DD262367A1 - METHOD FOR PRODUCING A MEDICAMENT WITH NOOTROPIC EFFECT - Google Patents

Abstract

The invention relates to the preparation of a drug with a nootropic effect, which contains 6-methyluracil as active compound. This medicine, which can be used in human medicine, especially for the treatment of impaired mental performance, is effective and uncomplicated to use. So far, no toxic side effects or signs of drug dependency formation are known.

Description

Field of application of the invention

The invention relates to a drug with a nootropic effect, which can be used in human medicine, especially for the treatment of impaired mental performance

 The invention is used by the pharmaceutical industry.

Characteristic of the known technical solutions

6-Methyluracil (I) is a non-physiologically occurring pyrimidine derivative; its preparation is known per se (for example, according to GDR patent WP 69130).

CHENG et al. (Progress in Medicinal Chemistry 7, 1970, pp. 285-341) described numerous biological effects on the central nervous system.

H-

H ₃ CCG = O

HG IIH

•G

6-Methyluracil has already been extensively experimentally pharmacologically and clinically studied; The substance is attributed numerous biological modulating effects.

Thus, 6-methyluracil is said to enhance the immune status of the body, that is, both antibody production (MALINOVSKAYA, 1980, Vyestsi Akad., Navuk, BSSR Syer, Syelskohospod Navuk0 [116]: BURMISTROVA, A.L., 1974, and Zap. Jarosh. Gos. Pedagogue Inst, 131: 161) as well as interferon formation (TOROSOV, TM, et al., 1972, Vopr., Virolol., 17: 460: 460). But also in combination with antibiotics on the one hand, the body resistance (DAVIDOVA, VA, 1974, Antibiotiki 18 [12]: 1094), on the other hand, the effectiveness of the antibiotic (ORDSHONIKIDSE, 1979 ,, Antibiotiki 24 [9]: 659) increased. Gastrointestinal ulcers of various origins can be cured by treatment with 6-methyluracil (MYAGKOVA, LP, et al., 1980, Patol, Fiziol, Eksp., Ter. 0 [6]: 41 [Aspirin Caused]; LESCHCHINSKI, LA, et al. 1972, KMa., Med. 50 [3]: 68 (peptic ulcer); SVISTUNOVA, IA, 1970, Sov. Med. 33 [12]: 58; KOCHKAREV, VM, 1970, Azerb. Med. Zh. 7: 6; AKIMOV ₁ AA, 1968, Farmakol. I Toksikol. 31: 1).

There are references that the substance has mild antiarrhythmic properties. This effect was described on the model of strophanthin and aconitin arrhythmia (KARAPETYAN, AE, and RA GEVORKYAN, 1972, Farmakol, i Toksikol, 35 [3]: 297), model of the BaCI ₂ -induced arrhythmia of the rabbit (LVOV, 1973, Zh. Eksp. Klin. Med. 0 [6]: 24) and in humans, in whom the arrhythmias were caused by digitalis treatment (BEDALOVA, SM, 1978, Kardiologiya 18 [4]: 134).

Protective effects have been demonstrated in experimental myocardial infarction in dogs (Vinogradov, V.M., et al., 1970, Ref. Zh Otd Vyp., Farmakol Khimioter, Sredstra Toksikol, No.8.54.225).

Wound healing of various causes (surgery, corneal injuries, burns, X-rays) is also promoted by the use of 6-methyluracil (RUSKAKOV, V.J., 1972, Khirurgiya48 [2u: 107, EGOROV, E.A., 1971, Vestn.

Oftalmol. 4:76; BILICH, G.L., et al., 1971, Khirurgiya 47 (4): 32; RAAKE ,, W., and K. TEMPEL, 1978, Radiotherapy 153 [12]:

In addition, the literature still describes some therapeutic effects in other somatic diseases.

In human medicine, the use of 6-methyluracil is known as a radiation protection agent (Arzneimittelforschung 27 [1977] 1:

Effects of 6-methyluracil on the CNS or nootropic effects are unknown (Biolog. Abstr., 1965-1983;

SCHMIDT, 1984, "On the pharmacology of nootropics", contributions to drug discovery, Volume 17, Berlin) The structurally comparable compounds uracil (IV), thymine (-5-methyluracil) (III) and orotic acid (II) are as

HOOC-G C = -0 HG C = ^ O HG C = O

HG HH 'H ₃ G-C NH HC IH

I! 0

II III IY

naturally occurring pyrimidine derivatives are known.

According to CCCHENG and B.ROTH (Progress in Medicinal Chemistry 7, 1970, pages 285-341), these compounds are physiologically active pyrimidine derivatives; in the medical and in the patent literature corresponding publications are available, in particular for orotic acid. Thus, orotic acid or its anorgansichen and / or organic salts are part of preparations for increasing the learning and memory.

In the given review of CHENG u.a. 26 derivatives of orotic acid are described.

Orotic acid acts z. B. in rats in training in the Y-chamber not acqusitionsfördernd, but significantly retards the extinction when the animals 12-14 days with 100 mg / kg i.p. pretreated. The influence of acute doses is low, probably due to low oral absorption. Extensive work has already been done on the effect of orotic acid and its compounds on the learning behavior of animals of MATTHIES, OTT and co-workers (H.MATTHIES et al., Acta biol.

1967 / 19.1053; H. MATTHIES et al., Supra. 1967/19, 785; T. OTT et al., Supra. 1971 / 26.79).

Thus, US Pat. No. 3,708,585 has also described a pharmaceutical composition for improving learning, which i.a. contains the native pyrimidine uracil and thymine.

Object of the invention

The aim of the invention is the development of a nootropic agent, which is uncomplicated to use and as free of side effects as possible.

Explanation of the essence of the invention

The object is achieved by the use of 6-methyluracil as a nootropic agent with pronounced effectiveness, which is virtually non-toxic and at the same time by a series of "positive side effects", as they have been indicated in the prior art and not possess the other nootropics ,

Surprisingly, it was found that 6-methyluracil has nootropic effects as a xenobiotic. This is particularly surprising because, for the structurally adjacent body compounds, orotic acid and uracil, since the early seventies, learning-improving effects have been known. The nootropic effect of 6-methyluracil is surprising because, according to the current ideas on memory formation, the effectiveness of this substance was unlikely (OTT, T., and H. MATTHIES, "Psychologie des 20. Jahrhunderts", Vol.4, Zürich The pharmacological investigations for the proof of the nootropic efficacy of 6-methyluracil are listed below.

1) The spinal cord fixation time test on the rat is suitable for detecting nootropic effects of substances. In this method, the drug-mediated time interval between the setting of the lesion in the cerebellum and the transection of the spinal cord is crucial, which has a one-sided inflection of the hind limb as a criterion (GIURGEA, C.E., et al., 1971, Arch. Int Pharmacodyn., 191, 279). 6-Methyluracil has convincing effects in this test and is comparable to the reference substance piracetam. The results of the findings for 6-methyluracil and piracetam on this model are shown in Table 1.

Table 1:

Effects in the SFT test of 6-methyluracil and piracetam.

The effect is reported as the number of positive response animals (time reduction) compared to treated animals.

substance kind dose Time d. Sub effect punching staff ν. narcotization .p. (Min) 6-methyluracil .p. 3 0 0/6 .p. 10 0 0/5   Ρ- 30 0 6/10 ^{| a |}   Ρ- 100 0 4.11 .p. 300 0 2.5 Piracetam p.o. 100 0 6.10 6-methyluracil p.o. 100 0 3.10 p.o. 100 30 5/10 ^(a) p.o. 30 50 4/10 ^(al p.o. 100 50 _7/10 (ai p.o. 150 50 8/10 ^lal Piracetam 150 50 8/10 ^la)

(a) = ρ <0.05 2) In the learning model of the active avoidance test of the light-dark discrimination reaction (OTT, T., 1977, "Mechanisms of memory formation - Behavioral Physiological and Pharmacological Study" Jena) with rats, the following results were obtained for the substance obtained as shown in Table 2.

Table 2:

Results on the model of the light-dark discrimination reaction in the rat

Substance dose Appl. training error Relearningfehl. retention Index η (± SEM) (± SEM) (%, ± SEM) NaCl i.p. 7.25 ± 0.6 3.83 ± 0.5 - 41.33 ± 10 12 6-Methyl uracil 100 mg / kg i.p. 7.27 ± 0.5 2.45 ± 0.4 66.64 ± 3.9 ^(al 11 NaCl i.p. 7.07 ± 0.37 4.5 ± 0.7 41.12 ± 6.4 14 6-Methyi- uracil 30 mg / kg i.p. 6.5 ± 0.4 2.7 ± 0.34 ^{| al} 68.5 + 4.1 ^(b) 14 NaCl i.e. v. 7.22 ± 0.4 5.56 ± 0.6 26.92 + 5.9 18 6-Methyl uracil 100μg / kg i.e. v. 7.42 + 0.7 3.17 ± 0.4 ^(a) 57.20 ± 5.1 12

(b) = ρ <0.01

The substance 6-Methyluracil does not lead to any significant influence on the frequency of errors during training. The relearning errors and retention indices indicate that the substance is particularly in doses of 30mg / kg i.p. and 100pg / kg i.c.v. has a promoting effect on the training of retention performance.

3) The effect of 6-methyluracil on ECS-induced retrograde amnesia on the active-metal-reaction model - bar-leap - is detectable and dose-dependent.

10 mg / kg i. p. of 6-methyluracil does not dissolve yet, 30 mg / kg i. p. triggers a blurry effect. In contrast, a dose increase to 100 mg / kg leads to significant differences between the percentages of the conditional reactions of both groups (preparation + ECS and NaCI solution + ECS) from days 2 to 4. This clear effect can be achieved by increasing the dose to 300 mg / kg i. p. no longer reinforce.

Corresponding results were obtained after oral administration, see Table 3.

Piracetam as reference substance has in this model after i. p.-Application same, after oral administration weaker effects.

Table 3:

The effect of 6-methyluracil on ECS-induced retrograde amnesia on the model of an active conditional escape reaction (dip-stick)

Shown is the number of conditional reactions (%)

χ + sj; η = number of animals; (a) = ρ <0.05; (b) ρ = <0.01

substance Dose (mg / kg) Appl. Art 1 day 2 day 3rd day 4th day π NaCl 6-methyluracil 10 i.p. i.p. 26 ± 1.6 26 ± 2.2 50 ± 2.6 55 ± 2 "7 61 ± 2.3 68 ± 2.0 70 ± 2.6 74 + 1.6 10 10

- f - e- \ ji.

Continuation of Table 3

substance Dose (mg / kg) Appl. Art 1 day 2 day 3rd day 4th day η NaCl 6-methyluracil 30 i.p._ i.p. 28 ± 1.3 28 ± 1.3 52 ± 3.1 55 ± 5.6 59 ± 2.3 68 ± 5.1 ^(al 65 ± 1.7 75 ± 5.8 10 1.0 NaCl 6-methyluracil 100 i.p. i.p. 28 ± 1.3 29 ± 1.0 46 ± 3.7 77 ± 3.7 ^(bl 58 ± 2.9 76 ± 3.1 (b) 62 + 2.5 79 ± 2.8 ^lbl 10 10 NaCl 10 6-methyluracil 300 i.p. i.p. 28 ± 1.3 29 ± 1.0 28 ± 1.3 72 ± 3.3 ^lbl 52 ± 3.1 81 ± 4.1 ^lbl 58 ± 2.0 80 ± 2.6 ^{| bl} 58 ± 4,2 10 Type 6-methyluracil 30 p.o. p.o. 32 ± 2.5 31 ± 1.8 52 ± 2.5 52 ± 2.5 62 ± 2.5 64 ± 3.1 67 ± 3.0 71 ± 5.5 10 10 Tylose 6-methyluracil 100 p.o. p.o. 25 ± 2.2 25 ± 1.7 53 ± 3.7 64 ± 2.2 ^(al 62 ± 2.9 73 ± 2.1 ^lbl 72 ± 2.0 85 ± 2.2 ^(b) 10 10 Tylose 6-methyluracil 300 p.o. p.o. 31 ± 2.3 31 ± 2.3 48 ± 2.9 72 ± 3.9 ^{| bl} 62 ± 2.9 81 ± 2.3 ^(bl 67 ± 2.6 86 ± 3.1 ^<b) - 10 10

4) 6-Methyluracil significantly increases the survival rate of mice when exposed to hypoxic normobaric hypoxia. Piracetam was slightly superior here. The results are shown in Table 4.

Table 4:

Survival after substance administration on the Hypoxic Normobar hypoxia model. Shown is the ratio of the surviving animals to the total number of animals used.

dose Appl. Results preparation substance control 6-Methyl 600 i.p. 20/40 ^(b) uracil 5/40 6-Methyl 600 p.o. • 17/60 ^(a) uracil 7/60 Pirace 300 i.p. 18/60 ^(al tam 6/60 Pirace 300 i.p. 15/50 ^{| a |} tam 6/50

(a) = ρ = 0.54

(b) = ρ = 0.01

5) Transcallosal induced potentials can be facilitated by nootropics, and also on this model, an effect of 6-methyluracil was detected.

The electrical stimulation of the left frontal cortex of the rat leads at the corresponding point of the contralateral side to a stimulus-dependent evoked potential with pronounced surface-positive and subsequent surfaces of negative potential components (GIURGEA, C. and H. SALAMA, 1977, Progr. Neuro. Psychopharmac. 1: 235). 6-methyluracil at a dose of 30 mg / kg i. p. shows a significant effect: Amplitude increase up to 144% compared to the pre-value.

Significant effects were obtained at both half-maximal and maximum stimulus intensity, whereas for the reference substance piracetam only at 500 mg / kg i.p. and half maximum stimulus intensity.

6) The swimming behavior of the mouse in the "behavioral despair test" according to PORSOLT (swimming test) (PORSOLT, RD, et al., 1979, Eur. J. Pharmacol 57: 201) is activated, inter alia, by nootropics, which is remarkable. since the nootropics in other models show no influence on the spontaneous locomotor activity, 6-methyluracil has significant effects on ip administration in small doses, unlike piracetam, and after oral administration the effect of 6-methyluracil corresponds to that of piracetam, see table 5th

Table 5:

The influence of 6-methyluracil and piracetam in the swimming test

substance dose Appl.- Total duration of stay (s) kind 6-Methyl uracil 3 i.p. 210.6 ± 5.1 ^lal 10 i.p. 218.8 ± 3.4 ^(a) 30 i.p. 196.4 ± 5.2 ^(a)

Continuation of Table 5

Pirace-

tam .100 i'.p. 222.4 ± 2.7

300 ip 208.8 ± 4.2 ^(al

500 ip 197.2 ± 2.3 ^lal

Control i.p. 229.3 + 2.1

6-Methyl

uracil 300 p.o. 224.5 ± 1.7

500 po 201.3 ± 4.4 ^(al

1000 po 198.0 ± 4.4 ^(a) Piraceous

tam 100 p.o. 219.2 ± 2.9

300 300 p.o. <a> 212.2 ± 3.9

500 po 203.6 ± 3.3 ^(al

Control p.o. 228.5 ± 2.0

(a) = ρ = 0.05

The daily dose per patient is 1-4g 6-methyluracil.

The invention will be explained below with reference to exemplary embodiments.

embodiments

Example 1 Capsules

6-Methyluracil is suspended in polyethylene glycol and made into a gelatine mixture of the composition:

Gelatin 1 part by weight

Glycerol 5 parts by weight

Water 2 parts by weight

incorporated.

Example 2 capsules

A mixture is made with the following ingredients:

Lactose 5 parts by weight

Potato starch 5 parts by weight

Magnesium stearate 1 part by weight

To this mixture is added the required amount of 6 ^: methyluracil.

Example 3 Infusion Solution

A solution is prepared with the following components:

N-methylacetamide 2.1 g

6-methyluracil 5.0 g

fill up on double-distilled water. 1000 g

5 g of 6-methyluracil is triturated with 2.1 g of N-methylacetamide and redistilled with water. filled up to 1000g. The above examples are intended to explain the invention without restricting it.

Other preparations are possible as dragees, tablets, lozenges, pastilles, granules, powders, aqueous suspensions or solutions, syrups and the like.

Claims (3)

1. A process for the preparation of a drug with nootropic effect, characterized in that 6-methyluracil (I) and / or one of its physiologically acceptable addition compounds with physiologically acceptable binders which dissociate in the organism, to tablets, granules, dragees, capsules, suppositories and / or infusion / injection solutions. - 2. The method according to claim 1, characterized in that the preparation for oral administration is surrounded with a thin coating layer. 3. The method according to claim 1 and 2, characterized in that 6-methyluracil is combined with other nootropic compounds.