WO1995011239A1

WO1995011239A1 - Novel phenoxyalkylpiperazine derivative

Info

Publication number: WO1995011239A1
Application number: PCT/JP1994/001720
Authority: WO
Inventors: Yoichi Kawashima; Junzo Matsumoto; Kiyoshi Matsuno; Toshihiko Senda; Keiko Hirano
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 1993-10-22
Filing date: 1994-10-13
Publication date: 1995-04-27
Also published as: JPH07118249A; JP3104005B2

Abstract

A novel compound represented by general formula (I), wherein R represents at least one group selected from among hydrogen, hydroxy, lower alkoxy and lower alkylenedioxy; and A represents lower alkylene. It is useful as a remedy for cranial nerve function disorders such as dementia, schizophrenia and anxiety, diseases accompanying dysimmunization and dyscrinism, digestive ulcer, and so forth.

Description

11 Description New phenoxyalkylpiperazine derivatives

Technical field

The present invention relates to a novel phenoxyalkyl useful as a therapeutic agent for cerebral nerve dysfunction such as dementia, schizophrenia and anxiety disorder, diseases associated with immune disorders and endocrine disorders, and gastrointestinal ulcers. It relates to a piperazine derivative.

Background art

Recently, a great deal of research has been conducted on the receptor, and compounds with strong affinity for the sigma receptor have been identified as dementia, schizophrenia, anxiety, etc. It is becoming useful as a therapeutic agent for diseases such as ulcers. (Journal o {Neuropsychiatry h_ 7-15 (1989); Eur. J. Biochem., 200, 633-642 (1991) J. Pharmacol. Exp. Ther,, 255, 1354-1359 (1990)). On the other hand, it has been reported that compounds in which phenylalkyl groups are substituted at the 1- and 4-positions of piperazine, respectively, have affinity for the σ receptor (WO 91 9095 9 4). However, no study has been made on the affinity of piperazine derivatives having a phenoxyalkyl group having an oxygen atom introduced between a phenyl ring and an alkyl group as a substituent for the receptor. In studies of the affinity of piperidine derivatives, which are heterocyclic compounds having one nitrogen atom, for the receptor, the 4-position is substituted with a phenoxyalkyl group, and the 1-position is a cyclopropyl or cyclopropylalkyl group. It has been reported that each substituted piperidine derivative has affinity for the receptor (W09103324). However, this report does not examine cycloalkyl groups other than cyclopropyl groups, and studies how the ring size of the cycloalkyl groups affects the affinity for σ receptor. Had not been.

Compounds in which two nitrogen atoms of a piperazine ring are substituted with a phenyloxyalkyl group and a straight-chain alkyl group, for example, a piperazine derivative in which a phenyloxypropyl group and a methyl group are substituted have a dopamine antagonism. (J. Med. Chem., 24, 678 (1 1981)), and no report was given of its affinity for the receptor.

Further, in a series of studies on compounds having benzyl lactam as a main skeleton, a compound having a piperazine ring is also disclosed in Japanese Patent Application Laid-Open No. 62-116567, Derivatives in which a phenoxyalkyl group and a cycloalkyl group were substituted on the nitrogen atom of, respectively, were hardly studied o

As described above, almost no research has been conducted on the creation of compounds in which two nitrogen atoms of a piperazine ring are substituted with a phenoxyalkyl group and a cycloalkyl group, respectively, and on the effects thereof. However, finding a new piperazine derivative having strong affinity for the σ receptor was an important issue.

Accordingly, the present inventors have conducted intensive studies on this problem, and as a result, a novel piperazine derivative in which two nitrogen atoms of a piperazine ring are substituted with a phenoxyalkyl group and a cyclohexyl group, respectively, has been developed for the receptor. Found to have strong affinity o

Furthermore, the present inventors have studied the action of this novel compound. As a result, this novel compound not only has an affinity for the sigma receptor, but also has an improving effect on learning impairment due to cerebrovascular disorders and an amount of acetylcholine in the brain. It also has an increasing effect on the brain, and was found to be useful as a therapeutic agent for brain neurological dysfunction. Disclosure of the invention

The present invention provides a compound represented by the following general formula [I] and a salt thereof (hereinafter, referred to as the compound of the present invention).

[In the formula, R represents one or more groups selected from a hydrogen atom, a hydroxy group, a lower alkoxy group, and a lower alkylenedioxy group.

Α represents a lower alkylene group. ]

To elaborate on the above definitions, lower alkoxy refers to those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, t-butoxy, etc. A lower or higher alkylene is a straight or branched chain having 1 to 6 carbon atoms such as methylene, ethylene, propylene, butylene, (dimethyl) methylene, and (getyl) methylene; And a lower alkylenedioxy group refers to an alkylenedioxy group having 1 to 6 carbon atoms between two oxygen atoms, such as methylenedioxy and ethylenedioxy.

Examples of the salts include pharmaceutically acceptable salts such as hydrochloride, sulfate, maleate and fumarate.

A typical synthesis method of the compound of the present invention is shown below.

ヽ, V "0— AN (CH ₂ CH ₂ 〇H) ₂

[II] [Hi]

[I]

[In the formula, X represents a reactive group such as a halogen atom or a lower alkane sulfonyloxy group. ] In this method, a compound of the formula [III] is reacted with diethanolamine to give a compound of the formula [III], which is then reacted with thionyl chloride or methansulfonyl chloride to give a compound of the formula [III] In this method, the compound of the formula [IV] is led to a compound of the formula [IV], which is then reacted with cyclohexylamine to obtain the compound [I] of the present invention. The compound obtained by the above method can be converted into a salt as described above by a conventional method.

—The compound represented by the general formula [I] may have optical isomers, and they are all included in the present invention.

Representative examples of the compounds of the present invention include 1-cyclohexyl 4- (3-phenoxypropyl) piperazine, 1-cyclohexyl-14- (2-phenoxicetyl) piperazine, 1-six mouth hexyl 4 -— [2-[(3,4-methylenedioxy) phenyl] ethyl] piperazine or salts thereof.

In order to examine the usefulness of the compound of the present invention, an experiment was conducted on the affinity of the compound of the present invention for a receptor. Although shown in detail For the pharmacological tests described below ^{section, [3 Η] (+)} SKF - 1 0 0 4 7 The results of examining the affinity of the labeled ligand and Shitebi receptor, the compounds of the present invention, And a strong affinity for the receptor.

Furthermore, four arteries are occluded by the method of Pulsinelli et al. (Strokeil, 267 (1979)), which is a learning impairment model due to ischemia, which is known as a disease model of dementia due to cerebrovascular disorders. When an experiment was performed using a rat in a blood state, The compound of the present invention had an improving effect on learning disabilities. In addition, it has been reported that a compound that increases the amount of acetylcholine in the brain is useful as a therapeutic agent for dementia and the like (The New England Journal of Medicine, 315, 1241-1245 (1986) ), Based on the literature of Matsuno et al. (Brain Research, 575, 315-319 (1992)), the acetylcholine content in rat brain was measured. Indicated.

Based on the results of the above pharmacological tests, the compound of the present invention has a strong affinity for biceptors, and further has an improving effect on learning disorders due to cerebrovascular disorders and an effect of increasing the amount of acetylcholine in the brain. It is useful as a remedy for cerebral nerve dysfunction such as dementia, schizophrenia, anxiety, immune disorders and endocrine disorders, diseases associated with digestive system ulcers, etc. all right.

The method of administration of the compound of the present invention may be oral or parenteral. Examples of the dosage form include tablets, capsules, soft capsules, granules, and injections. It can be formulated using commonly used techniques. For example, oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in the form of bulking agents such as lactose, starch, microcrystalline cellulose, vegetable oil, etc., lubricants such as magnesium stearate, talc, etc. Uses binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as calcium carboxymethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and coating agents such as gelatin film. Can be formulated. The dosage is appropriately selected depending on the condition, dosage form, etc., but it is usually sufficient to administer lmg to: LOOO mg once or several times a day.

BEST MODE FOR CARRYING OUT THE INVENTION

Example

1-cyclohexyl 4-one (3-phenoxypropyl) perazine dihydrochloride (Compound 1)

1) Sodium sodium iodide was added to a solution of 3-phenoxypropyl bromide (6.45 g) and ethanol (18.9 g) in ethanol (30 ml). (4.50 g) was added and refluxed for 5 hours. The insoluble material is removed by filtration, and the mixture is concentrated under reduced pressure. The solution is washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 5.55 g (77%) of N, N-bis (2-hydroxyxethyl) -13-phenoxypropylamine

1 R (Film, cm " ¹ ) 3 3 7 7, 2 9 4 9, 1 6 0 0, 1 4 9 5, 1 2 4 4, 1 0 4 4, 7 5 5, 6 9 3

2) To a solution of N, N-bis (2-hydroxyxethyl) -13-phenoxypropylamimine (4.62 g) in methylene chloride (25 ml) was added thionyl chloride (6.8) under ice-cooling. After 9 g) was added dropwise, the mixture was refluxed for 1 hour. The reaction solution is concentrated under reduced pressure to obtain 5.17 g (86%) of N, N-bis (2-chloroethyl) -13-phenoxypropylaminium hydrochloride. mp 6 7 ~ 7 1 ° C

IR (KBr, cm " ¹ ) 2930, 2526, 16 00, 14 9 8, 1 4 7 2, 1 2 4 8, 7 56, 691

3) N, N-bis (2-chloroethyl) -1-dimethylhexamyl hydrochloride (313 mg) and cyclohexylamine (298 mg) in dimethylformamide (20 mg) ml) solution, add anhydrous sodium carbonate (415 mg) and sodium iodide (450 mg), and stir at 60 for 4 hours. Water is added to the reaction mixture under ice-cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography. The obtained oil was dissolved in methanol, 6N hydrochloric acid (0.7 ml) was added, and the mixture was cooled on ice to obtain 277 mg (74%) of the title compound (Compound 1). .

m p 280 ° C or higher

IR (KBr, cm " ¹ ) 2 9 3 3, 2 3 2 6, 1 5 8 7, 1 4 6 5, 1 2 5 1, 1 0 4 6, 7 6 2, 6 9 4

The following compound is obtained using a method similar to the above method

• 1-cyclohexyl 4- (2-phenoxicetyl) piperazine dihydrochloride (Compound 2)

m p 26 6 to 26 9 ° C (decomposition)

IR (KBr, cm ^-1 ) 2 95 1, 2 26 0, 1 45 2, ¹ 24 5, 10 8 9, 9 2 4, 7 5 5, 6 9 3

• 1-cyclohexyl 4-1 [2— [(3, 4—methyl range Oxy) funinoxy] ethyl] piperazine dihydrochloride (Compound 3)

m p 26 9 to 27 1 ° C (decomposition)

IR (KBr, cm " ¹ ) 2 9 3 4, 2 3 3 9, 1 4 9 7, 1 2 8 1, 1 1 9 3, 1 0 3 5, 9 3 8, 7 9 5

• 1—cyclohexyl-1-41 [3- (3,4-dimethoxyfunoxy) propyl] piperazine dihydrochloride (Compound 4) • 1—cyclohexyl-1-4-1 (4 1-phenoxyptyl) pirazindi hydrochloride (compound 5)

· 1-cyclohexyl-4-1 [2- (4-hydroxyphenoxy) ethyl] piperazine dihydrochloride (Compound 6)

[Formulation example]

An example of the formulation of the compound of the present invention is shown below.

(Tablets)

Compound of the present invention l mg Lactose 120 mg Crystalline cellulose 38 mg Low substituted hydroxypropyl cellulose 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate l mg

70 mg in total -10-Compound of the present invention 5 mg Lactose 7 5 mg Microcrystalline cellulose 6 8 mg Low-substituted hydroxypropyl cellulose cellulose 10 mg Hydroxypropyl cellulose 10 mg Mg stearate 2 mg

270 mg in total

(Soft capsule)

Compound of the present invention 50 mg

Vegetable oil 150 mg

Gelatin film 1 400 mg

1 † 3 4 0 mg

(Injection)

Compound of the present invention 100 mg

0.9 g of sodium chloride

Sodium hydroxide

Sterile purified water

Total 0 0 ml Effect of the invention

`` Pharmacological test ''

An experiment was conducted on affinity for the σ receptor to examine the usefulness of the compound of the present invention. According to the literature of Matsuno et al. (European Journal o {Pharmacology 231, 451-457 (1993)), the affinity for the sigma receptor was determined by the following method. Note that as the ^[3 Eta] labeled ligand of the non-receptor ^{[3 H] (+) SKF} - with 1 0 0 4 7.

(experimental method)

The membrane preparation was prepared by the following method according to the paper by Tam et al. (Proc. Natl. Acad. Sci. USA O, 6703-6707 (19)).

The brain was isolated from a Hartley guinea pig (body weight: 300 to 400 g), and tris-HCl buffer (50 mM, pH 7.7, 0.3 After homogenization (containing 2 M sucrose), the mixture was centrifuged to obtain a supernatant. The supernatant was ultracentrifuged for 20 minutes, and the resulting pellet was suspended in Tris-HCl buffer (50 mM, pH 7.7; the same applies hereinafter). I got

The specific binding amount of [ ^a H] (+) — SKF — 10047 was determined in advance by the following method. Doo Risu membrane specimen suspended in HCl buffer, was dissolved in Application Benefits sous-HCl buffer ^{[3 H] (+) -} SKF - 1 0 0 4 7 a (5 n M) was added (test compound Was added) and reacted at 25 ° C. for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, [ ³ H] (+)-SKF-100 4 7 (5 nM), which has no radioactivity (+) — SKF — 100 4 7 Two one

(100 jcz M) was added (without adding the test compound), and the amount of binding to the membrane standard was determined using the same method as described above, and the result was defined as the amount of non-specific binding. The difference between the total binding amount and the non-specific binding amount thus obtained was defined as the specific binding amount.

Next, the amount of binding between the membrane sample and [ ³ H] (+) — SKF—10747 was measured in the presence of the test compound, and was determined earlier by changing the concentration of the test compound. The concentration of the test compound at which the specific binding amount of [ ³ H] (+)-SKF-1 0 0 4 7 is suppressed by 50%

The (I c ₅₀₎ was determined.

(Result)

The results of the experiments, the present compound has a strong affinity to fine receptors both, for example, IC _{5 Q} of compound 1 1. was 3 n M.

Industrial applicability

The compound phenoxyalkylpiperazine derivative of the present invention has an affinity for a sigma receptor. It is useful as a therapeutic agent for gastrointestinal ulcers.

Claims

The scope of the claims

(1) Compounds represented by the following general formula [I] and salts thereof

[I]

A represents a lower alkylene group. ]

(2) The compound according to (1), wherein R is a hydrogen atom, and salts thereof.

(3) The compound according to (2) or a salt thereof, wherein A is-(CH ₂ ) ₃ —.

(4) A therapeutic agent for cranial nerve dysfunction, comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient.

A represents a lower alkylene group. ]

(5) The therapeutic agent for cranial nerve dysfunction according to claim U), wherein R is a hydrogen atom. (6) The therapeutic agent for cranial nerve dysfunction according to claim (5), wherein A is-(CH ₂ ) J 1.