WO1997028152A1 - Composes de dihydropyridine et composition medicinale les comprenant - Google Patents

Composes de dihydropyridine et composition medicinale les comprenant Download PDF

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Publication number
WO1997028152A1
WO1997028152A1 PCT/JP1996/002590 JP9602590W WO9728152A1 WO 1997028152 A1 WO1997028152 A1 WO 1997028152A1 JP 9602590 W JP9602590 W JP 9602590W WO 9728152 A1 WO9728152 A1 WO 9728152A1
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Prior art keywords
group
compound
propyl
ester
compound according
Prior art date
Application number
PCT/JP1996/002590
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English (en)
Japanese (ja)
Inventor
Teruhisa Miura
Shigeyuki Tasaka
Akira Kiue
Original Assignee
Nikken Chemicals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP03308796A external-priority patent/JP3897371B2/ja
Application filed by Nikken Chemicals Co., Ltd. filed Critical Nikken Chemicals Co., Ltd.
Publication of WO1997028152A1 publication Critical patent/WO1997028152A1/fr

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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

Definitions

  • the present invention relates to dihydroxypyridine compounds and pharmaceutical compositions containing the same.
  • the present invention relates to a novel dihydropyridin compound having an effect of overcoming an anticancer drug resistance or an effect of enhancing an anticancer agent effect, and a pharmaceutical composition comprising the compound or a pharmacologically acceptable salt or hydrate thereof and a carrier.
  • the present invention relates to an anticancer drug resistance overcoming agent or an anticancer agent effect enhancer.
  • dihydroxypyridine derivatives Many compounds are already known as dihydroxypyridine derivatives. Most of these known dihydropyridine derivatives have pharmacological activity on the circulatory system, and few other pharmacological activities have anti-inflammatory activity, hepatoprotective activity, etc. It is just that.
  • JP-A-2-40383, JP-A-2-240081, JP-B-6-92391, and JP-B-6-92401 disclose a dioxen ring or a dichain at the 4-position of dihydropyridine.
  • Compounds having a ring bonded thereto are disclosed in JP-A-5-117235 and JP-A-2-138221. It is described that a compound in which an aromatic ring such as a phenyl group is bonded to the 4-position of dropyridine has an action of overcoming anticancer drug resistance.
  • dihydropyridines described in the above-mentioned publications have an anticancer agent effect enhancing effect or an anticancer agent resistance overcoming effect.
  • some compounds have some favorable properties because they have almost no calcium pathway-blocking effect, and these compounds are not sufficiently satisfactory in terms of the effect of overcoming the anticancer drug resistance.
  • the dihydropyridin compounds described in these publications each have, as a substituent at the 4-position, a heterocyclic group such as a dioxene ring or a dichen ring or an aromatic ring group such as a phenyl group.
  • a heterocyclic group such as a dioxene ring or a dichen ring or an aromatic ring group such as a phenyl group.
  • an object of the present invention is to provide a compound having an effect of significantly increasing the sensitivity of cancer cells to an anticancer drug, particularly the sensitivity of cancer cells that have acquired resistance to the anticancer drug (an effect of overcoming anticancer drug resistance), or an effect of enhancing the effect of the anticancer agent.
  • An object of the present invention is to provide a compound having (an anticancer drug effect enhancing action).
  • Another object of the present invention is to provide a compound which exhibits an effect of extending the survival time of a tumor-bearing animal when used in combination with an anticancer agent, has little or no blocking action on the calcium pathway, and has low toxicity.
  • R 1 represents one A— (3-pyridyl)
  • A represents a C 3 -C e linear alkylene group
  • R 2 represents a C 2 -C 6 alkyl group, an alkenyl group Or an alkynyl group, a lower alkyl group or a lower alkenyl group having a substituent, or a cycloalkyl group optionally having a substituent
  • R 3 represents a phenyl group optionally having a substituent.
  • n represents an integer of 1 to 4.
  • an anticancer drug resistance overcoming agent or an anticancer agent effect enhancer BEST MODE FOR CARRYING OUT THE INVENTION
  • R 1 examples include groups in which A is a trimethylene group, a tetramethylene group, and particularly a group in which A is a trimethylene group.
  • R 3 represents a group having one or two fluorinated groups which may have a substituent such as a methoxy group, a methyl group, an ethyl group, a halogen atom and a nitro group.
  • Preferred examples of R 3 include a group having one or two phenyl groups, specifically, a benzhydryl group, a benzyl group, and a phenyl group. And a diphenylacetyl group (benzhydrylcarbonyl group), in particular, a benzhydryl group.
  • n represents an integer of 1 to 4, preferably an integer of 2 or 3.
  • Preferred examples of R 2 include a C 3 -C 6 alkyl group, an alkenyl group, an alkynyl group, a lower (eg, C, mono) alkyl group or a cycloalkyl group substituted by a phenyl group. Can be.
  • preferable compounds include Compounds 1 to 12 described in the following Examples.
  • the 1,4-dihydropyridine compound represented by the formula (I) provided by the present invention can be any of the well-known 1,4-dihydropyridine compounds conventionally used in the production of 1,4-dihydropyridine compounds. It can be manufactured according to the method.
  • the compound represented by the formula (I) is composed of an aldehyde represented by the formula ( ⁇ ), an acetate acetate represented by the formula ( ⁇ ⁇ ⁇ ) and a 3-amino compound represented by the formula (IV)
  • a method in which a crotonic acid ester is reacted in the presence or absence of an organic solvent (method A), or an aldehyde represented by the formula (II) and an acetate represented by the formula (V) It can be produced by, for example, a method (method B) in which an ester and a 3-amino carboxylic acid ester represented by the formula (VI) are reacted in the presence or absence of an organic solvent.
  • R 1 , R 2 , R 3, etc. have the same meanings as those of the formula (I).
  • the reaction used in these production methods is a known reaction conventionally used in the production of dihydropyridin compounds.
  • the dropyridine compound can also be produced by appropriately applying other reactions described in these known documents.
  • acetate acetate is obtained by reacting diketene with alcohols.
  • 3-Aminocrotonates can be produced by reacting the above acetate acetate with ammonia gas.
  • Aldehydes can be produced by a known method widely used in their synthesis.
  • the compound of formula (I) obtained by the present method which can be easily produced by reduction of certain esters or oxidation of alcohols, can be obtained by a known treatment method (eg, extraction, chromatography, recrystallization, etc.). Separation, purification CT / JP96 / 02590.
  • the dihydropyridine compound represented by the formula (I) has an asymmetric carbon atom and thus has an optical isomer.
  • any of the optical isomers and a mixture of the isomers are included.
  • the compound in which R 2 is an alkenyl group may have a geometric isomer in addition to the optical isomer in some cases.
  • both isomers 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, further exhibits an effect of overcoming the anticancer agent resistance against adriamicin-resistant cancer and vincristine-resistant cancer, and shows the effect of using a cancer-bearing animal in combination with an anticancer agent. It is useful as an anticancer drug resistance overcoming agent or an anticancer drug effect enhancer because it extends the survival time.
  • 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 carboxymethylcellulose and quinopenyl cellulose
  • calcium stearate Lubricants such as magnesium stearate, tanolek, polyethylene glycol, hydrogenated oil, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polypropylene Nyl alcohol, gelatin, arabic gum, and other binders, glycerin, wetting agents such as ethylene glycol, and other surfactants and flavoring agents as needed to achieve the desired dosage form.
  • Lubricants such as magnesium stearate, tanolek, polyethylene glycol, hydrogenated oil, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polypropylene Nyl alcohol, gelatin, arabic gum, and other binders, glycerin, wetting agents such as ethylene glycol, and other surfactants and flavoring agents as needed to achieve the desired dosage form.
  • diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and tragarant gum are used. If necessary, a dissolution aid, a buffer, a preservative, a fragrance, a coloring agent, and the like can be used.
  • the dosage unit of the compound of the present invention is 5 to 1,000 mg per adult per day for oral administration and 5 to 1,000 mg per day for oral administration. 5 to 200 mg, preferably 1 to 500 mg / day, preferably 1 to 200 mg / day for parenteral administration, and a desired therapeutic effect can be expected by each 1 to 3 times a day in divided doses. .
  • NMR data shows a signal of NMR-NMR measured in a CDCh solvent.
  • Acetate acetic acid 3-(3-pyridyl) propyl ester 2.2 g, amino crotonic acid 3-(4-benzhydrinolepiperazine-1 1 -yl) 4.0 g and caprolaldehyde l.lg were reacted in 20 ml of ethanol at room temperature for 3 days. After completion of the reaction, the reaction solution is concentrated to dryness under reduced pressure, and extracted with ethyl acetate. The extracted solution is washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure. The oily substance was purified by silica gel chromatography to obtain 5.5 g (80.9%) of the target compound.
  • Example 2 The compounds of each of the examples synthesized according to Example 1 or Example 2 are listed below together with the starting materials used and the analysis values of NMR.
  • the purification of the compound was carried out by recrystallizing the obtained crude substance with an appropriate solvent or, if necessary, by subjecting it to silica gel chromatography chromatography.
  • each enantiomer which is an optical isomer, eluted.
  • lactose and constarch are mixed until uniform, a 5 W / V% ethanol solution of hydroxyquine propylcellulose is added, and the mixture is 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 mg, a diameter of 7 mm, and a main drug content of 25 mg. (Test example)
  • test cells Human nasopharyngeal carcinoma-derived KB cells (susceptible cells) and their multidrug-resistant clones, VJ-300 cells (resistant cells), were used as test cells.
  • the culture solution was 10% fetal bovine serum (Flow Laboratories) and 0.29 mg Zml L-Glumin (Fab Laboratories) containing Eagle MEM medium (Yuisui Pharmaceutical Co., Ltd.). Manufactured).
  • the test of the combined use of the test compound and doxorubicin (adriamycin, ADM), which is an anticancer drug, for the effect of overcoming the anticancer drug resistance or enhancing the effect of the anticancer drug was carried out as follows.
  • each test cell Suspend each test cell in the culture medium and adjust the cell density to about 200 cells / ml.
  • the cell suspension was dispensed in a 2 ml Zutsushi petri dish, and cultured for 24 hours at 37 ° C in carbonate gas wells down Kyubeta one (5% C0 2, 95% air). Thereafter, add 5 to 10 1 of each of the ADM aqueous solution of the specified concentration and the DMS0 solution of the test compound of the specified concentration, and continue culturing for another 7 days. After completion of the culture, the cells were fixed with methanol, stained with Giemsa, the number of colonies in each dish was counted, and a volume response curve was prepared.
  • LD 5 D 50% ADM concentration of cell viability
  • ADM + verapamil refers to the combination group of ADM and verapaminole (1 fig / ml)
  • ADM + dicardipine Represents the combination of ADM and dicardipine (3M)
  • VCR bincristin
  • a dose response curve was prepared, and the degree of resistance was calculated.
  • the results are shown in Table 3.
  • VCR alone (control) represents the VCR alone group
  • VCR + compound 2 represents the VCR + compound 2 (I fig / ml) combined group.
  • veravamil represents the combination group of VCR and verapa minole (1 gZml).
  • VCR vincristine
  • VCR resistant murine leukemia P3 88 / VCR
  • VCR VCR resistant murine leukemia
  • TZ C survival rate
  • VCR alone was dissolved in physiological saline, and the compound of the present invention was used by suspending it in a 0.5% carboxymethylcellulose sodium solution containing 0.1% Tween-80.
  • Tables 4 and 5 In the table, control is the non-administration group, VCR alone is the VCR (100 g / kg) administration group, VCR + Compound 1 is the VCR (100 / zg / kg) and Compound 1 (100 mg / kg) combination group, and Similarly, VCR + Compound 6 represents the combination group of VCR (100 ⁇ g / kg) and Compound 6 (100 mg / kg).
  • VCR + Compound 2 * marked with * indicates a group in which VCR (100 g Zkg) and Compound 2 (10 mg / kg) were used in combination.
  • mice Animals used: ddY male mice (Japan SLC-1) 4-5 weeks old, 3-5 mice per group were used.
  • Test method 0.5% carboxymethyl cellulose sodium (CMC-Na) containing 0.1% Tween 80 or 0.1% Tween 80 0.5% CMC_Na containing 10% ethanol containing the compound of the present invention And no deaths in 3-5 animals per group from 100 mgZkg to 1 / root 2 Mice until intraperitoneal injection. The survival of the animals is monitored up to 7 days after administration, and LDs are obtained by the Probit method. The value was calculated.
  • 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, are 709.1 times as large as cells that have not acquired resistance.
  • the same effect (50% cell viability) cannot be obtained without using an anticancer agent at a concentration of 2%, whereas the same effect can be obtained at a concentration of 2.0 times with the compound 2 of the present invention (compound 1 g Zml). can get.
  • the compounds of the present invention have low toxicity and weak calcium antagonism, and are effective in both in vitro (in vitro) and in vivo (in vivo) tests. Useful as an effect enhancer.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de dihydropyridine représentés par la formule générale (I), ou des sels de ces composés acceptables du point de vue pharmacologique, ainsi qu'un reconstituant de la tolérance aux produits anticancéreux ou un produit augmentant la puissance d'agents anticancéreux comprenant lesdits composés ou sels comme ingrédient actif. Dans la formule, R1 représente -A-(3-pyridyle) (A représentant l'alkylène C¿3-6? linéaire); R?2¿ représente alkyle C¿2-6?, alcényle ou alkynyle, alkyle ou alcényle inférieur éventuellement substitués, ou cycloalkyle éventuellement substitué; R?3¿ représente un groupe ayant un ou deux groupes phényle éventuellement substitués, et n est un nombre entier de 1 à 4.
PCT/JP1996/002590 1996-01-29 1996-09-11 Composes de dihydropyridine et composition medicinale les comprenant WO1997028152A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP03308796A JP3897371B2 (ja) 1995-03-13 1996-01-29 抗癌剤耐性克服剤
JP8/33087 1996-01-29

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Publication Number Publication Date
WO1997028152A1 true WO1997028152A1 (fr) 1997-08-07

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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 (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6117562A (ja) * 1984-04-11 1986-01-25 ブリストル−マイア−ズ　コムパニ− 薬剤に有用なジヒドロピリジニルジカルボン酸アミド及びエステル
JPH0525168A (ja) * 1991-07-15 1993-02-02 Kyorin Pharmaceut Co Ltd 癌細胞に対する感受性増強剤及びその製造方法
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
JPH0841052A (ja) * 1994-07-29 1996-02-13 Nikken Chem Co Ltd １，４−ジヒドロピリジン誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6117562A (ja) * 1984-04-11 1986-01-25 ブリストル−マイア−ズ　コムパニ− 薬剤に有用なジヒドロピリジニルジカルボン酸アミド及びエステル
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
JPH0525168A (ja) * 1991-07-15 1993-02-02 Kyorin Pharmaceut Co Ltd 癌細胞に対する感受性増強剤及びその製造方法
JPH0841052A (ja) * 1994-07-29 1996-02-13 Nikken Chem Co Ltd １，４−ジヒドロピリジン誘導体

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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