WO1998049144A1 - Nouveau derive de dihydropyridine - Google Patents
Nouveau derive de dihydropyridine Download PDFInfo
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- WO1998049144A1 WO1998049144A1 PCT/JP1998/001878 JP9801878W WO9849144A1 WO 1998049144 A1 WO1998049144 A1 WO 1998049144A1 JP 9801878 W JP9801878 W JP 9801878W WO 9849144 A1 WO9849144 A1 WO 9849144A1
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel dihydropyridine derivatives and the use of dihydropyridine derivatives as pharmaceuticals.
- Progressive cerebral degenerative diseases such as cerebral infarction, cerebral hemorrhage (including subarachnoid hemorrhage), cerebral damage caused by ischemia in the acute phase after onset, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, cerebrovascular dementia, and ALS progress neurodege nerative disease), neuropathy due to head injury, pain associated with spinal cord injury or diabetes or obstructive thromboangitis, post-operative pain, migraine, visceral pain, bronchial asthma, Activation of N-type calcium channels during various conditions involving psychogenic stress, such as stable angina and irritable bowel inflammatory disease, mood disorders, and drug addiction withdrawal symptoms, such as ethanol addiction withdrawal symptoms.
- the compounds of the present invention show an inhibitory effect on the activation of N-type calcium channels, thereby indicating compounds useful as therapeutic agents for the above-mentioned diseases. That.
- N-type calcium channels are widely distributed in the central nervous system, peripheral nerves and adrenal parathyroid cells, and are known to be involved in sensory control such as nerve cell death, blood force control of tecolamine, and perception. I have.
- Omegaconotoxin a peptide that selectively inhibits N-type calcium channels
- GVIA and its omega-conotoxin, MVIIA have been shown to suppress excitatory neurotransmitter release from brain slice preparations and to prevent the progression of neuronal necrosis during cerebrovascular disorders in animal experiments.
- Compounds that have an inhibitory effect on N-type calcium channels are commonly used in the acute phase of onset after onset It is thought to be effective in treating brain disorders caused by blood, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, cerebral blood dementia, progressive cerebral degenerative diseases such as ALS, and neuropathy due to head injury.
- omega-conotoxin MVI IA is capable of suppressing formalin-induced pain, hot plate pain, and pain caused by peripheral nerve neuropathy in animal experiments.
- omega-conotoxin GVI A inhibits the release of catecholamine from cultured sympathetic neurons, the contraction of isolated blood vessels by electrical stimulation of the innervating nerve, and the suppression of catecholamine secretion from dog adrenal parasites.
- Compounds having N-type calcium channel inhibitory activity are clinically thought to be effective in various diseases involving psychogenic stress, such as bronchial asthma, unstable angina and irritable bowel inflammatory disease (Neuropharmacol ., 32, 1141 (1993)).
- N-type calcium channels Several peptide and non-peptidic compounds that selectively act on N-type calcium channels have been disclosed (eg, W09313128), but none of them have been used as actual drugs. In addition, some compounds that act on N-type calcium channels up to now also act on calcium channels other than N-type (British Journal of Pharmacology. 122 (1) 37-42, 1997). Compounds that also antagonize L-type calcium channels, which are highly relevant for their effects, are contraindicated in the indications of N-type antagonists (such as stroke, neuralgia, pain relief in terminal cancer and spinal cord injury).
- N-type antagonists such as stroke, neuralgia, pain relief in terminal cancer and spinal cord injury.
- An object of the present invention is to provide a novel compound having a selective antagonistic action on N-type calcium channels.
- Another object of the present invention is to provide an N-type calcium channel antagonist.
- the present invention also relates to cerebral infarction, cerebral injury due to ischemia in the acute stage after the onset of cerebral hemorrhage, Alhaima, AIDS-related dementia, Parkinson's disease, progressive cerebral degenerative disease, neuropathy due to head injury, obstructive
- the purpose of the present invention is to provide a therapeutic agent for pain associated with thromboangiitis, post-operative pain, migraine, visceral pain, bronchial asthma, unstable angina, irritable bowel inflammatory disease, drug addiction withdrawal symptom. I do.
- the present invention provides a dihydropyridine derivative represented by the following general formula (1), or a pharmaceutically acceptable salt thereof.
- [ ⁇ represents the following general formula (2), 1-naphthyl, 2-naphthyl, thiophene-2-yl, furan-3-yl, furan-12-yl, pyridine-14-yl, pyridine-13- Or pyridine-1-yl,
- R 1 , R 3 , and R 5 may be the same or different
- R 2 and R 4 may be the same or different
- B represents a carbamoyl group, a cyano group, a nitro group, an acetyl group, or a carboxyl group
- C represents a hydrogen atom, a methyl group, an ethyl group, a dimethoxymethyl group,
- D is hydrogen atom, lower alkyl group, hydroxy lower alkyl group, aryl lower Represents a alkyl group,
- E represents a hydrogen atom, a methyl group, an ethyl group, a dimethoxymethyl group, or a cyano group
- F represents the following general formula (3), thiophen-1-yl, thiophen-2-yl, furan-3-yl, and furan Represents any one of 2-yl, pyridine-1-yl, pyridine-3-yl, and pyridine-12-yl,
- R 6, R 7, R 8 , R 9, R ie may be the same or different, a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, Amino group, 'Shiano group, nitro group, lower alkyl Group, lower alkoxy group, lower alkenyl group, lower alkynyl group, lower alkylamino group, lower alkylthio group, lower alkanol group, hydroxy lower alkyl group, hydroxy lower alkoxy group, hydroxy lower alkenyl group, halogeno lower alkyl group A halogeno lower alkoxy group, a halogeno lower alkenyl group, an aryl lower alkoxy group, a lower alkoxycarbonyl group, or an arylo group.)
- X represents an interatomic bond, —CH 2 —, one CH 2 CH 2 one, —CH2 CH—, one C ⁇ C one,
- Y represents any of the following general formulas (4) to (13).
- any two of R 1 to R 3 may combine to form a ring.
- A, C, D, E and X are the same as above,
- R 1 , R 2 , R 3 , R 4 , and R 5 may be the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group, a lower alkyl group, a lower alkoxy group, and a halogeno.
- B represents a carbamoyl group, a nitro group, or an acetyl group
- F is the general formula (3), cyclohexyl group, thiophene-3-yl, thiophene
- R 6 , R 7 , R s , R 9 , and R 1Q may be the same or different, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a lower alkyl group, a lower alkoxy group, or a lower alkoxycarbonyl group. Represents
- the present invention also provides an N-type calcium channel antagonist comprising a dihydropyridine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- [A represents the following general formula (2), 1-naphthyl, 2-naphthyl, thiophene-3-yl, thiophen-1-yl, furan-3-yl, furan-2-yl, pyridine-1-4-yl Or pyridine-1-yl or pyridine-1-yl,
- R 1 , R 2 , R 3 , R 4 , and R 5 may be the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a cyano group, a nitro group, or a lower alkyl group.
- a lower alkoxy group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanol group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a hydroxy lower alkenyl group, a halogeno lower alkyl group Represents a halogeno lower alkoxy group, a halogeno lower alkenyl group, an aryl lower alkoxy group, a lower alkoxycarbonyl group, or an arylo group.
- B represents a carbamoyl group, a cyano group, a nitro group, an acetyl group, or a carboxyl group
- C represents a hydrogen atom, a methyl group, an ethyl group, a dimethoxymethyl group,
- D represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, or an aryl lower alkyl group;
- E represents a hydrogen atom, a methyl group, an ethyl group, a dimethoxymethyl group, a cyano group,
- F is the following general formula (3): cyclohexyl group, thiophen-3-yl, thiophen-2-yl, furan-3-yl, furan-2-yl, pyridine-14-yl, Represents either pyridin-1-yl or pyridine-12-yl,
- R 6 , R 7 , R 8 , R 9 , and R 1 Q may be the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an amino group, a cyano group, a nitro group, or a lower alkyl group.
- X represents an interatomic bond, one CH 2 —, —CH 2 CH 2 one, — CH2 CH—, — C ⁇ C one,
- Y represents any of the following general formulas (4) to (16);
- R 'to R 3 may form a ring by bonding two one.
- the present invention also provides cerebral infarction, cerebral injury due to ischemia in the acute phase after the onset of cerebral hemorrhage, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, comprising the above dihydropyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- Progressive brain degenerative disease, neuropathy due to head injury, pain associated with obstructive thromboangiitis, postoperative pain, migraine, visceral pain, bronchial asthma, unstable angina, irritable bowel inflammatory disease Provide a therapeutic agent for any of drug addiction withdrawal symptoms.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the above dihydropyridine derivative or a pharmaceutically acceptable salt thereof, and a carrier and / or diluent.
- the term "lower” in the present invention indicates a group having 1 to 6 carbon atoms.
- the alkyl group as a component of the alkyl group, the alkoxy group, the alkenyl group, the alkylamino group, the alkylthio group, and the alkanol group can be linear or branched. Methyl, ethyl, propyl, isopropyl, butyl, secondary and tertiary butyl are examples of such alkyl groups. Of these, groups having 1 to 3 carbon atoms are preferred. Examples of the aryl lower alkoxy group include a benzyloxy group. Halogen atoms represent fluorine, chlorine, bromine and iodine.
- aryl groups are phenyl and substituted phenyl groups, halogen, alkyl and alkoxy being particularly considered as substituents.
- arylo group examples include a benzoyl group and a pyridylcarbonyl group.
- N-type calcium channel antagonist containing the above-mentioned dihydropyridine derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient cerebral infarction, cerebral injury due to ischemia in acute phase after onset of cerebral hemorrhage, Alzheimer's disease, AIDS Related dementia, Parkinson's disease, progressive cerebral degenerative disease, neuropathy due to head injury, pain associated with obstructive thromboangiitis, postoperative Pain, migraine, visceral pain, bronchial asthma, unstable angina, irritable bowel inflammatory disease, drug addiction withdrawal symptom,
- R 1 , R 2 of general formula (2), R 3 , R 4 , R 5 may be the same or different, respectively, hydrogen atom, halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, lower alkyl group, lower alkoxy group, halogeno lower alkyl group, or It is preferably a lower alkoxycarbonyl group.
- A is represented by the general formula (2) (where R 1 , R 3 , R 4 , and R 5 represent a hydrogen atom, R 2 represents a chlorine atom, a bromine atom, Represents an iodine atom or a cyano group.), B is a carboxyl group, C is a methylenol group, D is a hydrogen atom, E is a methylenol group, F is a fuunyl group, X is an interatomic bond, and Y is a general formula (1 Those that are 1) are also preferred.
- R 1 , R 3 and R 5 in the general formula (2) may be the same or different,
- R 2 and R 4 may be the same or different
- a dihydropyridine derivative according to the general formula (1) which is a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a lower alkyl group, a lower alkoxy group, a halogeno lower alkynole group, or a lower alkoxycarbonyl group, or a pharmaceutically acceptable derivative thereof; Acceptable salts are preferred (preferred embodiment I).
- D is a hydrogen atom
- X is an interatomic bond
- Y is a general formula (11).
- B is preferably a carboxyl group.
- A is represented by the general formula (2) (wherein R 1 , R 3 , R 4 , and R 5 represent a hydrogen atom, R 2 represents a chlorine atom, a bromine atom, an iodine atom, and a cyano group), B is a carboxyl group, C is a methyl group, D is a hydrogen atom, and E is methyl.
- the group F is a phenyl group and X is an interatomic bond.
- A is represented by the general formula (2) (where R, R 3 , R 4 , and R 5 represent a hydrogen atom, and R 2 represents a chlorine atom, a bromine atom, an iodine atom, and a cyano group) It is preferable that B is a carboxyl group, C is a methyl group, D is a hydrogen atom, E is a methyl group, F is a phenyl group, and Y is a general formula (11).
- A is represented by the general formula (2) (where R 1 , R 3 , R 4 , and R 5 represent a hydrogen atom, and R 2 represents a chlorine atom, a bromine atom, an iodine atom, and a cyano group). It is preferable that C represents a methyl group and E represents a methyl group.
- A is represented by the general formula (2) (where R 1 , R 3 , R 4 , and R 5 represent a hydrogen atom, and R 2 represents a chlorine atom, a bromine atom, an iodine atom, and a cyano group) And C is preferably a hydrogen atom or a methyl group, and F is preferably a phenyl group.
- A is represented by the general formula (2) (wherein R ′, R 3 , R 4 and R 5 represent a hydrogen atom, and R 2 represents a chlorine atom, a bromine atom, an iodine atom and a cyano group) , B is a carboxyl group, C is a methyl group, E is a methyl group, F is a phenyl group, X is an interatomic bond, and Y is preferably a general formula (11).
- A is represented by the general formula (2) (where R 1 , R 3 , R 4 , and R 5 represent a hydrogen atom, and R 2 represents a chlorine atom, a bromine atom, an iodine atom, and a cyano group) ), E is preferably a methyl group and F is preferably a phenyl group.
- A is represented by the general formula (2) (where R 1 , R 3 , R 4 , and R 5 represent a hydrogen atom, and R 2 represents a chlorine atom, a bromine atom, an iodine atom, and a cyano group) It is preferred that C is a methyl group, E is a methyl group, and F is a phenyl group.
- C is a methyl group
- E is a methyl group
- F is a phenyl group
- A is represented by the general formula (2) (where R ', R 3 , R 4 and R 5 are water And R 2 represents a chlorine atom, a bromine atom, an iodine atom, or a cyano group).
- A is represented by the general formula (2) (wherein R 1 and R 3 may be the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, Group, lower alkyl, lower alkoxy, lower alkenyl, lower alkylamino group, lower alkylthio group, lower alkanoyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, hydroxy lower alkenyl group, halogeno lower alkyl group, halogeno lower alkoxy group, Represents a halogeno lower alkenyl group, an aryl lower alkoxy group, or an arylo group,
- R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a lower alkyl, a lower alkoxy, a lower alkenyl, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroquin lower alkyl group, a hydroxy lower alkoxy group, a hydroxy group
- R 4 and R 5 represent a hydrogen atom.
- R 1 to R 3 may be bonded to form a ring.
- B is a carboxyl group
- C is a methyl group
- D is a hydrogen atom, a lower alkyl group, a hydroquine lower alkyl group, an aryl lower alkyl group
- E is a methyl group
- F is represented by the general formula (3).
- each represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a lower alkyl, a lower alkoxy, a lower alkenyl, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, and a hydroquino lower.
- X represents an interatomic bond
- Y represents a general formula (5), (11) or (12).
- Hydropyridine derivatives or pharmaceutically acceptable salts thereof are preferred.
- an N-type calcium channere antagonist, a pharmaceutical composition, and a cerebral injury due to ischemia in the acute phase after the onset of cerebral infarction and cerebral hemorrhage which comprises the above-mentioned preferred dihydropyridine derivative or a pharmaceutically acceptable salt thereof.
- Alzheimer's disease Alzheimer's disease, AIDS-related dementia, Parkinson's disease, progressive cerebral degenerative disease, neuropathy due to head injury, pain associated with obstructive thromboangitis, postoperative pain, migraine, visceral pain, bronchial asthma, It also provides a therapeutic agent for stable angina, irritable bowel inflammatory disease, drug addiction withdrawal symptom, or any other.
- the dihydropyridine derivative (1) of the present invention can be produced by the following method.
- a dihydropyridine derivative (1-1) in which D is a hydrogen atom and B is a carboxyl group can be produced using the following flow.
- dihydropyridine dicarboxylic acid ester (22) By reacting this with alcohol (26) in the presence of a condensing agent such as WSC, dihydropyridine dicarboxylic acid ester (22) can be obtained.
- a condensing agent such as WSC
- dihydropyridine dicarboxylic acid ester (22) can be obtained.
- the dihydropyridine dicarbonate diester is treated with a base such as sodium hydroxide, the dihydropyridine carboxylic acid derivative (1-1) of the present invention can be produced.
- the dihydropyridincarboxylic acid derivative (1-2) in which the ester substituent is carboxyl-substituted cinnamyl can be produced by the following method.
- the dihydropyridine dicarboxylic acid diester (28) is subjected to a Heck reaction in the presence of a palladium catalyst, and then treated with a base such as sodium hydroxide to obtain the dihydropyridine carboxylic acid derivative (1-2) of the present invention.
- the dihydropyridine derivative (1-3) in which B is a carbamoyl group is an aldehyde (17), a 3-aminocrotonate (18) and an acetoacetamide (31) ) Can be produced by the following flow.
- dihydropyridine derivative (1-4) in which ⁇ is a cyano group is a derivative which reacts aldehyde (17) acetoacetate (20) and 3-aminocrotononitrile (32) with Can be manufactured in one.
- the dihydropyridine derivative (1-5), in which B is a nitro group, is prepared by reacting aldehyde (17), 3-aminocrotonate (18) and ditroacetone (33) according to the following flow. Can be manufactured.
- dihydropyridine derivative (1-7) in which D is a substituent other than a hydrogen atom and ⁇ is a carboxyl group can be produced, for example, as follows. That is, by reacting aldehyde (17), 3-aminocrotonate (18) and acetoacetic acid 2-trimethylsilylethyl ester (35), dihydropyridindicarboxylic acid diester (36) is converted. When this is reacted with an alkyl halide or the like in the presence of a base such as sodium hydride, (37) is obtained. For example, when this is treated with tetrabutylammonium fluoride or the like, D is obtained. A substituted dihydroxypyridine derivative (1-7) can be produced. z
- the dihydropyridine derivative (E8) in which E is a hydrogen atom is, for example, a starting material of acetylene carboxylate (38). It can be manufactured according to the following flow.
- the dihydric pyridine derivative (1-9) in which C is a hydrogen atom starts from, for example, acetylene carboxylate (41). It can be manufactured by the following flow as a raw material.
- the dihydropyridine derivative (1-10) in which both C and ⁇ are hydrogen atoms can be produced, for example, by the following flow starting from acetylene carboxylate (38) and (41).
- dihydropyridine derivative (1-11) in which E is an ethyl group can be produced, for example, by using the following flow starting from 3-oxovaleric acid ester (45).
- dihydropyridine derivative (1-12) in which C is an ethyl group can be produced, for example, by using the following flow starting from 3-oxovaleric acid trimethylsilyl ester (47).
- the dihydropyridine derivative (1-13) in which E is a dimethoxymethyl group can be produced, for example, by the following flow using ketoester (49) as a starting material.
- the dihydropyridine derivative (1-14) in which E is a cyano group can be produced according to the following flow. That is, it can be produced by subjecting dihydropyridine diester (51) to an acid treatment, followed by oximation, dehydration reaction, and hydrolysis.
- 3-aminocrotonate (18) used as a starting material can be produced by the following method or the like.
- acetoacetate (20) can be obtained by heating alcohol (26), diketene (54) and a suitable base. It can be produced by reacting this with ammonia or ammonium acetate.
- the salt may be a pharmaceutically acceptable salt, for example, an alkali metal such as ammonium salt, sodium or potassium. Salts with alkaline earth metals such as calcium and magnesium, salts with organic amines such as aluminum salts, zinc salts, morpholine and piperidine, and salts with basic amino acids such as arginine and lysine. be able to.
- the compound represented by the general formula (1) or a salt thereof is administered as it is or as various pharmaceutical compositions.
- Such pharmaceutical compositions may be in the form of tablets, powders, pills, granules, capsules, suppositories, solutions, dragees or depots, for example, common carriers and diluents. It can be manufactured according to a conventional method using a formulation auxiliary.
- tablets may contain the active ingredient of the present invention, a dihydropyridine derivative, in the form of a known auxiliary substance, for example, an inert diluent such as lactose, calcium carbonate or calcium phosphate, a binder such as acacia, corn starch or gelatin, alginic acid, co
- -Leavening agents such as starch or pregelatinized starch, sucrose, lactose or sachets It can be obtained by mixing with a sweetening agent such as karin, a flavoring agent such as peppermint, cocoa oil or cheese, and a lubricating agent such as magnesium stearate, talc or carboxymethylcellulose.
- N-type calcium channel antagonists containing a compound represented by the general formula (1) or a salt thereof as an active ingredient include cerebral infarction, cerebral hemorrhage (including subarachnoid hemorrhage), cerebral damage due to ischemia in the acute phase after onset, and Alzheimer's disease.
- AIDS-related dementia progressive neurodegenerative disease such as Parkinson's disease, cerebral vascular dementia and ALS-neuropathy due to head injury, spinal cord injury and diabetes, obstructive thromboangiitis Pain associated with pain, post-operative pain, migraine, visceral pain, various diseases involving psychogenic stress such as bronchial asthma, unstable angina and irritable bowel inflammatory disease, mood disorders And for the treatment of drug addiction withdrawal symptoms such as ethanol addiction withdrawal symptom.
- the dosage used for the above purposes is determined by the desired therapeutic effect, administration method, treatment period, age, body weight, etc., but is usually administered orally as a daily adult dose by the oral or parenteral route.
- administration 1 g to 5 g
- parenteral administration use 0.01 g to lg.
- Example 3 4- (3-Cyanophenyl) 1,2,6-dimethyl-11,4-dihydropyridine pyridine-1,3-dicarboxylic acid mono (3-phenyl-12-propene-1-yl) ester
- Cinnamyl 3-aminocrotonate 65 3 mg (3.01 mmo 1), acetoacetamide 315 mg (9.96 mmo 1) and 3-cyclopentene aldehyde 0.34 m 1 (3.0 Ommo 1) was heated and stirred in 80 ml of 2-propanol at 80 ° C. for 2 days. After evaporating 2-propanol under reduced pressure, the residue was purified by silica gel chromatography (form: methanol 50: 1) to obtain the title compound.
- Cinnamyl acetate acetate 2.98 g (10 l mmo 1), 3-aminocrotonito linole 8 18 mg (9.96 mmo 1) and 3-chloro mouth benzaldehyde 1.15 ml (10.2 mmo 1) was heated and stirred in 80 ml of 2-propanol at 80 ° C for 2 days. After evaporating 2-propanol under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate 2: 1) to obtain the title compound.
- Example 1 24- (3-chlorophenyl) -1,2,6-dimethyl-1,4-dihydropyridine-1,3,5-dicarboxylic acid mono (3-phenyl-12-propyne-11-yl) ester
- Example 1 34- (3-chlorophenyl) -1,2,6-dimethyl-1,4-dihydropyridine-1,3,5-dicarboxylic acid mono (3- (4-chlorophenyl) -12-propene-1-yl) ester
- Example 17 4- (3-chlorophenyl) -1,2,6-dimethyl-1,4-dihydropyridine-1,3,5-dicarboxylic acid mono (3- (3,4-dichlorophenyl) —2 _Propene-11-yl) Ester 1) 4- (3-Chlorophenyl) -12,61-dimethyl-1,4-dihydropyridine-13,5-dicarboxylic acid 3- (2-cyanoethyl) ester 5- (3 — Synthesis of (3,4 dichloromouth phenyl) 1-2-probene 1-yl) ester
- Example 18 4- (3-chlorophenyl) -1,2,6-dimethyl-1,4-dihydropyridine-1,5-dicarboxylic acid mono (3- (4-methylphenyl) 1-2-propene-1- Yl) ester
- Example 2 54- (3-chlorophenol) 1,2,6-dimethyl-1,4-dihydropyridine pyridine-1,3,5-dicarboxylic acid mono (3- (2-methoxyphenyl) one Synthesis of 2-propene-1-yl ester
- Example 2 8 4- (3-chlorophenyl) -1,2,6-dimethyl-1,4-dihydropyridine pyridine-1,3,5-dicarboxylic acid mono (3- (thiophene-2-yl) 1-2-propene— 1-yl) Synthesis of ester
- Example 3 14- (4-Cyanophonyl) -1,2,6-dimethyl-1,4-dihydrochloride Mouth pyridine 1,3,5-dicarboxylic acid mono (3-phenyl-2-propene-1-yl) ester
- Example 3 4- (4-chlorophenol) 1,2,6-dimethyl-1,4-dihydropyridine Pyridine-1,3,5-dicarboxylic acid mono (3-phenyl-2-propene) Yl) ester
- Example 4 14- (3-Carboxyphenyl) -1,2,6-dimethyl-1,4-dihydropyridine-13,5-dicarboxylic acid mono (3-phenyl-2-propene-11-yl) ester
- Example 4 54- (3-chlorophenyl) 1-2-dimethoxymethyl-1-6-methyl1-1,4-dihydropyridine-1 3,5-dicarboxylic acid 3- (3-phenyl-1-2-propene-11-yl) ) Ester 1) Synthesis of 4,4-dimethoxy-3-oxobutyric acid (3-phenyl-2-propene-1-yl) ester
- Example 4 6 4- (3-chlorophenyl) -12-cyano-16-methyl-1,4-dihydropyridine-13,5-dicarboxylic acid 3- (3-phenyl-2-propene-11) Le) ester
- Example 4 8 4- (3-chlorophenyl) 1,2,6-dimethyl-1,4-dihydropyridine pyridine-13,5-dicarboxylic acid mono (4-phenylphenyl) ester 1) 4-1 (3- Synthesis of 2,6-dimethyl-1,4-dihydropyridin-1,3,5-dicarboxylic acid 3- (2-cyanoethyl) ester 5- (4-phenylbutyl) ester
- 1,4-dihydroxypyridine-1,3,5-dicarboxylic acid mono (2-cyanoethyl) ester 300 mg (0.85 mmo 1), 2-phenylcyclopropyl methanoe 18 8 mg (1.27 mmo 1 ), 1- (3-Dimethylaminopropyl) -13-ethylcarposimid hydrochloride, 24 43 mg (1.27 mmol), 4-dimethylaminopyridine, 23 mg (0.18 mm 01) The mixture was stirred at room temperature for 1 hour.
- Example 5 4- (3-chlorophenol) 1-2-ethyl-6-methyl-1,4-dihydropyridine-13,5-dicarboxylic acid 3- (3-phenyl-2-propene-1-1-) Le) ester
- 3-oxovaleric acid (3-phenyl-2-propene-1-yl) ester 4 65 mg (2.0 mmo 1), 3-aminocrotonic acid (2-cyanoethyl) ester 309 mg (2 .0 mmo 1) and 0.227 ml (2.0 mmo 1) of 3-cyclopentene aldehyde were heated and stirred at 70 ° C. for 1 ° in 10 ml of 2-propanol. Further, the mixture was heated and stirred at 120 ° C. for 3 hours while distilling off 2-propanol under normal pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate 2: 1) to give the title compound.
- Example 5 4 4- (3-chlorophenyl) -12-methyl-1,4-dihydropyridine-13,5-dicarboxylic acid 5 _ (3-phenyl-2-propene-11-yl) ester
- Acetoacetic acid (2-cyanoethyl) ester 4 66 mg (3. Ommo 1), 3 monomethyl benzyl aldehyde 0.34 ml (3.0 mmo 1) and piperidine 0.0 297 It was heated and refluxed in 3.0 ml for 7 hours while removing water. The reaction solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue and propiolic acid (3-phenyl-2-propene-1-yl) ester 55,9 mg (3.0 mm 01), ammonium acetate 23,2 mg (3.0 mmo 1) was heated and stirred at 70 ° C.
- Example 5 54- (3-chlorophenyl) 1-1,4-dihydropyridine-13,5-dicarboxylic acid mono (3-phenyl-12-propene-11-yl) ester
- Propiolic acid (2-cyanoethyl) ester 499.3 mg (4 ⁇ Ommo 1), propiolic acid (3-phenyl-2-propene-1-yl) ester 7 4 5 mg (4.0 mmo 1) , 3-cyclohexene benzyl aldehyde 0.45 3 m 1 (4.0 mmo 1) and ammonium acetate 617 mg (mmo 1) were heated and stirred at 60 ° C for 12 hours in 8 ml of acetic acid. did. The acetic acid was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 1: 1) to obtain the title compound.
- Example 5 6 4- (3-chlorophenyl) -12-methyl-1,4-dihydropyridin-3,5-dicarboxylic acid 3- (3-phenyl-2-propene-1-yl) ester
- the water was refluxed for 1 ⁇ while removing water.
- the reaction solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
- the obtained residue and propiolic acid (2-cyanoethyl) ester 37 mg (3.0 mmo 1) and ammonium acetate 23 2 mg (3.O mmo 1) were added to 70 ° C. in 70 ml of acetic acid 3 m 1.
- the mixture was heated and stirred with C at 2 ⁇ .
- Acetic acid was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 2) to obtain the title compound.
- Example 6 4- (4-bromophenyl) -1,2,6-dimethyl-4-dihydro Synthesis of monopyridine (3,5-dicarboxylic acid) mono (3_phenylene 2-propene) ester
- Example 6 4- (3-Methoxycarbonyl) -1,2,6-dimethyl-1,4-dihydropyridine_3,5-dicarboxylic acid mono (3-phenyl-2-propene)
- Example 6 4- (3-chlorophenyl) 1-2-ethyl-1-6-methyl-1,4-dihydropyridine-1 3,5-dicarboxylic acid 5- (3-phenyl-2-propene-1-yl ) Ester
- the inhibitory activity of the dihydropyridinine derivative of the present invention on the N-type lucidum channel was measured by using the following method for detecting the calcium current of the upper rat cervical sympathetic ganglion cells by whole cell voltage clamp method.
- Wistar rats (2-4 weeks old) were incised in the neck under pentobarbital anesthesia to expose the superior cervical ganglion.
- the removed ganglia were immediately washed with ice-cold Ca 2 ⁇ -free Tyrode solution, cut into 3-4 pieces each, and left in the Ca-free Tyrode solution for 15 minutes.
- papain Washington Biochemicals (lot # 35J557); 20 U / ml) for 20 minutes, type 2 collagenase (Washington Biochemicals (CLS2); 5900 U / ml) and dispase (Calbiochem (lot 1312973); 16 mg / ml) ml) of the mixture for 1 hour.
- ganglion cells were mechanically isolated by pipetting. The isolated ganglion cells were used for the experiments within 6 hours.
- the calcium current was measured by the whole-cell voltage clamp method while fixing the membrane potential.
- the pit electrode was made by two-step drawing of a glass tube (1.5 inner diameter; Narishige) using an electrode maker (PB-7, Naringe). Ion current is measured by a patch amplifier (CEZ-230 0, Nihon Kohden), cut the noise at 10kHz (E-3201B, NF Electronic Instrument), monitor with a storage oscilloscope (DS-9121, Iwatsu), and at the same time, use a DAT data recorder (RD-120TE). , TEAC). After that, the data was recorded on a computer (Compaq DeskPro) using a pCLAMP software (Axon Instrument) at 3 kHz through a 1 kHz filter.
- Test compounds were rapidly administered by the Y tube method of Murase et al., Brain Res. 525, 84 (1990). The compound was dissolved in DMS0 to prepare a 10 mM mother liquor. At the highest drug concentration used, the vehicle (0.1 »had no significant effect on calcium currents.
- Table 12 shows the measurement results of the inhibitory activity of the dihydropyridine derivative at 0.1 uM.
- the novel dihydric pyridine derivative showed excellent N-type calcium channel inhibitory activity.
- the P-harmful activity of the L-type calcium channels was measured, and all the activities were weak.
- novel dihydropyridine derivative of the present invention selectively showed N-type calcium channel inhibitory activity. Therefore, the novel dihydropyridine derivative of the present invention is useful for cerebral infarction and cerebral hemorrhage.
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002288083A CA2288083A1 (en) | 1997-04-25 | 1998-04-23 | Novel dihydropyridine derivative |
JP54681398A JP4332902B2 (ja) | 1997-04-25 | 1998-04-23 | 新規ジヒドロピリジン誘導体 |
US09/403,592 US6350766B1 (en) | 1997-04-25 | 1998-04-23 | Dihydropyridine derivative |
AU70806/98A AU7080698A (en) | 1997-04-25 | 1998-04-23 | Novel dihydropyridine derivative |
EP98917654A EP0985667A4 (en) | 1997-04-25 | 1998-04-23 | NEW DIHYDROPYRIDINE DERIVATIVE |
US10/013,656 US6995179B2 (en) | 1997-04-25 | 2001-12-13 | Dihydropyridine derivative |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP9/109283 | 1997-04-25 | ||
JP10928397 | 1997-04-25 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
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US09/403,592 A-371-Of-International US6350766B1 (en) | 1997-04-25 | 1998-04-23 | Dihydropyridine derivative |
US09403592 A-371-Of-International | 1998-04-23 | ||
US10/013,656 Continuation US6995179B2 (en) | 1997-04-25 | 2001-12-13 | Dihydropyridine derivative |
Publications (1)
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WO1998049144A1 true WO1998049144A1 (fr) | 1998-11-05 |
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PCT/JP1998/001878 WO1998049144A1 (fr) | 1997-04-25 | 1998-04-23 | Nouveau derive de dihydropyridine |
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US (2) | US6350766B1 (ja) |
EP (1) | EP0985667A4 (ja) |
JP (1) | JP4332902B2 (ja) |
KR (1) | KR20010020267A (ja) |
CN (1) | CN1261348A (ja) |
AU (1) | AU7080698A (ja) |
CA (1) | CA2288083A1 (ja) |
TW (1) | TW446700B (ja) |
WO (1) | WO1998049144A1 (ja) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000024716A1 (fr) * | 1998-10-23 | 2000-05-04 | Ajinomoto Co., Inc. | Derives de dihydropyridine et compositions medicamenteuses contenant ces derives |
EP1043314A1 (en) * | 1997-12-22 | 2000-10-11 | Ajinomoto Co., Inc. | Novel dihydropyridine derivative |
WO2000078719A1 (fr) * | 1999-06-23 | 2000-12-28 | Ajinomoto Co., Inc. | Derive de la dihydropyridine |
WO2002022588A1 (fr) * | 2000-09-14 | 2002-03-21 | Ajinomoto Co.,Inc. | Nouveau derive de pyrimidine et nouveau derive de pyridine |
US6610717B2 (en) | 1999-06-23 | 2003-08-26 | Ajinomoto Co., Inc. | Dihydropyridine derivatives |
US6855716B2 (en) | 1999-06-23 | 2005-02-15 | Ajinomoto Co., Inc. | Dihydropyrimidine compounds and compositions containing the same |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0985667A4 (en) * | 1997-04-25 | 2000-03-22 | Ajinomoto Kk | NEW DIHYDROPYRIDINE DERIVATIVE |
AU2003207219A1 (en) | 2002-02-05 | 2003-09-02 | Ajinomoto Co., Inc. | Medicinal compositions containing gabapentin or pregabalin and n-type calcium channel antagonist |
JP2005343790A (ja) * | 2002-05-31 | 2005-12-15 | Ajinomoto Co Inc | カルシウムチャネル拮抗薬を含有する医薬組成物 |
AU2003259846A1 (en) * | 2002-08-16 | 2004-03-03 | The General Hospital Corporation | Non-invasive functional imaging of peripheral nervous system activation in humans and animals |
JP2007512338A (ja) * | 2003-11-21 | 2007-05-17 | メモリー・ファーマシューティカルズ・コーポレイション | L型カルシウムチャンネルブロッカーとコリンエステラーゼ阻害剤を用いた組成物及び処置方法 |
EP1868616A2 (en) * | 2005-03-29 | 2007-12-26 | The University of Maryland, Baltimore | Inhibitors for extracellular signal-regulated kinase docking domains and uses therefor |
WO2006109164A2 (en) * | 2005-04-15 | 2006-10-19 | Research & Innovation Soc. Coop. A R.L. | A method for preventing, delaying or reverting abnormal amyloid deposition |
CN105237465B (zh) * | 2015-11-13 | 2017-07-21 | 吉林大学 | 一种具有神经保护作用的化合物及医用用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6168488A (ja) * | 1984-09-05 | 1986-04-08 | バイエル・アクチエンゲゼルシヤフト | 新規なピリジルエチル‐ジヒドロピリジン類 |
JPS63258874A (ja) * | 1987-04-11 | 1988-10-26 | バイエル・アクチエンゲゼルシヤフト | 1,4−ジヒドロピリジン |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1455502A (en) | 1973-02-20 | 1976-11-10 | Yamanouchi Pharma Co Ltd | 1,4-dihydropyridine derivatives |
DE2658804A1 (de) | 1976-12-24 | 1978-07-06 | Bayer Ag | Kreislaufbeeinflussende mittel |
DE3239273A1 (de) | 1982-10-23 | 1984-04-26 | Bayer Ag, 5090 Leverkusen | Tetrahydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
JPS60233058A (ja) | 1984-05-04 | 1985-11-19 | Fujirebio Inc | 1,4−ジヒドロピリジン誘導体 |
JP2528899B2 (ja) * | 1987-09-16 | 1996-08-28 | 日本商事株式会社 | 3−アミノカルボニル−1,4−ジヒドロピリジン−5−カルボン酸エステル誘導体 |
DE3737340A1 (de) | 1987-11-04 | 1989-05-24 | Bayer Ag | Neue fluormethoxyphenyl-dihydropyridine, verfahren zur herstellung und ihre verwendung in arzneimitteln |
JPH02121967A (ja) * | 1988-10-31 | 1990-05-09 | Fujirebio Inc | 1,4−ジヒドロピリジン誘導体 |
JPH03240773A (ja) * | 1990-02-16 | 1991-10-28 | Sanyo Kagaku Kenkyusho:Kk | 塩酸ニカルジピンの製造法 |
WO1993013128A1 (en) | 1991-12-30 | 1993-07-08 | Neurex Corporation | Methods of producing analgesia and enhancing opiate analgesia |
WO1994005637A1 (en) | 1992-08-31 | 1994-03-17 | Mercian Corporation | Optically active 1,4-dihydropyridine compound and process for producing the same |
DE4313697A1 (de) | 1993-04-27 | 1994-11-03 | Bayer Ag | Chinolyl-dihydropyridinester, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln |
WO1996006829A1 (fr) * | 1994-08-29 | 1996-03-07 | Mercian Corporation | Derive de 1,4-dihydropyrydine |
EP0985667A4 (en) * | 1997-04-25 | 2000-03-22 | Ajinomoto Kk | NEW DIHYDROPYRIDINE DERIVATIVE |
-
1998
- 1998-04-23 EP EP98917654A patent/EP0985667A4/en not_active Withdrawn
- 1998-04-23 US US09/403,592 patent/US6350766B1/en not_active Expired - Lifetime
- 1998-04-23 CN CN98806564A patent/CN1261348A/zh active Pending
- 1998-04-23 JP JP54681398A patent/JP4332902B2/ja not_active Expired - Fee Related
- 1998-04-23 AU AU70806/98A patent/AU7080698A/en not_active Abandoned
- 1998-04-23 KR KR1019997009867A patent/KR20010020267A/ko not_active Application Discontinuation
- 1998-04-23 CA CA002288083A patent/CA2288083A1/en not_active Abandoned
- 1998-04-23 WO PCT/JP1998/001878 patent/WO1998049144A1/ja not_active Application Discontinuation
- 1998-04-24 TW TW087106398A patent/TW446700B/zh active
-
2001
- 2001-12-13 US US10/013,656 patent/US6995179B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6168488A (ja) * | 1984-09-05 | 1986-04-08 | バイエル・アクチエンゲゼルシヤフト | 新規なピリジルエチル‐ジヒドロピリジン類 |
JPS63258874A (ja) * | 1987-04-11 | 1988-10-26 | バイエル・アクチエンゲゼルシヤフト | 1,4−ジヒドロピリジン |
Non-Patent Citations (4)
Title |
---|
MASAHIRO HOSONO, ET AL.: "INHIBITORY EFFECT OF CILNIDIPINE ON VASCULAR SYMPATHETIC NEUROTRANSMISSION AND SUBSEQUENT VASOCONSTRICTION IN SPONTANEOUSLY HYPERTENSIVE RATS", JAPANESE JOURNAL OF PHARMACOLOGY., THE JAPANESE PHARMACOLOGICAL SOCIETY, KYOTO, JP, vol. 36, no. 02, 1 January 1995 (1995-01-01), KYOTO, JP, pages 127 - 134, XP002917215, ISSN: 0021-5198 * |
NAKAYAMA N. et al., "Antihypertensive Activity of OPC-13340, a New Potent and Long-Acting Dihydropyridine Calcium Antagonist, in Rats", JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1990, Vol. 15, No. 5, p. 836-844. * |
See also references of EP0985667A4 * |
UNEYAMA H. et al., "Blockade of N-Type Ca2+ Current by Cilnidipine (FRC-8653) in Acutely Dissociated Rat Sympathetic Neurones", BRITISH JOURNAL OF PHARMACOLOGY, 1997, Vol. 122, No. 1, p. 37-42. * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6350762B1 (en) | 1997-12-22 | 2002-02-26 | Ajinomoto Co., Inc. | Dihydropyridine derivative |
EP1043314A1 (en) * | 1997-12-22 | 2000-10-11 | Ajinomoto Co., Inc. | Novel dihydropyridine derivative |
EP1043314A4 (en) * | 1997-12-22 | 2001-01-24 | Ajinomoto Kk | NEW DIHYDROPYRIDINE DERIVATIVE |
WO2000024716A1 (fr) * | 1998-10-23 | 2000-05-04 | Ajinomoto Co., Inc. | Derives de dihydropyridine et compositions medicamenteuses contenant ces derives |
EP1191021A4 (en) * | 1999-06-23 | 2002-08-07 | Ajinomoto Kk | Dihydropyridine derivative |
WO2000078719A1 (fr) * | 1999-06-23 | 2000-12-28 | Ajinomoto Co., Inc. | Derive de la dihydropyridine |
US6610717B2 (en) | 1999-06-23 | 2003-08-26 | Ajinomoto Co., Inc. | Dihydropyridine derivatives |
US6855716B2 (en) | 1999-06-23 | 2005-02-15 | Ajinomoto Co., Inc. | Dihydropyrimidine compounds and compositions containing the same |
US7247645B2 (en) | 1999-06-23 | 2007-07-24 | Ajinomoto Co., Inc. | Dihydropyridine derivatives |
WO2002022588A1 (fr) * | 2000-09-14 | 2002-03-21 | Ajinomoto Co.,Inc. | Nouveau derive de pyrimidine et nouveau derive de pyridine |
JPWO2002022588A1 (ja) * | 2000-09-14 | 2004-01-22 | 味の素株式会社 | 新規ピリミジン誘導体及び新規ピリジン誘導体 |
US7288544B2 (en) | 2000-09-14 | 2007-10-30 | Ajinomoto Co., Inc. | Pyrimidine compounds useful as N-type calcium channel antagonists |
US7494989B2 (en) | 2000-09-14 | 2009-02-24 | Ajinomoto Co., Inc. | Pyridine compounds useful as N-type calcium channel antagonists |
JP4623354B2 (ja) * | 2000-09-14 | 2011-02-02 | 味の素株式会社 | 新規ピリミジン誘導体及び新規ピリジン誘導体 |
Also Published As
Publication number | Publication date |
---|---|
EP0985667A1 (en) | 2000-03-15 |
AU7080698A (en) | 1998-11-24 |
CN1261348A (zh) | 2000-07-26 |
EP0985667A4 (en) | 2000-03-22 |
JP4332902B2 (ja) | 2009-09-16 |
US6995179B2 (en) | 2006-02-07 |
KR20010020267A (ko) | 2001-03-15 |
US6350766B1 (en) | 2002-02-26 |
TW446700B (en) | 2001-07-21 |
US20020111494A1 (en) | 2002-08-15 |
CA2288083A1 (en) | 1998-11-05 |
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