, 20, 21, 22, 23, 24)
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25. 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;
orO(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. - View Dependent Claims (26, 27, 28, 29)
- or
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42. A compound of the formula:
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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;
ortetrazole, triazole, imidazole, thiazole, oxazole, thiophene, or pyridyl;
when R7 represents C1-C6 alkyl, R1 represents C1-C6 alkyl, cyclopentyl, or cyclopropylmethyl;
orR1 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;
orO(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;
orNR8R9 forms 5-, 6-, or 7-membered heterocyclic ring;
R3 represents C1-C6 alkyl;
R4 represents C1-C6 alkoxy;
orR4 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. - View Dependent Claims (43, 44, 45, 46, 47, 48)
contacting with the sample a detectably-labeled compound of claim 42 under conditions that permit binding of the compound to the receptors, washing the sample to remove unbound compound, and detecting the bound compound.
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44. The method of claim 43, wherein the receptors modulate blood glucose levels.
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45. The method of claim 43, wherein the receptors are GLP-1 receptors.
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46. A pharmaceutical composition comprising a compound as claimed in claim 42 and a pharmaceutically acceptable carrier or excipient.
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47. A method of treating diabetes, comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 42, or a pharmaceutically acceptable salt thereof.
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48. A method of treating obesity or eating disorders, comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 42, or a pharmaceutically acceptable salt thereof.
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49. 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;
oramino, 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;
orO(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;
orC1-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. - View Dependent Claims (50, 51)
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Specification
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Current AssigneeNeurogen Corporation (Ligand Pharmaceuticals, Inc.)
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Original AssigneeNeurogen Corporation (Ligand Pharmaceuticals, Inc.)
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InventorsHutchison, Alan, DeSimone, Robert W.
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Primary Examiner(s)DENTZ, BERNARD I
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Application NumberUS09/539,835Time in Patent Office494 DaysField of Search548/309.7, 548/252, 548/266.4, 546/118, 546/273.4, 544/236, 544/335, 544/350, 514/303, 514/338, 514/394, 436/63US Class Current514/303CPC Class CodesC07D 235/14 Radicals substituted by nit...C07D 471/04 Ortho-condensed systemsG01N 2333/72 for hormones for neuromedia...
