WO1984002702A1 - Derives de dihydropyridine - Google Patents

Derives de dihydropyridine Download PDF

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Publication number
WO1984002702A1
WO1984002702A1 PCT/JP1983/000008 JP8300008W WO8402702A1 WO 1984002702 A1 WO1984002702 A1 WO 1984002702A1 JP 8300008 W JP8300008 W JP 8300008W WO 8402702 A1 WO8402702 A1 WO 8402702A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
acid
yield
same manner
elemental analysis
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PCT/JP1983/000008
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English (en)
Japanese (ja)
Inventor
Kanji Meguro
Akinobu Nagaoka
Original Assignee
Takeda Chemical Industries 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
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to PCT/JP1983/000008 priority Critical patent/WO1984002702A1/fr
Priority to AT83302139T priority patent/ATE50987T1/de
Priority to DE2003199012 priority patent/DE10399012I2/de
Priority to DE8383302139T priority patent/DE3381313D1/de
Priority to EP83302139A priority patent/EP0094159B1/fr
Priority to IE897/83A priority patent/IE56057B1/en
Priority to IL68494A priority patent/IL68494A/xx
Priority to JP58075913A priority patent/JPS58201765A/ja
Priority to AU14155/83A priority patent/AU556150B2/en
Priority to GR71283A priority patent/GR78252B/el
Priority to DK203083A priority patent/DK160984C/da
Priority to PT76653A priority patent/PT76653B/pt
Priority to NO831613A priority patent/NO159593C/no
Priority to KR1019830001951A priority patent/KR880002357B1/ko
Priority to CA000427690A priority patent/CA1333487C/fr
Priority to ES522199A priority patent/ES8607966A1/es
Priority to FI831604A priority patent/FI79700C/fi
Publication of WO1984002702A1 publication Critical patent/WO1984002702A1/fr
Priority to US06/693,196 priority patent/US4892875A/en
Priority to ES541668A priority patent/ES541668A0/es
Priority to ES547275A priority patent/ES8701171A1/es
Priority to MYPI87002229A priority patent/MY102082A/en
Priority to SG1114/92A priority patent/SG111492G/en
Priority to HK32/93A priority patent/HK3293A/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • 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
    • 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
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel dihydropyridine derivative useful as a pharmaceutical.
  • the present invention relates to novel dihydropyridine derivatives having excellent pharmacological activity.
  • the present invention has a potent and sustained blood pressure lowering effect, a peripheral vasodilatory effect, a coronary artery dilatory effect, a cerebral vasodilatory effect, and a renal vasodilatory effect, and is useful as a pharmaceutical.
  • OMPI Lower key alkoxy, Shiano, a an alkoxycarbonyl ball di- or A key Norechi old, B 6 is;?
  • X is ⁇ , sulfur, bi- -Len, azomethine or or a group represented by S,
  • A is alkylene,
  • Ar represents aryl- or viridyl
  • m represents an integer of ⁇ to 3
  • ⁇ represents an integer of 0 to 2]
  • beta 1, lower ⁇ Luki (0 ⁇ _ 6) is preferably an A key represented by E 2 preliminary!? 3, linear, may be a Branch-like displacement, for example methyl, E Platinum, Probiol, Isoprobi, Buty, Isobuti, S6C-butyl, t-buty, Pinch, Isobentil, Neissantil, and the like are preferred.
  • I have these A key terminal to further lower bag Kuroanoreki ⁇ (c 3 _ 6) (Shitarobu port Birumechiru, Shikurobuchi Echiru, Kurobenchi;.
  • Cycloalkyl is preferable, for example, Prokyl, cyclobuty, cyclist bench, hexyl hexyl, etc.
  • akoxy alkyl having a total of 3 to 7 carbon atoms is preferable, for example, methoxeti, ethoxy.
  • the substituents represented by ⁇ and S 5 may be the same or different, and may be substituted at a different position on the ring. No 3
  • Halogen as such a substituent is fluorine, And i> preferably fluorine or chlorine, and for alkyl and chloroalkyl! ? 1 - those exemplified as S 3 are preferred.
  • the alkoxy and alkyl are preferably those having low-bag alk (C 1 _ 3 ), respectively, and include methoxy, ethoxy, proxy, isopropoxy and methylthio, ethyl / ⁇ / chi, and brovirchi. And isoprovirchi are examples.
  • alkyl and cycloalkyl represented by ⁇ ° are the above-mentioned ⁇ ! ? Examples illustrated in 3 are given.
  • These benzene rings may have the same or different substituents at arbitrary positions. Examples of the substituent on the benzene ring include those described above and as B5.
  • Examples of pyridyl include 2-viridyl, 3-pyridyl, and 4-pyridyl.
  • # 5 may have the substituents.
  • the alkylene represented by ⁇ is preferably C 2 __ 4 , which may be linear or branched, and includes ethylene, trimethylene, provylene, tetramethylene, 1,2-dimethylethylene and the like. No.
  • the ⁇ Li - ⁇ preliminary Birijinore represented by Arufaiota, the!? 6 can be mentioned those exemplified may have the same substituent.
  • AT may be the same aryl or pyridyl, or may be different.
  • n represents an integer of 0 to 2.
  • n 0, it means that a nitrogen atom and Ar are directly connected.
  • heterocycles or condensed heterocycles may be bonded at any position to the 4-position of the dihydridopyridine, particularly preferably X is adjacent to the bond to dihydroviridine.
  • X is adjacent to the bond to dihydroviridine.
  • preferred complex ring groups and condensed heterocyclic groups include 2-fluoro, 2-che-, 2-bilidine, 3-—bilidine, 2,1,1,3-pentoxoxazole. , 2, 1, 3-Benzthiasiasol-4-3 ⁇ 4.
  • the compound of the present invention represented by formula (I) can be produced, for example, by any of the following methods.
  • compounds (2), (31) and (IV) are reacted in an appropriate solvent to produce (I).
  • This reaction is usually carried out at about 20 to about 1 S0, preferably about 5 CTC to about 130, and particularly conveniently at the boiling point of the solvent used.
  • a solvent may be any solvent as long as it is inert to the reaction, for example, methanol, ethanol, or p? Pano-
  • (Eg, ethylene oxide, propylene oxide) or (II) is synthesized by reacting with a halohydrin represented by the formula (K).
  • the reaction between (VI) and the epoxy compound is usually carried out in an appropriate solvent (eg, water, methanol, ethano-A ', dioxane, tetrahydrofuran, etc.) with 2 (PC-100X).
  • an appropriate solvent eg, water, methanol, ethano-A ', dioxane, tetrahydrofuran, etc.
  • the reaction is preferably carried out in the presence of sodium carbonate or carbonic acid, which base is preferably 9 and the solvent is not limited to the above, but may be acetate. , Methylethylketone, w, dimethyiformamide, etc.
  • the reaction can be carried out at 20-100.
  • the halogen represented by ⁇ is chlorine, bromine, etc.
  • the reaction is accelerated, so about 0, 1 per 1 mol of sodium iodide and potassium trioxide (VI) — About 1 m may be used.
  • (W) is then reacted with diketene or / 3-ketoester represented by (X) to synthesize (W).
  • the reaction with diketene and P is usually about 40.
  • the reaction is carried out by heating to about C-, and at this time, a solvent inert to the reaction may be appropriately added.
  • (W) can be produced by reacting (3 ⁇ 4) with -keto estenol represented by (X).
  • This reaction is performed, for example, by sodium methoxide, sodium ethoxide, potassium b-butoxide, hydrogenation. It can be carried out at about 20'C to about 10 in a suitable inert solvent or in the presence of any group such as sodium, sodium amide, and metal sodium. 2)
  • n ′ is an integer of ⁇ to 2, all other symbols are as defined above.
  • the n class of the family compound (W), that is, the compound (W ') is obtained.
  • the reaction between (XI) and () is the reaction between the above () and (K), and the reaction between (W ') and the diketene or (X) is the above (1) with the dikete or (X) And under the same conditions.
  • Production method B It can be carried out under substantially the same conditions as production method A.
  • the starting compound (YI) can be synthesized by reacting the starting compound (IV) used in the production method ⁇ with an ammonium salt. That is, (W) is dissolved in an appropriate solvent (eg, methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran) and excess ammonia gas is dissolved in about 0 to about 6 (13 ⁇ 4 in TC or ammonia).
  • an appropriate solvent eg, methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran
  • excess ammonia gas is dissolved in about 0 to about 6 (13 ⁇ 4 in TC or ammonia).
  • a solution of -a in the above solvent is added, and the reaction is carried out at about 0 C to about 60 ° C in a closed vessel, or (W) can be easily synthesized by any method.
  • the target compound (I) is obtained by reacting the benzylidene-ketoester (W) with the compound (VI).
  • the reaction conditions of this reaction are also substantially the same as those in Production method A, and the reaction is carried out by reacting 0.8 mol of (Y1) with 1 mol of compound (W).
  • Benzylidene ⁇ -ketoester ( ⁇ a) used as a raw material is known or can be produced from aldehyde (m) and -ketoester (V) according to a known method [for example, Organic Reactions No. 15 Vol., 204-599 (1967)].
  • the amount of (W) used per mole of ( ⁇ 3 ⁇ 4) is usually 0.8-1.5 moles, and the amount of ammonia used is 1-5 moles.
  • This method reverses (H) and () under substantially the same reaction conditions as in Production Method C. By responding to it].
  • Benzylidene / 9-ketoester (11) used as a raw material can be synthesized by reacting aldehyde (H) with 9-ketoester (W) according to a known method, similarly to (II). See, for example, Organism Eactions, Vol. 15, pp. 204-599 (19667). The reaction is usually carried out using (H) 0.8-1.5 moles per mole.
  • This method is carried out by simultaneously reacting an ampa and (V) with the ( ⁇ ) in production method E)).
  • the reaction produces a (E), (E) it is considered that it) to react, the reaction line at the same reaction conditions and substantially produced V E I can.
  • the dose of (V) used per mole of (W) is usually 0.8-1.5 moles, and the dose of ammo is 1-5 moles.
  • the novel dipyridine-pyridine derivative (I) produced by the above method can be obtained by appropriately using known separation and purification means such as condensation, extraction, chromatography, reprecipitation, and recrystallization! ) It can be detected as any purity.
  • (I) has a soil-based group, so that it is well known! It can be an acid-added module.
  • pharmaceutically acceptable non-toxic salts are preferred, for example, salts with inorganic acids (such as sulphate, hydrobromic acid, phosphoric acid, and Ryukyu), and organic acids ( ⁇ ). Drunk, amberjack, maleate, bumaric acid, malate, tartaric acid, methanesulfonate, etc.). ⁇
  • inorganic acids such as sulphate, hydrobromic acid, phosphoric acid, and Ryukyu
  • organic acids ⁇
  • the compound (I) of the present invention and a salt thereof are low-toxic and have a potent and sustained blood pressure lowering effect in mammals (eg, mice, pets, rabbits, dogs, cats, and humans), peripheral vasodilation, Coronary artery dilatation, tubule dilatation, renal vasodilatation Has hypertension in humans, for example, hypertension in humans, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral and peripheral circulatory disorders (infarct, transient lg ischemic attack, renal artery) Stenosis *, etc. 3 ⁇ 4 Useful as a preventive and therapeutic agent for any cardiovascular disease.
  • ®H Compared with conventional dihydropyridine derivatives (eg, -Puezibin, -Cabibi), the strength and duration of action of ®H are higher than those of conventional compounds, which increase the renal blood flow and increase renal blood flow. It is highly useful in that it has, for example, when used as a preventive or remedy for blood pressure, a stable antihypertensive treatment can be obtained with a small number of doses (for example, once or twice a day).
  • an increase in Xu blood flow due to renal vasodilatory action promotes sodium excretion and suppresses sodium storage in the body. This ameliorates sodium retention in the body due to overdose and reduced sodium excretion in hypertensive patients, leading to superior antihypertensive effects.
  • overdose of salt is known to promote not only hypertension, but also the onset of stroke.J ?, Xu, a diuretic effect that is mitigated through an increase in blood flow, is useful for the prevention of stroke and any hypertensive vascular disorders. It is believed that there is.
  • Ren an angiotensin-producing enzyme, a low-pressure substance
  • the compound of the present invention for improving renal circulation can be expected to suppress renin secretion, and is therefore useful as a blood pressure lowering drug.
  • compound (I) and its salts are used as the above-mentioned pharmaceuticals, they are mixed with appropriate pharmaceutically acceptable carriers, excipients, and diluents, and are mixed with powders, granules, tablets, capsules, and injections. It can be administered orally or parenterally in any form. Dosage will vary depending on the dose, symptoms, breath weight and age of the patient, but if administered orally to adult hypertensive patients, for example,
  • test compound was orally administered as a 5 gum arabic suspension.
  • the dose was unified to 1 A of all compounds.
  • animals to which only gum arabic solution was administered were set as a control group.
  • Blood pressure measurement was performed with test compound given ⁇ , 5, 8 and
  • the compound of the present invention has the same action intensity as that of the known dihydroviridine derivatives (diphedivine, -cadipin). The duration of action was clearly longer.
  • test compound was dissolved in polyethylene glycol 400 and used as a stock solution.
  • the stock solution was diluted 5-fold with physiological saline and intravenously administered in a volume of 0.5 W per rat.
  • the dose was set to 0.0 ⁇ for all test compounds.
  • the measurement time of renal blood flow was 40 minutes after administration.
  • Table 2 shows the effect of the compound of the present invention on renal blood flow. Number Post-drug renal blood flow 3 ⁇ 4 Drug pre-renal blood flow
  • Example 3 11 In the same manner as in real life, 0 trobens aldehyde, aceto severe 2-1 ( ⁇ -Penzhi dobi biverazino) etinole, methyl 3-aminocrotonate isopropano -The reaction is carried out in water, and the product is further treated with methanolic hydrogen chloride.], 2,6-Dimethyi-141- (1,2-dihydroviridine) 1,3,5-Methyl dicarboxylate OMPI
  • Example 33 m-Clobenzaldehyde, acetoacetic acid 2— [4- (4,4-dimethynolebenzhydrido) piverazino] ethy 3-aminoclotone as in Example 1 By reacting it in isopropano-
  • Example 35 WIP M-Methoxymethoxybenzene as in Example 1; ⁇ dehyde, acetodic acid 21 [4- (4, -dimethinolebenzhydri piberazino]
  • Example 51'- m-Nitrobenzaldehyde, acetoacetic acid 2-([4- (21-methyl-V-phen)) piverazino] ethyl and methyl 3-aminocrotonate were prepared in the same manner as in Example 1 in isopropanol.
  • 2,6-Dimethyi / ⁇ 1-41 (3-12 trofuryl)-1,4 dihydropyrrolidine 1,3,5-dicanolevon sulphate methyl 2 -— [-4-1 (2-methinorefue -Nore) piperazino] ⁇ tinole was obtained as colorless crystals. Yield 72.1 Melting point 156-! At 57 (recrystallized from isopropyl-tenol-hexane).
  • Example 9 The free base obtained in Example 9 was dissolved in a small amount of methanol,
  • Example 17 The free radical obtained in Example 17 was dissolved in a small amount of methanol, and excess methanolic hydrogen chloride was added, followed by concentration. Precipitated crystals are collected by filtration and recrystallized from methano-, to give 2,6-dimethy-4- (3-nitrotrophyl) -1,4-dihydroviridine-13,5 methicolebonic acid 2-C 4- (3-Chronorefe-norre) biperazino] ⁇ tyl 'salt salt was obtained as yellow crystals. With a melting point of 1992—196.
  • the compound (I) of the present invention when used as an antibody, it can be used, for example, as follows.
  • the corn flour of (1), (2) and (17) were mixed and granulated together with the vest of the corn flour of (7), and the corn flour of ( 5 ) and ( 4 ) were added to the granules.
  • the mixture is compressed with a compression tablet machine to produce 0 to 10 tablets having a diameter of 7 and containing 1 tablet per tablet.
  • Penzhydr bromide (21.7 da) was mixed with 1-viverazine ethanol (1149), powdered calcium carbonate (24.3), and E, ⁇ -dimethylformamide (10) while stirring. It was dropped. After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with saturated corrosive water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (dissolved in hexane-decanoic acid-tinole (2: 1) ffi) to obtain an oil of 4-benzhydrin-1-piberazinethanol at 21.9 (84.2 « )Obtained.
  • Acetic acetic acid 2 [4-1 (4,4'-difluorobenzhydr) piverazino] et; u: oil IR (Neat): 1740, 1 15 cm 1 ⁇ .
  • Nshydrido bromide (12.4) was added, and the mixture was further stirred at room temperature for & hour, diluted with water, and extracted with ether. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed. The residual oil was eluted with silica gel (eluted with black-mouthed methanol (20: 1)).
  • the novel dihydropyridine derivative represented by the formula (I) provided has an excellent pharmacological activity and is useful as a pharmaceutical product.

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Abstract

Dérivés de dihydropyridine représentés par la formule (I), où R1, R2 et R3, qui peuvent être identiques ou différents, représentent chacun un alkyle, un cycloalkyle ou un alkoxyalkyle, R4 et R5, qui peuvent être identiques ou différents, représentent chacun de l'hydrogène, un halogène, du nitro, du trifluorométhyle, un alkyle, un cycloalkyle, un alkoxy, un cyano, un alkoxycarbonyle ou un alkylthio, R6 représente de l'hydrogène, un alkyle, un cycloalkyle, un aralkyle, un aryle ou un pyridyle, X représente de l'oxygène, du soufre, du vinylène, de l'azométhine, ou un groupe représenté par$(5,)$A représente un alkylène, Ar représente un aryle ou un pyridyle, m représente un nombre entier entre 1 et 3, et n représente un nombre entier entre 0 et 2. Ces dérivés ainsi que leurs sels d'addition acide sont utiles en tant qu'agents prophylactiques et thérapeutiques contre les affections du système circulatoire.
PCT/JP1983/000008 1982-05-10 1983-01-11 Derives de dihydropyridine WO1984002702A1 (fr)

Priority Applications (23)

Application Number Priority Date Filing Date Title
PCT/JP1983/000008 WO1984002702A1 (fr) 1983-01-11 1983-01-11 Derives de dihydropyridine
AT83302139T ATE50987T1 (de) 1982-05-10 1983-04-15 Dihydropyridinderivate, deren herstellung und verwendung.
DE2003199012 DE10399012I2 (de) 1982-05-10 1983-04-15 Dihydropyridinderivate, deren Herstellung und Verwendung.
DE8383302139T DE3381313D1 (de) 1982-05-10 1983-04-15 Dihydropyridinderivate, deren herstellung und verwendung.
EP83302139A EP0094159B1 (fr) 1982-05-10 1983-04-15 Dérivés de la dihydropyridine, leur préparation et leur application
IE897/83A IE56057B1 (en) 1982-05-10 1983-04-20 Dihydropyridine derivatives,their production and use
IL68494A IL68494A (en) 1982-05-10 1983-04-26 Dihydropyridine derivatives,their production and pharmaceutical compositions comprising them
JP58075913A JPS58201765A (ja) 1982-05-10 1983-04-28 ジヒドロピリジン誘導体，その製造法および用途
AU14155/83A AU556150B2 (en) 1982-05-10 1983-05-02 Dihydropyridine derivatives
GR71283A GR78252B (fr) 1982-05-10 1983-05-03
NO831613A NO159593C (no) 1982-05-10 1983-05-06 Analogifremgangsm te for fremstilling av terapeutisk virksomme dihydropyridinderivater.
DK203083A DK160984C (da) 1982-05-10 1983-05-06 Analogifremgangsmaade til fremstilling af dihydropyridinderivater eller farmaceutisk acceptable syreadditionssalte deraf
PT76653A PT76653B (en) 1982-05-10 1983-05-06 Dihydropyridine derivatives their production and use
KR1019830001951A KR880002357B1 (ko) 1982-05-10 1983-05-07 디히드로피리딘 유도체의 제조방법
CA000427690A CA1333487C (fr) 1982-05-10 1983-05-09 Derives dihydropyridine, leur production et leur utilisation
ES522199A ES8607966A1 (es) 1982-05-10 1983-05-09 Un procedimiento para preparar un derivado de dihidropiridina.
FI831604A FI79700C (fi) 1982-05-10 1983-05-09 Foerfarande foer framstaellning av nya, farmaceutiskt anvaendbara dihydropyridin-derivat.
US06/693,196 US4892875A (en) 1982-05-10 1985-01-22 Substituted heterocyclylalkyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acids
ES541668A ES541668A0 (es) 1982-05-10 1985-03-28 Un procedimiento para preparar derivados de dihidropiridina
ES547275A ES8701171A1 (es) 1982-05-10 1985-09-25 Un procedimiento para preparar derivados de dihidropiridina
MYPI87002229A MY102082A (en) 1982-05-10 1987-09-29 Dihydropyridine derivatives, their production and use
SG1114/92A SG111492G (en) 1982-05-10 1992-10-24 Dihydropyridine derivatives,their production and use
HK32/93A HK3293A (en) 1982-05-10 1993-01-14 Dihydropyridine derivatives,their production and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1983/000008 WO1984002702A1 (fr) 1983-01-11 1983-01-11 Derives de dihydropyridine

Publications (1)

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WO1984002702A1 true WO1984002702A1 (fr) 1984-07-19

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WO (1) WO1984002702A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174654A2 (fr) * 1984-09-14 1986-03-19 Ciba-Geigy Ag Dérivés carbonyles
WO1988007531A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux composes optiquement actifs
EP0314038A1 (fr) * 1987-10-27 1989-05-03 Byk Gulden Lomberg Chemische Fabrik GmbH Pyrrolidines
US4851331A (en) * 1986-05-16 1989-07-25 Allied Corporation Method and kit for polynucleotide assay including primer-dependant DNA polymerase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No relevant documents have been disclosed. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174654A2 (fr) * 1984-09-14 1986-03-19 Ciba-Geigy Ag Dérivés carbonyles
EP0174653A2 (fr) * 1984-09-14 1986-03-19 Ciba-Geigy Ag Dérivés phénylalkyles
EP0174653A3 (fr) * 1984-09-14 1987-06-16 Ciba-Geigy Ag Dérivés phénylalkyles
EP0174654A3 (fr) * 1984-09-14 1987-07-22 Ciba-Geigy Ag Dérivés carbonyles
US4851331A (en) * 1986-05-16 1989-07-25 Allied Corporation Method and kit for polynucleotide assay including primer-dependant DNA polymerase
WO1988007531A1 (fr) * 1987-03-27 1988-10-06 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouveaux composes optiquement actifs
EP0314038A1 (fr) * 1987-10-27 1989-05-03 Byk Gulden Lomberg Chemische Fabrik GmbH Pyrrolidines
WO1989003824A1 (fr) * 1987-10-27 1989-05-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles pyrrolidines

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