JPS63258879A - Vinylthiazole derivatives and leukotriene antagonists containing them as active ingredients - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is H or 1-5C straight or branched chain alkyl; R2 is lower alkoxycarbonyl, carboxyl or tetrazolyl; R3 is R1 or (substituted)phenyl; R4 is H or together with R3 form butadienylene of formula VII (R5-R8 are R1, OH, OCH3, halogen, etc.) which forms a condensed benzene ring] and its salt. USE:A drug. A leucotriene antagonistic agent. Effective in the prevention and remedy for allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, stenocardia caused by cerebral vessel constriction or decrease in coronary blood flow, etc. PREPARATION:The compound of formula I wherein R2 is lower alkoxycarbonyl can be produced by carrying out dehydrative condensation reaction of a compound of formula II (Ra is lower alkyl) with a compound of formula III, breaking the phenyl ether bond of the resultant compound of formula IV with Lewis acid, etc., to obtain a compound of formula V and reacting the product with a compound of formula VI (Rb is 1-5C alkyl; X is Cl, Br or I).

Description

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

[Problems to be solved by the prior art and the invention] K for preventing or treating allergic diseases is anaphylactic.
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. Jindilum Cromoglycate [The Merck Index (The
Merck engineering index) 2nd edition 2nd edition 11th (/26th)
], Toranilast [Japanese Pharmacological Journal, Mukai ni Tata (/?7/
)) are typical drugs that cause KR in the former category, and drugs that antagonize histamine, which is one of the seven mediators of allergic reactions, such as diphenhydramine,
Chlorpheniramine, astemizole, terfenazine, flemasten, etc. are well known. However, in the lungs of bronchial asthma patients, there is a substance that cannot be antagonized by antihistamines, namely BRB (Slow Reacting 5ubs).
tance) was liberated [Progress of Allergy (Progr, Allergy)].
) , & , jJ9 (/ri≦2)], recently,
This BRB (leukotriene c4 (LTC4), leukotriene D4 (LTD4) and leukotriene 1lt
4 (r, +TI!! 4) are collectively called EJRB (Proceeding Op National Academy of Science Ninisny (Froa, Natl,
AOIL (1, Elci, ff, 8.A,), ej
.

4tx2t (/ri2ri) and '77.20/41 (/9
10); Nature, J/j,
104t(/de”))) is considered to be an important factor involved in human asthma attacks (Proceedings of the National Academy of Sciences USA).
, Natl, Acad, Bci, tr, J, A,
), 10゜ri/ko (/rir3)].

Several leukotriene antagonists are known in patents or literature. For example, the following formula: IPPr, +-777/λ [Agents
and act
ions).

Eh, 13! (/ri7ri)], the following formula: KC-y: o4t (Japanese Journal Op 77- Merci
harm,).

33, 247 (/ri r3)], the following formula: 0NO-/θ7r (Organic Synthetic Chemistry 2. Otsu 4 (
2) 1/34 (/derri)] The following formula: LX-17/r♂3 [Journal Op 7 Almacology and Experimental Therapeutics (, y, PharmaCO1+Exp.

Ther,), JJJ(1) /4tr(/ri?ri)
etc. are known, but no practical example has been reported to date.

Examples of compounds similar to the compounds of the present invention can be found in Japanese Patent Application Laid-Open No. 2001-30977! -(p-alkylbenzoyl)amino-λ-(, t-tetrazolyl)-/, and goobenzodioxane are described. The compound of the present invention is similar to the above compound in that it has a benzodioxane ring, but
It has a completely different chemical structure in that it does not contain an amide bond, has a vinyl group intervening, and has a thiazole ring that is different from a benzene ring.

The present inventors searched for compounds that have an antagonistic effect on leukotrienes and are effective as therapeutic agents for various diseases caused by leukotrienes, and as a result, they found that a new cabinylthiazole derivative has an excellent leukotriene antagonistic effect. Heading: The present invention has been completed.

[Rounding method to solve problems]

The gist of the present invention is represented by the following general formula (I) (in the above formula, R represents a hydrogen atom or a linear or branched alkyl group having carbon number/~!, and R2 represents a lower alkoxycarbonyl group, a carboxyl group). or represents a tetrazolyl group, R3 represents a hydrogen atom, a linear or branched alkyl group having carbon number/~!, or a phenyl group which may have a substituent, and R4 represents a hydrogen atom.
and R4 together form a condensed benzene ring. The following R11R@R7 and R. each independently represent a hydrogen atom, a straight chain or branched alkyl group with carbon number/~,
Represents a hydroxyl group, methoxy group, ethoxy group, halogen atom, carboxyl group, alkoxycarbonyl group, nitro group, amino group or nitrile group. ) and pharmaceutically acceptable salts thereof.

The compound of the general formula (1) will be explained in more detail. Note that the range of compounds included in the above general formula (2) is not limited by these specific examples.

RIs "8, R5, R6, R7, and R8 may include a straight chain or branched alkyl group having carbon number/-j, such as methyl group, ethyl group, n-propyl group, 1-propyl group, n -butyl group, 5ea-butyl group, t-butyl group, n-pentyl group, 1-pentyl group, t-pentyl group, etc. ; As the oxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, 1-propoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group, n
-Pentyloxycarbonyl group, 1-pentyloxycarbonyl group, etc. are exemplified, and substituents of the substituted phenyl group that can be included in R8 include alkyl groups such as methyl group and ethyl group; hydroxyl group; alkoxy group such as ethoxy group. ;
Halogen atoms such as chlorine atom and bromine atom; carboxyl group;
Examples include alkyl groups such as methoxycarbonyl group and ethoxycarbonyl group; oxycarbonyl group; a, mino group; nitro group; cyano group. The vinylthiazole derivative of the present invention is
Not limited to specific isomers, geometric isomers,
It includes all optical isomers and mixtures thereof, such as race i forms.

The vinylthiazole preconductor of the present invention can be synthesized by various methods. For example, the synthetic route (A-
/-4) and/or (B-/~)K.

In the above reaction formula, RI qh Ra and R4 are as defined in the above general formula (RI), & represents a lower alkyl group, X represents a chlorine atom, a bromine atom, or an iodine atom, and Rb represents a carbon atom. It represents a number/~! of straight chain or branched alkyl groups, and Ml represents a sodium atom or a potassium atom.

First, in step (A-/), comethylthiazole (III) is added to benzaldehyde (rl) in o, r~/,
! Equivalent amount and lower fatty acid anhydride 0. Compound (IV) is produced by a dehydration condensation reaction by reacting with j -, 2 equivalents. Examples of lower fatty acid anhydrides include acetic anhydride, propionic anhydride,
N-butyric anhydride was used, and the reaction solvent was xylene,
A high boiling point solvent such as dimethyl sulfoxide or dimethyl formamide may be used, but the reaction may be carried out without a solvent. The reaction temperature is room temperature to 100°C, preferably 710 to 11°C.
It is 0°C. Compound (V) is obtained by converting compound (■) in step (A-J) by a conventional method using an acid such as hydrogen chloride or hydrogen bromide, a Lewis acid such as aluminum chloride or boron tribromide, or iodotrimethylsilane. Obtained by condensation of phenyl ether bonds. Compound (Engineering a) can be obtained by reacting compound (V) with 0.7 to 2.0 equivalents of α,β-dihalocarboxylic acid ester (■) in the presence of a base in step (A-, ?). It is mowed down. The base used here is an alkali metal inorganic base such as sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, etc., and the reaction temperature is within the temperature range of 0° C. to the boiling point of the solvent. As the reaction solvent, a ketone solvent such as acetone or methyl ethyl ketone or an ether solvent such as tetrahydrofuran or dioxane is used. In step scA-g), the compound (a) is prepared by a conventional method, and an alkali metal base such as sodium hydroxide, potassium hydroxide, or potassium carbonate is reacted with the compound (a) in aqueous alcohol to form an ester group. It can be easily obtained by hydrolyzing. Compound (■) was prepared by [A-J
] It is obtained by reacting a-halonitrile (■) with t-in place of the reagent (M) under the same conditions as in the step.

Compound (IC) is obtained in step [B-2] by reacting compound (■) with 7 to 10 equivalents of alkali metal salt of azide acid (■) in the presence of pyridine hydrochloride.

As the reaction solvent, an aprotic polar solvent such as dimethylformamide, heyasamethylphosphoramide, or dimethyl sulfoxide is used, and the reaction temperature is from room temperature to 000C.
℃, preferably 10~/-0℃.

The compound (I) of the present invention has significant leukotriene antagonistic activity. That is, using the isolated ileum of a guinea pig, the compound of the present invention was shown to have an antagonistic effect on 13R8.
When tested in vitro, it was found that it has a selective antagonistic effect against 8R8 even at low concentrations9.
Therefore, the compounds of the present invention can be used to prevent various diseases caused by leukotrienes, such as allergic diseases such as asthma, cerebral edema caused by cerebral ischemia, cerebrovascular monofilament, or angina pectoris caused by decreased coronary flow. /or therapeutically effective.

The roy;triene 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 include 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, etc. Examples include salts, aluminum salts, and the like. Ammonium salts, lower alkylamine [e.g. triethylamine] salts, hydroxy lower alkylamine [e.g. co-hydroxyethylamine, bis-(co-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane or N-methyl-D-glucamine] salts , cycloalkylamine [e.g. dicyclohexylamine] salts, benzylamine, (e.g. When focusing on the basicity of the thiazole ring of the compound of the present invention, preferred salts include hydrochloride, methanesulfonate, hydrobromide, -acid, phosphate, and fumarate. Examples include non-toxic salts such as succinate, etc. These salts are water-soluble and are therefore optimal for use as injections.

In the oleotriene antagonist, the proportion of therapeutically active ingredient to carrier ingredient can vary between 1% by weight and 0% by weight. The leukotriene antagonist may be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids, or it may be administered orally. It may be administered intravenously, intramuscularly, or subcutaneously as a drug, or it may be formulated into a layer, nasal spray, eye drops, or inhaler and used as a preparation for local administration to the rectum, nose, eyes, or lungs. You can also do that. It may also be used as an injectable powder by cutting it at the appropriate time. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, rectal, parenteral or topical administration can be used to carry the leukotriene antagonists of the present invention. Excipients used when manufacturing solid preparations include:
For example, lactose, sucrose, starch, talc, cellulose,
Textiles, kaolin, calcium carbonate, etc. are used. Liquid preparations for oral administration, ie, emulsions, syrups, suspensions, solutions, etc., contain commonly used inert diluents 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. Formulations for parenteral administration, i.e. injections, layers, nasal sprays, eye drops, which may be in liquid formulations and enclosed in capsules of absorbable substances such as gelatin.
Examples of solvents or suspending agents used in the production of inhalants include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like.

Examples of the base used in the layering agent include cocoa butter, emulsified cocoa butter, lauric butter, Quitepsol, and the like. ! Agent A may be prepared by a conventional method.

Clinical administration of the compounds of the present invention for adults when administered orally is generally at a daily dose of θ, θ/
~/θσ0 Ki, fE is preferably 0.07 to 1100
tn, but 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 7-day dose of the leukotriene antagonist is given 7 times every 7 days, or every 7 days at appropriate intervals! Alternatively, it may be administered in three divided doses or may be administered intermittently.

When used as an injection, the compound of the present invention is preferably administered continuously or intermittently to adults at a dose of go, oθ/~100 vq/dose. - [Effects of the Invention] According to the present invention, a novel vinylthiazole derivative having remarkable leukotriene antagonistic activity is provided. The same vinylthiazole derivative is used as a leukotriene antagonist.
Roy: It is useful for the prevention and treatment of various diseases involving triene.

〔Example〕

The present invention will be explained in more detail below based on synthesis examples, examples, and test examples of reaction intermediates, but these should not limit the scope of the present invention in any way. In the synthesis examples and examples, "RJ, rTLOJ, and rNMRJ represent "infrared absorption spectrum,""thin layer chromatography," and "nuclear magnetic resonance spectrum," respectively, and are described in the section on separation by chromatography. The proportion of the solvent indicates the volume ratio, the solvent in parentheses of rTLOJ indicates the developing solvent, and "R" is the value measured by the KBr tablet method unless otherwise specified, and the unit is mouth! J, “The solvent in parentheses in NMRJ indicates the measurement solvent) The unit is FPI.

Further, the amounts of compounds listed in the examples correspond to the descriptions in Tables 1, 2 and 3.

Synthesis of p-vanillin io, st% Guingropyrucomethylthiazole 10. A mixture of Of and acetic anhydride/gml was added to θ
After the reaction was completed, the reaction mixture was heated and stirred for a while, and then 0% hydrochloric acid was added to adjust the pH and the resulting precipitate was washed with toluene.

Next, this solid was stirred vigorously for 7 hours at room temperature with 10 ml of methanol and 0 t of potassium tanoate. Insoluble matter was removed from the solution, 20 d of water was added to the solution F, and concentrated water was added to make it par. The resulting crystals were filtered, washed with water, and dried to obtain the title compound t, 0/l (yield jJ%).

mp [:℃]: Ta λ ~ ri 3 IRC low 1
]: νtomi/! RiQ1/! θθ, /gu/! , 12&!
t, 103θ, ri! 0 Synthesis example λ Boron tribromide/da, dat with dichloromethane! In addition to θd,
Next is the compound obtained in Synthesis Example 1! , J f dichloromethane (/!Od) solution was added dropwise at -7rC to adjust the reaction temperature to 3. ! The reaction was completed by gradually warming to room temperature over a period of time. After adding ice♂oy to the reaction solution and distilling off dichloromethane under reduced pressure,
After adjusting the temperature to -70 by adding saturated MM water, the mixture was extracted with ethyl acetate according to a conventional method. The crude product was recrystallized from ethyl ether-n-hexane to give the compound jJP (yield high!).
I swallowed.

mpl:℃〕: it-~/! 3 Engineering R(crII-':l: ν=/!ri0./d;
t20. / Koto.

1/litre θ Talo θ Synthesis Example 3 To acetone 6d, 63 g η of potassium abdominal acid, 241 'I pt of -1 chloroacrylonitrile and the compound obtained in Synthesis Example λ were added and refluxed for 2 hours. After completion of the reaction, acetone t- After evaporation under reduced pressure, the residue was extracted and washed according to a conventional method, and the crude product was recrystallized from ether-ethyl acetate to obtain the title compound 222η (yield: 4t, r%).

mpl: ℃): Tako-ri 3 Engineering R (cPII-”): y=/!ri!, /4t
90. /Co rθ, /Co10 917 Example 1 Synthesis of compound Nn/A7tone rIIjK% Potassium carbonate 2?3 Misaki, Co, 3-
Methyl dichloropropionate 4t! Coμt and the compound obtained in Synthesis Example 2 were added and refluxed for several hours.

After completion of the reaction, acetone was distilled off under reduced pressure, the residue was extracted and washed according to a conventional method, and the crude product was recrystallized from ethyl ether-n-hexane to obtain the title compound 4t? o vq (yield 74
tchi) was obtained.

mp(℃:l:!Rigo0 IR(tM-'): C/74tO1/j00,
/λGo01TataQ♂00 Example KO In the same manner as in Example/, the title compounds shown as Compounds N12.3 and G in Table 1 were obtained. In Table 1 below, the substitution position of the vinyl group is α, α',! or β′
This means that it is not possible to specify which of the two positions the substitution position is. The same applies to Table 2.

Example 3 Compound Yin! Synthesis Example 200 of the 9 compounds obtained in / were added to a methanol solution jd containing 2d of an aqueous potassium hydroxide solution and a drop of N-benzyltrimethylammonium hydroxide.
Hydrolysis was carried out by refluxing for a period of time. After distilling off methanol under reduced pressure, add concentrated hydrochloric acid to the residue to adjust the pH! The mixture was extracted with ethyl acetate. The crude product was recrystallized from ethyl ether-n-hexane to obtain the title compound (yield: 2).

mI) (C): 101-104 engineering R (cIN-
', l: y-/710/! 70 /4t
the law of nature! /λio io'p.

Example 2 Synthesis of various carboxy/cubenzodioxanes The title compounds shown in Table 1 as compound numbers 4.7 and 2 were obtained in the same manner as in Example 3.

Example! Synthesis of Compound Yin r Compound 200wy synthesized in Synthesis Example 3, sodium azide 2jO■ and 4t4t pyridine hydrochloride η were added to dimethylformamide-2WLl, /00b"'
r: Reacted for 2.1 hours. Extraction was performed using ethyl acetate-toluene (/:/) according to a conventional method, and the crude product was recrystallized from ethyl ether to obtain the title compound/3.2K (
yield! ♂chi>tata.

mpc℃+: /14t~/6! Engineering R[:z-'
, l: y=/j70%/4t9! , / 2t
O.

10?0 94tO Example g Synthesis Examples of Various Tetrazolyl/4t-Benzodioxanes Same as Example 3 a! The title compound shown in Table 1 as Compound 10 and // was obtained.

Compounds Nh/-2 to 4tJ shown in Table 2 below can be synthesized according to the methods of the examples described above.

Table 1 Example 7 # of tablets # Finely crushed propyl carboxyl/4t-benzodioxane conductor (compound shade) 10θθt1 lactose! 90o
f, crystalline cellulose-2000f, low-substituted hydroxypropyl cellulose 10θ0t.

Magnesium stearate/θO2 was thoroughly mixed and plain tablets containing 70 caps of the above compound in 100 tablets were prepared by direct compression. Sugar-coated tablets and film-coated tablets were produced by sugar-coating or film-coating these uncoated tablets.

Example t Preparation of Capsules Well-ground propylcarboxy/4t-benzodioxane derivative (compound 47) 10oθf1 corn starch 3000F, lactose ttoot.

Crystalline cellulose 1000? , magnesium stearate was mixed with 700 ft/capsule/20 cm to prepare capsules containing the compound/θη.

Example? Production of inhalants Thoroughly ground tetrazolyl/4t-benzodioxane derivative (compound <r>tt, medium-chain saturated fatty acid triglyceride 10f, and 0.-22% of nrubitan monooleate are mixed well, and each mixture is mixed with /!, λ Cape Add !- to the aluminum ξ container for aerosol, add 1 more to the container, and add Freon /2///
Da(/:/mixture) r da,? After cold filling the cape, /injection/ 00 pl metering adapter is attached, /container! In step d, a metered dose inhaler containing the compound jq was produced.

Example 10 BR8 antagonism in vitro.

Male Hartley weighing between 200 and 200 kg.
y) Remove the terminal ileum of a type guinea pig, wash the lumen, and then place the ileum in a JD tissue bath containing Tyrode's solution consisting of the following components:
11/JtmM%IC0I2.7mM%
NaHOO3//, 2mM% MgG11/, O
j Sushi, 01LO11/, r mM, NaH2PO
40,41mM, glucose! , ImM. Keep the liquid temperature in the bath at 32℃, ? ! Chi oxygen/! Aerated with carbon dioxide. To eliminate contractions caused by histamine and acetylcholine, the buffer contains /0-'f7'
d with mepyramine! Isometric measurements of x/θ-f/wl with atribin added were performed with an isotonic transducer (TD-//-Nihonko M) tension displacement transducer, and the change in grams of tension was measured using a recticcorder. (RTG
-4t/2 da 2 Nihon Kohden). A passive tension of K o, r t was applied to the ileum, and the ileal contractile response to 8R8 extracted from morsit lung was investigated. EIR8/
Continuous state shrinkage due to unit (equivalent to histamine jnf) was used as a control. Add various concentrations of the test drug into the tissue bath and observe control contractions! The test drug concentration at which the test drug was attenuated by θ% (0ao) was defined as the minimum effective concentration, and the results are shown in Table 3.

Table 3 Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase - Others/names

Claims (2)

[Claims] (1) The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R_1 represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms. , R_2 represents a lower alkoxycarbonyl group, carboxyl group or tetrazolyl group, R_3 represents a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent, R_4 represents a hydrogen atom. In addition, R_3 and R_4 come together to form a condensed benzene ring. There are the following butadienylene groups ▲ Numerical formulas, chemical formulas, tables, etc.
6, R_7 and R_8 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom,
carboxyl group, alkoxycarbonyl group, nitro group,
Represents an amino group or a nitrile group. ) may also be expressed. ) and pharmaceutically acceptable salts thereof. (2) The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R_1 represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms. , R_2 represents a lower alkoxycarbonyl group, carboxyl group or tetrazolyl group, R_3 represents a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, or a phenyl group which may have a substituent, R_4 represents a hydrogen atom. In addition, R_3 and R_4 come together to form a condensed benzene ring. There are the following butadienylene groups ▲ Numerical formulas, chemical formulas, tables, etc.
6, R_7 and R_8 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom,
carboxyl group, alkoxycarbonyl group, nitro group,
Represents an amino group or a nitrile group. ) may also be expressed. ) A leukotriene antagonist containing a vinylthiazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.