WO1997028125A1 - Derives de dihydropyridine et compositions medicinales les contenant - Google Patents

Derives de dihydropyridine et compositions medicinales les contenant Download PDF

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Publication number
WO1997028125A1
WO1997028125A1 PCT/JP1997/000084 JP9700084W WO9728125A1 WO 1997028125 A1 WO1997028125 A1 WO 1997028125A1 JP 9700084 W JP9700084 W JP 9700084W WO 9728125 A1 WO9728125 A1 WO 9728125A1
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WIPO (PCT)
Prior art keywords
group
compound
ester
propyl
ethyl
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PCT/JP1997/000084
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English (en)
Japanese (ja)
Inventor
Akira Kiue
Teruhisa Miura
Shigeyuki Tasaka
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Nikken Chemicals Co., Ltd.
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Application filed by Nikken Chemicals Co., Ltd. filed Critical Nikken Chemicals Co., Ltd.
Publication of WO1997028125A1 publication Critical patent/WO1997028125A1/fr

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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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a novel dihydropyridin compound having an anticancer drug resistance overcoming action or an anticancer drug effect enhancing action and a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient, particularly overcoming anticancer drug resistance.
  • the present invention relates to an agent or an anticancer agent effect enhancer.
  • dihydropyridine derivatives Many compounds are already known as dihydropyridine derivatives. Most of these known dihydropyridine derivatives have pharmacological activity on the circulatory system, and few other pharmacological activities have anti-inflammatory, hepatoprotective, etc. It is just being done.
  • a compound in which a dioxene ring or a dichen ring is bonded to the 4-position of 1,4-dihydropyridine as disclosed in Japanese Patent Application Laid-Open No. HEI 5-1177235.
  • Japanese Patent Application Laid-Open No. 2-1382822 discloses that a compound in which an aromatic ring such as a fuunyl group is bonded to the 4-position of 1,4-dihydropyridin has an action of overcoming anticancer drug resistance. Have been.
  • the present inventors have synthesized dihydroxypyridin compounds having various substituents, and have screened these compounds extensively to determine whether or not they have an effect of being used in combination with an anticancer agent.
  • a new compound a dihydropyridinine compound represented by the formula (I) responds to cancer cells against anticancer drugs. It has been found that the compound has an effect of remarkably increasing the sensitivity of cancer cells, particularly the sensitivity of cancer cells that have acquired resistance to an anticancer drug (an effect of overcoming anticancer drug resistance).
  • these compounds show an effect of prolonging the survival period of a carrier animal when used in combination with an anticancer agent, and furthermore, have been found that they have almost no calcium pathway blocking effect and low toxicity, and That is, according to the present invention, the formula (I):
  • R is a disubstituted aminoalkyl group, piperazinylalkyl group, thiazolylalkyl group, piperidinylalkyl group, morpholinylalkyl group, aziridinylalkyl group, imidazolylalkyl group, pyrrolidinylalkyl group or pyridinylalkyl group.
  • R 2 represents a C 3 alkyl, alkenyl or alkynyl group;
  • R 3 represent a group in the same range as or a lower alkyl group, a pyridylmethyl group, a pyridylethyl group or an alkoxyalkyl group).
  • a pharmaceutical composition comprising a dihydropyridin compound of the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, in particular, an anticancer drug resistance overcoming agent or an anticancer agent effect enhancer.
  • a pharmaceutical composition comprising a dihydropyridin compound of the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, in particular, an anticancer drug resistance overcoming agent or an anticancer agent effect enhancer.
  • R is 2 — (N, N — dimethylamino) ethyl group, and 2 — (N, N-acetylamino) ) Ethyl group, disubstituted aminoalkyl group such as 2-((N-benzyl-1-N-methylamino) ethyl group, 3- (4-benzylpiperazine-11-yl) propyl group, 3 — (4 — ethoxyquinyl pyridine 1 1-yl) propyl group, 3 — (4 — benzhydrinolepiperazine 1 1-yl) propyl group, 3 — (4 — Cylbiperazine-1 1-yl) propyl group, 3 _ (4 — diphenylacetylpiperazine — 1 — yl) propyl group, 3 — [4 — (3, 4 — dichlorophenyl) Piperazinylalkyl group such as prop
  • substituents include disubstituted aminoalkyl, pyrazinylalkyl, thiazolylalkyl, morpholinylalkyl, piapinidinylalkyl and pyridinylalkyl. You can do it.
  • substituents include 2— (N—benzyl-N—methylamino) ethyl group, 3— (4—benzylpiperazin-1-yl) propyl group, 3 — (4 — ethoxyquinylpyridine) propyl group, 3 _ (4 — benzohydrylpy Perazine 1-yl) Propyl group, 3— (4—Diphenylacetylpiperazine-1 1-yl) Propyl group, 2— (4—Methyl-1-5-thiazolyl) Ethyl group, 2-((1-pyrrolidinyl) ethyl group, 2- (1-piperidinyl) ethyl group, 2-morpholinoethyl group and the like.
  • R examples include groups in the same range as R, lower alkyl groups such as methyl group and ethyl group, and alkoxyalkyl groups such as pyridylmethyl group, pyridylethyl group and methoxymethyl group.
  • Preferred examples of R 3 include groups in the same range as R 3 and a pyridylmethyl group.
  • C — C,. Alkyl, alkenyl, or aralkyl Kiniru group and rather is preferred, C 3 - C alkyl group, in particular C 4 - to C alkyl group can and Ageruko.
  • n-propyl iso-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 1-methylpropyl, 1 1-methylbutyl group, 1-ethylpropyl group, 1-ethylpentyl group, 2,2-dimethylpropyl group, 2,4,4 1-methylpentyl group, 2-methyl-1-propenyl group, 2 , 6-dimethyl-1-5-heptenyl group, 1-heptynyl group and the like.
  • preferred compounds include the compounds (compounds 1 to 32) described in Examples. Also, especially Preferred compounds include compound 1 to compound 4, compound 6, compound 9 to compound 14, compound 20, compound 24, compound 25, compound 28 and compound 31.
  • any of the dihydropyridin compounds represented by the formula (I) provided by the present invention can be produced according to well-known methods conventionally used for producing dihydropyridin compounds.
  • the compound represented by the formula (I) comprises an aldehyde represented by the formula (11), an acetate acetate represented by the formula (II!), And a 3-amino compound represented by the formula (IV).
  • the crotonate is reacted in the presence or absence of an organic solvent (method A) or the aldehydes of formula (II) and the aldehydes of formula (1)
  • the acetate acetate of II) can be produced by reacting in an organic solvent in the presence of aqueous ammonia (method B).
  • the reaction used in these production methods has conventionally been dihydropyridyl Known methods used in the production of the compound (for example, JP-B-46-40625, JP-B-56-37225, JP-A-60-214748) No. 6, etc.). Therefore, the dihydropyridine compound of the present invention can be produced by appropriately applying other reactions described in these known documents in addition to the above-mentioned methods.
  • the starting compounds used in these production methods are all known compounds and can be easily obtained or produced by those skilled in the art as needed.
  • acetate acetate can be produced by reacting diketene with alcohols.
  • 3-amino crotonate can be produced by reacting the acetoacetate with ammonium gas.
  • Aldehydes can be easily produced by reducing esters or oxidizing alcohols, which are known methods widely used for their synthesis.
  • the compound of the formula (I) obtained by this method can be isolated and purified by a known treatment means (eg, extraction, chromatography, recrystallization, etc.).
  • a known treatment means eg, extraction, chromatography, recrystallization, etc.
  • those having an asymmetric carbon atom include optical isomers, and the present invention includes any optical isomer and a mixture of isomers.
  • the compound having an alkenyl group may have a geometric isomer in addition to the optical isomer in some cases.
  • any isomer and a mixture of isomers are included.
  • the isomer mixture can be separated into the respective isomers by a fractional crystallization method or chromatography, if necessary.
  • the compound according to the present invention exhibits an effect of enhancing the effect of an anticancer agent, and furthermore, an anticancer agent against adriamicin-resistant cancer and vincristine-resistant cancer It exhibits an effect of overcoming resistance and prolongs the survival time of tumor-bearing animals when used in combination with an anticancer drug. Therefore, it is useful as an anticancer drug resistance overcoming drug or an anticancer drug effect enhancer.
  • Oral dosage forms include, for example, tablets, granules, capsules, pills, powders, and liquids.
  • Parenteral dosage forms include, for example, injections, suppositories, and the like.
  • Can be These preparations can be prepared by a conventional method using the compound of the present invention or a pharmacologically acceptable salt thereof and a usual preparation carrier.
  • excipients such as lactose, glucose, corn starch, and sucrose
  • disintegrants such as calcium carboxymethyl cellulose and hydroxypropyl cellulose, calcium stearate, and stearate
  • Lubricants such as magnesium phosphate, tanolek, polyethylene glycol, hydrogenated oil, hydroxyquine propylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin, arabia gum
  • a binder can be prepared into a desired dosage form by using a humectant such as glycerin and ethylene glycol, and a surfactant or a flavoring agent, if necessary.
  • diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and tragarant gum.
  • Solubilizers, buffers, preservatives, fragrances, coloring agents and the like can be used accordingly.
  • the dosage unit of the compound of the present invention is one adult per adult, and oral administration is 5 to 10 per day. 0 0 mg, preferably 5-20 0 mg, for parenteral administration, in the range of l-500 mg / day, preferably 1-20 mg / day, the desired therapeutic effect can be obtained by divided doses 1-3 times daily. Can be expected.
  • NMR data is mainly a signal of the measured 'H- NMR in CDC 1 3 solvent indicated by (5 values. Each time when measured in other solvents, in the examples Example 1
  • Acetic acetic acid 3-pyridylmethyl ester 2.Og and 2.6 g of 3_aminocrotonic acid 2- (N-benzyl-N-methylamino) ethyl ester, 0.81 g of n-barrelaldehyde Heat to reflux in 10 ml of sopropanol for 6 hours.
  • the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 1N hydrochloric acid, washed with a cross-linked form, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. Do. The extracted solution is washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure.
  • the oily substance was purified by silica gel column chromatography to obtain 2.4 g (52 mg) of the target compound.
  • 3-Aminocrotonic acid 2- (N-benzyl-N-methylamino) ethylester 3.13 g and cabronaldehyde 0.57 g are stirred in 10 ml of acetic acid for 18 hours at room temperature. After completion of the reaction, the reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 1N hydrochloric acid, washed with a cross-linked form, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. . The extracted solution is washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The oily substance was purified by silica gel chromatography to obtain 0.94 g (29) of the desired compound.
  • Acetacetic acid 3- (4-benzylpiperazinyl) propyl ester 4.6 g and nonyl aldehyde 1.0 g are heated to reflux in 10 ml of isopropanol for 6 hours in the presence of 3.0 ml of aqueous ammonia. .
  • the reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 1N hydrochloric acid, washed with a cross-section form, then made alkaline with sodium hydrogen carbonate, and then added with ethyl acetate. Extract with The extracted solution is washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure.
  • the oily substance was purified by silica gel column chromatography to obtain 1.7 g (333 ⁇ 4i) of the target compound.
  • Example 4 The compounds of each example synthesized according to Examples 1 to 3 are listed below together with the raw materials used, the yield, and the NMR analysis values. The compound was purified by recrystallizing the obtained crude substance with an appropriate solvent or, if necessary, by subjecting it to silica gel chromatography.
  • Example 4
  • Tables 1 to 3 show the structures of the respective substituents of the compounds (Compound 1 to Compound 32) obtained in the above Examples.
  • lactose and corn starch are mixed until uniform, a 5 W / V% ethanol solution of hydroxypropyl cellulose is added and kneaded and granulated. After passing through a 16-mesh sieve and sieving, the tablets were compressed in a conventional manner to give tablets each having a weight of 130 m, a diameter of 7 mni, and a drug content of 25 mg.
  • Human nasopharyngeal carcinoma-derived KB cells (sensitive cells) and their multidrug-resistant clone VJ-300 cells (resistant cells) were used as test cells.
  • the culture solution is an eagle containing 10% fetal bovine serum (Flow Laboratories) and 0.292 mg / ml L-glutamine (Flow Laboratories).
  • MEM medium manufactured by Nissui Pharmaceutical Co., Ltd. was used.
  • the following tests were conducted to examine the effect of using doxorubicin (Adriamicin, ADM), which is an anticancer drug, with a test compound to overcome the anticancer drug resistance or enhance the anticancer drug effect.
  • each test cell Suspend each test cell in the culture medium and adjust the cell density to about 200 cells / ml.
  • This cell suspension is dispensed into 2 ml schales at 37 ° C in a carbon dioxide incubator (5% C0295% air). Incubate for 4 hours. Thereafter, a predetermined concentration of an aqueous solution of ADM and a predetermined concentration of a dimethyl sulfoxide (DMSO) solution of the test compound are added in 5 to 101 parts each, and the culture is further continued for 7 days. After the completion of the culture, the cells were fixed with methanol, stained with Giemsa, the number of colonies in each of the dishes was counted, and a volume response curve was prepared.
  • DMSO dimethyl sulfoxide
  • the ADM concentration (LD 5 ) of the 50% cell viability was calculated, and the effect of overcoming the anticancer drug resistance and the effect of enhancing the anticancer agent effect were determined.
  • LD 5 of A DM results in KB cells A DM alone group. The concentration is shown as resistance level 1 and each LD 5 is shown below. Tables 4 to 6 show the degree of tolerance, which was calculated using the degree as a relative ratio.
  • ADM alone refers to the ADM alone group
  • ADM + Compound 1 refers to the ADM + Compound 1 (1 g / ml) combination group
  • ADM + Compound 32 refers to ADM and Compound 3 2 ( 1 g / ml) represents a combined group (however, compound 24 is 0.3 g / ml).
  • Table 4 shows the results using verapamil as a control compound.
  • ADM + verapamil represents the combination group of ADM and verapa minole (1 g / ml).
  • ADM + compound 13 1.0 1.2
  • ADM + compound 14 0.5 1.0
  • ADM + compound 20 1.0 1.4
  • ADM + compound 21 1.1 1.0
  • VCR bincristin
  • Table 7 VCR alone (control) refers to the VCR alone group
  • VCR + Compound 2 refers to the VCR + Compound 2 (1 g / mi) combination group
  • VCR + Compound 8 refers to VCR + Compound 8 (1 ng / mi).
  • VCR + veranomil represents a combination group of VCR and verapaminole (1 g ml).
  • VCR vincristine
  • control refers to the non-administration group
  • VCR alone refers to the VCR (100 g / kg) administration group
  • VCR + Compound 7 refers to VCR (100 g / kg) and Compound 7 (100 mg / kg). kg) combination group
  • VCR + compound 20 represents a combination group of VCR (100 g / kg) and compound 20 (100 mg / kg).
  • the VCR + Compound 13 * and VCR + Compound 14 * marked with * are the combination of VCR (100 / g / kg) and Compound 13 (10 mg / kg) and VCR (1 0 ⁇ g / kg) and Compound 14 (10 mg / kg) combination group.
  • inject the potassium chloride solution into the Manugs tube to a final concentration of 50 M and then The positive control compound or the compound of the present invention was dissolved in dimethyl sulfoxide when the contraction reaction generated in the sample reached equilibrium, and the solution was cumulatively injected from 1 ⁇ 10 to 10 M to 1 ⁇ 10 to 4 M.
  • the contraction force was recorded via FD-Pickup (Nihon Kohden) and polygraph (Nihon Kohden). The results are shown in Tables 12 and 13 at the 50 % inhibitory concentration (IC50 value) of high calcium contraction.
  • mice used: d d Y male mice (Japan SLC, Inc.) 4-5 weeks candy, 3-5 animals per group.
  • Test method 0.5% carboxymethylcellulose sodium (CMC-Na) containing 0.1% Tween 80 or 0.1% Tween 80 / 0.5 containing the compound of the present invention
  • the mice were suspended in% CMC-Na and administered intraperitoneally from 100 mg / kg to a common ratio of 1 / root 2 in 3-5 mice per group until no deaths were observed.
  • the life and death of animals is monitored up to 7 days after administration, and LD 5 n value is calculated by the Probit method. 7 ": o
  • the dihydropyridine compound according to the present invention enhances its action when used in combination with an anticancer agent.
  • the effect is particularly remarkable for clones that have acquired resistance to anticancer drugs.
  • VJ-300 cells which are multidrug-resistant clones of KB cells derived from human nasopharyngeal carcinoma, have 91% of those in cells that have not acquired resistance.
  • the same effect (50% cell viability) cannot be obtained without using an anti-pharmaceutical agent at 7.4 times the concentration, whereas the compound 4 of the present invention (compound 1 g / ml) is used in combination.
  • the same effect can be obtained at 1.4 times the concentration.
  • the compound of the present invention has low toxicity and is effective in both in vitro (in vUro) and in vivo (in vivo) tests. Therefore, it is useful as an anticancer drug resistance overcoming agent or an anticancer drug effect enhancer. is there.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne des compositions médicinales, en particulier des antagonistes de la tolérance aux médicaments anticancéreux ou des produits augmentant la puissance de médicaments anticancéreux, qui contiennent, comme ingrédient actif, des dérivés de dihydropyridine représentés par la formule générale (I), ou des sels de ces dérivés acceptables du point de vue pharmacologique. R1 représente aminoalkyle disubstitué, pipérazinylalkyle, thiazolylalkyle, pipéridinylalkyle, morpholinylalkyle, aziridinylalkyle, imidazolylalkyle, pyrrolidinylalkyle ou pyridylalcényle; R2 représente alkyle C3-10, alcényle ou alkynyle, et R3 représente un groupe du même domaine que R1 ou alkyle inférieur, pyridylméthyle, pyridyléthyle ou alcoxyalkyle.
PCT/JP1997/000084 1996-01-29 1997-01-17 Derives de dihydropyridine et compositions medicinales les contenant WO1997028125A1 (fr)

Applications Claiming Priority (4)

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JP3308896 1996-01-29
JP8/33088 1996-01-29
JP26379996A JP4046379B2 (ja) 1996-01-29 1996-09-13 ジヒドロピリジン化合物
JP8/263799 1996-09-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306853B1 (en) 1998-02-10 2001-10-23 Nikken Chemicals Co., Ltd. 1,4-Dihydropyridine derivatives

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6431781A (en) * 1987-07-17 1989-02-02 Inst Organ Sinteza An Latv Ssr 1,4-dihydropyridine derivative
JPS6431780A (en) * 1987-07-17 1989-02-02 Inst Organ Sinteza An Latv Ssr 1,4-dihydropyridine derivative
JPH0240383A (ja) * 1988-07-28 1990-02-09 Nikken Chem Co Ltd １，４−ジヒドロピリジン誘導体
JPH02138221A (ja) * 1988-08-02 1990-05-28 Nissan Chem Ind Ltd 抗癌剤薬効増強剤
JPH02240081A (ja) * 1989-03-14 1990-09-25 Nikken Chem Co Ltd １，４―ジヒドロピリジン誘導体
JPH05117235A (ja) * 1991-04-26 1993-05-14 Ajinomoto Co Inc 新規１，４−ジヒドロピリジン誘導体及びそれを含有する癌耐性克服剤
WO1996004268A1 (fr) * 1994-07-29 1996-02-15 Nikken Chemicals Co., Ltd. Compose de 1,4-dihydropyridine et composition medicinale contenant ledit compose

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6431781A (en) * 1987-07-17 1989-02-02 Inst Organ Sinteza An Latv Ssr 1,4-dihydropyridine derivative
JPS6431780A (en) * 1987-07-17 1989-02-02 Inst Organ Sinteza An Latv Ssr 1,4-dihydropyridine derivative
JPH0240383A (ja) * 1988-07-28 1990-02-09 Nikken Chem Co Ltd １，４−ジヒドロピリジン誘導体
JPH02138221A (ja) * 1988-08-02 1990-05-28 Nissan Chem Ind Ltd 抗癌剤薬効増強剤
JPH02240081A (ja) * 1989-03-14 1990-09-25 Nikken Chem Co Ltd １，４―ジヒドロピリジン誘導体
JPH05117235A (ja) * 1991-04-26 1993-05-14 Ajinomoto Co Inc 新規１，４−ジヒドロピリジン誘導体及びそれを含有する癌耐性克服剤
WO1996004268A1 (fr) * 1994-07-29 1996-02-15 Nikken Chemicals Co., Ltd. Compose de 1,4-dihydropyridine et composition medicinale contenant ledit compose

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306853B1 (en) 1998-02-10 2001-10-23 Nikken Chemicals Co., Ltd. 1,4-Dihydropyridine derivatives

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JP4046379B2 (ja) 2008-02-13

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