Patent EA-002984-B1 (EA)
Title: Calcilytic compounds, pharmaceutical compositions and method of screening for calcilytic compounds
Inventor: VAN WANEGEN BRADFORD C
IPC: A61K31/135
Filed: 1997-04-04
Abstract: 1. A compound having the chemical formula:   wherein R1 is selected from the group consisting of: aryl, (C4-C20)-alkyl and and cycloalkyl; R2 is selected from the group consisting of: (C1-C4)-alkyl, cycloalkyl, alkoxy, H, OH, =O, C(O)OH, C(O)O-(C1-C4)-alkyl, C(O)NH-(C1-C4)-alkyl, C(O)N((C1-C4)-alkyl)2, SH, S-(C1-C4)-alkyl, NH2, NH-(C1-C4)-alkyl, and N((C1-C4)-alkyl)2; R3 and R4 is each independently (C1-C4)-alkyl or together cyclopropyl; R5 is either an optionally substituted naphthyl having one to four substituents independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, Cl, F, Br, and halo-(C1-C4)-alkoxy, or a substituted phenyl having one to four substituents with at least one substituent in a meta or para position selected from the group consisting of: (C1-C4)-alkyl, methoxy, Cl, F, Br, and lower halo-(C1-C4)-alkoxy, provided that said substituted phenyl may also have 2 to 3 additional substituents; R6 if present is either hydrogen, (C1-C4)-alkyl or (C2-C4)-alkenyl, wherein R6 is not present if R2 is =O; Y1 is either covalent bond, (C1-C6)-alkylene; Y2 is (C1-C6)-alkylene; Y3 is (C1-C6)-alkylene; Z is selected from the group consisting of: O, S, and alkylene, provided that if Z is either O or S, then Y1 is not a covalent bond; further provided that Y1 and Z may together be a covalent bond; provided that R1 is not 6-CN-2-pyridyl, substituted 6-CN-2-pyridyl or 3-CN-2-pyridyl or para-hydroxyphenyl or substituted para-hydroxyphenyl; further provided that if R1 is an optionally substituted phenyl, then its optional substituent is not benzyl (-CH2Ph); further provided that if R5 is a substituted phenyl, then it can not be 3,5-dimetoxyphenyl; further provided that if R5 is 3,5-dimetoxyphenyl, then R1 is not CH3(CH2)5O-phenyl; 2-cyclopentyl-phenyl; 2-Cl-phenyl; 2-CN-phenyl; 2-(3-furanyl)phenyl; or 4-(1,2,-benzisothiazol); further provided that if R5 is 4-methoxy-phenyl, then R1 is not 2-cyclopentyl-phenyl; 2-CH3-phenyl; 2-benzyl-phenyl; 3-CH3, 4-CH4SO2-phenyl;4-(1,2,-benzisothiazol); further provided that if R5 is 4-Cl-phenyl, then R1 is not 2-CH3-phenyl, 5-iso-propyl-phenyl; 2-CH3-phenyl; 4-CH3-phenyl; phenyl; 2-Cl-phenyl; 4-Cl-phenyl; 2-methoxy, 4-CH3CHCH-phenyl; 3,4-CH3-phenyl; 2,4-CH3-phenyl; 2,3-CH3-phenyl; 2-iso-propyl, 5-CH3-phenyl; pyridyl; 1-imidazole; or  4-(1, 2, -benzisothiazol); and further provided that if R5 is 3,5-dimethyl, 4-methoxy-phenyl, then R1 is not 4-CH3, 6-CN-2-pyridyl; or thiophenecarboxamide; and pharmaceutically acceptable salts thereof; wherein said compound has an IC50 < 10 μM using the Calcium Receptor Inhibitor Assay. 2. A compound having the chemical formula:   wherein R1 is either 2-CN-phenyl, 2,3-dichloro phenyl, 2-nitro-phenyl, 2-cyano-3-chloro-phenyl, an optionally substituted pyridyl, an optionally substituted benzothiopyranyl, an optionally carbazole, or (C4-C20)-alkyl; R2 is selected from the group consisting of: (C1-C4)-alkyl, cycloalkyl, (C1-C12)-alkoxy, H, OH, =O, C(O)OH, C(O)O-(C1-C4)-alkyl, C(O)NH-(C1-C4)-alkyl, C(O)N((C1-C4) alkyl)2, SH, S-(C1-C4)-alkyl, NH2, NH-(C1-C4)-alkyl, and N((C1-C4) (C1-C4)-alkyl)2; R3 and R4 is each independently (C1-C4)-alkyl or together cyclopropyl; R5 is either an optionally substituted naphthyl having one to four substituents independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, Cl, F, Br, and lower haloalkoxy, or a substituted phenyl having one to four substituents with at least one substituent in a meta or para position selected from the group consisting of: (C1-C4)-alkyl, methoxy, Cl, F, Br, and a halo-sibstituted alkoxy, comprising one carbon atom, provided that said substituted phenyl R5 may also have 2 to 3 additional substituents; R6 if present is either hydrogen, (C1-C4)-alkyl or (C2-C4)lower alkenyl, wherein R6 is not present if R2 is =O; Y1 is either covalent bond, (C1-C6)-alkylene or (C2-C6)-alkenylene; Y2 is (C1-C6)-alkylene; Y3 is (C1-C6)-alkylene; Z is selected from the group consisting of: covalent bond, O, S, N-(C1-C4)-alkyl, (C1-C6)-alkylene, (C2-C6)-alkenylene, and (C2-C6)-alkynylene, provided that if Z is either O, S, NH, or N-(C1-C4)-alkyl, then Y1 is not a covalent bond; further provided that Y1 and Z may together be a covalent bond; provided that R1 is not 6-CN-2-pyridyl, substituted 6-CN-2-pyridyl or 3-CN-2-pyridyl or para-hydroxyphenyl or substituted para-hydroxyphenyl; further provided that if R5 is a substituted phenyl, then it can not be 3,5-dimetoxyphenyl; and pharmaceutically acceptable salts and complexes thereof. 4. The compound of claim 2, wherein Y1 is methylene; Y2 is methylene; and Y3 is methylene. 5. The compound of claim 3, wherein R1 is either said optionally substituted pyridyl, said optionally substituted benzothiopyranyl, or said optionally carbazole wherein said optionally substituted pyridyl, said optionally substituted benzothiopyranyl, or said optionally carbazole is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: unsubstituted C1-C7 alkyl, C1-C7 alkoxy, halo-(C1-C4)-alkoxy, CF3, F, Cl, Br, CN, and NO2. 6. The compound of claim 3, wherein R1 is unsubstituted (C4-C20)-alkyl; (C4-C20)-alkyl, monosubstituted with an optionally substituted cycloalkyl having up to four substituents each independently selected from the group consisting of: alkoxy, (C1-C4)-haloalkyl, S-unsubstituted alkyl, (C1-C4)-haloalkoxy, unsubstituted alkyl, unsubstituted alkenyl, halogen, SH, CN, NO2, NH2 and OH; (C4-C20)-alkyl monosubstituted with an optionally substituted phenyl having up to four substituents each independently selected from the group consisting of: alkoxy, (C1-C4)-haloalkyl, S-unsubstituted alkyl, (C1-C4)-haloalkoxy, unsubstituted alkyl, unsubstituted alkenyl, halogen, SH, CN, NO2, NH2 and OH; ; or an optionally substituted cycloalkyl having up to four substituents each independently selected from the group consisting of: alkoxy, (C1-C4)-haloalkyl, S-unsubstituted alkyl, (C1-C4)-haloalkoxy, unsubstituted alkyl, unsubstituted alkenyl, halogen, SH, CN, NO2, NH2 and OH. 7. The compound of claim 6, wherein R1 is either unsubstituted (C4-C20)-alkyl or said optionally substituted cycloalkyl. 8. The compound of any of claims 2-7, wherein R2 is OH or methoxy, R6 is hydrogen, R2 and R4 is independently methyl or ethyl; and Z is O, S, or unsubstituted alkylene. 9. The compound of claim 8, wherein R1 is OH, and Z is O. 10. The compound of claim 8, wherein said compound is N-[2-hydroxy-3-(3-chloro-2-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine or a pharmaceutically acceptable salt thereof. 11. The compound of claims 2-7, wherein R2 is hydrogen, R6 is hydrogen, R3 and R4 is independently methyl or ethyl; and Z is O or methylene. 12. A pharmaceutical composition for treating a disease or disorder characterized by one or more of the following: (1) an abnormal bone or mineral homeostasis; (2) an abnormal amount of an extracellular or intracellular messenger which is ameliorated by a compound able to effect one or more calcium receptor activities; or (3) an abnormal effect of an intracellular or extracellular messenger which is ameliorated by a compound able to affect one or more calcium receptor activities, wherein said composition comprising a therapeutically effective amount of the calcilytic having the formula:   wherein R1 is selected from the group consisting of: aryl, (C4-C20)-alkyl and cycloalkyl; R2 is selected from the group consisting of: (C1-C4)-alkyl, cycloalkyl, alkoxy, H, OH, =O, C(O)OH, C(O)O-(C1-C4)-alkyl, C(O)NH-(C1-C4)-alkyl, C(O)N((C1-C4)-alkyl)2, SH, S-(C1-C4)-alkyl, NH2, NH-(C1-C4)-alkyl, and N((C1-C4)-alkyl)2; R3 and R4 is each independently (C1-C4)-alkyl or together cyclopropyl; R5 is aryl; R6 if present is either hydrogen, or (C1-C4)-alkyl or (C2-C4)-alkenyl, wherein R6 is not present if R2 is =O; Y1 is (C1-C6)-alkylene; Y2 is methulene; Y3 is (C1-C6)-alkylene; Z is selected from the group consisting of: O, S, and alkylene, provided that R1 is not 6-CN-2-pyridyl, substituted 6-CN-2-pyridyl or 3-CN-2-pyridyl or para-hydroxyphenyl or substituted para-hydroxyphenyl; or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or excipient. 13. The composition of claim 12, wherein said composition is used for treating a disease or disorder characterized by said abnormal bone or mineral homeostasis. 14. The composition of claim 12, wherein said composition is used for treating a disease or disorder is selected from the group consisting of: osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy, and osteoporosis. 15. The composition of claim 14, wherein said disease or disorder is osteoporosis. 16. A pharmaceutical composition comprising a calcilyc compoundin a theraputically effective amount sufficient to increase serum PTH level, said compound having the formula:   wherein R1 is selected from the group consisting of: aryl, (C4-C20)-alkyl and cycloalkyl; R2 is selected from the group consisting of: (C1-C4)-alkyl, cycloalkyl, alkoxy, H, OH, =O, C(O)OH, C(O)O-(C1-C4)-alkyl, C(O)NH-(C1-C4)-alkyl, C(O)N((C1-C4)-alkyl)2, SH, S-(C1-C4)-alkyl, NH2, NH-(C1-C4)-alkyl, and N((C1-C4)-alkyl)2; R3 and R4 is each independently (C1-C4)-alkyl or together cyclopropyl; R5 is aryl; R6 if present is either hydrogen, or (C1-C4)-alkyl or (C2-C4)-alkenyl, wherein R6 is not present if R2 is =O; Y1 is (C1-C6)-alkylene; Y2 is methulene; Y3 is (C1-C6)-alkylene; Z is selected from the group consisting of: O, S, and alkylene, provided that R1 is not 6-CN-2-pyridyl, substituted 6-CN-2-pyridyl or 3-CN-2-pyridyl or para-hydroxyphenyl or substituted para-hydroxyphenyl; or pharmaceutically acceptable salts thereof. 17. The composition of claim 16, wherein administering an amount of said compound effective to cause an increase having a duration of up to one hour. 18. The composition of claim 1