CA2397681A1 - Partially saturated calcium channel blockers - Google Patents
Partially saturated calcium channel blockers Download PDFInfo
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- CA2397681A1 CA2397681A1 CA002397681A CA2397681A CA2397681A1 CA 2397681 A1 CA2397681 A1 CA 2397681A1 CA 002397681 A CA002397681 A CA 002397681A CA 2397681 A CA2397681 A CA 2397681A CA 2397681 A1 CA2397681 A1 CA 2397681A1
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- 229940127291 Calcium channel antagonist Drugs 0.000 title 1
- 150000001669 calcium Chemical class 0.000 title 1
- 239000000480 calcium channel blocker Substances 0.000 title 1
- 125000003118 aryl group Chemical group 0.000 claims abstract 48
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract 42
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 28
- 150000001875 compounds Chemical class 0.000 claims abstract 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract 16
- 125000005843 halogen group Chemical group 0.000 claims abstract 16
- 125000005842 heteroatom Chemical group 0.000 claims abstract 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 10
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 claims abstract 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract 8
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract 8
- 150000003839 salts Chemical class 0.000 claims abstract 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 12
- 108090000312 Calcium Channels Proteins 0.000 claims 7
- 102000003922 Calcium Channels Human genes 0.000 claims 7
- 238000000034 method Methods 0.000 claims 7
- 230000002159 abnormal effect Effects 0.000 claims 6
- 230000000694 effects Effects 0.000 claims 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 5
- 239000000556 agonist Substances 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 3
- 102000004129 N-Type Calcium Channels Human genes 0.000 claims 2
- 108090000699 N-Type Calcium Channels Proteins 0.000 claims 2
- 230000004308 accommodation Effects 0.000 claims 2
- 102000004310 Ion Channels Human genes 0.000 claims 1
- 108090000862 Ion Channels Proteins 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000005557 antagonist Substances 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
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- Heart & Thoracic Surgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
Compounds of formula (1a) or (1b) or the salts thereof, wherein each Z is independently N or CH, but one Z must be N; wherein n1 is 1 and n2 is 0 or 1 ; X1 and X2 are linkers; Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings, and Cy represents one or two substituted o r unsubstituted aliphatic cyclic or heterocyclic rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring; each of Ya and Yb is two substituted or unsubstituted aromatic or heteroaromatic rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic rin gs or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring; with the proviso that said rings cannot both be phenyl when both Ar includes a single phenyl ring and X1 contains less than 5C; and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring; 11 is 0 or 1; R1 is substituted or unsubstituted alkyl (1- 6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstitut ed arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, S R, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, CN or NO2, wherein R is H or alkyl (1- 6C).
Claims (29)
1. Use of a compound of formula (1a) or (1b) in the preparation of a medicament for of treating conditions associated with abnormal N-type calcium channel activity in a subject, wherein said compound is of the formula or the salts thereof, wherein, each of Z1 and Z2 is independently N or CH, but one of Z1 and Z2 must be N;
wherein n1 is 1 acid n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y n cannot both be phenyl when A r represents a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring 1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
wherein n1 is 1 acid n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y n cannot both be phenyl when A r represents a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring 1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
2. The use of claim 1 wherein 1 1 is 0.
3. The use of claim 1 or 2 wherein the compound is of formula (1a) and Ar represents one or two unsubstituted phenyl moieties and wherein n2 is 1 and X2 represents a linker which spaces Ar from Z2 at a distance of 3-20.ANG..
4. The method of claim 3 wherein X2 contains at least one heteroatom selected from N and O, or wherein Ar represents one unsubstituted phenyl moiety and X2 represents -(CH2)1-8-or -(CH2)1-5-CH=CH-(CH2)0-3- or -NH(CH2)1-6-, or wherein Ar represents two phenyl moieties and X2 is of the formula -(CH2)0.6-CH.
5. The use of claim 1 or 2 wherein the compound is of formula (1b) and Cy represents one or two unsubstituted cyclohexyl moieties or an unsubstituted cyclohexyl moiety and an unsubstituted phenyl moiety, and wherein n2 is 1 and X2 represents a linker which spaces Cy from Z2 at a distance of 3-20.ANG..
6. The use of claim 5 wherein X2 contains at least one heteroatom selected from N
and O, wherein Cy is a cyclohexyl moiety, and X2 represents -(CH2)1-8-, -(CH2)1.5-CH=CH-(CH2)0-3- or -NH(CH2)~-6-, or wherein Cy represents two cyclohexyl moieties or a cyclohexyl moiety and a phenyl moiety, and X2 is -(CH2)0-6-CH-.
and O, wherein Cy is a cyclohexyl moiety, and X2 represents -(CH2)1-8-, -(CH2)1.5-CH=CH-(CH2)0-3- or -NH(CH2)~-6-, or wherein Cy represents two cyclohexyl moieties or a cyclohexyl moiety and a phenyl moiety, and X2 is -(CH2)0-6-CH-.
7. The use of claim 1 or 2 wherein X1 represents a linker which spaces the Y a and Y b from Z1 at a distance of 3-20.ANG..
8. The use of claim 7 wherein X1 contains at least one heteroatom selected from O
and N or wherein X1 represents CH(CH2)0-6 or -CH(CH2)1-6CO.
and N or wherein X1 represents CH(CH2)0-6 or -CH(CH2)1-6CO.
9. A pharmaceutical composition for use in treating conditions characterized by abnormal N-type calcium channel activity which composition comprises, in admixture with a pharmaceutically acceptable excipient, a dosage amount of a compound of the formula or the salts thereof, wherein, each of Z1 and Z2 is independently N or CH, but one of Z1 and Z2 must be N;
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are linkers;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic scale rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when both Ar represents a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently he halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, CN or NO2, wherein R is H or alkyl (1-6C).
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are linkers;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic scale rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when both Ar represents a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently he halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, CN or NO2, wherein R is H or alkyl (1-6C).
10. Use of a compound of formula (1a) or (1b) to prepare a medicament for treating conditions associated with abnormal calcium channel activity in a subject wherein said a compound is of the formula or the salts thereof, wherein, each of Z1 and Z2 is independently N or CH, but one of Z1 and Z2 must be N;
X1 is a linker that spaces Y a or Y b from Z1 a distance of 3-20.ANG., and X2 is selected from the group consisting of (CH2)1-8, (CH2)1-5CO(CH2)0-5, (CH2)1-5NH(CH2)0-3, (CH2)0-5CONH(CH2)0-3, -(CH2)0-5CH=CH(CH2)0-3- and (CH2)1-5NHCO(CH2)0-3, with accommodation as required for two rings;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when Ar represents a single phenyl ring, X1 contains less than 5C, and X2 is (CH2)1-8 or -(CH2)0-5CH=CH(CH2)0-3;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
X1 is a linker that spaces Y a or Y b from Z1 a distance of 3-20.ANG., and X2 is selected from the group consisting of (CH2)1-8, (CH2)1-5CO(CH2)0-5, (CH2)1-5NH(CH2)0-3, (CH2)0-5CONH(CH2)0-3, -(CH2)0-5CH=CH(CH2)0-3- and (CH2)1-5NHCO(CH2)0-3, with accommodation as required for two rings;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when Ar represents a single phenyl ring, X1 contains less than 5C, and X2 is (CH2)1-8 or -(CH2)0-5CH=CH(CH2)0-3;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
11. The use of claim 10 Wherein 1 1 is 0.
12. The use of claim 10 or 11 wherein the compound is of formula (1a) Ar represents one or two unsubstituted phenyl moieties.
13. The use of claim 12 wherein Ar represents one unsubstituted phenyl moiety and X2 represents -(CH2)1-8- or -(CH2)1-5-CH=CH-(CH2)0-3- or -NH(CH2)1-6-, or wherein Ar represents two phenyl moieties and X2 is of the formula -(CH2)0-6-CH.
14. The use of claim 10 or 11 wherein the compound is of formula (1b) and Cy represents one or two unsubstituted cyclohexyl moieties or an unsubstituted cyclohexyl moiety and an unsubstituted phenyl moiety.
15. The use of claim 14 wherein Cy is a cyclohexyl moiety, and X2 represents -(CH2)1-8-, -(CH2)1-5-CH=CH-(CH2)0-3- or -NH(CH2)1-6-, or wherein Cy represents two cyclohexyl moieties or a cyclohexyl moiety and a phenyl moiety, and X2 is -(CH2)0-6-CH-.
16. A pharmaceutical composition for use in treating conditions characterized by abnormal calcium channel activity which composition comprises, in admixture with a pharmaceutically acceptable excipient, a dosage amount of a compound of the formula or the salts thereof, wherein, each of Z1 and Z2 is independently N or CH, but one of Z1 and Z2 must be N;
X1 is a linker that spaces Y a or Y b from Z1 a distance of 3-20.ANG., and X2 is selected from the group consisting of (CH2)1-8, (CH2)1-5CO(CH2)0-3, (CH2)1-5NH(CH2)0-3, (CH2)0-5CONH(CH2)0-3, -(CH2)0-5CH=CH(CH2)0-3- and (CH2)1-5NHCO(CH2)0-3, with accommodation as required for two rings;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted of unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when Ar represents a single phenyl ring, X1 contains less than 5C, and X2 is (CH2)1-5 or -(CH2)0-5CH=CH(CH2)0-3-and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
X1 is a linker that spaces Y a or Y b from Z1 a distance of 3-20.ANG., and X2 is selected from the group consisting of (CH2)1-8, (CH2)1-5CO(CH2)0-3, (CH2)1-5NH(CH2)0-3, (CH2)0-5CONH(CH2)0-3, -(CH2)0-5CH=CH(CH2)0-3- and (CH2)1-5NHCO(CH2)0-3, with accommodation as required for two rings;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted of unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when Ar represents a single phenyl ring, X1 contains less than 5C, and X2 is (CH2)1-5 or -(CH2)0-5CH=CH(CH2)0-3-and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
17. Use of a compound of formula (1a) or (1b) for preparation of a medicament for treating conditions associated with abnormal calcium channel activity in a subject wherein compound is of the formula or the salts thereof, wherein, each of Z1 and Z2 is independently N or CH, but one of Z1 and Z2 must be N;
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted heteroaromatic single rings or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents two substituted or unsubstituted aliphatic cyclic single ring or one or two substituted or unsubstituted heterocyclic single rings, or consists of one substituted or ~substituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when both Ar represents a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted heteroaromatic single rings or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents two substituted or unsubstituted aliphatic cyclic single ring or one or two substituted or unsubstituted heterocyclic single rings, or consists of one substituted or ~substituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when both Ar represents a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
18. The use of claim 17 wherein 1 1 is 0.
19. The use of claim 12 or 18 wherein the compound is of formula (1a) and Ar represents two phenyl moieties, and n2 is 1 and X2 represents a linker which spaces Ar from Z2 at a distance of 3-20.ANG..
20. The use of claim 19 wherein X2 contains at least one heteroatom selected from N
and O, or wherein X2 is of the formula -(CH2)0-6-CH.
and O, or wherein X2 is of the formula -(CH2)0-6-CH.
21. The use of claim 17 or 18 wherein the compound is of formula (1b) and Cy represents two unsubstituted cyclohexyl moieties or an unsubstituted cyclohexyl moiety and an unsubstituted phenyl moiety, and wherein n2 is 1 and X2 represents a linker which spaces Cy from Z2 at a distance of 3-20.ANG..
22. The method of claim 21 wherein X2 contains at least one heteroatom selected from N and O, or wherein X2 is -(CH2)0-6-CH-.
23. The use of claim 17 wherein X1 contains at least one heteroatom selected from O
and N, or wherein X1 represents CH(CH2)0-6 or -CH(CH2)1-6CO.
and N, or wherein X1 represents CH(CH2)0-6 or -CH(CH2)1-6CO.
24. A pharmaceutical composition for use in treating conditions characterized by abnormal calcium channel activity which composition comprises, in admixture with a pharmaceutically acceptable excipient, a dosage amount of a compound of the formula or the salts thereof, wherein, each of Z1 and Z2 is independently N or CH, but one of Z1 and Z2 must be N;
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted heteroaromatic single rings or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents two substituted or unsubstituted aliphatic cyclic single ring or one or two substituted or unsubstituted heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when both Ar represents a single phenyl ring and X1 contains less than 5C:
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted heteroaromatic single rings or two substituted or unsubstituted aromatic or heteroaromatic single rings, and Cy represents two substituted or unsubstituted aliphatic cyclic single ring or one or two substituted or unsubstituted heterocyclic single rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic single rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic single rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic single ring and one substituted or unsubstituted aromatic or heteroaromatic single ring;
with the proviso that said rings of Y a cannot both be phenyl when both Ar represents a single phenyl ring and X1 contains less than 5C:
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (1-6C).
25. A library comprising at least ten different compounds of the formula or the salts thereof, wherein each Z is independently N or CH, but one Z must be N;
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic single ring or heterocyclic rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic rings or consists of one substituted or unsubstituted ~~phatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring;
with the proviso that said rings cannot both be phenyl when both Ar includes a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, CN or NO2, wherein R is H or alkyl (1-6C).
wherein n1 is 1 and n2 is 0 or 1;
X1 and X2 are straight chain linkers;
Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings, and Cy represents one or two substituted or unsubstituted aliphatic cyclic single ring or heterocyclic rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring;
each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic rings or consists of one substituted or unsubstituted ~~phatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring;
with the proviso that said rings cannot both be phenyl when both Ar includes a single phenyl ring and X1 contains less than 5C;
and with the proviso that formula (1b) must contain at least one aromatic or heteroaromatic ring;
1 1 is 0 or 1;
R1 is substituted or unsubstituted alkyl (1-6C), substituted or unsubstituted aryl (6-10C) or substituted or unsubstituted arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, CN or NO2, wherein R is H or alkyl (1-6C).
26. A method to identify a compound which antagonizes a target receptor which method comprises contacting host cells displaying said target receptor in the presence of an agonist for said receptor and with the members of the library of claim 25;
assessing the ability of the members of the library to affect the response of the receptor to its agonist; and identifying as an antagonist any member of the library which diminishes the response of the receptor to its agonist.
assessing the ability of the members of the library to affect the response of the receptor to its agonist; and identifying as an antagonist any member of the library which diminishes the response of the receptor to its agonist.
27. The method of claim 26 wherein the receptor is an ion channel
28. The method of claim 26 wherein the receptor is a calcium ion channel.
29. The method of claim 28 wherein the calcium ion channel is an N-type calcium ion channel.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17276599P | 1999-12-20 | 1999-12-20 | |
| US60/172,765 | 1999-12-20 | ||
| US47692999A | 1999-12-30 | 1999-12-30 | |
| US09/476,929 | 1999-12-30 | ||
| PCT/CA2000/001558 WO2001046166A2 (en) | 1999-12-20 | 2000-12-20 | Partially saturated calcium channel blockers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2397681A1 true CA2397681A1 (en) | 2001-06-28 |
| CA2397681C CA2397681C (en) | 2011-03-15 |
Family
ID=26868438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2397681A Expired - Fee Related CA2397681C (en) | 1999-12-20 | 2000-12-20 | Partially saturated calcium channel blockers |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1242398A2 (en) |
| JP (1) | JP2003518107A (en) |
| AU (1) | AU784848B2 (en) |
| CA (1) | CA2397681C (en) |
| MX (1) | MXPA02006137A (en) |
| NO (1) | NO326939B1 (en) |
| WO (1) | WO2001046166A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008031227A1 (en) * | 2006-09-14 | 2008-03-20 | Neuromed Pharmaceuticals Ltd. | Diaryl piperidine compounds as calcium channel blockers |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA200701782A3 (en) | 2003-04-24 | 2008-04-28 | Инсайт Корпорейшн | DERIVATIVES OF AZASPYROALKANES AS METHOD PROTEASIS INHIBITORS |
| BRPI0412263B1 (en) | 2003-07-22 | 2019-10-15 | Arena Pharmaceuticals, Inc. | Diaryl and aryl heteroaryl urea derivatives, use and pharmaceutical composition containing them, as well as process for preparing said composition |
| US7737163B2 (en) | 2004-06-15 | 2010-06-15 | Pfizer Inc. | Benzimidazolone carboxylic acid derivatives |
| BRPI0512046A (en) | 2004-06-15 | 2008-02-06 | Pfizer | benzimidazolone carboxylic acid derivatives |
| AU2005279600A1 (en) | 2004-08-30 | 2006-03-09 | Neuromed Pharmaceuticals Ltd. | Urea derivatives as calcium channel blockers |
| US7511077B2 (en) | 2005-02-09 | 2009-03-31 | Neuromed Pharmaceuticals Ltd. | Diamine calcium channel blockers |
| EA012615B1 (en) | 2005-02-22 | 2009-10-30 | Пфайзер Инк. | Oxyindole derivatives as 5htreceptor agonists |
| TWI415845B (en) | 2006-10-03 | 2013-11-21 | Arena Pharm Inc | Pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
| MY148880A (en) | 2006-10-20 | 2013-06-14 | Astrazeneca Ab | N-(2-hydroxyethyl)-n-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide, the process of making it as well as its use for the treatment of pain, anxiety and depression |
| EP2190844B3 (en) | 2007-08-15 | 2013-07-17 | Arena Pharmaceuticals, Inc. | Imidazo[1,2-a]pyridine derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
| WO2009123714A2 (en) | 2008-04-02 | 2009-10-08 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-ht2a serotonin receptor |
| CA2741731A1 (en) | 2008-10-28 | 2010-06-03 | Arena Pharmaceuticals, Inc. | Compositions of a 5-ht2a serotonin receptor modulator useful for the treatment of disorders related thereto |
| US9126946B2 (en) | 2008-10-28 | 2015-09-08 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto |
| JP5841529B2 (en) * | 2010-05-27 | 2016-01-13 | あすか製薬株式会社 | Heterocyclic compounds and H1 receptor antagonists |
| CN107548387B (en) | 2015-04-28 | 2020-08-25 | 荷兰联合利华有限公司 | N-arylalkyl carbonyldiamine compounds and personal care compositions containing them |
| MX379822B (en) * | 2015-04-28 | 2025-03-11 | Unilever Ip Holdings B V | N-aralkylcarbonyl-piperazine and -homopiperazine compounds and personal care compositions comprising the same |
| EP4119141A1 (en) | 2015-06-12 | 2023-01-18 | Axovant Sciences GmbH | Nelotanserin for the prophylaxis and treatment of rem sleep behavior disorder |
| EP3322415A4 (en) | 2015-07-15 | 2019-03-13 | Axovant Sciences GmbH | ARYLHERETOARYL UREA DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONINERGIC RECEPTOR USEFUL FOR THE PROPHYLAXIS AND TREATMENT OF HALLUCINATIONS ASSOCIATED WITH NEURODEGENERATIVE DISEASE |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5703071A (en) * | 1990-08-29 | 1997-12-30 | Pharmacia & Upjohn Company | Tropolone derivatives and pharmaceutical composition thereof for preventing and treating ischemic diseases |
| DE4111861A1 (en) * | 1991-04-11 | 1992-10-15 | Schwabe Willmar Gmbh & Co | BENZOPYRANONE, PROCESS FOR THEIR PREPARATION AND USE |
| US5292726A (en) * | 1991-05-22 | 1994-03-08 | Merck & Co., Inc. | N,N-diacylpiperazines |
| JP3150155B2 (en) * | 1993-12-08 | 2001-03-26 | アルコン ラボラトリーズ，インコーポレイテッド | Compounds having both potent calcium antagonistic and antioxidant activities and their use as cytoprotective agents |
| WO1998057643A1 (en) * | 1997-06-16 | 1998-12-23 | Janssen Pharmaceutica N.V. | Use of draflazine-analogues for treating pain |
| AU1600599A (en) * | 1998-02-27 | 1999-09-15 | Warner-Lambert Company | Heterocyclic substituted aniline calcium channel blockers |
| US6011035A (en) * | 1998-06-30 | 2000-01-04 | Neuromed Technologies Inc. | Calcium channel blockers |
-
2000
- 2000-12-20 AU AU24957/01A patent/AU784848B2/en not_active Ceased
- 2000-12-20 MX MXPA02006137A patent/MXPA02006137A/en unknown
- 2000-12-20 JP JP2001547077A patent/JP2003518107A/en active Pending
- 2000-12-20 CA CA2397681A patent/CA2397681C/en not_active Expired - Fee Related
- 2000-12-20 EP EP00988532A patent/EP1242398A2/en not_active Withdrawn
- 2000-12-20 WO PCT/CA2000/001558 patent/WO2001046166A2/en not_active Ceased
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2002
- 2002-06-19 NO NO20022948A patent/NO326939B1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008031227A1 (en) * | 2006-09-14 | 2008-03-20 | Neuromed Pharmaceuticals Ltd. | Diaryl piperidine compounds as calcium channel blockers |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20022948L (en) | 2002-08-19 |
| NO20022948D0 (en) | 2002-06-19 |
| CA2397681C (en) | 2011-03-15 |
| AU2495701A (en) | 2001-07-03 |
| JP2003518107A (en) | 2003-06-03 |
| AU784848B2 (en) | 2006-07-06 |
| WO2001046166A2 (en) | 2001-06-28 |
| MXPA02006137A (en) | 2002-12-05 |
| NO326939B1 (en) | 2009-03-16 |
| WO2001046166A3 (en) | 2002-03-07 |
| EP1242398A2 (en) | 2002-09-25 |
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