Title:
CALCIUM CHANNEL BLOCKERS
Document Type and Number:
WIPO Patent Application WO2000001375
Kind Code:
A3
Abstract:
Compounds of formula (1) wherein m is 0, 1 or 2; wherein when m is 0, Z is 0; when m is 1, Z is N, and when m is 2, Z is C; Y is H, OH, NH2, or an organic moiety of 1-20C, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S and halo; each 1<1> and 1<2> is independently 0-5; 1<3> is 0 or 1; each of R<1>, R<2> and R<3> is independently alkyl (1-6C), aryl (6-10C) or arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R<1> and R<2> may independently be halo, COOR, CONR2, CF3, CN or NO2, wherein R is H or lower alkyl (1-4C) or alkyl (1-6C); n is 0 or 1; X is a linker; with the proviso that Y is not a tropolone, a coumarin, or an antioxidant containing an aromatic group and with the further proviso that if 1<3> is 0, neither R<1> nor R<2> can represent F in the para position; and are useful as calcium channel blockers. Libraries of these compounds can also be used to identify antagonists for other targets.
Inventors:
SNUTCH TERRANCE PRESTON (CA)
ZAMPONI GERALD WERNER (CA)
ZAMPONI GERALD WERNER (CA)
Application Number:
PCT/CA1999/000612
Publication Date:
August 31, 2000
Filing Date:
June 30, 1999
Export Citation:
Assignee:
NEUROMED TECH INC (CA)
SNUTCH TERRANCE PRESTON (CA)
ZAMPONI GERALD WERNER (CA)
SNUTCH TERRANCE PRESTON (CA)
ZAMPONI GERALD WERNER (CA)
International Classes:
C12Q1/02; A61K31/4427; A61K31/445; A61K31/4468; A61K31/451; A61K31/4515; A61K31/454; A61K31/4545; A61K31/495; A61K31/496; A61K31/498; A61K31/506; A61K31/535; A61K31/5375; A61K31/538; A61K31/5415; A61P9/00; A61P9/10; A61P9/12; A61P25/00; A61P25/04; A61P25/08; A61P29/00; A61P43/00; C07D211/14; C07D211/16; C07D211/46; C07D211/58; C07D239/42; C07D241/04; C07D295/02; C07D295/03; C07D295/18; C07D295/22; C07D401/04; C07D401/14; (IPC1-7): A61K31/495; A61K31/535; A61K31/435
Domestic Patent References:
| WO1999025686A1 | 1999-05-27 | |||
| WO1999015129A2 | 1999-04-01 |
Foreign References:
| US4918073A | 1990-04-17 | |||
| ES514167A | ||||
| ES504202A | ||||
| EP0187524A2 | 1986-07-16 | |||
| US4188485A | 1980-02-12 | |||
| US5646149A | 1997-07-08 | |||
| US5428038A | 1995-06-27 | |||
| US5703071A | 1997-12-30 | |||
| EP0458387A1 | 1991-11-27 | |||
| US3288795A | 1966-11-29 | |||
| GB1513883A | 1978-06-14 |
Other References:
VADODARIA, D.J. ET AL: "Synthesis and central nervous system depressant activity of new piperazine derivatives and related compounds. II", THE JOURNAL OF MEDICINAL CHEMISTRY, vol. 12, 1969, pages 860 - 865, XP000867847
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002133053
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002133054
GRANTHAM, C.J. ET AL: "Fluspirilene block of N-type calcium current in NGF-differentiated PC12 cells", BRITISH JOURNAL OF PHARMACOLOGY, vol. 111, no. 2, 1994, pages 483 - 488, XP000874810
GOULD, R.J. ET AL: "Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 80, 1983, USA, pages 5122 - 25, XP000867760
KING, V.F. ET AL: "Substituted diphenylbutylpiperidines bind to a unique high affinity site on the L-type calcium channel", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 264, no. 10, 1989, pages 5633 - 5641, XP000867759
ESTEP, K.G. ET AL: "Synthesis and structure-activity relationships of 6-heterocyclic-substituted purines as inactivation modifiers of cardiac sodium channels", JOURNAL OF MEICINAL CHEMISTRY, vol. 38, no. 14, 1995, pages 2582 - 2595, XP000867801
GLAMKOWSKI, E.J. ET AL: "Synthesis of 3-(4-acylaminopiperazin-1-ylalkyl)indoles as potential antihypertensive agents", THE JOURNAL OF MEDICINAL HEMISTRY, vol. 20, no. 11, 1977, pages 1485 - 1489, XP000867800
OHTAKA, H. ET AL: "Benzylpiperazine derivatives. IV. Syntheses and cerebral vasodilating activities of 1-benzyl-4-diphenylmethylpiperazine derivatives", CHEM. PHARM. BULL., vol. 35, no. 8, 1987, pages 3270 - 3275, XP000867798
OHTAKA, H. ET AL: "Benzylpiperazine derivatives. V. Quantitative structure-activity relationships of 1-benzyl-4-diphenylmethylpiperazine derivatives for cerebral vasodilating activity", CHEM. PHARM. BULL., vol. 35, no. 10, 1987, pages 4117 - 4123, XP000867799
MIYANO, S. ET AL: "The synthesis and antilipidperoxidation activity of 4,4-dibutylamines and 4,4-dibutanamides", CHEM. PHARM. BULL., vol. 38, no. 6, 1990, pages 1570 - 1574, XP000867852
PRASAD, R.J. ET AL: "Potential antihypertensive agents. II. Unsymmetrically 1,4-disubstituted piperazines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 11, no. 6, 1968, pages 1144 - 1150, XP002133052
TYTGAT, J. ET AL: "Flunarizine inhibits a high threshold inactivating calcium channel (N-type) in isolated hippocampal neurons", BRAIN RESEARCH, vol. 549, no. 1, 1991, pages 112 - 117, XP000874651
COHAN, S.L. ET AL: "Depolarization-induced presynaptic calcium accumulation may occur by an N-type channel that is blocked by flunarizine", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 635, 1991, pages 397 - 399, XP000874652
UNEYAMA, H. ET AL: "Non-L-type actions of organic Ca2+ channel blockers: Implications for Na+ and N-type Ca2+ channels blockades", CALCIUM ION MODULATORS, SEL. PAP. SATELL. SYMP., 1998, pages 13 - 23, XP000874711
DATABASE WPI Week 9711, Derwent World Patents Index; AN 1997-115265, XP002133055
LEHMANN, J. ET AL: "Zur struktur und Pharmakologie gamma-lactonverbrückter Diphenylalkylamine", ARCHIV DER PHARMAZIE, vol. 321, no. 11, 1988, pages 807 - 12, XP000874763
DHAINAUT, A. ET AL: "New triazine derivatives as potent modulators of multidrug resistance", THE JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 13, 1992, pages 2481 - 2496, XP000867846
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002133053
DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002133054
GRANTHAM, C.J. ET AL: "Fluspirilene block of N-type calcium current in NGF-differentiated PC12 cells", BRITISH JOURNAL OF PHARMACOLOGY, vol. 111, no. 2, 1994, pages 483 - 488, XP000874810
GOULD, R.J. ET AL: "Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 80, 1983, USA, pages 5122 - 25, XP000867760
KING, V.F. ET AL: "Substituted diphenylbutylpiperidines bind to a unique high affinity site on the L-type calcium channel", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 264, no. 10, 1989, pages 5633 - 5641, XP000867759
ESTEP, K.G. ET AL: "Synthesis and structure-activity relationships of 6-heterocyclic-substituted purines as inactivation modifiers of cardiac sodium channels", JOURNAL OF MEICINAL CHEMISTRY, vol. 38, no. 14, 1995, pages 2582 - 2595, XP000867801
GLAMKOWSKI, E.J. ET AL: "Synthesis of 3-(4-acylaminopiperazin-1-ylalkyl)indoles as potential antihypertensive agents", THE JOURNAL OF MEDICINAL HEMISTRY, vol. 20, no. 11, 1977, pages 1485 - 1489, XP000867800
OHTAKA, H. ET AL: "Benzylpiperazine derivatives. IV. Syntheses and cerebral vasodilating activities of 1-benzyl-4-diphenylmethylpiperazine derivatives", CHEM. PHARM. BULL., vol. 35, no. 8, 1987, pages 3270 - 3275, XP000867798
OHTAKA, H. ET AL: "Benzylpiperazine derivatives. V. Quantitative structure-activity relationships of 1-benzyl-4-diphenylmethylpiperazine derivatives for cerebral vasodilating activity", CHEM. PHARM. BULL., vol. 35, no. 10, 1987, pages 4117 - 4123, XP000867799
MIYANO, S. ET AL: "The synthesis and antilipidperoxidation activity of 4,4-dibutylamines and 4,4-dibutanamides", CHEM. PHARM. BULL., vol. 38, no. 6, 1990, pages 1570 - 1574, XP000867852
PRASAD, R.J. ET AL: "Potential antihypertensive agents. II. Unsymmetrically 1,4-disubstituted piperazines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 11, no. 6, 1968, pages 1144 - 1150, XP002133052
TYTGAT, J. ET AL: "Flunarizine inhibits a high threshold inactivating calcium channel (N-type) in isolated hippocampal neurons", BRAIN RESEARCH, vol. 549, no. 1, 1991, pages 112 - 117, XP000874651
COHAN, S.L. ET AL: "Depolarization-induced presynaptic calcium accumulation may occur by an N-type channel that is blocked by flunarizine", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 635, 1991, pages 397 - 399, XP000874652
UNEYAMA, H. ET AL: "Non-L-type actions of organic Ca2+ channel blockers: Implications for Na+ and N-type Ca2+ channels blockades", CALCIUM ION MODULATORS, SEL. PAP. SATELL. SYMP., 1998, pages 13 - 23, XP000874711
DATABASE WPI Week 9711, Derwent World Patents Index; AN 1997-115265, XP002133055
LEHMANN, J. ET AL: "Zur struktur und Pharmakologie gamma-lactonverbrückter Diphenylalkylamine", ARCHIV DER PHARMAZIE, vol. 321, no. 11, 1988, pages 807 - 12, XP000874763
DHAINAUT, A. ET AL: "New triazine derivatives as potent modulators of multidrug resistance", THE JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 13, 1992, pages 2481 - 2496, XP000867846
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