EP0091436A1 - New drugs having an activity on the central nervous system - Google Patents

Abstract

Medicament with activity on the central nervous system; it is characterized by the fact that it contains, as active substance, (Beta) - (7-hydroxy-naphiethyl- (1)) - alanine and / or its alkyl ester having 1 to 4 carbon atoms in the alkyl residue .

Description

 New drug with an effect on the central nervous system

L-tryptophan, an essential amino acid, is known to have sleep-promoting properties. It is therefore used in medicines that induce sleep. D, L-β- (naphthy1-1) alanine has a similar activity (cf. Pharmacol. Biochem. Behav. 1979, Vol. 11, 319-323).

The present invention relates to medicaments with an effect on the central nervous system, in particular with sleep-promoting activity, which act as

Active ingredient ß-j £ 7-hydroxy-naphthyl- (l,) J-alanine and / or their alkyl esters, as well as the new alkyl esters of ß -] (7-hydroxy-naphthyl- (ljj-alanine.

It has surprisingly been found that β-f (7-hydroxy-naphthyl- (1) J -alanine and its lower alkyl esters have a pronounced effect on the central nervous system with a broad spectrum of activity. They show above all a strong general hypnotic activity with in particular sleep-promoting effects Effect, but also effectiveness against overactivity, antidepressant, antispasmodic and analgesic effect, especially for headaches. detrimental effect outperforms in various ways, e.g. B. with intraperitoneal administration, the previously known compounds of this class (L-Tryp¬ tophan, D, L-ß-Naphthy1-1) -alanine), which is why they can be used in a variety of ways in drugs with sleep-inducing activity.

In particular, they greatly reduce the sleep latency and extend the duration of the slow sleep phase (slόw wave sleep) to an extremely high degree.

Alkyl esters are esters with 1 to 4 carbon atoms in the alkyl radical, and in particular the ethyl ester. The active substances can also be used in the form of their salts with physiologically tolerable inorganic or organic acids and bases. The lower alkyl esters are preferably used in the form of their salts with physiologically compatible acids, in particular with HCl. In the case of β-7-hydroxy-naphthyl- (l) J-alanine, the salt with glutamic acid in particular has proven to be expedient in order to achieve an improvement in solubility.

In addition to the optically inactive D, L form of β- | 7-hydroxy-naphthyl- (l) J-alanine and its esters, the optically active D- and / or L-forms with which the Part of even better results can be achieved. The antipodes can be separated by the methods known per se for antipode separations.

In rats (Wistar, 150 to 200 g), the compounds used according to the invention showed a pronounced effect on the central nervous system in the sense of a hypnotic effect after intraperitoneal (i.p.) administration.

OMPI The following amounts were applied:

For β-7-hydroxy-naphthyl- (l) J-alanine: 30 mg / kg, suspended in physiological sodium chloride solution, 2 ml each, and 150 mg / kg, suspended in 40% aqueous propylene glycol, 2 ml each, for ß- 7-hydroxy-naphthyl- (l) J-alanine ethyl ester hydrochloride: 120 mg / kg, aqueous solution, 2 ml each.

For comparison, 30 mg / kg D, L-β- (naphthyl-1) -alanine-HCl i.p. administered. The same test showed no change in the previous behavior of the animals.

All common forms are suitable as pharmaceutical preparations, such as, for. B. tablets, capsules,

Dragees, suppositories, syrups, injection solutions, etc. The preparations are prepared according to the usual known methods.

The choice of pharmaceutical forms depends in particular on the intended form of administration, β-7-hydroxy-naphthyl- (l) _J-alanine is sparingly soluble in water and is therefore preferably administered intraperitoneally, subcutaneously or orally, while the lower alkyl esters are due to their water solubility can also be administered intracardially and intravenously.

The pharmaceutical preparations generally contain β-7-hydroxy-naphthyl- (l)]] - alanine and / or its lower alkyl esters as the sole active ingredients in addition to the usual pharmaceutical carriers; However, there may also be other active substances in the medicinal product which do not influence the desired effect and possibly even support it, and which do not lead to an intolerance reaction, such as. B. vitamins, analgesic Substances, etc. In order to support the effectiveness, the presence of a decarboxylase inhibitor has proven to be particularly advantageous.

In general, a dosage unit of the drug contains 10 to 1000 mg, in particular 100 to 500 mg of active ingredient. When used on humans, 1 to 5 dosage units are generally administered, preferably approximately 30 to 60 minutes before bedtime. The dosage depends primarily on the severity of the sleep disorder and the general condition of the patient.

The starting substance for the synthesis of ß-j_7-hydroxy-naphthyl- (l) J-alanine and its lower alkyl esters is 7-benzyloxy-l-hydroxymethyl-naphthalene (V), which is derived from 7-hydroxynaphthoic acid- (1) (I ) Karol Dziewδnski, H. Galitzerowna and A. Kocwa, Bull.Intern, de l'Acad. Polon. des Sciences et Lettres, Classe D. 0 Sc. Math, et Naturelles, Ser.A, 1926, 209-242, Univ. Krakow): a) esterification with diazomethane to give 7-hydroxynaphthoic acid (1) methyl ester (II) (LC Anderson and DG Thomas, J. Amer. Chen. Soc. 65, 234, 1943), then 5 ß benzylation and reduction of the resulting 7-benzyloxynaphthoic acid (I) methyl ester (III) with LiAlH .;

b) LiAlH. reduction of the 7-benzyloxynephthoic acid (I) - _Q benzyl ester (IV), which can be obtained directly from 7-hydroxynaphthoic acid (I). V supplies with SOC1- 7-benzyloxy-1-chloromethyl-naphthalene (VI), the condensation of which with acylaminomalonic acid esters (formylaminomalonic acid dimethyl ester, diethyl ester, acetylaminoma- 5 ionic acid diethyl ester) to give the corresponding 3- j -Beτι- cyl- oxynaphthyl- {1) 3-2-acylamino-2-carbomethoxy- (or 2-carbäthoxy-) propionic acid esters (Vlla-c) leads. (Instead of the acylaminomalonic acid esters, acylaminocyanacetic acid esters can also be used). Alkaline saponification of these condensation products gives the corresponding dicarboxylic acids, which can be used for decarboxylation without further purification. The resulting N-formyl- or N-acetyl-D, L-ß- | 7-benzyloxy-naphthyl- (lj -alanine (IXa or b), also as crude products, become D, L -ß-j7-Benzyloxynaphthyl- (1) J-alanine (X) saponified. Catalytic debenzylation finally gives D, L-ß- (1) J-alanine

(XIa), the esterification of which with fithanol / HCl leads to D, L-ß-j_7-hydroxy-naphthyl- (l) J-alanine-ethyl ester (Xlb).

Examples

7-hydroxynaphthoic acid (1) methyl ester (II):

A solution of 20 g of 7-hydroxy-naphthoic acid (1) in 300 ml of acetone is added dropwise with stirring and ice-cooling ethereal diazomethane solution until a constant yellow color. The excess diazomethane is destroyed by careful addition of acetic acid, and after the solvent has been spun off, the residue (18.2 g = 84% of theory) is recrystallized from ethyl acetate / petroleum ether: slightly yellowish colored needles of mp 125 ° C.

^C 12 ^H 10 ° 3 < ^{202 '21} >

Ber. C 71.28 H 4.99

Found 71.58 5.02

C..FI ' 7-benzyloxynaphthoic acid (l) methyl ester (III):

43.4 g of II are heated with 28.5 g of benzyl chloride and 29.6 g of anhydrous K_CO- in 500 ml of dimethylformamide with stirring on the water bath for 2 hours. It is then poured onto ice water and III extracted from this mixture with toluene. After washing, first with dilute sodium hydroxide solution and then with water, the combined toluene phases are brought to dryness and the residue (59.4 g = 94% of theory) is recrystallized from toluene / petroleum ether: III forms coarse Crystals of mp 48 ° C.

^C 19 ^H 16 ° 3 ^: (292. .34)

Ber. C: 78.07 H5.52

Found 78, 38 5, 40

1- -Benzyloxynaphthoeisäure- -benzylester (IV).

35.7 g of 7-hydroxy-naphthoic acid (l) with 56 g

Benzyl chloride and 55 g of anhydrous K ₂ ^CO ₃ in 500 ml of dimethylformamide were heated on the water bath with stirring for 2 hours. The processing takes place as in III. The residue (58.7 g = 80% of theory) is recrystallized from ethanol: IV forms colorless needles with a melting point of 89 ° C.

C ₂₅ H ₂₀ O ₃ : (368.44)

Ber. C: 81.50 H: 5.47 Found. 81.76 5.57 7-benzyloxy-l-hydroxymethyl-naphthalene (V):

a) from III: To 3.5 g of LiAlH. in 250 ml of anhydrous tetrahydrofuran, a solution of 15.3 g of III in 70 ml of anhydrous tetrahydrofuran is slowly allowed to flow at room temperature with stirring. Then stir for another hour. After hydrolysis with water, the mixture is filtered and the filtrate is brought to dryness. V crystallizes from toluene / petroleum ether in colorless needles, mp. 126 ° C

^C 18 ^H 16 ° 2 ^: < ^{264 '33} ~>

Ber. C: 81.79 H: 6.10

Found 82.17 6.05

b) from IV: 11 g of LiAlH. a solution of 53.3 g of IV in 200 ml of anhydrous tetrahydrofuran is slowly allowed to flow into 700 ml of anhydrous tetrahydrofuran at room temperature with stirring. The workup, as above, leads to 32 g (= 83% of theory) of V, which also melts at 126 ° C. and shows no mp depression with the product obtained from III.

7-benzyloxy-l-chloromethyl-naphthalene (VI):

In a run-off flask provided with a reflux condenser and a CaCl ₂ tube, 30 g of V in 150 ml of toluene are mixed with 20 ml

Gently warmed thionyl chloride. The reaction proceeds with evolution of gas, after which it is heated to 60 ° C. for 90 minutes. Then the solvent and excess thionyl chloride are rotated off and the residue (26.5 g = 82% of theory) Toluene / petroleum ether recrystallized: Colorless drusen, mp 89 ° C

C ₁₈ H ₁₅ OCls (282.78)

Ber. C: 76.45 H: 5.35 Cl: 12.54 Found 76.86 5.21 12.01

2-Acetylamino-2-carbäthoxy-3-r7-benzyloxynaphthyl- (1) J -propionic acid ethyl ester (VII a):

In 40 ml abs. Ethanol, 0.6 g of sodium and 5.7 g of acetylaminomalonic acid diethyl ester are dissolved in succession, 7.4 g of VI are added, and the mixture is heated to boiling under reflux for 5 hours. The mixture is then filtered off from the precipitated NaCl and the filtrate is concentrated. The residue is taken up in ethyl acetate, the ethyl acetate solution is washed with water and evaporated after drying. 9.5 g of VII a (= 78% of theory) remain, which crystallize from ethyl acetate / petroleum ether in colorless needles of mp 98 ° C.:

^C 27 ^H 28 ^N ° 6 ^{: (} 463.52 ⁾

Ber. C: 69.96 H: 6.31 N: 3.02 Found. 69.69 6.29 3.00

Analogously, the condensation of VI with formylaminomalonic acid diethyl ester or formylarainomalonic acid dimethyl ester leads to 2-formylamino-2-carbäthoxy-3- (7-benzyloxynaphthyl- (lj-propionic acid ethyl ester (VII b): Colorless needles of mp 111 ° C:

^C 26 ^H 27 ^N0 6 ^: - ⁽ 449.51 ⁾ calc. N: 3.12

Found 2.96 respectively.

2-Formylamino-2-carbomethoxy-3- ^ 7-benzyloxynaphthyl- (l.J-propionic acid methyl ester (VII c): Colorless needles, mp 152 ° C:

C ₂₄ H ₂₃ N0 ₆ : (421.45)

Ber. C: 68.40 H: 5.50 N: 3.32 Found ^• 68.42 5.57 3.52

VII c crystallizes from BEnzol / petroleum ether with 1/2 mol of benzene:

^C 24 ^H 23 ^N0 6 ^{'1/2 C} 6 ^H 6 ^: (460.52) calc. C: 70.42 H: 5.69 N: 3.04

Found 70.61 5.77 3.30

D, L-ß - [/ 7-benzyloxynaphthyl- (l) J-alanine (X):

A solution of 18 g VII a and 15 g KOH in 100 ml 50% aqueous methanol is heated to boiling under reflux for 20 hours. When the reaction mixture is cooled, the dipotassium salt of 2-acetylamino-2-carboxy-3- 7-benzyloxy-naphthyl- (1)] -propionic acid (VIII a) precipitates. It is brought back into solution by adding water and the free dicarboxylic acid VIII a is precipitated by acidification with acetic acid. For decarboxylation, VIII a is heated to boiling in 250 ml of 50% acetic acid until the CO ~ evolution has ended. When the reaction solution is cooled, a precipitate of D, L-N-acetyl-β- {j7-benzyloxynaphthyl- (l) 3-alanine (IX a) separates out. It is suctioned off and refluxed in 800 ml of 20% aqueous KOH for 72 hours. When the reaction solution is neutralized, X precipitates, which is caused by falling over

"BUREA _ OMFI is cleaned from ethanolic hydrochloric acid solution with water and sodium acetate. X forms colorless crystals

mp 223 ° C (dec.), 8.5 g (= 68% of theory)

C ₂₀ H ₁₉ O ₃ : (321.38)

Ber. C: 74.74 H: 5.96 N: 4.36 Found. 74.31 6.07 4.42

After careful addition of ether, X-HC1 crystallizes from a solution of X in ethanolic HCl in the form of colorless needles at mp 230 ° C.

^C 20 ^H 19 ^NO 3 ^"HC1 (357.85 ⁾

Ber. C: 67.13 H: 5.63 N: 3.82 Found. 66.91 5.64 3.82

D, L-ß- £ 7-hydroxynaphtyl- (l) 3-alanine (XI a):

1.5 g of X-HC1 are hydrogenated in 30 ml of ethanol in the presence of Pd (prehydrated from 200 mg of PdO) at room temperature and atmospheric pressure. After the hydrogen uptake has ended, the catalyst is filtered off and the filtrate is largely concentrated. By adding water, XI a precipitates out as a colorless precipitate. It is reprecipitated from hydrochloric acid solution with sodium acetate and forms small crystals of mp 300 to 305 ° C .; Yield 775 mg = 80% of theory Th.

^C 13 ^H 13 ^N0 3 ^: (231.25)

Ber. C: 67.52 H: 5.66 N: 6.06 Found 67.54 5.70 6.05 D, L-ß-C7-Hydroxynaphtyl- (1) -Jalanin-ethyl ester hydrochloride (XI b-HCl)

In a suspension of 1.3 g XI a in 20 ml abs. Ethanol, dry HCl-Gaε is introduced, a clear solution being formed when heated. It is then cooled with ice and saturated with HCl gas. The reaction solution is then left at room temperature for a few hours before solvent and excess HCl are removed in a rotary evaporator. The residue forms colorless crystals of XI b-HCl, mp. 193 ° C from ethanol / ether; Yield 1.3 g (= 86% of theory). Another crystal form melts at 145 ° C.

C ₁₅ H ₁₇ N0 ₃ HCl: (295.779) calc. C: 60.91 H: 6.13 N: 4.74 Found. 60.89 6.22 4.73

O PI

Claims

Patent claims

1. Drugs with an effect on the central nervous system, d a d u r c g e k e n n z e i c h n e t that it as

Contains active substance ß- £ 7-hydroxy-naphthyl- (1) 3-alanine and / or their alkyl esters with 1 to 4 carbon atoms in the alkyl radical.

2. Medicament according to claim 1, d a d u r c h g e k e n n z e i c h n e t that it contains ß- 7-hydroxy-naphthy1- (1) _- alanine as the active substance.

3. Medicament according to claim 1, d a d u r c h g e k e n n z e i c h n e t that it contains ß- 7-hydroxy-naphthyl- (l) j -alanine ethyl ester hydrochloride as the active substance.

4. Alkyl ester of β-7-hydroxy-naphthy1- (1) L -alanine with 1 to 4 carbon atoms in the alkyl radical.