JPH07113007B2 - Novel cinnamic acid amide derivative and pharmaceuticals containing them - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (I)

[0002]

[Chemical 7]

[In the formula, all symbols have the same meanings as described below. ] The novel cinnamic acid amide derivative shown by these, and the 5 (alpha) -reductase inhibitor containing them as an active ingredient.

[0004]

Background: Traditionally, the causes of male pattern baldness are:
(1) hormone imbalance theory, (2) genetic theory,
Many theories such as (3) blood circulation insufficiency theory and (4) nutrition theory have been proposed, but it has long been suggested that the male hormone testosterone plays an important role in hair development. It was According to Adachi et al.'S theory [Biochem. Biophys. Res. Commun., 41 , 884 (1970)] that experimentally demonstrated the causal relationship between testosterone and androgenetic alopecia at the biochemical level, it was biosynthesized in the testis. Testosterone is converted into dihydrotestosterone (Dihydorotestosterone) in the head by 5α-reductase (5α-reductase) present in hair follicles, capsular glands, and the like, and this dihydrotestosterone is adenyl cycla.
Se) significantly decreases the activity of intracellular cyclic-AMP, resulting in decreased energy production in and around hair and inhibition of protein synthesis. Therefore, it is thought that these series of phenomena cause the hair in the growing phase to shift to the resting phase, and during this state, it progresses from the terminal hair to the vellus hair and finally to the male baldness. . In support of this theory, Schweikert [HV. Schweikert] et al. Showed that male hair bald follicles contained more abundant metabolites of 5α-reductase, such as dihydrotestosterone, than female hair follicles and non-bald human hair follicles. Reported [J. Clin. Endocr., 38 , 811 (1974)].

In addition to androgenetic alopecia, dihydrotestosterone produced from testosterone by 5α-reductase has been reported to play an important physiological role in the development and exacerbation of acne (acne, acne, etc.). ing.
That is, JBHay et al. Compared the metabolic rate of testosterone between affected skin and normal skin in acne patients and reported that the metabolism of testosterone by 5α-reductase was enhanced in the affected areas of acne [Br.J. De
rmatol., 91 , 123 (1974)]. In addition, G. Sansone et al. Found that the ability to synthesize testosterone to dihydrotestosterone in the affected skin of acne patients was abnormally enhanced by 2 to 20 times that of normal humans, and 5α for the occurrence and exacerbation of acne. -Suggests that dihydrotestosterone produced by reductase is greatly involved
[See J. Invest. Dermatol., 56 , 366 (1971)].

Furthermore, dihydrotestosterone is also involved in prostate hypertrophy. Cowan et al. Reported that a large amount of dihydrotestosterone was present in the prostate of patients with benign prostatic hyperplasia [J. Steroid Biochemistry, 11 , 609 (19
79)], and more recently, it has been known that the activity of 5α-reductase is abnormally elevated in the prostate of patients with benign prostatic hyperplasia [J. Clinical Endocrinol and Metabolis].
m, 56 , 139 (1983)], and dihydrotestosterone has been shown to play an important role in the development and progression of benign prostatic hyperplasia.

[0007]

2. Description of the Related Art Under the above background, recently, 5α
-Research and development of reductase inhibitors have been extensively conducted, but most of them are mainly steroids or their derivatives. As a result of repeated studies to create a compound having a non-steroidal structure having a 5α-reductase inhibitory activity, the applicant has found that a group of compounds in which cinnamic acid or benzoic acid and aniline are amide-bonded meet the above object. Filed a patent application [Japanese Patent Laid-Open No. 60-97946
Issue 60-116657, Issue 60-142936, Issue 60-142941
No. 60-146855, No. 61-126061, No. 62-198652 and No. 62-198653]. For example, JP-A-6
Although the specification of 1-126061 describes that a very wide range of amide compounds has a 5α-reductase inhibitory action, it is a part closely related to the compound of the present invention represented by the general formula (I) in terms of chemical structure. From the general formula (A1)

[0008]

[Chemical 8]

In the formula, A ^a represents a vinylene group which may be substituted with an alkyl group having 1 to 10 carbon atoms, and B ^a
Represents a divalent group represented by —O—CH ₂ , and R ^a1 represents a general formula.

[0010]

[Chemical 9]

(Wherein R ^a5 and R ^a6 are each independently a hydrogen atom or a halogen atom, or any one of 1 to 5)
Carbon atoms are oxygen atom, sulfur atom, halogen atom, nitrogen atom, benzene ring, thiophene ring, naphthalene ring, carbon ring having 4 to 7 carbon atoms, carbonyl group, carbonyloxy group, hydroxyl group, carboxy group, azido group or An alkyl having 1 to 20 carbon atoms which may be replaced by a nitro group,
Represents an alkenyl or alkynyl group. Represents a group represented by), T ^a represents an oxygen atom, R ^a2 represents a hydrogen atom, R ^a3 represents a hydrogen atom, R ^a4 is - (C
H ₂ ) _ap —COOR ^a8 (wherein ap represents an integer of 1 to 10 and R ^a8 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), that is, a compound represented by the general formula (A2)

[0012]

[Chemical 10]

A compound represented by the formula (wherein all symbols have the same meanings as described above) is proposed. Also,
On the other hand, a group of compounds having a chemical structure similar to that of the compound of the present invention is disclosed in JP-A-51-1438 and French Patent Publication No. 2164481. For example, in JP-A-51-1438, the general formula (B)

[0014]

[Chemical 11]

[In the formula, R ^b1 and R ^b2 each represent a hydrogen atom or a lower alkyl group, R ^b3 and R ^b4 form a chemical bond with each other, X ^b represents a halogen atom, a lower alkyl group, It represents a lower alkoxy group or a cyclic alkyl group, bn represents an integer of 1 to 3, R ^b5 represents a hydrogen atom, and Y ^b represents an oxyalkylene group bonded to the benzene ring via an oxygen atom. ] (The definitions of symbols are partially extracted.) It is disclosed that the compound is useful as an antiallergic agent. Furthermore, in French publication 2164481, the general formula (C)

[0016]

[Chemical 12]

[In the formula, A ^c represents an alkylene group having 1 to 3 carbon atoms, B ^c is an ethylene-based divalent hydrocarbon having 1 to 5 carbon atoms, R ^c is a hydrogen atom, R ^c1 is alkyl and cycloalkyl. , Aryl, aralkyl, halogen, alkoxy, aryloxy and alkylthio groups, and 1 or 2 substituents, and Z ^c represents an oxygen atom. ]
It is disclosed that the compound represented by (the definition of symbols is an excerpt from a part) has anti-inflammatory and antipyretic effects.

[0018]

DETAILED DESCRIPTION OF THE INVENTION The present inventors have investigated a compound represented by the general formula (I), which is largely included in the general formula (B) in the superordinate concept but not specifically described as a subordinate concept. It was synthesized and it was found that these compounds have excellent 5α-reductase inhibitory activity. Since the compound represented by the general formula (B) has an antiallergic action,
It is not suggested at all that the compound (I) has a 5α-reductase inhibitory action.

Further, the compounds represented by the general formula (I) are broadly classified into two, that is, those contained in the general formula (A2) and those not contained in the general formula (A2). Regarding the former, when a compound not specifically described was newly synthesized and its 5α-reductase inhibitory action was observed, it was found that the compound has an activity far beyond the original expectation. It was totally unexpected that such a compound having extremely excellent activity was contained. In addition, it was found that the latter has a 5α-reductase inhibitory action even though the structures are remarkably different.

A detailed examination of French publication 2164481, which discloses compounds of the general formula (C), reveals that there is only one compound which has actually been identified. Further, the group of compounds represented by the general formula (C) is said to have an anti-inflammatory action, but this does not suggest that the compound of the general formula (I) has a 5α-reductase inhibitory action at all. . Therefore, the present invention has the general formula (I)

[0021]

[Chemical 13]

[In the formula, (i) R ¹ , R ² and R ³ may be the same or different;
~ 7 straight or branched chain alkoxy group, 1 to 7 carbon atoms
Represents a group selected from a straight chain or branched chain alkyl group and a nitro group, wherein one of R ⁴ and R ⁵ represents a methyl group and the other represents a hydrogen atom, or (ii)
Any one of R ¹ , R ² and R ³ is a 4-butyl group, a 4-propyl group, a 4-butoxy group and a 4-se group.
represents a group selected from a c-butyl group, the remaining two groups represent hydrogen atoms, R ⁴ represents a methyl group, and R ⁵ represents a hydrogen atom. ] The cinnamic acid amide derivative shown by these, its non-toxic salt, and the 5 (alpha) -reductase inhibitor containing them as an active ingredient.

In the general formula (I), the configuration of the vinylene group to which R ⁴ and R ⁵ are bonded is E. When any ^{one of} R ¹ , R ² and R ³ represents a 4-sec-butyl group and the other 2 represent a hydrogen atom, an asymmetric carbon atom is generated in the butyl group and two types of optical isomerism occur. The body arises. The present invention includes these two isomers and mixtures thereof. The compounds represented by the general formula (I) are all preferable, and among them, preferable compounds are (i) R ¹ and R ²
And R ³ may be the same or different,

[0024]

[Chemical 14]

The group represented by: 3,5-dichloro-4-pentyloxyphenyl group, 3,5-dimethoxy-4-pentyloxyphenyl group, 3,4,5-tripentyloxyphenyl group, 3,5- Dimethyl-4-pentyloxyphenyl group, 3,5-di-tert-butyl-4-methoxyphenyl group, 2,3-dichloro-4-pentyloxyphenyl group, 3,5-dichloro-4-butoxyphenyl group, 3,4,5-tripropoxyphenyl group, 3,4
A group selected from a 5-tributoxyphenyl group, a 2-nitro-4,5-dipentyloxyphenyl group and a 3,4,5-triethoxyphenyl group, R ⁴ represents a methyl group, and R ⁵ represents hydrogen. Represents an atom, or (ii)

[0026]

[Chemical 15]

The group represented by represents a 3,4,5-tripentyloxyphenyl group or a 3,5-dichloro-4-pentyloxyphenyl group, R ⁴ represents a hydrogen atom, and R ⁵ represents a methyl group. Or (iii) ^one of R ¹ , R ² and R ³ is a 4-butyl group, a 4-propyl group, a 4-butoxy group and a 4-sec-butyl group. Compounds which represent the selected radicals, the remaining two represent hydrogen atoms, R ⁴ represents a methyl group and R ⁵ represents a hydrogen atom. More preferred compounds include (i) R ¹ , R ² and R ³
May be the same or different,

[0028]

[Chemical 16]

The group represented by is 3,5-dichloro-4-pentyloxyphenyl group or 3,5-di-tert-
A butyl-4-methoxyphenyl group, and R ⁴
Represents a methyl group and R ⁵ represents a hydrogen atom,
(ii) R ¹ , R ² and R ³ may be the same or different,

[0030]

[Chemical 17]

The group represented by represents a 3,4,5-tripentyloxyphenyl group or a 3,5-dichloro-4-pentyloxyphenyl group, R ⁴ represents a hydrogen atom, and R ⁵ represents a methyl group. Or a compound (i
ii) Any one group of R ¹ , R ² and R ³ is 4
-Butyl group, 4-propyl group, 4-butoxy group and 4
Represents a group selected from -sec-butyl group, the remaining two groups represent hydrogen atoms, R ⁴ or methyl group, and R ⁵
R ⁴ represents a methyl group, R ⁵ represents a hydrogen atom, and R ¹ , R ² and R ³ represent 3,5-dichloro-4.
Represents a pentyloxy group, R ¹ , R ² and R ³
Any one of the groups is a compound which represents a 4-butyl group.

[0032]

[Nontoxic Salt] The compound of the present invention represented by the general formula (I) can be converted into a salt by a known method. The salt is preferably non-toxic and water-soluble. Suitable salts include, for example, alkali metal salts such as sodium and potassium, calcium,
Alkaline earth metal salts such as magnesium, ammonium salts, and pharmaceutically acceptable (non-toxic) amine salts, for example tetraalkylammonium salts such as tetramethylammonium, and methylamine, dimethylamine, Trimethylamine, cyclopentylamine,
Benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N
Mention may be made of salts of organic amines such as -methyl-D-glucamine.

[0033]

According to the present invention, a compound of the general formula
The compound of the present invention represented by (I) has the general formula (II)

[0034]

[Chemical 18]

(In the formula, R'represents an alkyl group having 1 to 4 carbon atoms, and other symbols have the same meanings as described above.)
It can be produced by subjecting a compound represented by to a saponification reaction. The saponification reaction is known, and for example, an organic solvent miscible with water (tetrahydrofuran (TH
F), dioxane, ethanol, methanol, etc.) in alkali (potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, etc.). This reaction is usually performed at -10 ° C to 100 ° C.

[0036]

[Method for producing intermediate] The compound represented by the general formula (II) is
According to the reaction scheme shown below, the general formulas (VI), (VII), (V
It is produced by a known method using the starting compounds represented by III), (IX), (XI) and (XII). In the following reaction process formula, R ′ and R ″ each independently have 1 carbon atom.
Represents an alkyl group of ~ 4.

[0037]

[Chemical 19]

The reaction product can be obtained by an ordinary purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography or washing, recrystallization and the like. It can be purified. Purification may be carried out for each reaction, or may be carried out after the completion of some reactions.

[0039]

[Starting Material] Each starting material and each reagent in the present invention are known per se or can be synthesized by known methods. For example, carboxylic acids represented by the general formula (IV) are disclosed in JP-A-60-97946, JP-A-60-116657,
It can be produced by the method described in 60-142936, 60-142941 or 60-146855. The amine represented by the general formula (III) can be produced by the method described in JP-A No. 61-126061.

[0040]

[Pharmacological activity of the compound of the present invention] Since the compound of the present invention represented by the general formula (I) has a 5α-reductase inhibitory action, treatment of diseases caused by overproduction of dihydrotestosterone by 5α-reductase in mammals, particularly humans. And / or is useful for prevention. Examples of such diseases include alopecia including androgenetic alopecia, acne and benign prostatic hyperplasia. The 5α-reductase inhibitory action of the compound of the present invention was confirmed by the screening system described below.

Inhibitory effect on 5α-reductase (1) Experimental method J. Shimazaki et al. [Endocrinol, Japon., 18, 179 (197)
1) Refer to]] for reference. That is, 4 g of male rat prostate contains 3 volumes of 0.25 M sucrose
The mixture was homogenized with 0.1M HEPES (pH 7.4) and then centrifuged (3,000 rpm for 10 minutes). Suspend the precipitate in 10 ml of the above buffer solution and centrifuge again (3000 rpm for 5 minutes).
To the precipitate thus obtained, 3 ml of the above buffer solution was added and suspended to obtain an enzyme solution.

The enzyme activity was measured by [4- ¹⁴ C] -testosterone (1.5 nmol, 1.5 × 10 ⁵ cpm), NADPH (0.5
μmol), the above enzyme solution (0.03 ml), and a total volume of 0.1 ml of the reaction solution containing several concentrations of the compound of the present invention.
Incubated at 60 ° C for 60 minutes. The enzymatic reaction was stopped by adding 0.4 ml of a mixture of chloroform and methanol (1: 2), and then centrifuged (2000 rpm for 3 minutes), and 50 μl of the obtained supernatant was spotted on a silica gel thin layer plate. , Chloroform, methanol and acetic acid (99.2:
0.6: 0.2) was used for separation. The plate is subjected to autoradiography, and the radioactivity of the produced dihydrotestosterone is measured using a TLC scanner,
The enzyme activity inhibition rate was calculated. The results are shown in Table 1.

[0043]

[Table 1]

[0044]

[Table 2]

(2) Results From the experimental results, it can be seen that all the compounds of the present invention have a 5α-reductase inhibitory action. General formula (A
As a control compound for the compound of the present invention included in the general concept of 2), an invention including the compound of the present invention as a general concept (the invention described in JP-A-61-126061; hereinafter referred to as prior invention).
In the compound whose chemical structure is specifically described, and the degree of 5α-reductase inhibitory action is specifically described, the compound having the strongest action was selected. It was confirmed that the compound of the present invention has a potent 5α-reductase inhibitory activity which is 5.3 to 10 times stronger than that of the control compound. The existence of such potent compounds is completely unexpected from the prior invention.

Sufficient activity was observed for the compounds of the present invention having completely different structures which are not included in the general concept of formula (A2). Thus, the compound of the present invention is 5α-
Since it has a reductase inhibitory action, it is useful for treating and / or preventing a disease caused by overproduction of dihydrotestosterone by 5α-reductase in mammals, particularly humans. Furthermore, the toxicity of the compound of the present invention is extremely low, and it was confirmed that the compound of the present invention can be used safely as a drug.

[0047]

[Indications for Pharmaceuticals] The compounds included in the present invention are used for the above-mentioned purposes, usually systemically (mainly in the case of treatment and / or prevention of benign prostatic hyperplasia) or locally (mainly in the treatment of alopecia and acne and (Or in case of prevention)
Orally or parenterally. The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but in the case of the treatment and / or prevention of benign prostatic hyperplasia, it is usually in the range of 1 mg to 1 g per adult at one time. 1
It is orally administered once to several times a day, or parenterally in the range of 100 μg to 100 mg once per adult once to several times a day. In the case of treatment and / or prevention of alopecia and / or acne, it is usually percutaneously administered per adult in the range of 10 μg to 50 mg once to several times a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above range may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases.

Solid compositions for oral administration according to the present invention include tablets, powders, granules and the like. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate. Mixed with magnesium acid. According to a conventional method, the composition comprises additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. This composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.
Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid).
These are, for example, filtration through bacteria-retaining filters,
It is sterilized by blending a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.
Other compositions for parenteral administration include external preparations containing one or more active substances and formulated by a method known per se, coating agents such as soft koh, suppositories for rectal administration. Agents and pessaries for vaginal administration and the like are included.

Compositions for transdermal administration, especially for the treatment and prevention of alopecia or acne, include lotions, tonics, sprays, solutions, suspensions, topical solutions such as emulsions and soft koh, gels, Includes cream-like coatings. In such compositions, one or more of the active agents is at least one inert diluent such as distilled water, lower alcohols such as ethanol, higher alcohols such as cetanol, polyethylene glycol, propylene glycol. Such as polyhydric alcohols, celluloses such as hydroxypropyl cellulose, animal and vegetable fats, petrolatum, waxes, silicones, vegetable oils such as olive oil, surfactants, zinc oxide and the like. In addition to the diluents mentioned above, the composition may also contain adjuvants such as wetting agents, suspending agents, fragrances and preservatives.

[0052]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. "TLC" in Reference Examples and Examples
And "IR" means "thin layer chromatography"
And "infrared absorption spectrum". The solvent in parentheses described in the column of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. Unless otherwise specified, IR is KB
It is measured by the r method.

Reference Example 1 3- (3,5-Dichloro-4-pentyloxyphenyl) -2E-butenoic acid ethyl ester

[0054]

[Chemical 20]

Sodium hydride (content: 63%) 1.53
g was suspended in 60 ml of tetrahydrofuran, and 9.0 g of triethylphosphonoacetate dissolved in 20 ml of tetrahydrofuran was added dropwise thereto over 30 minutes under ice cooling. 3,5-dissolved in the obtained solution in 20 ml of tetrahydrofuran
7.4 g of dichloro-4-pentyloxyacetophenone was added, and the mixture was stirred at 60 ° C. for 15 hours and then heated under reflux for 1 hour. Tetrahydrofuran was distilled off from the reaction mixture, acidified with diluted hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 99: 1 → 98: 2 → 95: 5) to obtain 9.01 g (E-form) of the title compound having the following physical properties. TLC (benzene): Rf 0.68.

Reference Example 2 3- (3,5-dichloro-4-pentyloxyphenyl) -2E-butenoic acid

[0057]

[Chemical 21]

25 ml of methanol and tetrahydrofuran 2
To 9 g of the ester (prepared in Reference Example 1) dissolved in 5 ml of the mixed solution, 26 ml of a 4N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 30 minutes and then at 50 ° C. for 30 minutes. The reaction mixture was extracted with ether to remove neutral substances, the aqueous layer was acidified with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 8.25 g of crude crystals. The crystals were recrystallized from n-hexane to give the title compound having the following physical data: 3.9
6 g was obtained. TLC (n-hexane: ethyl acetate = 2: 1): Rf
0.38.

Reference Example 3 4- (2-Nitrophenoxy) butanoic acid ethyl ester

[0060]

[Chemical formula 22]

16.5 g of sodium hydroxide (content: 62.4%) suspended in 500 ml of N, N-dimethylformamide
Then, 60 g of o-nitrophenol dissolved in 100 ml of N, N-dimethylformamide was cooled with ice water and added dropwise over about 20 minutes while stirring. After the mixture was stirred at room temperature for 1 hour, 84.2 g of 4-bromobutanoic acid ethyl ester dissolved in 200 ml of N, N-dimethylformamide was added, and the mixture was stirred at about 70 ° C. for 15 hours. After N, N-dimethylformamide was distilled off from the reaction mixture under reduced pressure, 800 ml of ethyl acetate was added, washed with water and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 3: 1) to obtain 77.3 g of the title compound having the following physical properties. TLC (n-hexane: ethyl acetate = 2: 1): Rf
0.35.

Reference Example 4 4- (2-Aminophenoxy) butanoic acid ethyl ester

[0063]

[Chemical formula 23]

Chloroform 100 ml and ethanol 500
Palladium-carbon (content: 10
%) 13.1 g was added with 77.0 g of a nitro compound (produced in Reference Example 3) dissolved in 500 ml of ethanol, and the mixture was stirred at room temperature for 10 hours in a hydrogen gas atmosphere. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 79 g of a white solid.
Got The obtained solid was dissolved in 1000 ml of ethyl acetate, 500 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate: methylene chloride = 90: 5: 5 → 70: 15: 1).
Purified in 5), 60.0 g of the title compound having the following physical data.
Got TLC (n-hexane: ethyl acetate: methylene chloride =
2: 1: 1): Rf 0.43.

Reference Example 5 4- [2- (3,5-dichloro-4-pentyloxy-
β-Methylcinnamoylamino) phenoxy] butanoic acid ethyl ester

[0066]

[Chemical formula 24]

Butenoic acid (prepared in Reference Example 2) 3.16
After stirring a mixture of g and 8.7 ml of oxalic acid chloride at room temperature for 1 hour, the obtained solution was concentrated under reduced pressure to obtain the corresponding acid chloride. 10 ml of methylene chloride and 3 ml of pyridine
Amine compound dissolved in the mixed solution of (produced in Reference Example 4)
A solution of the acid chloride obtained above in 10 ml of methylene chloride was added dropwise to 2.45 g under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, the organic layer was washed successively with dilute hydrochloric acid, dilute aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 4.5 g of the title compound having the following physical data. Obtained as a crude product. The product was subjected to the next reaction without purification. TLC (n-hexane: ethyl acetate = 2: 1): Rf
0.70.

Example 1 4- [2- (3,5-dichloro-4-pentyloxy-
β-Methylcinnamoylamino) phenoxy] butanoic acid

[0069]

[Chemical 25]

30 ml of methanol and 1 of tetrahydrofuran
Crude ethyl ester compound dissolved in 5 ml of mixed solution (Reference Example 5)
Manufactured in. ) 4.5 g of 2N sodium hydroxide solution
17.2 ml was added little by little and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, 10 ml of 4N hydrochloric acid was added to the residue to acidify it, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3.92 g of crude crystals. This was recrystallized from a mixture of n-hexane and benzene (2: 1),
2.9 g of the title compound having the following physical data was obtained.

Melting point: 122 ° C .; TLC (n-hexane: ethyl acetate = 2: 1): Rf
0.29; IR: ν 3370, 3100 to 2300, 1710, 1650, 1620, 160
0, 1535, 1450, 1290, 1255, 1220, 1175, 1035, 860,
800, 745 cm ^-1 . Hereinafter, in place of 4-pentylacetophenone used in Reference Example 1, a corresponding acetophenone derivative was used, and in the same manner as in Reference Examples 1 to 5 and Example 1, the following Tables 2 and 3 were used.
To obtain the compound of the present invention.

[0072]

[Table 3]

[0073]

[Table 4]

[0074]

[Table 5]

[0075]

[Table 6]

Further, instead of the triethylphosphonoacetate used in Reference Example 1, triethylphosphonopropionate was used, and the compounds of the present invention shown in the following Table 3 were prepared in the same manner as in Reference Examples 1 to 5 and Example 1. Obtained.

[0077]

[Table 7]

Formulation Example 1 4- [2- (3,5-dichloro-4-pentyloxy-
Preparation of tablets containing β-methylcinnamoylamino) phenoxy] butanoic acid 4- [2- (3,5-dichloro-4-pentyloxy-
β-methylcinnamoylamino) phenoxy] butanoic acid (5 g), calcium fibrin glycolate (disintegrant; 2
00mg), magnesium stearate (lubricant; 100
mg) and microcrystalline cellulose (4.7 g) were mixed by an ordinary method and compressed to give 100 tablets each containing 50 mg of the active ingredient.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display area A61K 31/19 AEJ C07C 235/38 9547-4H

Claims (5)

[Claims] 1. A compound represented by the general formula (I): [In the formula, (i) R ¹ , R ² and R ³ may be the same or different, and may be a halogen atom, a linear or branched alkoxy group having 1 to 7 carbon atoms, or a C 1 to 7 carbon atom. Represents a group selected from a straight chain or branched chain alkyl group and a nitro group, one of R ⁴ and R ⁵ represents a methyl group and the other represents a hydrogen atom, or (ii) R ¹ , R ²
And any one of R ³ is a 4-butyl group, 4
Represents a group selected from -propyl group, 4-butoxy group and 4-sec-butyl group, the remaining two groups represent a hydrogen atom, R ⁴ represents a methyl group and R ⁵ represents a hydrogen atom. ] The cinnamic acid amide derivative shown by these, or its nontoxic salt. 2. The general formula (I):[In the formula, R¹, R²And R³Are the same or different
May be a halogen atom, a straight chain having 1 to 7 carbon atoms, or
Is a branched chain alkoxy group, a straight or branched chain having 1 to 7 carbon atoms
Represents a group selected from a branched chain alkyl group and a nitro group
And R^FourAnd R ^FiveEither represents a methyl group
And the other represents a hydrogen atom. ] Claim 1 shown by
The cinnamic acid amide derivative described above or a non-toxic salt thereof. 3. General formula (I): [Wherein any ^one of R ¹ , R ² and R ³ represents a group selected from a 4-butyl group, a 4-propyl group, a 4-butoxy group and a 4-sec-butyl group, and the remaining The two groups represent hydrogen atoms, R ⁴ represents a methyl group, and R ⁵ represents a hydrogen atom. ] The cinnamic acid amide derivative of Claim 1 shown by these or its nontoxic salt. (4) (i) The group represented by is 3,5-dichloro-4-pentyloxyphenyl group, 3,5-dimethoxy-4-pentyloxyphenyl group, 3,4,5-tripentyloxyphenyl group, 3,5-dimethyl-4 -Pentyloxyphenyl group, 3,5-di-tert-butyl-4-methoxyphenyl group, 2,3-dichloro-4-pentyloxyphenyl group, 3,5-dichloro-4-butoxyphenyl group, 3,
Represents a group selected from a 4,5-tripropoxyphenyl group, a 3,4,5-tributoxyphenyl group, a 2-nitro-4,5-dipentyloxyphenyl group and a 3,4,5-triethoxyphenyl group, And R ⁴ represents a methyl group and R ⁵ represents a hydrogen atom, or (ii) The group represented by represents a 3,4,5-tripentyloxyphenyl group or a 3,5-dichloro-4-pentyloxyphenyl group, R ⁴ represents a hydrogen atom, and R
The derivative according to claim 1 or 2, wherein ⁵ represents a methyl group. 5. A compound represented by the general formula (I): [In the formula, (i) R ¹ , R ² and R ³ may be the same or different, and may be a halogen atom, a linear or branched alkoxy group having 1 to 7 carbon atoms, or a C 1 to 7 carbon atom. Represents a group selected from a straight chain or branched chain alkyl group and a nitro group, one of R ⁴ and R ⁵ represents a methyl group and the other represents a hydrogen atom, or (ii) R ¹ , R ²
And any one of R ³ is a 4-butyl group, 4
Represents a group selected from a -propyl group, a 4-butoxy group and a 4-sec-butyl group, the remaining two groups represent a hydrogen atom, R ⁴ represents a methyl group and R ⁵ represents a hydrogen atom. ] The 5 (alpha) -reductase inhibitor containing the cinnamic acid amide derivative shown by these or its nontoxic salt as an active ingredient.