JP2000297070A - Phenylalanine ester derivative - Google Patents

Abstract

(57) [Problem] To provide a novel phenylalanine ester derivative or a pharmacologically acceptable salt thereof, which has an antipruritic effect and is useful as a therapeutic agent for various pruritus represented by atopic dermatitis. To do. SOLUTION: General formula (I) (Wherein X represents fluorine, bromine or iodine, R ¹ represents hydrogen or lower alkyl, R ² represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted polycycloalkyl or substituted or unsubstituted spiro. A phenylalanine ester derivative represented by the following formula: or a pharmacologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a phenylalanine ester derivative having an antipruritic effect or a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art Conventionally, L-dopa, which is a fanylalanine derivative, is known as a precursor of dopamine, and has been used in the medical field as a remedy for diseases associated with dopamine deficiency, such as Parkinson's disease.

[0003] L-dopa ester derivatives have been synthesized as prodrugs of L-dopa, and their uses have been studied. European Journal of Medicinal
Chemistry (Eur. J. Med. Chem.), Vol. 20, p. 459-
465 (1985) and the European Journal of Medicinal Chemistry (Eur. J. Med. Che
m.), 20, 467-470 (1985), discloses the synthesis method, physical properties, and reactivity to hydrolysis of L-dopa esters. Pharmaceutical Research, 7, 384-387 (1990) evaluates and discloses the effects of L-dopabutyl ester, 4-hydroxybutyl ester and isopropyl ester as prodrugs. ing. Japanese Journal of Pharmacology (Ja
panese Journal of Pharmacology), 39, 809-819
Page (1987), L-dopacyclohexyl ester, benzyl ester, phenethyl ester and p-
The prodrug properties of a number of ester derivatives such as chlorophenethyl esters have been disclosed. US466334
9, WO86 / 04579, EP167451, US4479947, BE868881, US40
38411, US4035507, US3998799, DE2626095, DE263632
8, US3939253, US3891696, DE2445584 and DE2153813
Discloses a method for producing an ester derivative as a prodrug of L-dopa, and its use as a therapeutic agent for Parkinson's disease and an antihypertensive agent.

[0004] L- in which halogen is substituted on the benzene ring portion
As the dopa esters, the following compound (Ia) is described in Chemical Abstract, Vol. 63, 14980d, but its use is not disclosed.

[0005]

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[0006] Pruritus represented by atopic dermatitis includes:
The mechanism of its onset has not yet been elucidated. On the other hand, the number of patients has been increasing remarkably in recent years, probably due to changes in lifestyle, environmental pollution, stress society and the like. Diseases associated with itching include atopic dermatitis, hives, contact dermatitis, pseudoallergens, drug eruptions, insect bites, athlete's foot, insects, metabolic disorders (liver disease, kidney disease, blood disease) Gestational herpes, hay fever, malignant tumors and senile pruritus are known. In general, histamine, serotonin, acetylcholine, prostaglandin, leukotriene, and the like are known as chemical mediators that induce itch. However, the mechanism of its pathogenesis remains largely unknown, and its cure has not yet been established.

[0007] Antihistamines and steroids, which are highly effective against inflammation and allergic diseases, have limited effects on pruritus. Therefore, development of an antipruritic agent effective for pruritus represented by atopic dermatitis has been awaited.

[0008]

SUMMARY OF THE INVENTION The present invention relates to a novel phenylalanine ester derivative or a pharmacologically acceptable derivative thereof which has an antipruritic effect and is useful as a therapeutic agent for various pruritus typified by atopic dermatitis. To provide a salt.

[0009]

Means for Solving the Problems The present inventors have proposed an L-dopacycloalkyl ester having a benzene ring moiety substituted with a halogen and an L-dopacycloalkyl ester having a benzene ring moiety substituted with a halogen.
As a result of synthesizing dopa polycycloalkylesters and L-dopaspiroalkylesters in which a benzene ring moiety is substituted with halogen, and earnestly studying its pharmacological activity,
They have found that they have an excellent antipruritic effect, and have completed the present invention. The present invention relates to a compound of the formula (I)

[0010]

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(Wherein X represents fluorine, bromine or iodine, R ¹ represents hydrogen or lower alkyl, R ² represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted polycycloalkyl or substituted or unsubstituted A phenylalanine ester derivative represented by the formula: or a pharmacologically acceptable salt thereof.
Among them, a phenylalanine ester derivative in which X is fluorine in the general formula (I) or a pharmacologically acceptable salt thereof is preferable.

The present invention relates to an antipruritic agent comprising a phenylalanine ester derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a medicament comprising at least one phenylalanine ester derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of each group in the general formula (I), lower alkyl is straight-chain or branched having 1 to 6 carbon atoms.
Of, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

Cycloalkyl has 3 to 8 carbon atoms, for example, cyclopropyl, cyclopentyl, cyclohexyl,
It means cycloheptyl, cyclooctyl and the like. The polycycloalkyl is composed of two or more cycloalkyls, and means, for example, bicyclooctyl, bicycloundecyl, adamantyl, noradamantyl and the like having 5 to 12 carbon atoms. Spiroalkyl contains one or more spiro bonds and has 5 to 12 carbon atoms, such as spirooctyl,
Spirodecyl and the like.

The substituent of the substituted cycloalkyl, substituted polycycloalkyl and substituted spiroalkyl is 1 to
Substitutable numbers, preferably 1 to 3, for example, halogen, hydroxy, aryl, aralkyl and the like can be mentioned. In the case of a substituted cycloalkyl, the case where the cycloalkyl forms a condensed ring with a phenyl ring is included, and examples thereof include indanyl having 8 to 12 carbon atoms and tetrahydronaphthyl.

Halogen represents fluorine, chlorine, bromine or iodine; aryl represents phenyl or naphthyl having 6 to 12 carbon atoms; aralkyl represents benzyl having 7 to 14 carbon atoms;
Represents phenethyl, benzhydryl, etc.

The pharmacologically acceptable salts of compound (I) include inorganic salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate and citrate. And the like.

Next, a method for producing the compound (I) will be described. Production method: Compound (I) can be produced by the method shown below. The compound (I) of the present invention can be obtained from the European Journal of Medicinal Chemistry (Eur. J. Med. Chem.), 20, 459-465 (1985).
Year) or a method analogous thereto. However, the production method of compound (I) is not limited to the above method.

[0021]

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(Wherein R ¹ , R ² and X have the same meanings as described above) As the starting compound (II), a commercially available product may be used or a method described in the literature [Journal of Labeled Compounds and Radio Pharmaceuticals (J. Labelled Co.)
mpounds and Radiopharmaceuticals), Volume XXVIII, 155
Pp.-166 (1990)] or a method analogous thereto.

Compound (I) can be produced by subjecting compound (II) to dehydration-condensation with compound (III) represented by R ² -OH, followed by esterification. Many methods are known for esterification of a carboxyl group [refer to Experimental Chemistry Course, 4th Edition, Maruzen, Vol. 22, p. 43 (1990)], and it is also possible to apply it. For example, compound (II)
Using a compound (III) represented by R ² —OH as a solvent, if necessary, in a mixed solvent of the compound (III) and an inert solvent, in an amount of a catalyst to a large excess of an acid, more preferably p-toluenesulfone The desired compound (I) can be obtained by treating in the presence of an acid or hydrochloric acid at a temperature between room temperature and the boiling point of the alcohol used for 5 minutes to 20 days.

Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid;
Organic acids such as toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid, and Lewis acids such as boron trifluoride, aluminum chloride, stannic chloride and titanium tetrachloride. As an inert solvent, tetrahydrofuran (T
HF), ether, dioxane, chloroform, toluene, benzene and the like.

The target compound in the above-mentioned production method is isolated and purified by a separation and purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like. Can be. When a salt of compound (I) is desired, it can be isolated and purified as it is when it can be obtained as a salt in the course of the reaction. When it is obtained as a free base, the free base is dissolved or suspended in an appropriate solvent, and the acid is dissolved. It may be isolated and purified. Alternatively, after completion of esterification, it can be isolated and purified as a salt with the acid used in the reaction.

The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. . Compound (I) may exist as a stereoisomer such as an optical isomer, but a mixture of any possible isomer in a ratio is included in the present invention.

The elements constituting the compound (I) include radioactive isotopes. It is also possible to synthesize compounds in which the content of these radioactive isotopes is higher than the naturally occurring isotope abundance, and compounds having these isotope abundances are also included in the present invention. Specific radioactive isotopes include ¹⁸ F, ¹²⁵ I,
Nuclides such as ¹⁴ C, ¹¹ C, ¹³ C, and ³ H are exemplified.

Specific examples of the compound (I) obtained by the present invention are shown below. 4,5-dihydroxy-2-fluoro-DL-phenylalanine cyclohexyl ester (6-fluoro-DL-dopacyclohexyl ester, compound 1) 4,5-dihydroxy-2-bromo-L-phenylalanine cyclohexyl ester (6-bromo-L -Dopacyclohexyl ester, compound 2) 4,5-dihydroxy-2-iodo-L-phenylalanine cyclohexyl ester (6-iodo-L-dopacyclohexyl ester, compound 3)

[0029]

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[0030]

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[0031]

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Next, the pharmacological action of compound (I) will be described with reference to the following test examples. Test example: Antipruritic effect: Compound 48 / 80-induced scratching behavior (s
Effect on cratching behavior) The experiment used 10 ddy male mice (Japan SLC) weighing 19 to 21 g per group, using the method of Kuraishi et al. [European Journal of Pharmacology (Eur. J. Pharmacol.),
275, pp. 229-233 (1997)].

The test drug (Compound 1 hydrochloride) was 0.5% MC
(Methyl cellulose 400, Wako Pure Chemicals Lot TPQ 1935) and administered intraperitoneally. In addition, the amount of liquid for administration was 20 g for mice.
0.1 mL per unit. One hour after administration, Compound 48/80
(Sigma, Lot. 114F-0523) in physiological saline (Otsuka Pharmaceutical)
Was subcutaneously administered at 0.5 mg / kg. Compound 4
10 minutes after administration of 8/80, s per unit time (10 minutes)
The number of occurrences of cratching behavior was measured.
The inhibition rate of the drug administration group relative to the solvent (0.5% MC) administration comparison group was calculated, and the ED ₅₀ value was determined from the inhibition rate.

Table 1 shows the results.

[0035]

[Table 1]

As shown in Table 1, Compound 1 was found to have an antipruritic effect. Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans. The pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient. In addition, these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.

As the administration route, it is desirable to use the one which is most effective in the treatment. Oral administration or parenteral administration such as buccal, intratracheal, rectal, subcutaneous, intramuscular, and intravenous administration is mentioned. Can be. In addition, administration methods such as application and spraying may be used in order to expect a localized action. Dosage forms include sprays, dry powders, capsules, tablets, powders, granules, syrups,
Emulsions, suppositories, injections, ointments, tapes and the like can be mentioned.

Liquid preparations suitable for oral administration, for example, emulsions and syrups, include water, sucrose, sorbitol,
Sugars such as fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil,
It can be produced using oils such as soybean oil, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Also,
Capsules, tablets, powders and granules include excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, magnesium stearate,
It can be produced using a lubricant such as talc, a binder such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.

Formulations suitable for parenteral administration comprise sterile aqueous solutions containing the active compound, which is preferably isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier composed of a salt solution, a glucose solution or a mixture of saline and a glucose solution. Formulations for enteral administration are prepared, for example, using carriers such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids, and are provided as suppositories. Sprays are also prepared using the active compound itself or a carrier which does not irritate the oral and respiratory tract mucosa of the recipient and which disperses the active compound as fine particles to facilitate absorption. Specific examples of the carrier include lactose, glycerin and the like. Formulations such as aerosols and dry powders are possible, depending on the nature of the active compound and the carrier employed.

These parenteral preparations are also selected from the diluents, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for the oral preparation. One or more auxiliary components can also be added. The dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the mode of administration, the age and weight of the patient, the nature or severity of the condition to be treated, and the like. Oral, per adult
0.01 mg to 1 g, preferably 0.5 to 500 mg is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 10 mg, per adult is administered once or several times a day. However, these dosages vary depending on the various conditions described above.

Hereinafter, embodiments of the present invention will be described with reference to examples. The peak positions of the proton nuclear magnetic resonance spectrum ( ¹ H-NMR) used in the examples are expressed in parts per million (ppm) from tetramethylsilane to the low magnetic field side, and the parentheses after the δ value of each signal are shown in parentheses. The observed shape, coupling constant,
The number of protons is shown in order. The peak shape is represented as follows. s: singlet, d: doublet, t: triplet,
m: multiplet, br: broad.

[0042]

EXAMPLES Example 1 4,5-Dihydroxy-2-fluoro-DL-phenylalanine cyclohexyl ester hydrochloride (Compound 1 hydrochloride) Cyclohexanol (3.0 mL) was added to ether (0.15 mL).
And thionyl chloride (0.20 mL) was added thereto under ice cooling, followed by stirring. Furthermore, 4,5-dihydroxy-2-fluoro-DL-
Phenylalanine (150 mg) was added. After stirring at room temperature for 2 days, the precipitated crystals were collected by filtration and washed with ether. The obtained crystals are dissolved in water, and the resulting resin is a porous resin.
After adsorbing to HP20 (Mitsubishi Kasei, 20 mL), the product was washed with water and the target product was eluted with methanol. The obtained crude product was crystallized from ether to give the desired product (106 mg, 51.5%) as a white solid.

Melting point 180-182 ° C. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.12-1.73 (m, 10H), 2.84-
3.03 (m, 2H), 3.96 (dd, J = 5.9, 8.3Hz, 1H), 4.69 (br
s, 1H), 6.55 (d, J = 10.9Hz, 1H), 7.58 (d, J = 7.6Hz, 1
H), 8.32 (br s, 2H), 8.91 (br s, 1H), 9.40 (br s, 1
H). FAB-MASS (m / z); 298 (M + 1) Elemental analysis C ₁₅ H ₂₀ FNO ₄ As HCl: Found (%) C: 54.33, H: 6.71, N: 4.19 Calculated (%) C: 53.98, H: 6.34, N: 4.20

Example 2 4,5-Dihydroxy-2-bromo-L-phenylalanine cyclohexyl ester hydrochloride (Compound 2 hydrochloride) Thionyl chloride (12.5 mL) was added to cyclohexanol (200 mL) under ice cooling, followed by stirring. did. Further, 4,5-dihydroxy-2-bromo-L-phenylalanine (5 g) was added. After stirring at 50 ° C for 1 day, the reaction solution was cooled with ice water (100 m
L). It was extracted with ether and washed with a 1N aqueous hydrochloric acid solution. After evaporating the solvent, the obtained solid was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 9: 1). The obtained crude product was dissolved in ether, and further extracted with a 2N aqueous hydrochloric acid solution into an aqueous layer. The aqueous layer was washed with ether and then with chloroform.
The aqueous layer was allowed to stand, and the precipitated crystals were collected by filtration to obtain 0.55 g (7.7%) of the desired product as a yellow solid.

Melting point 195-200 ° C. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.22-1.73 (m, 10H), 2.50-
3.06 (m, 2H), 4.00 (t, J = 8.5Hz, 1H), 4.70 (br s, 1H),
6.73 (s, 1H), 6.95 (s, 1H), 8.57 (br s, 2H), 9.22 (s,
. 1H), 9.49 (s, 1H) FAB-MASS (m / z); 358 (M + 1), 360 (M + 1) Elemental Analysis C ₁₅ H Found as _{20 Br NO 4 HCl (%)} C: 45.57, H: 5.88, N: 3.31 Calculated value (%) C: 45.65, H: 5.36, N: 3.55

[0046]

Industrial Applicability According to the present invention, there is provided a novel phenylalanine ester derivative or a pharmacologically acceptable salt thereof which has an antipruritic effect and is useful as a therapeutic agent for various pruritus represented by atopic dermatitis. You.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Fumio Suzuki 1188 Shimotsukari, Nagaizumi-cho, Sunto-gun, Shizuoka Pref. BJ50 BN30 BT14 BU36

Claims (4)

[Claims] 1. A compound of the general formula (I) (Wherein X represents fluorine, bromine or iodine, R ¹ represents hydrogen or lower alkyl, R ² represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted polycycloalkyl or substituted or unsubstituted spiro. A phenylalanine ester derivative or a pharmacologically acceptable salt thereof. 2. The phenylalanine ester derivative according to claim 1, wherein X is fluorine, or a pharmaceutically acceptable salt thereof. 3. An anti-pruritic agent comprising the phenylalanine ester derivative according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient. 4. A medicament comprising at least one phenylalanine ester derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.