WO2004087172A1 - T型カルシウムチャネル阻害剤 - Google Patents
T型カルシウムチャネル阻害剤 Download PDFInfo
- Publication number
- WO2004087172A1 WO2004087172A1 PCT/JP2004/004432 JP2004004432W WO2004087172A1 WO 2004087172 A1 WO2004087172 A1 WO 2004087172A1 JP 2004004432 W JP2004004432 W JP 2004004432W WO 2004087172 A1 WO2004087172 A1 WO 2004087172A1
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- WO
- WIPO (PCT)
- Prior art keywords
- group
- substituted
- calcium channel
- type calcium
- alkyl
- Prior art date
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- 239000003205 fragrance Substances 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
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- A61P9/08—Vasodilators for multiple indications
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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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Definitions
- the present invention relates to a T-type calcium channel inhibitor which is an optically active dihydropyridine-1-5-phosphonate derivative in which the absolute configuration at the 4-position of the dihydropyridine ring is R-configuration, and also relates to a disease in which the T-type calcium channel inhibitor is effective. It relates to therapeutic or prophylactic drugs. Background art
- Dihydropyridine-15-phosphonate derivative shows oral antihypertensive effects and is known to be effective in improving circulatory diseases such as angina pectoris, cerebrovascular disorders and hypertension (See, for example, Patent Documents 1 to 7.)
- the above effects are mainly due to vasodilatory effects based on L-type calcium channel inhibitory effects, and are similar to many other L-type calcium antagonists including 1,4-dihydropyridine derivatives.
- T-type calcium channels Inhibitors include cardiac hypertrophy (see, for example, Non-Patent Document 2), heart failure (for example, see Non-Patent Document 2), cardiomyopathy (for example, see Non-Patent Document 3), atrial fibrillation And other tachyarrhythmias (for example, see Non-patent Document 4), arteriosclerosis (for example, see Non-Patent Document 5), nephritis and kidney disorders including nephropathy (for example, see Non-Patent Document 6) ), Renal failure (for example, see Non-Patent Document 6), inflammation and edema (for example, see Non-Patent Document 7), hyperaldosteronemia (for example, see Non-Patent Document 8), neuropathy It has been reported to be involved in the development of sexual pain (see, for example, Non-Patent Document 9) and epilepsy (for example, see Non-Patent Document 10), and thus, T-type calcium channels Inhibitors are believed to be effective in treating or
- Patent Document 1 JP-A-61-30591
- Patent Document 2 JP-A-60-69089
- Patent Document 3 JP-A-01-275591
- Patent Document 4 JP-A-61-63688
- Patent Document 5 JP-A-63-233992
- Patent Document 6 Japanese Patent Application Laid-Open No. 62-169795
- Patent Document 7 JP-A-62-169796
- Non-patent document 1 Masumiya H et al .: Eur J Pharmacol 335, p.15-21 (1997)
- Non-patent document 2 Mulder P et al .: J Am Coll Cardiol 29, p.416-421 (1997)
- Non Patent document 3 Villame J et al .: Cardiovasc Drugs Ther 15, p.41-48 (2001)
- Non-patent document 4 Fareh S et al .: Circulation 100, p.2191-2197 (1999)
- Non-patent document 5 Noll G and Luscher TF: Cardiology 89, p.10-15 (1998)
- Non-Patent Document 6 Baylis C et al .: Am J Kidney Dis 38 p.1292-1297 (2001)
- Non-Patent Document 7 Bilici D et al .: Pharmacol Res 44, p.527-531 (2001)
- Non-patent document 8 Lenglet S et al .: Endocri
- T-type calcium channel inhibitor comprising the formula (1)
- R 1 and R 2 are each independently a C ⁇ 6 alkyl group ⁇ 0 ⁇ 6 alkyl group, a phenyl group (the phenyl group is substituted by a C- 6 alkoxy group or a halogen atom) .
- C 2 "6 Arukeeru group or C 2 - 6 alkynyl group (said C 2 one 6 Aruke - Le group ⁇ Pi C 2 _ 6 alkynyl group, Fuweeru group (said Fuweniru group, 6 alkoxy Or 1 L 1 — NR 3 R 4 ⁇ R 3 and R 4 may be substituted with a group or a halogen atom.
- the C 6 alkyl group is a phenyl group (the phenyl group may be substituted with a C-e alkoxy group or a halogen atom. ) good be replacement by Les,.) or phenyl group (said phenyl group is location one 6 alkoxy group or a halogen atom By means also may) have, L 1 is, C 2 one 6 alkylene group (said C 2 -.
- R9R 1 primary or one CR 5 R 6 - CR 7 R 8 - CR 9 R 10 - CR "R 12 - (R, 5 Each R 12 independently represents a hydrogen atom or an alkyl group, or any two may be taken together to form a 5-, 6- or 7-membered ring with a carbon atom which is substituted; . ) Means
- X 1 and X 2 are each independently, O or NR 13 (R 13 means a hydrogen atom or a ⁇ preparative 6 alkyl group.) Means,
- Ar is a phenyl group, a pyridyl group, a furyl group or a 2,1,3-benzoxodiazole-4-yl group ⁇ the phenyl group, the pyridyl group, the furyl group and the 2,1,3-benzoxodiazol-1-yl group; I le group, N0 2, CF 3, B r, Cl, F, R (R denotes a C 2 0 alkyl group.), OH, OR 14 ( R 14 is means the Ji 6 alkyl group ), OCHF 2 , COOR 14 , NH 2 , NHR 14 , NR 14 R 15 (R 15 means a C- 6 alkyl group.), CONH 2 , CONHR 14 , CONR 14 R 15 , COSR 14 , SR 14, S ( ⁇ ) R 14, S (0) 2 R 14, S_ ⁇ 3 H, S0 3 R ", S 0 2 NH 2, S_ ⁇ 2 NHR 14, S 0 2 NR 14 R 15, CN And optional
- R a and R b are each independently a —6 alkyl group
- one L 2 — NR 16 R 17 ⁇ R 16 and R 17 are each independently a hydrogen atom
- a 6 alkyl group (the 6 alkyl group is Or a phenyl group (the phenyl group may be substituted by a 6- alkoxy group or a halogen atom).) Or a phenyl group (the phenyl group is a 6- alkoxy group or .
- L 2 is, C 2 _ 6 alkylene group (said C 2 - 6 alkylene group, C 3 alkyl group or full E - le group (said Fuweniru group May be optionally substituted with a halogen atom, a 1 to 3 alkyl group or a 1 to 3 alkoxy group.).
- Y is C— 2 .
- Alkyl group (said Ji:.. ⁇ Alkyl group, phenyl group (said Fuweniru group, which may be substituted by C _ 6 alkoxy groups or halogen atoms), C 2 _ 6 Aruke - group or C 2 6 alkyl - Le group (said C 2 6 alkenyl Moto ⁇ Piji 2 - 6 Arukini le group, phenyl group (said Fuweniru group is substituted by Ci 6 alkoxy group or a halogen atom May be substituted with a).).
- ⁇ Alkyl group (said Ji:.. ⁇ Alkyl group, phenyl group (said Fuweniru group, which may be substituted by C _ 6 alkoxy groups or halogen atoms), C 2 _ 6 Aruke - group or C 2 6 alkyl - Le group (said C 2 6 alkenyl Moto ⁇ Piji 2 -
- L 3 is C 2 6 alkylene group (the C 2 _ 6 alkylene group , DOO 3 alkyl group or Fueyuru group (said Fuweniru group, a halogen atom, ⁇ 3 alkyl or - 3 alkoxy group may be arbitrarily substituted with.). the may be optionally substituted by).
- An optically active 1,4-dihydropyridine compound represented by the formula: pharmaceutically acceptable salt or solvate thereof, a T-type calcium channel inhibitor;
- Y is one L 3 - NR 18 R 19 ⁇ R 18 ⁇ Pi R 19 are each independently, 6 Al kill group (the C Bok 6 alkyl group, phenyl group (said phenyl group is C bets 6 May be substituted with an alkoxy group or a halogen atom.) Or a phenyl group (the phenyl group may be substituted with a C 6 alkoxy group or a halogen atom).
- L 3 is a C 26 alkylene group (the C 26 alkylene group is a C ⁇ 3 alkyl group or a phenyl group (the phenyl group is a halogen atom, It may be optionally substituted by an alkyl group or a C- 3 alkoxy group. ) May optionally be substituted. ) Means ⁇ ,
- R a is an alkyl group.
- R b is alkyl group, an optically active 1 according to 2.
- CN or NH 2 4 Jihi Doropirijin compound, a pharmaceutically acceptable salt thereof or T-type calcium Channel Inhibition is solvates Agent,
- Y is. Alkyl group ⁇ the formula 1 — 2 . Alkyl group, phenyl group ( ⁇ Fu Eniru groups, C i 6 may be substituted with an alkoxy group or a C port Gen atom.), C 2 _ 6 alkenyl or C 2 _ 6 alkynyl group (said C 2 _ 6 Aruke - Le group ⁇ Pi C 2 _ 6 ⁇ Rukiniru group, Hue - Le group (. the Fuweniru group, the C 6 may be substituted by an alkoxy group or a halogen atom) with optionally substituted .) May be substituted.
- R b is _L 2 —NR 16 R 17 ⁇ R 16 and R 17 are each independently a hydrogen atom, a C 6 alkyl group (the alkyl group is a phenyl group (the Fuweniru groups CI_ 6 alkoxy group or may be substituted with a halogen atom.) may be substituted with.) or phenyl group (said phenyl group is substituted with C 6 alkoxy group or a C androgenic atoms even if it is.) means, L 2 is C 2 _ 6 alkylene group (the C 2 _ 6 alkylene group, C 3 alkyl group or a phenyl group (said phenyl group is Nono port Gen atom, C _ Optionally substituted by 3 alkyl groups or C 3 alkoxy groups You can.
- R 1 and R 2 are each independently a C 6 alkyl group (the ⁇ alkyl group is a phenyl group (the phenyl group may be substituted with a 6 alkoxy group or a halogen atom); 2 - 6 alkenyl group or C 2 - 6 alkynyl group (said C 2 - 6 an alkenyl group and a C 2 - 6 alkyl - le group, phenyl group (said Fuweniru group is a C bets 6 alkoxy group or a halogen atom Or R 1 and R 2 may be combined together to form one CR 5 R 6 — CR 7 R 8 - one CR 5 R 6 - CR 7 R 8 -.
- CR9R 1 one or one CR 5 R 6 - CR 7 R 8 -CR 9 R 10 -CR n R 12 -
- R 5 to R 12 are each independently May mean a hydrogen atom or an alkyl group, or any two of them may together form a 5-, 6- or 7-membered ring with a substituted carbon atom.
- X 1 and X 2 are, 2. an O together 3. or optically active 1 according to 4., 4-dihydropyridine compound, it is a pharmaceutically acceptable salt or solvate thereof T-type calcium channel inhibitor
- R 1 and R 2 together are _CH 2 —C (CH 3 ) 2 —CH 2 —, X 1 and X 2 are both O, Ar is 3-ditrophenyl, 6.
- a medicament comprising the T-type potentione channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for a disease in which a ⁇ -type calcium channel inhibitory effect is effective comprising the T-type calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for cardiac hypertrophy comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for heart failure comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for cardiomyopathy comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for atrial fibrillation comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for tachyarrhythmia comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for arteriosclerosis comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for nephritis comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for nephropathy comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for renal impairment comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for renal failure comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for edema comprising the type I calcium channel inhibitor according to any of 1. to 7.
- a therapeutic or prophylactic agent for inflammation comprising the type I potentium channel inhibitor according to any of 1. to 7.
- a therapeutic or preventive agent for hyperaldosteronemia comprising the type I calcium channel inhibitor according to any one of 1. to 7.
- a therapeutic or prophylactic agent for epilepsy comprising the T-type potentione channel inhibitor according to any of 1 to 7.
- n represents normal, “i” represents iso, ⁇ s J represents secondary, “t” represents tertiary, and “c” represents cyclo.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the ⁇ bets 3 alkyl group may be straight-chain, branched or C 3 cycloalkyl group, for example, methyl group, Echiru group, n- propyl group, i one propyl Moto ⁇ Pi c- propyl group and the like .
- the C ⁇ e alkyl group straight chain, may shall apply branched or ⁇ 3 _ 6 cycloalkyl group, for example, in addition to the substituents listed in the alkyl group, n- butyl group,
- the alkyl group a linear, branched or C 3 - 2. It may be a cycloalkyl group, for example, an n-heptyl group,
- alkenyl group include a straight-chain or branched, Eparu group, 1 - propenyl, 2 _ propenyl group, 1 one methyl one 1 - Eparu group, 1-Buteninore group, 2 —Butyr, 3-butyr, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethylethylenyl, 1-methyl-1-propenyl, 1-methyl— 2— Probel group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-n-propylethenyl group, 1-methyl-11-butenyl group, 1-methyl-2-butenyl Group, 1-methyl-3-butenyl group, 2-ethyl-2-propenyl group, 2-methyl_1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-13-butenyl group, 3- Methyl-1-butenyl group, 3-methyl-1-butenyl group
- the C 2 _ 6 alkynyl group includes straight-chain or branched ones, such as ethynyl group, 1-propyl group, 2-propynyl group, 1-butynyl group, 2-buturyl group, 3-butyl group, 1 -Methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group,
- the 3 alkoxy group may be a linear, branched or c 3 cycloalkoxy group, and includes, for example, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group and a c_propoxy group. .
- the Flip alkoxy group, a linear, branched or C 3 - 6 may be a cycloalkoxy group, for example, in addition to the substituents listed above C Bok 3 alkoxy group, n- butoxy group, i one butoxy group , S-butoxy group, t-butoxy group, c-butoxy group, n-pentyloxy group, 1-methinole_n-butoxy group, 2-methinole n-butoxy group, 3-methyl_n-butoxy group, 1,1_ Dimethyl n-propoxy, c-pentyloxy group, 2-methyl-c-butoxy group, ⁇ -hexyloxy group, 1_methyl-1- ⁇ -pentyloxy group, 2-methylino- ⁇ -pentynoleoxy group, 1,1-dimethyl- ⁇ -butoxy group Group, 1_ethyl_ ⁇ -butoxy group, 1,1,2-trimethinoleh ⁇ -propoxy group, c-hexinoleoxy group
- Examples of the 5-, 6- or 7-membered ring include c-pentyl, c-hexyl and c-heptyl.
- R 1 and R 2 include the following when described in a preferred order in the following.
- R 1 and R 2 together form one CR 5 R 6 — CR 7 R 8 —, one CR 5 R 6 — CR 7 ! ⁇ —! ⁇ ! ⁇ -or-j! ⁇ ! ⁇ -Ji! ⁇ ! ⁇ —Ji 9 ! ⁇ 10 —. ! ⁇ 11 ! ⁇ 12
- ⁇ ! ⁇ 5 to R 12 each independently represent a hydrogen atom or a P 6 alkyl group, or 5 together with a carbon atom having any two of which are substituted together. , Or may form a 6- or 7-membered ring).
- R 1 and R 2 together form one CR 5 R 6 — CR 7 R 8 — CR 9 R 10 — (R 5 or R 1 Q are each independently a hydrogen atom or C i _ 6 alkyl group).
- R 1 and R 2 together form one CH 2 — C (CH 3 ) 2 — CH 2 — or one CHCH 3 — CH 2 — represents CHCH 3 _
- R 1 and R 2 are each alkyl groups (said -. 6 alkyl group, phenyl group (said Fuweniru group may be S conversion in c Medical 6 alkoxy group or a halogen atom. ), C 2 _ 6 alkenyl group or C 2 - 6 alkynyl group (said C 2 - 6 an alkenyl Moto ⁇ Pi C 2 - 6 alkynyl group, phenyl group (said Fuweniru group, C bets 6 alkoxy group or a halogen It may be substituted by an atom.) It may be substituted by.) It may be substituted by.) It may be substituted by.) It may be substituted by.
- R 1 and R 2 each independently represent a C 6 alkyl group.
- R 1 and R 2 both represent a methyl group or an ethyl group.
- Preferred examples of X 1 and X 2 include the following when described in a preferred order in the following.
- X 1 and X 2 both represent o.
- Preferred Ar include the following.
- Preferred Ra include the following.
- R b Preferred examples of R b include the following when described in the order of preference as described below.
- L 2 - NR 16 R 17 ⁇ R 16 ⁇ Pi R 17 are each independently a hydrogen atom, Omicron chi _ 6 alkyl group (the C ⁇ 6 alkyl group, phenyl group (said Fuweniru group, May be substituted with an alkoxy group or a halogen atom.) Or a phenyl group (the phenyl group may be substituted with a C- 6 alkoxy group or a halogen atom). .) refers to, L 2 is C 2 - 6 alkylene group (the C 2 _ 6 alkylene emissions groups CI_ 3 alkyl group or phenyl group (the full We - le group, a halogen atom,
- Preferred ⁇ include the following in the order of preference in the following.
- Ci— 2 . Alkyl group (said Ji Bok 20 alkyl group, phenyl group (said Fuweniru group, an alkoxy group or a halogen atom may be substituted), C 2 -. 6 ⁇ alkenyl group or C 2 _ 6 alkynyl group (the The C 2 _ 6 alkenyl group and the C 2 _ 6 alkyl group may be substituted by a phenyl group (the phenyl group may be replaced by an alkoxy group or a halogen atom). )) May be substituted.
- —L 3 — NR 18 R 19 ⁇ R 18 and R 19 are each independently a 6 alkyl group (The C-6 alkyl group may be substituted by a phenyl group (the phenyl group may be substituted by an alkoxy group or a halogen atom.)) Or a fuel group (the phenyl group group is substituted by C i _ theta alkoxy or C port Gen atoms means les, which may be a), L 3 is C 2 -.
- optically active 1,4-dihydropyridine compound used in the present invention is a compound capable of forming a salt
- a pharmaceutically acceptable salt thereof can also be used as an active ingredient.
- Pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, methanesulfo Examples include phosphate, acetate, benzoate, tartrate, phosphate, lactate, maleate, fumarate, malate, dalconate, and salicylate.
- hydrochloride and methanesulfonate are used.
- the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.
- Therapeutic agents for T-type calcium channel inhibitory diseases containing the T-type calcium channel inhibitor are usually tablets, capsules, powders, granules, pills, syrups, etc., orally or rectally. It can be administered as transmucosal, nasal, vaginal and other mucosal absorbents, pulmonary absorbents, inhalants, eye drops, transdermal absorbents or injections.
- the drug can be administered as a single therapeutic agent or as a mixture with other therapeutic agents.
- compositions may be administered alone, but are generally administered in the form of a pharmaceutical composition.
- These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, for the oral preparation, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents can be used.
- Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or the like, or may be presented as a dry syrup prepared in water or other suitable solvent before use. Good. Said solutions may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers.
- Injectables can be aqueous or ready-to-use injectable forms such as distilled water for injection, physiological saline, 5% dextrose solution, solubilizers or solubilizers such as propylene glycol, pH regulators, isotonic agents Formulation components such as stabilizers are used.
- the dose is determined according to the age and condition of the patient. Usually, in the case of an adult, it is 0.1 to 1000 m for oral or rectal administration. g / human / day, about 0.05 mg to 50 Omg / human / day for injection. These figures are only examples, and the dose may be determined according to the patient's condition. .
- situations where the present invention is used include situations where the use of a compound having T-type calcium channel inhibitory activity can be expected to improve the disease state.
- cardiac hypertrophy, heart failure, cardiomyopathy, tachyarrhythmia including atrial fibrillation, arteriosclerosis, renal disorders such as nephritis and nephropathy, renal failure, inflammation and edema, hyperaldosteronemia It is useful for treating and preventing neuropathic pain and epilepsy.
- optically active 1,4-dihydropyridine compound represented by the formula (1) is disclosed in Japanese Patent Application Laid-Open Nos. H01-113398, H02-0115992, Chem. Bull., 40 (9), 2377-2381 (1992) and Chem. Pharm. Bull., 40 (9), 2370-2376 (1992).
- a styrylphosphonate (2) and an optically active aminocrotonic acid derivative (3) are heated in toluene under azeotropic dehydration conditions to obtain a 1,4-dihydropyridine derivative (1a).
- 1, 4-dihydropyridine derivative (1 a) perform Jiasutereoma separated by crystallization or chromatographic I Chief, (1 a -R) and then, eclosion rows main Tokishimechiru reduction, or performs main Tokishimechiru of Then, diastereomer separation is performed by crystallization or chromatography, etc., to give (1 b -R).
- a racemic 1,4-dihydropyridine compound can be produced and then separated by HPLC using an optically active column to produce an optically active 1,4-dihydropyridine compound.
- JP-A-63-68591 A compound in which the 5-position of the dihydropyridine ring is 4,6-dimethyl-2-oxo-l, 3,2-dioxaphospholinan-l-yl (Z3, Z4) is disclosed in JP-A-63-68591. Production was described with reference to the production method described in Japanese Patent Publication No. and Chem. Pharm. Bull., 40 (9), p.2370-2376, (1992).
- the compound (11a) shown below was produced by the method shown below.
- the optically active R and S isomers of efonidipine were dissolved in an extracellular measurement solution, applied by perfusion, and the change in Ca ion current 5 minutes after application was measured. The results were expressed as the Ca current inhibition rate (%) of the compound of the present invention relative to the Ca current amount (100%) of the solvent control.
- Efonidipine optically active substance R-form exhibits concentration-dependent inhibitory action on ⁇ -type Ca channels at concentrations of 0.1 ⁇ ⁇ or more, and inhibitory action on L-type Ca channels even at 10 ⁇ M Did not show.
- the S-isomer showed a strong inhibitory effect on L-type Ca channel at 55.6 ⁇ 7.1%. From these results, it was found that the efonidipine R-isomer has high selectivity for T-type Ca channel.
- the L-type Ca channel inhibitory effect was expressed only in one of the optically active forms (S-form), whereas the T-type Ca channel inhibitory effect was equally expressed in both optically active forms. . From this fact, if a 1,4-dihydropyridine compound showing T-type Ca channel inhibitory action in racemic form is found, one of its optically active forms (R-form) has high selectivity for T-type Ca channel, It was suggested that it would be a compound.
- Pharmacological test example 2 (Effect on T-type Ca channel expressed in mammalian cells (BHK cells))
- the inhibition rate of the T-type Ca channel was measured for the compound represented by at each drug concentration of 10 zM, and the results are shown in the following table.
- Z1 to: Z4, Y1 to Y7, Bl and ⁇ 1 to ⁇ 7 used in the table represent the types of substitution groups of the compound, and are shown below.
- Al 3-to-two-way nozzle
- A2 3-to-two-way nozzle
- A3 2-to-two-way nozzle
- A4 2-to-methoxyphenyl
- A5 3-to-methoxylayer
- A6 Feninole
- A7 3—triphnolelomethinolephenyl
- the compound represented by the formula (1) and lactose are passed through a 60-mesh sieve. Pass the corn starch through a sieve of 120 mesh. These are mixed with a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated (extrusion granulation pore size: 0.5 to lmm), and dried. The resulting dried granules are sieved through a vibrating sieve (12/60 mesh) to obtain granules.
- HPC-L low-viscosity hydroxypropylcellulose
- a powder for capsule filling containing the following ingredients is produced.
- a capsule-filling granule containing the following ingredients is produced.
- the compound represented by the formula (1) and lactose are passed through a 60-mesh sieve. Pass the corn starch through a sieve of 120 mesh. These are mixed with a V-type mixer. A low viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated. After drying. The resulting dried granules are sieved with a vibrating sieve (12/60 mesh), sized and filled with 15 Omg into a No. 4 hard gelatin capsule.
- HPC-L low viscosity hydroxypropylcellulose
- a tablet is prepared containing the following ingredients:
- the compound represented by the formula (1), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. This mixed powder is directly hit to obtain 15 Omg tablets.
- An intravenous formulation is prepared as follows.
- Solutions of the above components are usually administered intravenously to a patient at a rate of 1 ml per minute.
- the compound of the present invention has a selective T-type calcium channel inhibitory action, cardiac hypertrophy, heart failure, cardiomyopathy, atrial fibrillation without adversely affecting blood pressure, cardiac function and quality of life It can be used for the treatment of tachyarrhythmia including arrhythmia, arteriosclerosis, nephritis and nephropathy, renal disorders such as nephropathy, renal failure, edema, inflammation, hyperaldosteronemia, neuropathic pain, and epilepsy. Therefore, the present invention can provide a therapeutic agent for the above-mentioned diseases in consideration of the efficacy, safety and quality of life, and is therefore extremely useful in the medical and pharmaceutical fields, for example.
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Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004226547A AU2004226547B2 (en) | 2003-03-28 | 2004-03-29 | T-Type calcium channel blockers |
JP2005504223A JP4539862B2 (ja) | 2003-03-28 | 2004-03-29 | T型カルシウムチャネル阻害剤 |
UAA200510097A UA79374C2 (en) | 2003-03-28 | 2004-03-29 | T-t??pe calcium channel blockers |
CA2520628A CA2520628C (en) | 2003-03-28 | 2004-03-29 | T-type calcium channel blocker |
NZ542681A NZ542681A (en) | 2003-03-28 | 2004-03-29 | T-type calcium channel blockers comprising optically active 1,4-dihydropyridines |
EP04724154A EP1609504A4 (en) | 2003-03-28 | 2004-03-29 | T-TYPE CALCIUM CHANNEL BLOCKER |
US10/549,510 US7563782B2 (en) | 2003-03-28 | 2004-03-29 | T-type calcium channel blocker |
CN200480008085.2A CN1764462B (zh) | 2003-03-28 | 2004-03-29 | T型钙通道阻断剂 |
NO20055015A NO20055015L (no) | 2003-03-28 | 2005-10-27 | T-type calcium kanalblokkere |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-090916 | 2003-03-28 | ||
JP2003090916 | 2003-03-28 | ||
JP2003393893 | 2003-11-25 | ||
JP2003-393893 | 2003-11-25 |
Publications (1)
Publication Number | Publication Date |
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WO2004087172A1 true WO2004087172A1 (ja) | 2004-10-14 |
Family
ID=33134293
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/004432 WO2004087172A1 (ja) | 2003-03-28 | 2004-03-29 | T型カルシウムチャネル阻害剤 |
Country Status (11)
Country | Link |
---|---|
US (1) | US7563782B2 (ja) |
EP (1) | EP1609504A4 (ja) |
JP (1) | JP4539862B2 (ja) |
KR (1) | KR100870527B1 (ja) |
AU (1) | AU2004226547B2 (ja) |
CA (1) | CA2520628C (ja) |
NO (1) | NO20055015L (ja) |
NZ (1) | NZ542681A (ja) |
RU (1) | RU2326886C2 (ja) |
TW (1) | TW200503733A (ja) |
WO (1) | WO2004087172A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008007835A1 (en) * | 2006-07-13 | 2008-01-17 | Korea Institute Of Science And Technology | 2,4-quinazoline derivatives having activity to t-type calcium channel and preparation method thereof |
Families Citing this family (3)
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JP2010526073A (ja) * | 2007-05-02 | 2010-07-29 | ティーエーユー・セラピューティクス・エルエルシー | 癌または前癌性症状およびその他の症状の治療のためのジヒドロピリジン誘導体 |
CA2685753A1 (en) | 2007-05-09 | 2008-11-20 | Neuromed Pharmaceuticals Ltd. | Bicyclic pyrimidine derivatives as calcium channel blockers |
JP6017964B2 (ja) | 2010-03-01 | 2016-11-02 | ティーエーユー・セラピューティクス・エルエルシー | 癌診断および撮像 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05194393A (ja) * | 1991-02-20 | 1993-08-03 | Inst De Investigacion Y Desarrollo Quimico Biologico Sa | 2,6−ジメチル−4−(4´−ヒドロキシ−3´,5´−ジtert−ブチルフェニル)−1,4−ジヒドロピリジン誘導体、それらの製造方法およびそれらのフリーラジカルスカベンジャーとしての使用 |
WO2001004124A1 (en) * | 1999-07-12 | 2001-01-18 | Ortho-Mcneil Pharmaceutical, Inc. | OXATHIEPINO[6,5-b]DIHYDROPYRIDINES, AND RELATED COMPOSITIONS AND METHODS |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59161392A (ja) * | 1983-03-04 | 1984-09-12 | Nippon Shinyaku Co Ltd | ジヒドロピリジン誘導体及びその製法 |
JPS6069089A (ja) | 1983-09-26 | 1985-04-19 | Nissan Chem Ind Ltd | ジヒドロピリジン−5−ホスホネ−ト誘導体およびその製造法 |
JPS6163688A (ja) | 1984-08-03 | 1986-04-01 | Nissan Chem Ind Ltd | ジヒドロピリジン−5−ホスホン酸環状エステル類 |
JPS6130591A (ja) | 1984-07-20 | 1986-02-12 | Nissan Chem Ind Ltd | ジヒドロピリジン−5−ホスホネ−ト誘導体 |
JPS60248693A (ja) | 1984-04-19 | 1985-12-09 | Nippon Shinyaku Co Ltd | ピリジン誘導体及び製法 |
JPS60258194A (ja) | 1984-06-01 | 1985-12-20 | Otsuka Pharmaceut Factory Inc | ジヒドロピリジン誘導体 |
JPS6137793A (ja) | 1984-07-31 | 1986-02-22 | Nissan Chem Ind Ltd | ジヒドロピリジン−2−アミノ−5−ホスホネ−ト誘導体 |
JPS61210092A (ja) * | 1985-03-14 | 1986-09-18 | Nissan Chem Ind Ltd | ジヒドロピリジン−5−ホスホン酸ジアミド誘導体 |
MW2586A1 (en) | 1985-04-26 | 1987-12-09 | Hoffmann La Roche | 1,3-disubstituted imidazolium salts |
JPS61254596A (ja) * | 1985-05-02 | 1986-11-12 | Nissan Chem Ind Ltd | ジヒドロピリジン−5−ホスホン酸エチレンエステル類 |
US4885284A (en) | 1986-01-22 | 1989-12-05 | Nissan Chemical Industries Ltd. | Dihydropyridine-5-phosphonic acid cyclic propylene ester |
JPH0655751B2 (ja) | 1986-01-22 | 1994-07-27 | 日産化学工業株式会社 | ジヒドロピリジンホスホン酸環状エステル |
UA5590A1 (uk) * | 1986-01-23 | 1994-12-28 | Ніссан Кемікал Індастріз Лтд | Спосіб одержання пропіленглікового ефіру заміщеної 1,4-дігідропіріділ-5-фосфорної кислоти, або його фармацевтично прийнятной солі або сольвата |
JPH0678349B2 (ja) | 1986-01-23 | 1994-10-05 | 日産化学工業株式会社 | ジヒドロピリジン−5−ホスホン酸エステル類 |
JPH0615553B2 (ja) * | 1986-02-20 | 1994-03-02 | 日産化学工業株式会社 | ジヒドロピリジン−5−ホスホンアミド酸類 |
JPH0755955B2 (ja) | 1986-09-10 | 1995-06-14 | 日産化学工業株式会社 | 光学活性なジヒドロピリジン−5−ホスホン酸エステル |
JPH01113398A (ja) | 1987-10-28 | 1989-05-02 | Nissan Chem Ind Ltd | 光学活性なジヒドロピリジン−5−ホスホン酸エステル |
JPH01275591A (ja) | 1988-04-27 | 1989-11-06 | Nissan Chem Ind Ltd | ジヒドロピリジン−5−ホスホン酸誘導体 |
JPH0211592A (ja) * | 1988-06-29 | 1990-01-16 | Nissan Chem Ind Ltd | 光学活性なジヒドロピリジンホスホン酸エステル |
SI9200344B (sl) | 1992-11-26 | 1998-06-30 | Lek, | Postopek za pripravo amlodipin benzensulfonata |
GB9916076D0 (en) * | 1999-07-08 | 1999-09-08 | Smithkline Beecham Plc | Novel compounds |
-
2004
- 2004-03-29 KR KR1020057018357A patent/KR100870527B1/ko not_active IP Right Cessation
- 2004-03-29 TW TW093108552A patent/TW200503733A/zh not_active IP Right Cessation
- 2004-03-29 US US10/549,510 patent/US7563782B2/en not_active Expired - Fee Related
- 2004-03-29 WO PCT/JP2004/004432 patent/WO2004087172A1/ja active Application Filing
- 2004-03-29 JP JP2005504223A patent/JP4539862B2/ja not_active Expired - Fee Related
- 2004-03-29 CA CA2520628A patent/CA2520628C/en not_active Expired - Fee Related
- 2004-03-29 AU AU2004226547A patent/AU2004226547B2/en not_active Ceased
- 2004-03-29 RU RU2005133221/04A patent/RU2326886C2/ru not_active IP Right Cessation
- 2004-03-29 EP EP04724154A patent/EP1609504A4/en not_active Withdrawn
- 2004-03-29 NZ NZ542681A patent/NZ542681A/xx not_active IP Right Cessation
-
2005
- 2005-10-27 NO NO20055015A patent/NO20055015L/no not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05194393A (ja) * | 1991-02-20 | 1993-08-03 | Inst De Investigacion Y Desarrollo Quimico Biologico Sa | 2,6−ジメチル−4−(4´−ヒドロキシ−3´,5´−ジtert−ブチルフェニル)−1,4−ジヒドロピリジン誘導体、それらの製造方法およびそれらのフリーラジカルスカベンジャーとしての使用 |
WO2001004124A1 (en) * | 1999-07-12 | 2001-01-18 | Ortho-Mcneil Pharmaceutical, Inc. | OXATHIEPINO[6,5-b]DIHYDROPYRIDINES, AND RELATED COMPOSITIONS AND METHODS |
Non-Patent Citations (2)
Title |
---|
MASUMIYA H. ET AL: "Effects of Ca-2+ channel antagonists on sinus node: Prolongation of late phase 4 depolarization by efonidipine", EUR. J. PHARMACOLOGY, vol. 335, 1997, pages 15 - 21, XP002979798 * |
See also references of EP1609504A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008007835A1 (en) * | 2006-07-13 | 2008-01-17 | Korea Institute Of Science And Technology | 2,4-quinazoline derivatives having activity to t-type calcium channel and preparation method thereof |
Also Published As
Publication number | Publication date |
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RU2005133221A (ru) | 2006-05-10 |
EP1609504A1 (en) | 2005-12-28 |
NZ542681A (en) | 2009-01-31 |
CA2520628C (en) | 2012-08-14 |
NO20055015L (no) | 2005-11-15 |
TW200503733A (en) | 2005-02-01 |
EP1609504A4 (en) | 2010-07-21 |
TWI339581B (ja) | 2011-04-01 |
US7563782B2 (en) | 2009-07-21 |
RU2326886C2 (ru) | 2008-06-20 |
KR100870527B1 (ko) | 2008-11-26 |
JPWO2004087172A1 (ja) | 2006-06-29 |
KR20050119162A (ko) | 2005-12-20 |
CA2520628A1 (en) | 2004-10-14 |
US20070010490A1 (en) | 2007-01-11 |
AU2004226547B2 (en) | 2008-10-23 |
NO20055015D0 (no) | 2005-10-27 |
JP4539862B2 (ja) | 2010-09-08 |
AU2004226547A1 (en) | 2004-10-14 |
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