JPH02169584A - Vinylthiazole derivatives and drugs containing them as active ingredients - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel vinylthiazole derivative having leuco)IJ antagonistic activity and a drug containing the same as an active ingredient.

[Problems to be solved by the prior art and the invention] In order to prevent or treat allergic diseases, anaphylaxis is
There are two methods: one is to suppress the release of the mediator, and the other is to use an antagonist to act on the released mediator. Disodium chromocrycate [The Merck Index (The
MerckIndex) 9th edition 45g evening (/974) 3
Ya, Toranilast [Japanese Pharmacological Journal, LL, t, qq (/q
tg)) is a typical drug belonging to the former category, and drugs that antagonize histamine, which is one of the seven mediators of allergic reactions, are included in the latter category, such as diphenhydramine, chlorpheniramine, astemizole, terfenazine, and flemastine. etc. are well known. However, from the lungs of bronchial asthma patients, there is a substance that cannot be antagonized by antihistamines, namely SR8 (Slow Reacting 5ubs).
tance) was released [Progr., AIJerg.
y), A, 3r, 79, (/qx2)),
Recently, this SR8C leukotriene C4 (LTC4
), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) are collectively called SRS (
Proceedings of the National Academy of Sciences
d, Sci, U, S, A, ) + 7 is +
127S (/979) and 2,20/da (iqgo);
Naichi? -(Nature), xgr, 10q(i
qgo))] is considered to be an important factor involved in human asthma attacks (Procedures of Nasciminal Achemy, USA).
1lt1. Acad, Sci, U, S, A,
), K.O.

/ri/2 (tqg3)].

Several leukotriene antagonists are known in patents or literature. For example, the following equation: FPL, −! ;! ;7/, 2C Agents and Ac
tions).

9, /, 33C/979)), KC-tIO/I (Jap, J, Phar
m, ) +33, cork (/qg3)), LY-771gg3C represented by the following formula: Journal of Pharmacology and Experimental Therapeutics (J, Pharmacol, Exp.

Ther, ), x,? , 7(1) /Daza (/qJlr)), etc., but no practical example has been reported so far.

The present inventors have already discovered ONO-107gC organic synthesis chemistry represented by the following formula: and (2)
.

/3b(/qgq)) The following formula: [In the formula, R1 represents a hydrogen atom or a lower alkyl group having /~5 carbon atoms, and R2 and R3 each independently represent a hydrogen atom, an alkyl group having ~5 carbon atoms, , represents a lower alkoxycarbonyl group or a phenyl group which may have a substituent, and R2 and R3 together represent a tetramethylene group or -C=C-C=C- (in the formula, R4, R1, R5 and R7 each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, or a linear or branched lower alkyl group having a carbon number of up to 3. may be formed. Further, n represents an integer from ko to S. ] have been found to have leukotriene antagonistic activity in the thiazole derivatives and their pharmaceutically acceptable salts (
JP-A No. 621/1111bg), and the strength of the antagonistic action was determined by the IC6° value /(15
It was about M.

[Means for solving problems]

The present inventors have searched for a compound that has a stronger leukotriene antagonistic effect and is effective as a therapeutic agent for various diseases caused by leukotriene, and as a result, the novel vinylthiazole derivative having an α-substituted carboxyl group according to the present invention has been discovered. Discovered that it has excellent leukotriene antagonism,
The present invention has now been completed.

That is, the gist of the present invention is the following general formula (1) (in the above formula, R1 represents a hydrogen atom or a straight chain or branched alkyl group having carbon number/~j, and R2 and R3 each independently represent Represents a hydrogen atom, a linear or branched alkyl group having up to 5 carbon atoms, a phenyl group that may have a substituent, or a phenylalkyl group that may have a substituent on the benzene ring, R2 and R3 are never hydrogen atoms at the same time.Also, R2 and R3 may be combined to form a cyclopentane ring or a cyclohexane ring.R4 and R5 are each independently a hydrogen atom, carbon number/~ 5 represents a straight-chain or branched alkyl group or a phenyl group which may have a substituent, R4 and R5 together and R9 each independently represent a hydrogen atom, a halogen atom,
Straight chain or branched alkyl group with carbon number/-5, carbon number 1 to left alkoxy group, carboxyl group, total carbon number, 2
~B represents an alkoxycarbonyl group, an acyl group having a carbon number λ to S, an amino group, a cyano group, an acylamino group having 2 to 5 carbon atoms, or a nitro group. ) may form a butadienylene group. Further, n represents an integer from 0 to j. ) and pharmaceutically acceptable salts thereof, as well as leukotriene antagonists containing the compounds as active ingredients.

The present invention will be explained in more detail below.

The range of compounds included in the above general formula (I) is as follows:
The invention is not limited to the following specific examples.

R1, R2, R3, R4, R5, Re, R7, R8
and the straight chain or branched alkyl group on the left with the number of carbon atoms/~ that can be included in R9, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, 5ec -butyl group, t-butyl group, n-pentyl group,
Examples include l-pentyl group and t-pentyl group.

In addition, the phenyl group which may have a substituent and the phenylalkyl group which may have a substituent on the benzene ring which may be included in r(2 and R3 include a phenyl group,
Examples of substituents on the benzene ring include lower alkyl groups such as methyl, ethyl, and n-propyl; chlorine, bromine, and fluorine. halogen atoms such as atoms; methoxy group, ethoxy group, n-propoxy group, etc.) lower alkoxy group; lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group; carboxyl group; hydroxyl group; nitro group; amino group;
Cyano group: Examples include lower acylamino groups such as acetylamino group and propionylamino group. R6, R7, R
[The alkoxy group having carbon number/~S that can be included in l and R9 includes methoxy group, ethoxy group, n-propoxy group, l-propoxy group, n-butoxy group, 1-butoxy group and n-pentyloxy group. Similarly, examples of the alkoxycarbonyl group having a total carbon number of 2 to O include methoxycarbonyl group, ethoxycarbonyl group, n-
Examples include propoxycarbonyl group, 1-propoxycarbonyl group, r]-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group, and 1-pentyloxycarbonyl group, and examples of the acyl group having -5 carbon atoms include is acetyl group, globionyl group, n-
Examples include butyryl group, l-butyryl group, n-pentanoyl group, and 1-pentanoyl group, and furthermore, carbon number Ω to S
Examples of the acylamino group include an acetylamino group, a propionylamino group, an n-butyrylamine group, a l-butyrylamino group, and an n-pentanoylamino group.

Further, as substituents of the substituted phenyl group that can be included in R4 and R5, halogen atoms such as chlorine atom, bromine atom, and fluorine atom; hydroxyl group; methoxy group, ethoxy group, n
-Lower alkoxy groups such as propoxy groups; lower alkyl groups such as methyl, ethyl, n-propyl, 1-propyl, n-butyl groups; lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl groups; carboxyl group; amino group; nitro group; cyano group; 7-fluoramino group such as acetylamino group and propionylamino group.

Among the compounds represented by the above general formula (1), preferred are those in which the two substituents on the benzene ring are in the meta position, and in which the positional relationship between the substituents at both ends of the ethylene double bond is Entgegen ( E) is a compound.

The vinylthiazole derivative of the present invention is not limited to specific isomers, but includes all geometric isomers, optical isomers, and mixtures thereof, such as racemates.

The vinylthiazole derivative of the present invention can be synthesized by various methods. For example, it can be synthesized by the synthetic route shown in Reaction Formula-7 below.

Reaction formula -/ (II) (Ia) (Ib) In the above reaction formula, R2, R3, R4, R5 and n are as defined in the above general formula (1), and R represents a lower alkyl group.

That is, for benzaldehyde derivative (II),
Divinylthiazole derivative (Ia
). As the lower fatty acid anhydride, acetic anhydride, gropionic anhydride, n-butyric anhydride, etc. can be used, and as the reaction solvent, a high boiling point solvent such as xylene, dimethyl sulfoxide, dimethyl formamide, etc. can be used, but the reaction cannot be carried out without a solvent. You may go. The reaction temperature is room temperature to 230°C, preferably 770 to 7110°C. Vinylthiazole derivative (Ia) can be converted to vinylthiazole derivative (Ib) by hydrolyzing its ester group by a conventional method. This hydrolysis step uses an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and is carried out at θ°C in a water-containing organic solvent such as water-containing ethanol.
It can be easily carried out in the temperature range between ~ and the boiling point of the solvent.

The compound (1) of the present invention has significant leukotriene antagonistic activity. That is, the antagonistic effect of the compound of the present invention on SR8 was determined in v using isolated guinea pig ileum.
When tested in vitro, it was found that it had a selective antagonistic effect on SR8 even at low concentrations. Therefore, the compounds of the present invention can be used to treat various diseases caused by leuko-IJen, such as allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, total cerebral vasoconstriction, or angina pectoris due to decreased coronary flow. Effective for prevention and/or treatment.

The leukotriene antagonist of the present invention includes, as an active ingredient,
The compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof is contained together with a solid or liquid pharmaceutical carrier or diluent, that is, additives such as excipients and stabilizers. When the above compound has a carboxyl group, preferred salts are pharmaceutically acceptable non-toxic salts such as alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, Examples include aluminum salts. Ammonium salts, lower alkyl amines [e.g. triethylamine]
salts, hydroxy lower alkyl amines [e.g. -monohydroxyethylamine, bis-(2-hydroxyethyl)
amine, tris(hydroxymethyl)aminomethane or N-methyl-D~glucamine] salt, cycloalkylamine [e.g. dicyclohexylamine] salt, benzylamine [e.g. N,N'-dibenzylethylenediamine] salt and dibenzylamine Suitable non-toxic amine salts such as amine salts are also preferred. When focusing on the basicity of the thiazole ring of the compound of the present invention, preferred salts include hydrochloride, methanesulfonate, hydrobromide, sulfate, phosphate, fumarate, succinate, etc. Examples include non-toxic salts. Since these salts are water-soluble, they are most suitable for use as injections. In the leukotriene antagonist, the proportion of therapeutically effective component to carrier component can vary between 7% and 90% by weight. Leukotriene antagonists are available in granules, fine granules, powders,
It may be administered orally in the form of a tablet, hard capsule, soft capsule, syrup, emulsion, suspension, or liquid, or administered intravenously, intramuscularly, or subcutaneously as an injection. Good too. It can also be used in the form of suppositories, nasal drops, eye drops, or inhalants for local administration to the rectum, nose, eyes, and lungs.

Alternatively, it may be prepared as a powder for injection before use. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used to prepare the leukotriene antagonists of the invention. Excipients used in producing solid preparations include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions, etc., contain inert diluents used for dilution, such as water or vegetable oils.

In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents, or preservatives. Liquid preparations may be enclosed in capsules of absorbable material such as gelatin. Solvents or suspending agents used in the production of parenteral preparations, i.e. injections, suppositories, nasal drops, eye drops, inhalants, etc.
Examples include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like. Examples of bases used in suppositories include cacao butter, emulsified cacao butter, diurin fat, and lytepsol. The preparation method may be any conventional method.

Clinical dosages for a compound of the invention for adults when used by oral administration are generally 7 daily doses of O9θ/
~iooθ~, preferably 0.0/~ioo■
However, it is more preferable to increase or decrease the amount as appropriate depending on age, pathological condition, symptoms, presence or absence of simultaneous treatment, etc. The daily dose of the leukotriene antagonist may be administered once every 7 days, divided into 2 or 3 doses every 7 days at appropriate intervals, or administered intermittently.

When used as an injection, the compound of the present invention is preferably administered continuously or intermittently to adults in the same amount O9θθ/~100μ.

〔Effect of the invention〕

According to the present invention, a novel vinylthiazole derivative having significant leukotriene antagonism is provided. The same vinylthiazole derivative is used as a leukotriene antagonist.
It is useful for the prevention and treatment of various diseases involving leukotrienes, such as allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, and angina pectoris caused by cerebral vasoconstriction or decreased coronary flow.

〔Example〕

The present invention will be explained in more detail below based on synthesis examples, examples, and test examples of reaction intermediates, but these are not intended to limit the scope of the present invention in any way. In the synthesis examples and examples, "I RJ, l-T LCJ, and "NMR" respectively refer to "infrared absorption spectrum" and "thin layer chromatography."
and 1-Nuclear Magnetic Resonance Spectrum", the proportion of the solvent described in the section of separation by chromatography indicates the volume ratio, the solvent in parentheses of l'-T L CJ indicates the developing solvent, and [IRJ Unless otherwise specified, it was measured by the KBr tablet method and the unit is crn-', and the solvent in parentheses in l-NMRJ indicates the measurement solvent, and the unit is 699m.

Furthermore, the compound genus described in the examples corresponds to description 5 in Table 7, Table 2, Table 3, and Table 9.

In addition, in Tables 1 and 2, Me.

Et and Ph represent a methyl group, an ethyl group and a phenyl group, respectively.

Example/Synthesis of Compound Melon/4' to 3-(y-formylphenyl)-X,2-diethylpropionate ethyl ester! ;11,2 methyl-
q-t-butylthiazole 820I and acetic anhydride o,! i
The o- mixture was heated and stirred on a 770° C. oil bath for +, r hours. After the reaction was completed, the product was extracted with ethyl acetate, dried, and concentrated under reduced pressure.

The obtained crude product was subjected to column chromatography = (Silica gel: n-hebutane/acetic acid-1# = 50/l → 15/1
) to obtain 670 ml of the title compound as an oil (yield: 1%).

■RC1-rn ], ] shift 1 f 3θ, 15θ5. /ko'10/2/θ, l/3θNHR (CDCl2): 0.
90(AH, t), /, 2.3C3H, t).

/, 3ri (9H, S), /,! ;-/, 7(4
1H, m).

Ko, g? (JH, s), /, 1J (2H, q).

6, za/(/H, s), wa, θ5(/H,
d).

7. 2-7. J(lIH,m), ? , 4tO(/H
, ct) Example Synthesis of Various Vinylthiazole Derivatives Similarly to Examples/, Table 7 shows compound numbers/3. /7
, 13 and 21I were obtained.

Torue? After extraction and drying, the solvent was distilled off.

The residue was purified by column chromatography (silica gel; n-hebutane/ethyl acetate = 25/1 → 2/1),
76 g (yield: 33 g) of the title compound was obtained.

m, p, C°C); /22J-/2,1. ! ;! R
(m-'); ν=tqio, 1sio, /
Ko2! r, //3! ;, 50 Example q Synthesis of various vinylthiazole derivatives In the same manner as in Example 3, compound numbers i, r, ,
? ,4I,evening,A,? , g, de, /θ, //, /yo.

/A, 1g, /? , 10.2/and here
The title compound shown as was obtained.

Add Compound 51I/Misaki obtained in Example / to ethanol and add 7.4t of /IN-potassium hydroxide aqueous solution,
Stirring was continued under reflux for 76 hours. After cooling, the pH was adjusted to J with 3N-hydrochloric acid, and the product was treated in the same manner as in the above examples to synthesize the compounds λS~7.2 shown in Table 2 below. Table 2 Example S Preparation of tablets Pulverized vinylthiazole derivative (compound A 10
) 100011, lactose 5 qootz, crystalline cellulose sooog, low-substituted hydroxypropyl cellulose 10009 and magnesium stearate 100 g were thoroughly mixed, and a plain tablet containing 10 η of the above compound in 100 m9 of tablets was made by direct compression method. . Sugar-coated tablets and film-coated tablets were produced by sugar-coating or film-coating these uncoated tablets.

Example 6 Preparation of capsules Well-ground vinylthiazole derivative (compound Aio
)ioooy,, corn starch, 3000g,
Lactose 690011, crystalline cellulose 1000 g and magnesium stearate/θOI were mixed to prepare capsules containing 10 μm of the above compound in 20 m9/capsule.

Example 7 Preparation of inhalant Well-pulverized vinylthiazole derivative (compound &10)
! RL, medium-chain saturated fatty acid triglyceride 1011, and 0.2 g of sorbitan monooleate were mixed well, and each mixture was mixed with 2 ■! Weigh it into a r- aerosol aluminum container, and add Freon/2///lI゛(l
:/Mixture) After cold filling g tl, g■, /injection! Attach a 00μl quantitative adapter and place it in a container 5r.
During nt, a metered dose inhaler containing the compound 51rli was produced.

Example SR8 antagonism in vitro.

Male tray (Hart) weighing 200~tisoy
The terminal ileum of a le5/) type guinea pig was removed, and after cleaning the lumen, the ileum was placed in a JTD tissue bath containing Tyrode's solution consisting of the following components. The ingredients are sodium chloride/36mM, potassium chloride 2.7mM
M, sodium bicarbonate t/, 9 m1V1, magnesium chloride/, Oj mM, calcium chloride 8 g
mM, sodium dihydrogen phosphate 0. 'l mM and glucose! ;, bmM.

Keep the liquid temperature in the bath at 37℃? Aerated with S% oxygen 15% carbon dioxide. To eliminate contractions caused by histamine and acetylcholine, the above buffer contains /0-'11/m
l of mepyramine and 5 X/0-81! /ld of atropin was added. Isothermal measurements were performed with an isotonic transducer (TD-//, 2S, Nihon Kohden) tension displacement transducer, and the change in grams of tension was measured with a recticorder (RTG-q/2tt).

Recorded by Nihon Kohden). A tension of 0.5 g was passively applied to the ileum to obtain an ileal contraction response to SRS extracted from guinea pig lungs. /unit of SR3 (histamine 51
(equivalent to 100 g) was used as a control. Various concentrations of the test drug were added to the tissue bath, and the test drug concentration that attenuated the control contraction by 50% (IC5o) was defined as the minimum effective concentration, and the results are shown in Table 3.

Table 3 Example 7 LTD4 antagonism in viv.

A male Hartley weighing 350-5 oooy.
Y) type guinea pigs were placed under urethane anesthesia using a Barbard-type respirator, and were placed in a Konzenothoresler (Ko) series.
Airway resistance was measured by a modified version of the Nzett-Roessler method. LTD40. /~/, 0μm1
The suppression rate by oral administration of the test drug against the increase in airway resistance due to intravenous administration of /Is ((6) was calculated and the result was
Shown in the table.

Table 9 Test Examples Acute Toxicity Test The compound of the present invention was suspended in a 1% tragacanth solution and orally administered to 7 groups of SD male rats of up to 5 weeks of age.
Observations were conducted for S days to determine the number of deaths, and the results are shown in Table 1.

Table 5

Claims (4)

[Claims] (1) The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R^1 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 5 carbon atoms. represents, and R^2 and R^3 are each independently a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, a phenyl group which may have a substituent, or a benzene ring substituted. Represents a phenylalkyl group which may have a group, but R^2 and R^3
are never hydrogen atoms at the same time. Also R^2 and R^
3 may be taken together to form a cyclopentane ring or a cyclohexane ring. R^4 and R^5 each independently represent a hydrogen atom, a linear or branched alkyl group with carbon number/~s, or a phenyl group which may have a substituent, and R^4 and R^ Together with 5, there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^6, R^7, R^8 and R^9 each independently represent a hydrogen atom, a halogen atom, or a carbon number of 5 linear or branched alkyl group, alkoxy group having 1 to 5 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 6 total carbon atoms, acyl group having 2 to 5 carbon atoms, amino group, cyano group, carbon (representing an acylamino group or a nitro group of numbers 2 to 5) may also form a butadienylene group. Further, n represents an integer from 0 to 5. ) and pharmaceutically acceptable salts thereof. (2) The compound according to claim 1, wherein in the general formula (I), the substituent on the benzene ring is located at the meta position. (3) The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R^1 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 5 carbon atoms. represents, and R^2 and R^3 are each independently a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, a phenyl group which may have a substituent, or a benzene ring substituted. Represents a phenylalkyl group which may have a group, but R^2 and R^3
are never hydrogen atoms at the same time. Also R^2 and R^
3 may be taken together to form a cyclopentane ring or a cyclohexane ring. R^4 and R^5 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent, and R^4 and R^ Together with 5, there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^6, R^7, R^8 and R^9 each independently represent a hydrogen atom, a halogen atom, or a carbon number of 5 linear or branched alkyl group, alkoxy group having 1 to 5 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 6 total carbon atoms, acyl group having 2 to 5 carbon atoms, amino group, cyano group, carbon (representing an acylamino group or a nitro group of numbers 2 to 5) may also form a butadienylene group. Further, n represents an integer from 0 to 5. 1. A leukotriene antagonist comprising a vinylthiazole derivative represented by () and a pharmaceutically acceptable salt thereof as an active ingredient. (4) The leukotriene antagonist according to claim 3, characterized in that the active ingredient is a vinylthiazole derivative or a pharmaceutically acceptable salt thereof in which the substituent on the benzene ring in general formula (I) is in the meta position. .