WO1991000275A1

WO1991000275A1 - Butane compounds or salts thereof and their medical uses

Info

Publication number: WO1991000275A1
Application number: PCT/JP1989/000637
Authority: WO
Inventors: Mitsuhiro Konishi; Hiroshi Tanaka; Kunio Osuga; Keiichiro Haga
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1989-06-27
Filing date: 1989-06-27
Publication date: 1991-01-10

Abstract

The invention relates to butane compounds represented by general formula (I), [wherein R1 represents hydrogen, halogen, lower alkyl, lower alkoxy or -NHCO(CH¿2?)mCOOR?4¿ (wherein R4 represents hydrogen, lower alkyl or aralkyl, and m represents 0 or 1), R2 represents hydrogen, lower alkyl or aralkyl, R3 represents hydrogen, lower alkyl, phenyl, substituted phenyl, aralkyl or substituted aralkyl, Het represents pyridyl, substituted pyridyl, N-substituted pyridinium, dioxopyrimidinyl, benzimidazolyl, substituted benzimidazolyl or quinolyl, a, b, c and d each represents hydrogen, or a and b or c and d are bound to each other to form a single bond, and n represents 0 or 1] or salts thereof and their medical uses.

Description

Specification

Butane compound or its salt and its pharmaceutical use

"Technical field"

The present invention relates to a novel butane compound or a salt thereof useful as an anti-ulcer agent and its pharmaceutical use.

"Background technology"

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. Or 1 — (2 — pyridyl) 1 2 — methyl 1 4 — phenol 1, 3 — butadiene can be obtained strongly, Chem. Pharm. Bull. '2 Volume 6 (8) 2334-2339 (1978), the ring-opening reaction of benzo [a] -one and benzo [b] quinolidinium bromide with Grignard reagent resulted in 2 — (4-funyl-1, 3, 3-butagenyl). It is possible to obtain quinoline or 1- (4-phenol 1,3-butagenyl) isoquinoline, and US Pat. No. 2427286 discloses 2-quinoline. In addition, 2 — picolin, that is, 1 — (2 — pyridyl) 1 4 1 phenyl 1 1> 3 — butadiene, etc., has an insecticidal action. Digital'Chemistry I (J. Med. Chem.) No. 19 (9) pp. 1079-1088 (1978) describes the guinea pig supplement. As a synthetic intermediate for body inhibitors, 1- (3 — or 4 -pyridyl) — 4-phenyl (which may have dichloro, nitro, and phenyl as substituents) 1, 3 — butadiene Has been done.

In addition, as anti-ulcer agents, drugs that suppress gastric acid secretion, etc., and weaken attack factors are being actively developed, while in recent years, cell protective effects, gastric mucosal protective effects, etc. Drugs that have the effect of increasing the anti-fouling factor have been attracting attention, and as such drugs, 2'—carboxymethoxy-4,4'-bis (3-methyl-1 2-butyroxy) calcone [generic name: sofarcon 〕 It has been known.

Among the anti-ulcer agents, 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.

"Disclosure of Invention"

General formula according to the present invention

[Wherein 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. ]

And a salt thereof and a pharmaceutical use thereof.

Each substituent and atom of each symbol above is defined as follows. 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

(Wherein R ⁵ is hydrogen, lower alkyl, R ⁶ is hydrogen, lower alkyl, aralkyl, £ is 0 or 1) and the like;

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;

What is Dioxopyrimidinyl? 2,4—Dioxo-1-5—pyrimidinyl, 2,4—Dioxo-1-6—pyrimidinyl, 2,6—Dioxo-1-4 pyrimidinyl, 2,6—Dioxo5 — Bilimidinyl, etc .;

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. According to the present invention, a compound of the general formula (I) Can be manufactured, for example, by the following method.

Method 1:

General formula

(In the formula, X represents halogen and H et has the same meaning as described above.) And a Wittig reagent represented by

(In the formula, each symbol has the same meaning as described above.)

By subjecting it to a Wittig reaction with a compound represented by

(In the formula, each symbol has the same meaning as described above.)

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 trans-isomer of the obtained compound (IV) 'is reduced with iron' hydrochloric acid for 1 to 2 hours at room temperature to 50 ° C in alcohol such as ethanol or methanol to give a vanillin derivative. To do. After the reaction, neutralized with sodium hydroxide, filtered through Celite, and treated appropriately to give the compound of the general formula

(In the formula, each symbol has the same meaning as described above.)

A compound represented by is obtained.

Next, 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.

R ^Z 0C0 (CH ₂ ) „C0C1 (VI) (In the formula, each symbol has the same meaning as above.)

By reacting the compound represented by and at room temperature for 1 to 2 hours and treating appropriately, the compound of the general formula

(In the formula, each symbol is as defined above.)

A compound represented by is obtained.

The raw material compound (Π) has the general formula

Het-CH ₂ X (W)

(In the formula, each symbol has the same meaning as described above.)

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

(In the formula, each symbol has the same meaning as described above.)

And the general formula

R ³ —CH ₂ CH0 (K) (In the formula, each symbol has the same meaning as above.)

It can be obtained by reacting the compound represented by with in an aqueous solution of alkali (such as sodium hydroxide) under ice-cooling for 80 to 30 minutes to 8 hours.

Method 2:

General formula B ³

Het-CH = CH-CHO (X)

(In the formula, each symbol has the same meaning as described above.)

Represented by or, i5—Unsaturated aldehyde compound and general formula

(In the formula, each symbol has the same meaning as described above.)

By treating the Wittig reagent represented by

(In the formula, each symbol has the same meaning as described above.)

To obtain the compound represented by, and further treat as in Method 1.

(In the formula, each symbol has the same meaning as described above.)

A compound represented by is obtained.

The starting compound (X) has the general formula

Het-CHO (ΧΠΙ)

(In the formula, each symbol has the same meaning as described above.)

By reacting the compound represented by and triphenylphosphoranylideneacetaldehyde in a nitrogen stream in nitrogenobenzene at room temperature for 24 to 48 hours, the starting compound (XI) is General formula

(In the formula, each symbol has the same meaning as described above.)

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

Method 3:

General formula

Het-CH ₃ (XV) (In the formula, each symbol has the same meaning as above.)

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.

Method 4:

Of the compounds of the general formula (I), those in which Het is an N-substituted pyridinium are of the general formula

(I c)

rCn0n0DR 2 ^:

(In the formula, each symbol has the same meaning as described above.)

And the general formula

R ⁷ -Y (XVI) (In the formula, R ⁷ is lower alkyl, Y is an anion such as halogen. Indicates a residue. )

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.

Method 5:

Among the compounds represented by the general formula (I;), the compound having a butane chain is produced as follows. That is, the general formula

Het '(XVI)

(In the formula, Het 'indicates a group other than N-substituted virginium of Het, and other symbols have the same meanings as described above.)

The compound represented by and the general formula by catalytic reduction by adding hydrogen gas with 5 to 10% of palladium carbon in methanol or ethanol.

R ³

Het '-CH _Z -CH ₂ -CH- (Id)

(In the formula, each symbol has the same meaning as described above.)

To a compound represented by

The reaction proceeds from room temperature to 40 for 3 to 8 hours.

Method 6:

— In the compound of general formula (I), H et represents a group other than N-substituted vinylidene, R ¹ represents hydrogen, halogen, lower alkyl, lower alkoxy, and 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. Alternatively, 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.

Method 7:

In the compound of the general formula (I), H et represents a group other than N-substituted pyridinium, R ¹ represents hydrogen, halogen, lower alkyl or lower alkoxy, and R ^z represents lower alkyl or benzyl. In the compound of formula (I), H et represents a group other than N-substituted pyridinium, R ¹ represents hydrogen, halogen, lower alkyl, lower alkoxy, and 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.)

In the presence of a deoxidizing agent such as potassium carbonate, triethylamine, and viridine, 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.

The reaction proceeds from room temperature to 150 ° C. for several hours to several days, and preferably pyridine can be used as a deoxidizing agent and a reaction solvent. Method 8:

formula (CHzCl) (XK)

Reaction of the compound represented by and triphenylphosphine in a solvent inert to the reaction such as benzene, toluene, tetrahydrofuran, dimethylformamide, etc. for 8 to 24 hours from room temperature to approximately 50'C. Due to the general formula '

By reacting the compound represented by the formula (m) with a compound in which R ¹ is hydrogen.

^{N 1} ■ CH = CH- (XXI)

\

No

(In the formula, each symbol has the same meaning as described above.)

A compound represented by can be obtained.

Compound (XXI) was recrystallized to isolate its trans-form, and then reduced in the same manner as in Method 1 to give a compound of the general formula

(In the formula, each symbol has the same meaning as described above.)

Of the compound of the general formula (I) by reacting the compound (VI) with a compound represented by

(In the formula, each symbol has the same meaning as described above.)

And a compound in which R ² is alkyl 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. In addition, when it has a carboxyl group in the molecule, metal hydroxide (such as sodium hydroxide, lithium hydroxide, calcium hydroxide, and aluminum hydroxide), aluminum hydroxide, amine (Trethylamine, etc.), Amino acid (lysine, glutamine, etc.) and 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 χ'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 — Dimethyl ester.

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.

In the compound of the general formula (I) of the present invention, geometric isomers of cis and trans isomers, optical isomers and stereoisomers based on asymmetric carbon and mixtures thereof are all included in the present invention. It is a thing.

In 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. In the examples of the present invention, 2'-force lupoxymethoxy-1,4'-bis (3-methyl-1 2-butyroxy) calcone (generic name: sofarcon) was used as a control drug.

Experimental Example 1: Action on aspirin-hydrochloric acid ulcer

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.

Table 1

Test drug Dose Number of animals Ulcer index Suppression rate

(mg / kg) (Meiji S.E.) (%)

Control 16 4. 30 ± 0.41

Compound of Example 1 10 16 2.31 ± 0.4 5 ** 46 Control 16 5. 33 ± 0.61

Compound of Example 1 30 16 1. 79 ± 0.2 3 ** 66 Control 16 6. 31 ± 0.63

Software 100 16 2. 72 ± 0.5 51 ** 57 * means P <0.01, S.E. means standard error)

Experimental Example 2: Effect of ethanol on gastric mucosal disorders

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

Test drug Dose Number of animals Ulcer index Suppression rate

(mg / kg) (Average soil S.E.) (%)

Control — — 16 3.00 ± 0.36

Compound of Example 1 3 16 1.70 ± 0.24 '43 Control — — 16 4.05 ± 0.68

Compound of Example 1 10 16 1.56 ± 0.29 '61 Controlled — — 16 3.00 ± 0.36

Compound of Example 1 30 16 0.29 ± 0.11 '90 Controls — — 16 4.69 ± 0.53

Software control 10 16 4.47 ± 0.59 '5 control — — 16 4.28 ± 0.55

Software 100 16 0.87 ± 0.20 '80

(** means P <0.01, S.E. means standard error)

Experimental Example 3: Action on indomethacin ulcer

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

If test drug dose number of animals ulcer index suppression rate

(mg / kg) (Average soil S.E.) (%)

Control 16 4.05 ± 0.35

Compound of Example 1 100 16 1.84 ± 0.44 * '55 Control 18 4.91 ± 0.44

Software control 100 18 5.31 ± 0.47 * '-8 control 18 5.12 ± 0.26

Soft Norecon 300 18 3.29 ± 0.45 * '36 * means Ρ <0.01, S.E. means standard error)

Experimental Example 4: Acute toxicity

Compound of the present invention: 2 — [(Ε, Ε) — 4 — (4 — methoxalylamininophenyl) 1, 1, 3 — butagenyl] pyridin 'hydrochloride salt hydrate intravenously into male mice However, no death occurred on the 5th day and no death occurred on the 5th day after oral administration of 100, 300 or lOOOOmg kg. Further, the other compounds of the present invention were similarly low in toxicity <As is clear from the above examples and various pharmacological experiments, 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.

When 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.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1

(1) 2 — Suspended 4 4 g of Wittig reagent prepared from chlorometylviridin hydrochloride and triphenylphosphine in 1600 ia £ Allow it to cool for a while. To this suspension, 1.0 mol of lithium bis (trimethylsilyl) amide and 2 0 6 δώ of the tetratrahydrofuran solution are slowly added dropwise over about 1.5 hours. During this period, stirring is performed while maintaining the above temperature. After that, raise the reaction temperature to room temperature and stir for another hour. Add 20 g of N-nitrocinnamaldehyde to the reaction mixture and stir at room temperature for 5 hours. The above operation is performed in a nitrogen stream. After completion of the reaction, the insoluble material is filtered off, and the filtrate is concentrated under reduced pressure. The residue is dissolved in a mixed solvent of methanol-acetate, hydrochloric acid-ethanol is added to this, and the crystals that separate out are collected by filtration and washed thoroughly with acetone to give orange-yellow powdery crystals. About 23 g is obtained. The obtained crystals were recrystallized from methanol-acetone to give 2 — [(E, E) -4-(4 12 trophenyl) 1, 1, 3-butagenyl] viridine '. Hydrochloride (E form) 1 3.9 g and 2 — [(Z, E) — 4 1 (4 — Nittophenyl) 1 1, 3 — Butagenyl] viridin 'hydrochloride (Z form) 4.8 g is obtained.

(2) Suspend 13.9 g of the E-form compound obtained in (1) and 10.2 g of iron powder in 150 ffl £ of ethanol, and add about 4N hydrochloric acid 51 to the suspension with stirring at room temperature. Drip in 40 minutes. After dripping, stir for another 1 hour, and then add 50% sodium hydroxide solution 50 to this reaction solution. The reaction solution is filtered under reduced pressure using Celite. Concentrate the filtrate under reduced pressure to remove most of the ethanol. To the remaining aqueous solution, add mouth-form and extract. After drying the chloroform layer with magnesium sulfate, the black form is removed under reduced pressure. Isopropyl ether was added to the residue and filtered under reduced pressure to obtain an orange-yellow powder of 2 — [(E, E) — 4 — (4-amino phenyl) 1 1, 3 — butagenyl] pyridine. 8.6 g are obtained. Melting point 1 5 2 to 1 5 5'C

(3) Dissolve 8.6 g of the compound obtained in (2) in dichloromethane 120, and add triethylamine 9.8 to it. A solution of ethyl oxalyl chloride 8 in dichloromethane 8 »^ is added dropwise to this solution with stirring at room temperature for about 45 minutes. Stir for 30 minutes at room temperature, then add water to the reaction mixture for extraction. The organic layer is dried over magnesium sulphate and the solvent is distilled off under reduced pressure to give a pale tan powder. This powder was dissolved in acetone and treated with isopropyl alcohol hydrochloride to give an orange-yellow crystalline powder of 2 — [(E, E) -1 4 1 (4 — ethoxarylamine phenyl). This gives 1 0.8 g of 1,3-butagenyl] pyridine'hydrochloride. Melting point 187-189 (decomposition)

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)

The following compounds can be obtained by using the same method as in Examples 1 and 2 below.

* 2 — ((E, E) — 4 — (2 — Ethoxalylaminophenyl) — 1, 3 — Butagenyl) Pyridin. Hydrochloride, Melting point 1 89 ~: I 9 0 ( Disassembly)

* 4-[(E, E)-4-(2-ethoxalylaminophenyl) 1, 1, 3-butagenyl] pyridin.hydrochloride, melting point 189-9190 (decomposition)

* 4-((E, E) — 4 — (3 — Ethoxyarylamine Phenyl) 1 3 — Methyl-1, 3 — Butagenyl] Viridin 'Hydrochloride ¼ hydrate, melting point 1 8 2 ~ 1 8 5'C (disassembly)

* 2 — ((E, E) -4-(3-Ethoxyarylamine Phenyl) 1 3-Methyl-1, 3-Butagenyl] Viridine 'Hydrochloride, Melting point 1 64 ~ 1 6 6 'C (decomposition)

* 4-〔(E, E) -1 4 — (4 1-Ethoxyarylaminophenyl) 1 3 −methyl 1 1,3 −butagenyl] pyridin 'hydrochloride · hydrate, melting point 2 0 8 to 2 0 9 'C (disassembly)

* 2-[(E, E) 1 4 1 (4 —Ethoxyarylaminophenyl) 1 3 —methyl 1, 3 —butagenyl] pyridin 'hydrochloride, melting point 1 8 7 ~ 1 8 8 (disassembled) * 2 — [(E, E)-A-(4 1-Ethoxycarbonylacetylethylaminophenyl) 1 3 —methyl 1 1,3 —butagenyl] pyridine-hydrochloride, melting point 1 8 7 ~ 1 8 9 (disassembled)

* 4 — [(E, E) 1 4 1 (3 — ethoxyarylamino 1 4 — methoxyphenyl) 1 3 — methyl 1, 3 — butagenyl] viridin · hydrochloride · Monohydrate, melting point 183-3185 (decomposition)

* 2 — ((E, E) 1 '4 1 (4 — Ethoxylinamine 3 — Methoxyphenyl) 1 3 — Methyl 1, 3 — Butagenyl) viridin · Hydrochloride · 4/5 hydrate, melting point 180 ~ 182 (decomposition)

* 4-[(E, E)-4-(3 — ethoxycarbonylacetylamino 1 4-methoxyphenyl) 1 3 — methyl 1 1, 3 — butagenyl] pyridinic hydrochloride Melting point 174 to 177 (decomposition)

* 2 — [(E, E)-4-(3 — Ethoxyarylamino 4 — Toxifenyl) 1 3 — Methyl 1, 3 — Butagenyl] viridine hydrochloride, melting point 1 9 9 ~ 200 'C (decomposition)

* 2 — ((E, E)-4-(4 — Etoxycarbonylacetylamine 3 — Methoxyphenyl) 1 3 — methyl 1 1, 3 — butagenyl) Viridin hydrochloride, melting point 185 to 186 (decomposition)

* 2 — ((E, E) — 4 — (3 — Ethoxyarylamine Phenyl) 1 3 — Methyl 1 1, 3 — Butagenyl] quinolinine'hydrochloride · ½ hydrate , Melting point 2 0 7 ~ 2 0 9 'C (decomposition)

* 2 — [(E, E) 1 4 — (3 — ethoxycarbonylacetylamine'phenyl) 1 3 — methyl 1 1, 3 — butagenyl] quinolinic hydrochloride · 3 / Tetrahydrate, melting point 135-138 (decomposition)

* 2-[(E, E) 1- 4 1 (4 1-ethoxyarylamine) 1 3 — methyl 1, 3 — butagenyl] quinolinine'hydrochloride ' ½ hydrate, melting point 2 1 4 to 2 1 6'C (decomposition)

* 4 1 [(E, E) — 4 — (4 1-chloro 3 — etoxyaryl amine) 1 3 — methyl 1, 3 — butagenyl] pyridin · hydrochloride · 2/3 hydrate, melting point 177 to 179 (decomposition)

* 2 —! : (Ε, Ε) — 4 — (4 — Chloro 3 — Ethoxalyl. Aminophenyl) 1 3 — Methyl 1, 3 — Butagenyl] Pyridin · hydrochloride · 1 Hydrate Melting point 169-9172 (decomposition)

* 4 — ((Ε, Ε) — 4 — (2 — Chloro 5 — Ethoxaryl amine Phenyl) 1 3 — Methyl 1 1, 3 — Butagenyl] pyridin, melting point 1 9 7-: L 9 9

* 4 1 [(Ε, Ε) 1 4 1 (2 — Clos 1 – 5 — Ethoxyl bonylacetyl aminophenyl) 1 3 — Methyl 1 1, 3 — Butagenyl] pyridin, melting point 1 5 5 ~ 1 5 8

* 2-[(Ε, Ε)-4-(2 — Closing 1 5 — Ethoxyaryl aminophenyl) 1 3 — Methyl 1, 3 — Butagenyl] Pyridin hydrochloric acid Salt, melting point 207 to 209 (decomposition)

* 2-[(Ε, Ε) 1 4 — (3 — etoxycarbonylcarbonylacetylamino 4 — methoxyphenyl) 1 3 — methyl 1, 3 — butagenyl] viridin · hydrochloride ♦ Monohydrate, melting point 125-128 • C (decomposition)

* 4 1 [(Ε, Ε)-4-(3 — ethoxyarylaminophenyl) — 1, 3 — butagenyl] pyridin · hydrochloride '½ hydrate, melting point 18 2 ~ 1 8 4 (disassembly)

* 4-[(Ε, Ε) 1 4 1 (4 1 ethoxyarylamine) — 1, 3 —butagenyl] pyridin 'hydrochloride · hydrate, melting point 2 3 8 ~ 2440'C (decomposition) * 2 — [(E, E) -4 1 (3 —Ethoxyarylamine) — 1, 3 —Butagenyl] Pyridin · hydrochloride · 2/3 hydrate, melting point 15 4 to 1 5 5 (disassembled)

* 2 — ((E, E)-4-(4 — methoxalylaminophenyl) — 1, 3 — butagenyl) viridin 'hydrochloride · ¼ hydrate, melting point 18 9 to 191 (disassembly)

* 2 — [(E, E)-'4-(4 1-ethoxycarbonylacetylaminophenyl) 1, 3 — butagenyl] pyridin' hydrochloride, melting point 2 15 〜 2 1 8'C (disassembly)

* 2 — ((E, E)-4-(4 — Ethoxyarylaminophenyl) 1, 3 — Butagenyl] pyridin, melting point 173 〜 1 7 5 • C

* 2 — [(E, E) — 3 — Ethyl 4 1 (4 1 ethoxyarylaminophenyl) 1 1, 3 — butagenyl] pyridin 'hydrochloride' 2/3 hydrate, Melting point 187-: I 90'C (decomposition)

* 2-[(E, E) — 4 — (4 — Ethoxyarylamine Phenyl) 1 3 — Phenyl 1 3 — Butagenyl] Viridin 'HCl salt, melting point 2 0 6 ~ 209 (disassembled)

* 2 — ((E, E)-4-(4-methoxalylaminaminophenyl) 1 3 -methyl-1, 3 -butagenyl] viridin'hydrochloride · 1/3 hydrate, Melting point 184-186 (decomposition)

* 2 — ((E, E)-4-(4 — Ethoxyarylamine) 1 3 — Methyl 1 1, 3 — Butagenyl] pyridin, melting point

1 4 2 to 1 4 5

* 2-[(E, E) 1 4 1 (4 1 ethoxyarylaminophenyl) 1 3 — propyl 1 1, 3 — butagenyl] pyridin * 2-[(E, E) — 3 — Putyl 4 1 (4 — Ethoxalyl minophenyl) 1 1, 3 — Butagenyl] viridine

* 2 — [(E, E) — 3 — Benzyl 4 1 (4 — Etoxalyl minophenyl) 1 1, 3 — Butagenyl] pyridin Example 3

(1) Suspend 9 g of Witetzi reagent prepared from m-nitrobenzil chloride and triphenylphosphine in Tetrahydrofuran 20 to give 50-1300'C. Cooling. To this suspension, 1.0 mol of lithium bis-trimethylsilyl amide and 20% β-tetrahydrofuran solution are slowly added dropwise over about 1 hour. During this time, stirring is performed while maintaining the above temperature. Then, raise the reaction temperature to room temperature and stir for another 30 minutes. To this reaction solution, add 8 g of 3— (3—pyridyl) acryl aldehyde prepared from vinylidene aldehyde and triphenylphosphoranylidene aldehyde and stir at room temperature for 4 hours. .. Perform the above operation in a nitrogen stream. After completion of the reaction, the reaction and treatment were carried out in the same manner as in Example 1 (1) to give yellow crystals of 3 — C (E, E) -4-(3 — nitrophenyl) 1, 1, 3-butagenyl] viridine. '' 2.3 g of the hydrochloride are obtained.

(2) When the compound obtained in (1) was reduced with 1.8 g of iron powder and 4N hydrochloric acid 9 in the same manner as in Example 1 (2), and treated with 40% sodium hydroxide, Ozone powder of 3 — [(E, E) -1 4 — (3 — aminophenyl) 1 1, 3 — butagenyl] pyridine 1.3 g is obtained.

(3) The compound obtained in (2) was treated and treated in the same manner as in Example 1 (3) with ethyl oxalyl chloride 1.5 and triethylamine 2.8 M £ to produce an ocher powder. 1.2 g are obtained. This powder Furthermore, when recrystallized from methanol-acetone, the powder of ocher crystalline powder is 3 — [(E, E) — 4 — (3 — Ethoxylamine amide) — 1, 3 — Butagenyl] pyridin 'hydrochloride · hydrate 0.9 g is obtained. Melting point 1900 to 1911 (decomposition)

Then, the following compound can be obtained by using the same method as in Example 3.

* 4 — ((E, E) — '4 — (3, 5 — Dietoxalylamino phenyl) 1 1, 3 — Butagenyl] Viridine' hydrochloride '1 hydrate, melting point 1 91 ~ 1 9 3 'C (disassembly)

* 4-[(E, E)-4-(3, 5 — Dietoxycarbonylacetylamine phenyl) 1 1, 3 — Butagenyl] viridin • Hydrochloride · monohydrate, melting point 90 ~ 9 5 (disassembly)

* 3-[(E, E) — 4 1 (4 1 ethoxyarylamine) 1 1, 3 — butagenyl] pyridin · hydrochloride, melting point 197 7 〜 1 9 8 'C (Disassembly)

* 2 — [(E, E)-4-(4 — Ethoxalylaminophenyl) 1 1> 3 — Butagenyl] 1 6 — Methylviridin 'hydrochloride' ¼ hydrate, melting point 1 9 3 ~ 1 9 4'C (disassembly)

* 2-[(E, E) mono 4 — (3 — ethoxyarylaminophenyl) 1 1, 3 — butagenyl] 1 6 — methylbilidine'hydrochloride · ¼ hydrate, Melting point 152-155 (decomposition)

Example 4

(1) Dissolve 5 g of 4-methylbilimidin and 10.1 g of or-methyl-1-nitrocinnamaldehyde in acetic anhydride 9 and reflux for 72 hours. After the reaction is complete, water is added and the light brown powder that separates is collected by filtration. Approximately 300 g of this light brown powder was applied to the silica gel and the developing solvent was used. The obtained ocherous powder was purified by mouth form and recrystallized from methanol-isopropyl ether to give 4-o- (E, E) — 3 — methyl-one as ocherous crystalline powder. 4 — (4 — Nitrophenyl) — 1, 3 — Butagenyl] Bilimidin (4.5 g) is obtained. Melting point 160 ~ 163'C

(2) The compound obtained in (1) was reduced to iron powder and hydrochloric acid in the same manner as in Example 1 (2), and then treated with sodium hydroxide to give an ocher powder. This yields 2.8 g of 4 — [(E, E) -1 3 — methyl — 4 1 (4 — aminophenyl) 1 1, 3 — butagenyl] pyrimidin.

(3) The compound obtained in (2) was reacted and treated in the same manner as in Example 1 (3) using ethyl oxalyl chloride and triethylamine to give 4-brown crystals as red-brown crystals. E, E)-4-(4 1 ethoxalylaminophenyl) 1 3 -methyl 1 1,3 -butadienyl] pyrimidine hydrochloride 1.9 g are obtained. Melting point 190 ~ 192'C (decomposition)

Hereinafter, the following compound can be obtained by using the same method as in Example 4.

* 4-[(E, E) — 4 — (2 — Ethoxyarylamine) 1, 1, 3 — Butagenyl] Pyrimidine 'hydrochloride, melting point 162 ~ 16 5' C ( Disassembly)

Example 5

To 0.7 g of 2 — ((E, E) — 4 — (4 -toxaliluminaminophenyl) -1,1 —3 -butagenyl] pyridine obtained in Example 1 (3) Add methyl iodide 40 and stir at room temperature for 2 minutes After the reaction is complete, evaporate the solvent under reduced pressure and remove the residual isopropyruate. And then collect by filtration. By recrystallizing from methanolyl isopropyl ether, the reddish-orange color of 2 — [(E, Έ) — 4 — (4 — ethoxali noreaminophenyl) 1 1, 3 — butagenyl] 1

1 0.9 g of 1-methylpyridinium iodide is obtained. Melting point

2 2 1 to 2 2 2 (disassembled)

Example 6

2 obtained in the same manner as in Example 3! : (Ε, Ε) — 4 — (4 — Ethoxalylaminophenyl) 1 1, 3 — Butagenyl] 1 6 — Methylbillidine 'hydrochloride 1.9 g in methanol 1 0 0 Dissolve it in water, add 0.6% of 5% palladium carbon (water content 54%), and carry out catalytic reduction with hydrogen under normal pressure. Stir while blowing hydrogen for about 5 hours. After the reaction is complete, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-sopropyl ether to give 2 — [4 1 (4 1 (4 1 ethoxalylaminophenyl) butyl) 1 6 -methylbildiyl as colorless to pale yellow powdery crystals. 'Hydrochloride · 2/3 hydrate 0.85 g is obtained. Melting point 143-3 to 145 '(decomposition)

In the following, the following compound can be obtained by using the same method as in Example 6.

* 2 — (4 — (4 — ethoxalylaminophenyl) pentyl) pyridin · hydrochloride · monohydrate, melting point 156 6 to 15 8 (decomposition) Example Ί

2 — ί (Ε, Ε) -4-(3 1-ethyl malonylaminoamino 1- 4 -methoxyphenyl) -1 3 -methanol 1, 3 obtained in the same manner as in Example 1 — Butagenyl] viridine · hydrochloride (1.0 g) was dissolved in methanol (20) and 4N sodium hydroxide (about 2) was added. Leave at room temperature for 6 hours. After completion of the reaction, the solvent is distilled off under reduced pressure, and water is added to the obtained residue. Adjust the pH to about 4.0 by adding 4N hydrochloric acid to this aqueous solution. The crystals prayed out were collected by filtration and recrystallized from methanol-isopropyl alcohol to obtain an ocher crystalline powder 21 [(E, E)-4-(3 — carboxyacetyl amine 4- Toxifenyl) mono-3-methinolyl 1,3-butagenyl] pyridine · 1/3 hydrate 0.6 g is obtained. Melting point 1600-1616 (decomposition)

Hereinafter, the following compound can be obtained by using the same method as in Example 7.

* 2-[(E, E) — 3 — methyl 4 — (3 — oxalaminophenyl) 1 1, 3 — butagenyl] viridin 'sodium salt hydrate, melting point 26 3 to 2 6 6 (disassembled)

* 2 — ((E, E) — 3 — methyl 4 — (4 — oxalaminophenyl) 1 1, 3 — butagenyl) viridin 'sodium salt, melting point 300 0'C or higher (Disassembly)

* 2-[(E, E) — 4 — (3 — Carboxyacetylaminophenyl) 1 3 — Methyl 1 1, 3 — Butagenyl] Pyridin 'Hydrochloride, melting point 1 9 6 ~ 2 0 0' C (disassembly)

* 4 — ((E, E) — 3 — methyl 1 4 1 (4 — methoxy 3 — oxalamine phenyl) 1 1, 3 — butagenyl] pyridin monohydrate, melting point 2 1 5 to 2 1 6'C (disassembly)

* 4-[(E, E)-4-(3 — canoleboxycetylamino-1 4-methoxyphenyl) 1 3 — methyl-1 1,3-butagenyl) viridin · hydrochloride, melting point 15 5 ~ 1 5 6'C (disassembly)

* 2 — ((E, E)-4-(5 — Carboxyacetylamine 1 2 — Clophenyl) 1 3 — methyl 1 1, 3 — butagenyl] pyridin · hydrochloride · monohydrate, melting point 1550 to 1553 (decomposition)

* 2 — ((E, E) — 4 — (4 — Oxaluminomiphenyl) mono 1, 3 — butagenyl] pyridin 'monohydrate, melting point 2 1 3 to 2 1 4 ΐ (decomposition)

* 2 — ((Ε, Ε) — 3 — Methyl 1 4 1 (4 — Xoxalaminaminophenyl) 1 1, 3 — Butagenyl] pyridin 'monohydrate, melting point 2 09 〜 2 10' C ( Disassembly)

Example 8

(1) 2, 6-Suspension of 15.5 g of Weitzhi's reagent prepared from dihydrochrometylbillidine hydrochloride and 2 equivalents of triphenylphosphine in Atrahydrofran 50 Let it cool down. To this suspension, 1.0 moltetrahydrofuranfuran solution 66 of lithium bis (trimethylsilyl) amide is added dropwise over 1.5 hours. Then, stir at room temperature for 30 minutes, and adjust again to 150-1300 ° C. Next, a solution prepared by dissolving 8.6 g of P-nitrocinnamaldehyde in a tetrahydrofuran mouth flask 50 is added dropwise over 30 minutes. Keep the reaction temperature at -50 to -30'C. Then stir in the room for another hour. The above operation is performed in a nitrogen stream. After completion of the reaction, the reaction and treatment were carried out in the same manner as in Example 1 (1) to obtain a brown powder of 2,6 —bis [(E> E) —4— (4 twelve trophenyl) one.

1, 3 — Butagenyl] ϊ 'Zin' hydrochloride 4.0 g is obtained-

(2) The compound obtained in (1) was reduced with twice the molar amount of iron powder and hydrochloric acid in the same manner as in Example i (2), and treated with sodium hydroxide to give 2, 2, 3 2.1 g of 6-bis [(E, E) -4- (4-aminophenenyl) -1,3-butaenyl] pyridine are obtained. (3) By reacting the compound obtained in (2) with ethyl oxalyl chloride and triethylamine in the same manner as in Example 1 (3), an orange crystalline 2,6 —Bis [(Ε, Ε) — 4 — (4 —Ethoxalylaminaminophenyl) 1, 3 —butagenyl] pyridine 'hydrochloride · dihydrate 0.35 g is obtained. Melting point 183 to 187'C (decomposition) The following compounds can be obtained by using any of the methods of Examples 1 to 8 below.

* 2-[4 — (3-Ethoxalylamino phenyl) 1 3 — Methyl 1, 3 — Butagenyl] 1 5, 6 — Dimethyl 1 H — Benzoimidazo 1: Le · Hydrochloride · 1/3 Water Japanese product, melting point 22 8 ~ 2 3 1 ΐ (decomposition)

* 2 — [(Ε, Ε) — 4 — (2 — ethoxalylaminophen) 1 1, 3 — butagenyl] 1 5 — black mouth 1 H ^ Nzmidazol · hydrochloride · ½ Hydrate, melting point 2 12 2 to 2 1 3 'C (decomposition) Next,' of the compounds of the present invention 2 — [(Ε, Ε)-4-(4 ) An example of a formulation containing 1,1,3-butaenyl] pyridine · hydrochloride [the compound of Example 1] as an active ingredient is shown. :

Example 9: Potency agent

20 g of the compound of Example 1

Microcrystalline cellulose 6 5 g

Tomorokoshi starch 20 g

Lactose 2 2 g

Polyvinylpyrrolidone 3 g Total amount 130 g

The above ingredients are granulated by a conventional method and then hard gelatin capsules The compound of Example 1, 2 O nig, is contained in 1 capsule filled with 1, 00 capsules.

Example 10:

50 g of the compound of Example 1

Microcrystalline cellulose 400 g

Tomoroko Shikodenbun 5 5 0 g Total amount 1, 0 0 0 g

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 1:

Compound of 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.

Example 1 2: Injection drug

Working compound of 1 10 g

Solubilizer Nikkol HCO-60

(Product name of Nikko Chemical Co., Ltd.) 3 7 g Sesame oil 2 g

Sodium chloride 9 g

Propylene glycol 40 g

Phosphate buffer solution (0.1 M, pH 6.0) 100 g Distilled water Total 1,00 0 g

The compound of 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.

Claims

The scope of the claims

(1) General formula

abed

(CH ₂ ) _n C00R ²

(Wherein R ¹ is hydrogen, no, rogen, lower alkyl, lower alkoxy or mono NHCO (CH ₂ ) _m COOR ⁴ (wherein R ⁴ is hydrogen, lower alkyl, aralkyl, and m is 0 or 1 ), R ² is hydrogen, lower alkyl ', aralkyl, R ³ is hydrogen, lower alkyl, funyl, substituted phenyl, aralkyl, substituted aralkyl, H et is pyridyl, substituted benzyl, N-substituted benzyl, pyrimidinyl, dioxopyrimidinyl, benzimidazole, substituted benzimidazole, quinolyl, a, b and cd are each hydrogen, or a And b or c and d combine to form a single bond, and n represents 0 or 1. ]

A butane compound represented by: or a salt thereof.

(2) H et, j, pyridyl, substituted benzyl, N-substituted benzyl, and a and b or a and b or a and b of a, b, c and d form a single bond. A compound or a salt thereof according to claim 1,

(3) A pharmaceutical composition comprising the compound according to claim 1 or the salt thereof as an active ingredient.