JPS5877880A - Tetrazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R is H, lower tetrahydropyranylalkyl, etc.; A is lower alkylene; the carbon bond between the 3- and 4-positions of the carbostyril skeleton is single or double bond). EXAMPLE:6-{4-[ 1-( 2-Tetrahydropyranylmethyl ) tetrazol-5-yl]butoxy}-3, 4-dihydrocarbostyril. USE:Useful as a preventingagent and remedy for thrombosis, anti-inflammatory agent, antiulcer agent, antiasthmatic agent, a preventing agent and remedy for ischemic heart diseases, e.g. hypertension, angina pectoris, cardiac infarction, etc. and cerebral apoplexy, transient ischemic fit, etc., antihistaminic agent, antiallergic agent, etc. PROCESS:A hydroxycarbostyril of formula II is dehydrohalogenated with a novel tetrazole derivative of formula III (X is halogen) by the conventional method to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel tetrazole derivatives, more specifically,
The present invention relates to a tetrazole derivative represented by the following general formula (I).

[In the formula, k represents a hydrogen atom, a tetrahydropyranyl lower alkyl group, or a pyridyl lower alkyl group, and A represents a lower alkylene group. In addition, the 3rd and 4th positions of the carbostyril skeleton
The carbon bond at the position represents a single bond or a double bond] The tetrazole derivative represented by the above general formula (I) is
It has excellent platelet aggregation inhibitory effects, phosphogesterase inhibitory effects, thromboxane synthetase inhibitory effects, antiulcer effects, cardiotonic effects, antiinflammatory effects, antihypertensive effects, antihistamine effects, and antiallergic effects, and is effective in preventing thrombosis. Therapeutic agent, anti-inflammatory agent, anti-a! drugs, anti-asthmatic drugs, hypertension, angina,
It is useful as a prophylactic/therapeutic agent for ischemic heart diseases such as myocardial stiffness, brain diseases such as stroke, transient ischemic attack, and migraine, and as an antihistamine and antiallergic agent.

In this specification, each group represented by R and A more specifically includes the respective groups.

Examples of the tetrahydropyranyl lower alkyl group include 2-tetrahydropyranylmethyl, 3-tetrahydropyranylmethyl, 4-tetrahydropyranylmethyl, 2-(2-
Tetrahydropyranyl)ethyl/lz, 1-(3-tetrahydropyranyl)ethyl, 3-(4-tetrahydropyranyl)propyl, 4-(2-tetrahydropyranyl)butyl, 1,1-dimethyl-2-( 2-tetrahydropyranyl)ethyl, 5-C3-tetrahydropyranyl)pentyl, 6-(2-tetrahydropyranyl)hexyl, 2
Examples include -methyl-(4-tetrahydropyranyl)propyl.

Examples of the pyridyl lower alkyl group include 2-pyridylmethyl, 3-pyridylmethylpe, 4-pyridylmethyl, 2-(
2-pyridyl)ethyl, 1-(2-pyridyl)ethyl,
3-(4-pyridyl)propyl, 4-(2-pyridyl)
Buty/L/, 1,1-dimethyl-2-(2-pyridyl)
Examples include ethinope 5-(3-pyridyl)pentyl, 6-(2-pyrinol)hexyl, 2-methyl-(4-pyridyl)propyl, and the like.

tt: Examples of the low m alkylene group include methylene, ethylene, trimethylene, 1-methyltrimethylene, 2-methylmethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, and the like.

The compound of the present invention can be produced by various methods, for example,
It can be produced by the method shown in Reaction Formula-1.

[Reaction Formula-1] 1 [In the formula, X represents a halogen atom, and if R and A, the carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above].

As shown in the above reaction formula-1, the tetrazole derivative CI) of the present invention is produced by subjecting hydroquine carbostyril [...] and the tetrazole derivative C11l'l) to a dehydrohalogenation reaction by a conventional method. Ru. Examples of the halogen atom in formula Cu1l) include fluorine, bromine, chlorine, and iodine. This dehydrohalogenation reaction is carried out using a basic compound as a dehydrohalogenation agent. A wide range of known basic compounds can be used, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Inorganic bases such as silver carbonate, alkali metals such as sodium and potassium, alcoholades such as sodium methylate and sodium ethylate, triethylamine, pyridine, heteromethylaniline, N-methylmorpholine, 4
-dimethylaminopyridine, 1,5-diazabicyclo [
4,3,o]nonene-5 (DBN), 1,5-diazabicycloC5,4°O]laurensen-5 (DBU), 1
．． 4-DiazabicycloC2,2,2')octane (DA
Examples include organic bases such as BCO). The reaction is carried out without a solvent or in the presence of a solvent, and any inert solvent that does not adversely affect the reaction can be used as the solvent, such as methanol, ethanol, propanol, butanol, alcohols such as ethylene glycol, dimethyl ether, etc. , tetrahydrofuran, dioxane, monoglyme, diglyme and other ethers, acetone,
Ketones such as methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, and xylene, esters of methyl acetate and ethyl acetate, aprotic properties such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphate triamide. Examples include polar solvents. It is also advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide.

The ratio of hydroxycarbostyryl [■] and tetrazole derivative (m) to be used in the above method is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in equimolar to 5 times molar proportions to the former. , preferably equimolar −2
It is desirable to use double the molar amount. Further, the reaction temperature is not particularly limited, and is usually carried out at room temperature to 200°C, preferably 50 to 150°C. The reaction time is usually 1 to 30 hours, preferably 1 to 15 hours.

Hydroxycarbostyryl (II), one of the starting materials used in the above method, is a known compound, or the other starting material, the tetrazole derivative [■], is an unknown compound, for example, in reaction formula-2 below. Manufactured by the method shown.

Reaction formula-2: C15 X-A-CONH->(X-A-C=NR)II RCI CrV] [V) CIII) and K and A are the same as above].

That is, P Cl
s is reacted to form a haloimine derivative (V'), which is then reacted with hydrazoic acid (HN3) without isolation to obtain a tetrazole derivative [W].

The reaction of haloamide (rV) with PCls is generally carried out in a solvent. The solvent used is any inert solvent that does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, xylene, and toluene.
, halogenated aromatic hydrocarbons such as chlorobenzene and bromobenzene, ethers such as diethyl ether and dioxane, and hydrocarbons such as n-hexane and n-heptane. The ratio of haloamide CIV) and PGE1 used is usually equimolar to 2 times the molar ratio of the latter to the former.
It is preferable to use equimolar to 1 to 2 times the molar amount. The reaction temperature is usually -20 to 50''C, preferably 0 to 25C, and the reaction time is 30 minutes to 5 hours, preferably 1 to 3 hours.

The haloimine derivative [V] obtained as described above is not isolated, but is reacted with HN3 (usually used as a solution with benzene, xylene, diethyl ether, n-beef sanitation, etc.). haloimine derivative CV', 1
The ratio of HN1 and HN3 to be used is usually selected from the range of equimolar to 5 times the former, preferably equimolar to 3 times the latter. In addition, the reaction temperature is 0 to 150°C
The reaction time is 3 hours to 2 days.

The compound of general formula CI'J thus produced can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, solvent dilution, recrystallization, and liquid chromatography.

The carbostyryl derivative CI) of the present invention has optical isomers, and the present invention also includes these optical isomers.

The compounds of the present invention can be administered to animals and humans as such or together with conventional pharmaceutical carriers.

The dosage unit form is not particularly limited and may be appropriately selected and used as required. Examples of such dosage unit forms include oral preparations such as tablets, capsules, granules, and various oral liquid preparations, parenteral preparations such as injections, and suppositories. The amount of the active ingredient to be administered is not particularly limited and may be appropriately selected from a wide range, but in order to achieve the desired effect, the amount should be 0.06 to 10 μg/kg body weight per day.

In addition, the dosage unit form may contain 1 to 500 active ingredients.

In the present invention, oral preparations such as tablets, capsules, and oral liquid preparations are manufactured according to conventional methods. That is, the tablets are prepared by mixing the compound of the invention with the following pharmaceutical excipients: gelatin, starch, lactose, magnesium stearate, talc, arabicum,
Shaped. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. Oral liquid syrups and elixirs are prepared by mixing the compounds of the present invention with sweetening agents such as sucrose, preservatives such as methyl- and propylparabens, coloring agents, and flavoring agents. In addition, parenteral preparations are prepared by conventional methods, for example, by dissolving the compound of the present invention in a sterilized liquid carrier. The preferred carrier is water or saline. A solution having the desired clarity, stability, and suitability for parenteral use may be about 1 to 500
It is produced by dissolving the active ingredient q in water and an organic solvent, and further dissolving it in polyethylene glycol having a molecular weight of 200 to 5,000. Preferably, such a liquid agent contains a lubricant such as sodium carboxymethyl cellulose, methyl cellulose, pyrrolidone, or polyvinyl alcohol.

Furthermore, the above solution contains bactericidal and fungicidal agents such as benzyl alcohol, phenol, and thimerosal, and, if necessary, isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, and buffering agents. May be included. In addition, from the viewpoint of stability, drugs for parenteral administration may be filled into capsules, etc., frozen, water removed using normal freeze-drying techniques, and liquid preparations prepared from the freeze-dried powder immediately before use. can.

The results of pharmacological tests on the compounds of the present invention are shown below.

Platelet aggregation inhibitory effect: The platelet aggregation inhibitory effect of the compound of the present invention was determined by the Born method (
G, V, RoBorn, Nature 927-92
9 (1962)].

That is, a blood sample collected from a rabbit was centrifuged at 11,000 rpm for 10 minutes to determine the platelet concentration (PNP).
The sample is further centrifuged at 3000 rpm for 5 minutes to obtain serum with a low platelet concentration (PPP). Obtained P
RP was appropriately diluted with PPP to prepare a PRP sample for adenosine diphosphate (ADP)-induced aggregation test (platelet concentration: 300,000/1fl) and a PRP sample for collagen-induced aggregation test (platelet fi: 450).
．． OOO/wz2) Om'k.

A solution containing 10-4 to 10-5 moles of test compound.
Add 0.6 ml of each sample prepared above to 011E/, hold in a constant temperature bath at 37°C for 1 minute, add 0.07 ml of collagen or ADP solution, and measure the permeability. Based on these results and the separately measured permeability of PPP and PRP, the aggregation rate was calculated according to the following formula: Aggregation rate = -X 100 -a where a: PRP permeability b: test compound and collagen or ADP Contained liquid permeability c-: PPP permeability test The aggregation inhibiting effect was measured by the inhibition rate (%) relative to the agglutination rate when no compound was added (control).

The inhibitory effect on collagen-induced aggregation is shown in Table 1.
DP=inhibitory effect on induced aggregation is shown in Table 2. The test compounds are as follows. Note that acenalsalicylic acid was used as a control substance.

1, 6-14-C1-(2-tetrahydropyranylmethyl)tetrazol-5-yl"butoxy 1-3.4-
Dihydrocarbostyryl 2, 6-+4-[1-(3-pyridylmethyl)tetrazol-5-yl]butquin l-3,4-dihydrocarbostyryl 3,6-C3-Ctetrazol-5-yl)propoxy)- 3,4-dihydrolphostyryl Next, reference examples,
The present invention will be explained in more detail with reference to Examples and Formulation Examples.

Reference Example I 10 g of N-(2-tetrahydropyranylmethyl)-510-bareramide is dissolved in 100 l of benzene, and 98 g of phosphorus pentachloride is added while stirring while cooling on an ice-water bath, followed by stirring at room temperature for 15 hours. Then, 72 m+7 of a benzene solution of hydroazotic acid (1,2N) was added dropwise while stirring while cooling with water. After the dropwise addition, the mixture was stirred at room temperature overnight, and then the solvent was distilled off under reduced pressure. Dissolve the residue in chloroform and wash with water. After drying over sulfate, the solvent is distilled off. The residue was purified by gel column chromatography (eluent: chloroform), and
10.1 g of 1-(2-tetrahydropyranylmethyl)-5-(4-chlorobutyl)tetrazole as a colorless oil
get.

NMR(CDC, 13)δ: 1.17-1.7
3 (4H, m), 1.73-2.23 (6H, m), 2
．． 93 (2H, t, J=7Hz), 3.15-4.00
(5H, m), 4.00-4.52 (2)1, m
) Reference Example 2 The following compound is obtained in the same manner as in Reference Example 1 above using appropriate starting materials.

1-(3-pyridylmethyl)-5-(4-chlorobutyl)tetrazole, pale yellow oil, NMR (CDCe3
) δ: 1.7 to 2.1 (4H, m), 2.8 (21
(, L.

J=7H2), 3.5(2H, (, J=7Hz), 5.
55 (2) (, s), 7.25-7.7 (2H, m
), 8.6 (2H, br, s) Example 1 6-hydroxy-3,4-dihydrocarbostyryl 4.
2 g and 1.7 g of potassium hydroxide are added to 60 ml of Improper Tool and heated to reflux to dissolve.

Add 1-(2-tetrahydropyranylmethyl) to this solution.
Add 1 (l) of -5-(4-chlorobutyl)tetrazole and heat under reflux for 5 hours. After the reaction, the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform; methanol - 50:1). Purified and recrystallized from methanol to obtain colorless needle crystals of 6-14-CI-
(2-tetrahydropyranylmethyl)tetrazole-5
3.9 g of -yl]butoxyl-3,4-dihydrocarfostyryl are obtained. Melting point 120-121''C Examples 2-5 The following compounds are obtained in the same manner as in Example 1 using appropriate starting materials.

(216-14-CI-(3-pyridylmethyl)tetrazol-5-yl)butquine l-3,4-hydrolupostyril, colorless needles, melting point 135-136.5'
C(chloroform-acetone)(3+643-(tetrazol-5-yl)propoxy)-3,4-dihydrocarbostyryl, colorless edge-shaped crystals, melting point 242-244-C(
methanol)(416-(4-C1-(2-tetrahydropyranylmethyl)tetrazol-5-yl J-butoxy)carbostyryl, white crystals, melting point 160-163"C (515-(4-CI-(3-tri) /lmethyl)tetrazol-5-ylnobutoxyl -3,4-dihydrocarbostyryl, white crystals, melting point 156-168°C Formulation Example 1 Preparation of tablets 5 parts of 6-(4-El-(2-tetrahydropyranyl) methyl)tetrasol-5-yldibutoxy1-
1000 tablets for oral fecal use containing 3.4-dihydrocarbostyril are prepared according to the following formulation.

6-(4-CI-(2-tetrahydropyranylmethyl)tetrazol-5-yldibutoxy)-3,4-dihydrocarbostyryl
5 Lactose (Japanese Pharmacopoeia) 50 Cornstarch (Japanese Pharmacopoeia) 25 Crystalline cellulose (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) i, s
Magnesium stearate (Japanese Pharmacopoeia) 1
6-(4-CI-(2-tetrahydropyranylmethyl)
Tetrazol-5-yldibutoxy)-3,4-dihydrocarbostyrino, lactose, cornstarch and crystalline cellulose are thoroughly mixed and granulated into a 5% water-water solution of methylcellulose, passed through a 200 mesh sieve and carefully dried. The dried granules are passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets.

Formulation Example 2 Preparation of Injection A sterile aqueous solution suitable for parenteral administration is prepared according to the following formulation.

6-14-(1-(3-pyridylmethyl)tetrazol-5-yl]butoxyl-3,4-dihydrocarbostyryl monochloride) I
Jum (Japanese Mulberry Pharmacopoeia) 09 Sodium Metabisulfite
01 Methyl-paraben (Japanese Pharmacopoeia)
0.18 Propyl-paraben (Japanese Pharmacopoeia) 0.02 Distilled water for injection
100 (lII/) of the above parabens, sodium metabisulfite and sodium chloride are dissolved in about half the amount of distilled water above at 80°C without stirring. The resulting solution was cooled to 40°C and 614-CI-(3-pyridylmethyl)tetrazol-5-yl)butoxy)-
3,4-dihydrocarbostyl, then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the solution. Distilled water for injection is added to the solution to prepare the final container, and the solution is sterilized using a suitable filter paper to obtain an injection.

Special liver applicant Otsuka Pharmaceutical Co., Ltd. Representative: Patent Attorney Aohaku Aoba and 1 other person Continuation of page 1 13100 15100 257100) (C07D 403/12 15100 257100) (C07D 405/14 15100 57100 309100) 0 shots clearer Tatsuyoshi Tanaka 21-3, Yoshinari, Todoroki, Ojin-cho, Tokushima City 0 shots by Takao Nishi Sapporo type” Hitokita 16-jo Nishi 3-21 earth 0 shots light person medium dose 774-1 Omatsu, Kawauchi-cho, Tokushima City

Claims (1)

[Claims] (1) General formula A represents a lower alkylene group. In addition, the carbon bonds at the 3- and 4-positions of the calfostyryl skeleton represent a single bond or a double bond.] A tetrazole derivative represented by: