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WO1991000275A1 - Composes de butane ou leurs sels et leurs utilisations en medecine - Google Patents

Composes de butane ou leurs sels et leurs utilisations en medecine Download PDF

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Publication number
WO1991000275A1
WO1991000275A1 PCT/JP1989/000637 JP8900637W WO9100275A1 WO 1991000275 A1 WO1991000275 A1 WO 1991000275A1 JP 8900637 W JP8900637 W JP 8900637W WO 9100275 A1 WO9100275 A1 WO 9100275A1
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WO
WIPO (PCT)
Prior art keywords
compound
butagenyl
hydrochloride
melting point
substituted
Prior art date
Application number
PCT/JP1989/000637
Other languages
English (en)
Japanese (ja)
Inventor
Mitsuhiro Konishi
Hiroshi Tanaka
Kunio Osuga
Keiichiro Haga
Original Assignee
Yoshitomi Pharmaceutical 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 Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to PCT/JP1989/000637 priority Critical patent/WO1991000275A1/fr
Publication of WO1991000275A1 publication Critical patent/WO1991000275A1/fr

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Classifications

    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • the present invention relates to a novel butane compound or a salt thereof useful as an anti-ulcer agent and its pharmaceutical use.
  • Chem. Pharm. Bulletin (Chem. Pharm. Bull. Vol. 12) (11) pp. 134-1351 (1964) shows quinazolidinium bromide with Grignard reagent.
  • 1- (2-pyridyl) -1,4-phenyl-1,1,3-butadiene can be obtained by the ring-opening reaction.
  • Chem. Pharm. Bull., No. 13 (4) pp. 503-510 (1965) shows that 1 — (3 — methyl-1 2 — pyridyl) 1 4 — phenyl-1 1, 3 — butadiene was obtained by ring-opening reaction of monomethylquinazolium bromide with phenylmagnesium bromide.
  • the inventors of the present invention have conducted extensive studies to provide compounds that enhance the anti-corrosion factor, and as a result, certain novel butane compounds have been found to be asvilline-hydrochloric ulcer and ethanol gastric mucosa.
  • the inventors of the present invention have completed the present invention by finding that they have a strong antiulcer activity, exhibiting an inhibitory effect on disorders and indomethacin ulcers, and further exhibiting 15-hydroxyprostaglandin dehydrogenase antagonism.
  • R 1 is hydrogen, halogen, lower alkyl, lower alkoxy or mono-NHC 0 (CH 2 ) ra C 0 0 R 4 (here! 4 is hydrogen, lower alkyl, aralkyl, m is 0 Or 1)
  • R 2 is hydrogen, lower alkyl, aralkyl
  • R 3 is hydrogen, lower alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl Kill
  • H et represents pyridyl, substituted pyridyl, N-substituted pyridinium, pyrimidinyl, dioxopyrimidinyl, benzimidazolyl, substituted benzimidazolinole, quinolyl, a, b, c and d each represent hydrogen, or a and b or c and d are combined to form a single bond, and n is 0 or 1.
  • Halogen is chlorine, bromine, fluorine, iodine
  • Lower alkyl means alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl;
  • Lower alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy and other lower alkoxy having 1 to 6 carbon atoms;
  • Aralkyl means an alkyl group having an alkyl portion of 1 to 4 carbon atoms, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl;
  • Substituents on the phenyl nucleus of substituted phenyl and substituted aralkyl include halogen, hydroxyl group, nitro, amino, cyano, trifluoromethyl, lower alk ', and lower alkoxy;
  • Viridyl is 2- vizyl, 3-pyridyl, 4 monopyridyl; Substituent of substituted pyridyl is lower alkyl, group
  • R 5 is hydrogen, lower alkyl
  • R 6 is hydrogen, lower alkyl, aralkyl, £ is 0 or 1
  • the N-substituted viridinium is, for example, viridinium having a lower alkyl as a substituent, such as N-methyl virium dimethyl, N-ethyl virmidium, N-propyl pyrimidinium.
  • N-i Sopropilpirimidinium, N — Butylbilimidinium, N — Isobulbilimidinium, N — Tertiary pentylvirimidinium, N — Pentylbilimidinium, N — Hexylvirimidinium ;
  • Pyrimidinyl is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl;
  • Benzy Midazolinore is 4 ⁇ Nzy Midazolyl, 5 — ⁇ ⁇ Nzy Midazolyl, etc .;
  • Substituted benzimidazole substituents include halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, lower alkyl, lower alkoxy;
  • Quinoryl means 2-quinolyl, 4-quinolyl, 8-quinolyl, respectively.
  • the salts of the compound of the general formula (I) of the present invention include pharmacologically acceptable salts such as acid addition salts (hydrochloride, hydrobromide, sulfur Acid salts, phosphate salts, fumarate salts, maleate salts, succinate salts, tartrate salts, addition salts with inorganic or organic acids such as P-toluenesulfonate salts, metal salts (sodium salt) Salt, calcium salt, calcium salt, aluminum salt, etc.), quaternary ammonium salt, salt with amine (such as salt with triethylamine), and amino acid addition salt ( (Salts with lysine, glutamine, etc.), and when H et is N — substituted pyridinium, it forms a salt with halogen.
  • a compound of the general formula (I) Can be manufactured, for example, by the following method.
  • the compound represented by can be obtained.
  • the reaction is usually carried out in the presence of, for example, bis (methyl) methylsilylamine salt.
  • the reaction proceeds in a solvent inert to the reaction, such as tetrahydrofuran or dimethylformamide, preferably under a nitrogen stream for about 150 at room temperature for 4 to 24 hours.
  • the reaction product [compound (IV)] is a mixture of the trans form and the cis form, but recrystallization can isolate only the trans form of compound (IV) with good crystallinity. it can.
  • the compound (V) was treated with a compound represented by the general formula in a solvent such as chloroform or dichloromethane in the presence of a deoxidizing agent such as triethylamine.
  • the raw material compound ( ⁇ ) has the general formula
  • the compound represented by is triphenylphenylphosphine in a solvent inert to the reaction such as benzene, toluene, tetrahydrofuran, dimethylformamide, etc., at room temperature to about 50 at a temperature of 8 to 2 After reacting for 4 hours, the starting compound (EI) was
  • the starting compound (X) has the general formula
  • the compound represented by the formula and triphenylphosphine are reacted with benzene in a reaction-inert solvent such as toluene, tetrahydrofuran, or dimethylformamide at room temperature to about 50'C for 8 to 24 hours. It is obtained by
  • the compound (IV) can be obtained by refluxing the compound represented by and the compound (m) in a large excess of anhydrous acetic acid for 10 to 72 hours. By doing so, the compound (I 1 a) can be obtained.
  • R 7 -Y (XVI) (In the formula, R 7 is lower alkyl, Y is an anion such as halogen. Indicates a residue. )
  • reaction It is obtained by reacting with a compound represented by The reaction usually proceeds in the absence of a solvent or in a solvent inert to the reaction such as black mouth form, dichloromethane, butanol and the like at room temperature to 200 for several hours to several days.
  • a solvent or in a solvent inert such as black mouth form, dichloromethane, butanol and the like at room temperature to 200 for several hours to several days.
  • Het indicates a group other than N-substituted virginium of Het, and other symbols have the same meanings as described above.
  • the reaction proceeds from room temperature to 40 for 3 to 8 hours.
  • H et represents a group other than N-substituted vinylidene
  • R 1 represents hydrogen, halogen, lower alkyl, lower alkoxy
  • R 2 represents hydrogen.
  • the compound has the general formula (I) Among these compounds, H et represents a group other than N-substituted vinylidene, R 1 represents hydrogen, halogen, lower alkyl or lower alkoxy, and R 2 represents lower alkyl or aralkyl.
  • it can be obtained by hydrolyzing the ester in 2-4 N aqueous sodium hydroxide solution in distilled water ethanol.
  • the reaction usually proceeds at room temperature for 2 to '2' 4 hours.
  • H et represents a group other than N-substituted pyridinium
  • R 1 represents hydrogen, halogen, lower alkyl or lower alkoxy
  • R z represents lower alkyl or benzyl.
  • H et represents a group other than N-substituted pyridinium
  • R 1 represents hydrogen, halogen, lower alkyl, lower alkoxy
  • R 2 represents Compounds with hydrogen and general formula
  • R 2 '-X (XVD1) (In the formula, R 2 ' is lower alkyl and benzyl, and X is as defined above.)
  • the compound represented by is not affected by the reaction with tetrahydrofuran, chlorform, dimethylformamide, pyridin, etc. It can be obtained by reacting in an active solvent.
  • a deoxidizing agent such as potassium carbonate, triethylamine, and viridine
  • a compound represented by can be obtained.
  • the reaction proceeds by following the corresponding reaction conditions of Method 1.
  • the compound of the general formula (I) of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method or a chromatographic method.
  • the compounds of the general formula (I) of the present invention include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), organic acids (fumaric acid, maleic acid, succinic acid, tartaric acid, P-toluenesulfonic acid). Etc.) by a conventional method to give the above-mentioned acid addition salt.
  • metal hydroxide such as sodium hydroxide, lithium hydroxide, calcium hydroxide, and aluminum hydroxide
  • aluminum hydroxide aluminum hydroxide
  • amine Tethylamine, etc.
  • Amino acid lysine, glutamine, etc.
  • the corresponding salt can be prepared by a conventional method, and further, by a conventional method. It can be an ester that can be hydrolyzed in vivo.
  • the esters are, for example, acetoxoxymethyl, pinolloynoreoxymethyl, 1-acetoxetil, 1-pivaloynoreoxyethyl and other alkanoyloxynorequinolesteres, ethoxycarbonyloxymethytyl, 1- Alkoxycarbonoxyl alkyl esters such as ethoxycarbonyloxyl, phthalidyl, esters such as dimethoxyphthalidyl, carnomoinoremetyl, carn ⁇ 'moyletyl, N — methinorenororenoyl Moylmethyl, N, N—Dimethyltilcanoleno Moylmethyl, N, N One-jetyl Carbamoylmethyl and other powers Lunomoinolealkylester, Methoxymethyl, methoxytil and other alkoxyalkyl esters or 5-methyl-1,1,3 — Dioxolene 1 2 1 on 1 4
  • the compound of the general formula (I) or a salt thereof of the present invention also exists as a hydrate or a solvate ⁇ , and the present invention includes them.
  • the compound of the present invention when the above isomers exist, they are usually obtained as a mixture thereof, and these mixtures are separated into a number of isomers, optical isomers and stereoisomers by a conventional method. be able to. Each of these isomers can also be prepared by using the corresponding starting compound, and each of the isomers can be purified by fractional recrystallization or chromatography.
  • the strong antiulcer action of the compound of the present invention will be described in detail by the following pharmacological experiment examples.
  • 2'-force lupoxymethoxy-1,4'-bis (3-methyl-1 2-butyroxy) calcone was used as a control drug.
  • a male Wistar tar rat (body weight: 160-230 g) was fasted for about 20 hours and used.
  • the rat is filled with 0.3 N hydrochloric acid.
  • Aspirin suspended in 0.5% methylcellulose solution 10 O ig / kg was orally administered. Four hours later, the stomach was plucked and the area of injury was measured. The square root of the sum was taken as the number of ulcers.
  • the test solution was orally administered 30 minutes before the administration of asprin-hydrochloric acid. Also, a 0.5% methylcellulose solution was used as the control instead of the test solution. The results of this test are shown in Table 1.
  • a male Wistar tar rat (body weight 170 to 250 g) was fasted for about 48 hours and water for 20 hours before use. Rats were orally administered with 100% ethanol (5 / kg). One hour later, the stomach was removed and the lesion area that occurred was measured. The square root of the sum was taken as the ulcer index. The test solution was orally administered 30 minutes before the ethanol administration. As a control, a 0.5% methyl cell mouth solution was used instead of the test solution. The results of this test are shown in Table 2. 2
  • a male Donryu rat (body weight 170-220 g) was fasted for about 20 hours and used. Rats were subcutaneously administered with 20 mg of indomethacin. Six hours later, the stomach was removed and the length of the lesion that occurred was measured. The square root of the sum was taken as the ulcer index. The test solution was orally administered 30 minutes before the administration of indomethacin. A 0.5% methylcellulose solution was used as the control instead of the test solution. The results of this test are shown in Table 3. 3
  • the compound of the present invention or its salt was It has a remarkable anti-ulcer activity in ulcer models such as ethanol gastric mucosal disorder, indometacin ulcer, and water immersion restricted stress ulcer, and is also one of the closest action mechanism of ulcer. 1 5 — Hide! > Prostaglandin c-nase antagonism [European Journ. Of Pharmacology], Vol. 125, p. 185, 1 9 8 6]. Since it has a strong anti-ulcer activity, it is considered to be an anti-peptic ulcer agent. As an active ingredient, it can be used for treating and treating symptoms such as gastric ulcer, duodenal ulcer, gastritis and the like.
  • the compound of the general formula (I) of the present invention or a salt thereof is used as a medicine, it is usually mixed with a physiologically acceptable carrier, excipient, diluent or the like to give tablets, capsules, powders, injections, etc. It can be safely administered to patients in this form.
  • the dose may vary depending on the patient's symptoms and body weight.'However, it is usually about 1 to 500 ni / day for an adult orally.
  • Example 2 2 — [(Z, E) 1 4 — (4 — Nitrophenyl) 1 1, 3 — butagenyl] viridin'hydrochloride 4.8 g obtained in Example 1 (1) was added to Example 1 (2). , 2) [(Z, E) -4-(4 1 ethoxalylaminophosphyl) 1 1, 3 — butagenyl] viridine of yellow-orange crystalline powder by reacting and treating in the same manner as in (3). 2.7 g of hydrochloride are obtained. Melting point 174 to 175 (decomposition)
  • Example 1, 2 O nig The compound of Example 1, 2 O nig, is contained in 1 capsule filled with 1, 00 capsules.
  • Example 1 The compound of Example 1 was dissolved in acetone, adsorbed on microcrystalline cellulose, and then dried. This was mixed with corn starch and a 20-fold powder of the compound of Example 1 was prepared as a powder by a conventional method.
  • Example 1 10 g corn starch 10 g lactose 20 g carboxymethyl cellulose cellulose calcium 10 g microcrystalline cellulose 3 5 g polyvinylidene 5 g tanolec 1 0 g Total amount 100 g
  • the compound of Example 1 was dissolved in acetone, and this was adsorbed on microcrystalline cellulose and then dried. This was mixed with corn starch, lactose, and carboxymethyl cellulose calcium, and then an aqueous solution of boribylpyrrolidone was added as a binder to granulate by a conventional method. Using this as a lubricant, add talc The resulting mixture was mixed and compressed into tablets of 100 mg each. One tablet contains 10 mg of the compound of Example 1.
  • Phosphate buffer solution (0.1 M, pH 6.0) 100 g Distilled water Total 1,00 0 g
  • Example 1 Nikkol HCO-60. Sesame oil and half the amount of polypropylene glycol were mixed and dissolved by warming at about 80 ° C. The distilled water in which the glycol was previously dissolved was heated to about 80 and added to give an aqueous solution with a total volume of 1,000 id. This aqueous solution was dispensed into 2 ⁇ samples, sealed, and then sterilized by heating. In a tube, 20 mg of the compound of Example 1 was added.

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

Abstract

Composés de butane représentés par la formule générale (I), dans laquelle R1 représente hydrogène, halogène, alkyle inférieur, alcoxy inférieur ou -NKCO(CH¿2?)mCOOR?4 (où R4¿ représente hydrogène, alkyle inférieur ou aralkyle, et m représente 0 ou 1), R2 représente hydrogène, alkyle inférieur ou aralkyle, R3 représente hydrogène, alkyle inférieur, phényle, phényle substitué, aralkyle ou aralkyle substitué, Het représente pyridyle, pyridyle substitué, pyridinium à substitution N, dioxopyrimidinyle, benzimidazolyle, benzimidazolyle substitué ou quinolyle, a, b, c et d représentent chacun hydrogène, ou a et b ou c et d sont liés l'un à l'autre pour former une liaison simple, et n représente 0 ou 1. On décrit ces composés ou leurs sels, ainsi que leurs utilisations en médecine.
PCT/JP1989/000637 1989-06-27 1989-06-27 Composes de butane ou leurs sels et leurs utilisations en medecine WO1991000275A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP1989/000637 WO1991000275A1 (fr) 1989-06-27 1989-06-27 Composes de butane ou leurs sels et leurs utilisations en medecine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1989/000637 WO1991000275A1 (fr) 1989-06-27 1989-06-27 Composes de butane ou leurs sels et leurs utilisations en medecine

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WO1991000275A1 true WO1991000275A1 (fr) 1991-01-10

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6092268A (ja) * 1983-10-25 1985-05-23 Nippon Kayaku Co Ltd 抗アレルギ−作用を有する新規化合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6092268A (ja) * 1983-10-25 1985-05-23 Nippon Kayaku Co Ltd 抗アレルギ−作用を有する新規化合物

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