DE2329815A1 - PROCESS FOR THE PREPARATION OF 2HYDROXYMETHYL-3-PHENYL-4 (3H) -QUINAZOLINONE - Google Patents

Description

RATENTANWKLTE

DR. E. WIEGAND DIPL-ING. W, MFMANN DR. M. KOHlER DIPL-ING. C. GERNHARDT

MÖNCHEN HAMBURG

PHONE ₁ SS 547 * TELEGIAM: CARPATENT

8000 MONKS 2. MATHIIDENSTRASSE 12

W. 41664/73 - * o / Se

June 12, 1973

Michiro Inoue, Tokyo (Japan)

Masayuki Ishikawa, Tokyo (Japan)

Takeshi Tsuchiya, Tokyo (Japan) and

Takio Shimamoto, Tokyo (Japan)

Process for the preparation of 2-hydroxymethyl-3 - <- phenyl-4 ( 3H) -quinazolinone

The invention relates to a new process for the preparation of the known 2-hydroxymethyl-3-phenyl-4 (3H) -chinezolinoiis, a process for the preparation of acid salts of the same, pharmaceutical compositions containing this Contain quinazolinone or pharmaceutically acceptable acid salts thereof and a method of treatment of hemorrhage, thrombosis, or atherosclerosis.

The 2-hydroxyethyl-3-phenyl-4 (3H) -quinazolinone of the following formula:

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is a known compound with a melting point of 180 ° C (J. Indian Chem. Soc. 1Q68 _T 45 (4), 311-516). According to this reference, the compound is obtained by bromination of 2-methyl-3-phenyl-4 (3H) -quinazolinone with N-bromosuccinimide, treatment of the bromination product with potassium acetate and hydrolysis of the corresponding 2-acetoxymethyl derivative with sodium methoxide manufactured. There is no indication of any pharmaceutical effects of the compound, nor of possible uses in the publication.

According to the literature "Progress in Drug Research", Volume 14, pages 225 to 245 (1970), Birkhauser Verlag, have 2-methyl-3-pkenyl-4 (3H) ~ quinazolinone and its derivatives with a substituent in the 3-phenyl group biological effects that act on the central nervous system and are useful as hypnotics, anticonvulsants , analgesics, antipyretics and anti-inflammatory agents. With regard to 2-hydro3qymethyl-3-pheny.1-4 (3H) - quinazolinone, there is no literature which indicates any significant pharmaceutical activity, for example activity on the central nervous system or activity on the cardiovascular system.

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In the context of the invention it was found that the compound of formula (I) is a substance with pharmaceuticals Effects is, in particular for treatment including for. Prevention and cure of hemorrhage, Thrombosis and atherosclerosis and that they continue to have low toxicity (e.g. I ^ cq more than 5000 mg / kg in the mouse).

Further studies led to the invention that the compound of formula (I). very easy in high yield can be produced by one of the following processes:

a) a compound of the general formula

0OH ^ΐτ

wherein IL denotes a halogen atom or an acetoxy, benzoyloxy or benzyloxy, is reacted with aniline in the opposite waiting a condensing agent and then the product obtained is of the general formula:

III

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wherein B, the meaning indicated for formula II has hydrolyzed in a conventional manner or hydrogenated or

b) a compound of the general formula:

, NHCOCHpR ₂

IV

wherein E2 denotes a halogen atom or a hydroxy, acetoxy, benzoyloxy or bensyloxy group, treatment is carried out with a condensing agent and then, if Ep is not a hydroxyl group, the product of the formula obtained is obtained

where Ep has the same meaning as in formula IV, hydrolyzed or hydrogenated in a known manner or c) the 2-carboxaldehyde-3-phenyl-4 (3H) -quinazolinone is reduced with an alkali borohydride, aluminum isopropoxide or formaldehyde.

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According to the invention, the connection can thus: fertilize the formula (I) in high yields from cheap Materials through simple and safe implementation operations be prepared so that the reaction stages can be simplified very much compared to the prior art.

A main object of the invention thus consists in new pharmaceutical compositions which are particularly valuable for the treatment of atherosclerosis, thrombosis and hemorrhage are.

Another object of the invention is a process for the preparation of compounds of the formula (I) advantageously having the pharmaceutical effects listed above.

A third object of the invention is a method of treating hemorrhage, thrombosis and Atherosclerosis taking advantage of the pharmaceutical Effects that have now been noticed. ι

Numerous other objects of the invention, along with its advantages, will appear from the following description .

The starting compound (II) of the »process (a) can easily be prepared by reacting anthranilic acid with a derivative of acetic acid of the formula: R ^ CH ₂ OOCl, where R ^ has the same meaning as in the form] (II), and in a manner known per se. Examples of compounds of the formula (II) include N-acetoxyacetylanthranilic acid, N-chloroacetylanthranilic acid, N-benzoyloxyacetylanthranilic acid and N-benzyloxyacetylanthranilic acid. In the embodiment of process (a), the compound of formula (II) is in a solvent with aniline in the presence of a condensate

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Eating means condensed. A preferred combination of condensing agent and solvent in this process consists of phosphorus trichloride or phosphoryl chloride and an aromatic hydrocarbon such as toluene or xylene. Other combinations such as benzenesulfonyl chloride and pyridine, dicyclohexylcarbodiimide and tetrahydrofuran can also be used. Furthermore, an excess of phosphoric acid or polyphosphoric acid can also be used without a solvent. In this process, the aniline is used in an equimolar amount or in a slight excess per mole of the compound (III) and the phosphorus trichloride is used in an amount of 1/3 to 1 mole per mole of the compound (III). The reaction is carried out at temperatures between 30 ° and 180 ° C., preferably 100 ° to 150 ° C. *, and in most cases is complete in 1 to 5 hours. The condensation product (III) is then hydrolyzed to the product (I) in a manner known per se with an acid or an alkyl. If R ^ is a benzyloxy group in the product (III), this can also be reduced to the product (I) in a manner known per se by hydrogenation.

The exit link (IV) for the ancestor (b) can easily by reacting o-aminobensf.amid with a derivative of acetic acid of the formula: RpCHpC001 or BpCHpCOOCpfl, -, where Ro has the same meanings as for of the formula IV, can be prepared in a manner known per se * As examples of compounds of the formula (IV) be N-ryaroxyacetylaminobenzamide, o-chloroacetylaminobenzamide, o-benzoyloxyacetylaminobenzaraid and o-renzyloxyaeetyleiainobenzamide listed. In the embodiment of process (b), the compound of the formula

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(IV) dehydrated with a dehydrating agent. The preferred dehydrating agents are, for example, acetic anhydride, acetyl chloride, benzenesulfonyl chloride, phosphorus trichloride, phosphoryl chloride, dicyclohexylcarbodiimide, phosphoric acid and polyphosphoric acid. The dehydrating agent is used in an amount between 1/3 mol and a large excess per mol of the compound (IV). The reaction can also be carried out without a solvent, but is preferably carried out in a solvent such as benzene, toluene, acetic acid, tetrahydrofuran or pyridine. The reaction takes place at a temperature between 30 and 180 ° C., preferably 100 to 150 ° G _1, and in most cases is complete in 1 to 5 hours. If R2 does not represent a hydroxyl group, the condensation product (V) is then hydrolyzed to the product (I) in a manner known per se with an acid or an alkali. If Ep is a benzyloxy group in the compound (V), it can also be reduced to the product (I) by hydrogenation in a manner known per se.

The 2-carboxaldehyde-5-phenyl-4 (3H) -quinazolinone used as starting compound in process (c) can by oxidation of 2-methyl-3-phenyl-4 (3H) -quinazolinone with selenium dioxide (J. Indian Chem. Soc, see above). In the embodiment of the method (c) becomes the 2-carboxaldehyde-3-phenyl-4 (3H) -quin8zolinone to the compound (I) according to the customary alkali borohydride reduction, Meerwein-Pondorf reduction or crossed Cannizzaro reaction reduced. The reduction with the alkali borohydride, the Meerwein-Pondorfr reduction can be carried out with sodium borohydride in methanol can with a Meerwein-Pondorf reduction system

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such as aluminum isopropoxide and isopropanol will. The crossed Csnnizzaro reaction can be done with formaldehyde be carried out in the presence of an alkali hydroxide or alkali carbonate.

In any of the above processes, the product can be easily isolated and purified.

According to the invention, pharmaceutical compositions are obtained which contain an effective amount of a compound of the formula

or a pharmaceutically acceptable acid addition salt of these, as well as optionally containing a diluent.

These masses have excellent pharmaceutical effects especially for the treatment of etherosclerosis, Thrombosis and hemorrhage. The masses have therapeutic effects on cerebral thrombosis, Myocardial infarction and venous thrombosis, atherosclerotic Disorders such as cerebral atherosclerosis, coronary atherosclerosis and peripheral atherosclerosis and various vascular diseases such as thromboangiitis obliterans and diabetic angiopathy.

The effective amount of the compound of formula (I) may vary according to the particular dosage envisaged are varied, but is usually about 0.1 to 80% by weight, based on the combined amount of

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■ - ■■ 9 - ■ - '■■■ - ■

diluent and compound of formula (I). It can thus any desired concentration can be administered suitable for administration at a dosage of 1 to 100 mg / kg body weight / day is required.

The diluent can be liquid or solid and the term diluent also includes the auxiliaries or adjuvants. Examples of liquid diluents are distilled water for injection, isotonic sodium chloride solution, Einger's solution, Locke's solution, Polyethylene glycol, ethyl alcohol, propylene glycol, Glycerin, liquid paraffin and vegetable oils. The solid diluents include, for example, sodium chloride, Glucose, polyvinylpyrrolidone, lactose, starch, methyl cellulose, sucrose, polyethylene glycol, white Vaseline, cetyl alcohol, cocoa butter and spermaceti.

The masses according to the invention can be in different Forms, for example for injections, infusions, as powder, tablets, granules, capsules, suppositories, solutions, Elixirs, suspensions, oil solutions, syrups, lemonades, ointments, eye drops and suppositories.

Pie masses according to the invention can be used in various ways, for example by parenteral administration, for example injection including intravenous injection, intra-arterial injection, intracutaneous injection Injection and infusion, by brushing on, eye drops or on-site or by oral administration.

The following examples serve to further explain the invention.

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example 1

Preparation of 2-aceto3cymethyl-3-phenyl-4 (3H) quinazolynon

To a solution of 42 g of N-acetoxyacetylanthanilic acid and 22 g of aniline in 200 ml of toluene were added dropwise 9 g of PCI in 50 ml of toluene was added and then the

The reaction mixture was refluxed on an oil bath for 4 hours. The reaction mixture was poured into ice-water and then _{made alkaline with a 10% Na-CO 7} , solution. The organic layers were separated, dried and distilled under reduced pressure to leave a crystalline residue. The residue was recrystallized from Hexr.n / lther and gave 37 g of 2-acetoxymethyl-3-ph.enyl-4 (3H) -quinazolinone with a melting point of 103 to 1048 C.

Mass spectrum: 294 (M ⁺ ), 251, 221 IR spectrum: ^ΚΒ ^ γΐ74Ο, 1680, 1610, 1595, 1470.

^cm 1440, 139Q, 136O ₁ 1280, 1240,

1110, 1065, 940, 873, 770, 700.

2) Preparation of 2 ~ Hydro3 {yiiethyl-3-pheri.yl-4 (3H) -quinazolino n

A solution of 10 g of the 2-acetoxymethyl-3-phenyl-4 (3H) -quinazolinone obtained in Example 1 in 100 ml of ethanol containing 10 % hydrogen chloride was refluxed on a water bath for 30 minutes. The solution was then dried under reduced pressure and the residue was _{neutralized with 10% Na 0} CO... Solution. The precipitate was extracted with CHClI

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hiert and after distilling off CHCl- / and recrystallization from ethyl acetate 8 g of 2-hydroxymethyl-3-phenyl-4 (3H) -quinazolinone with a melting point of 155 to 157 ° C were obtained.
Elemental analysis:

CHN * Calculated (%) (C ₁₅ H ₁₂ O ₂ N ₂ ): 71.41 4.80 11.11

Found (%): 71.54 4.74 11.40

UV spectrum λ ίΐ8 ^Η mu 227, 268, 304, 316

The 2-hydroxymethyl-3-phenyl-4 (3H) -quinazolinone became the following acid addition salts are formed:

Hydrochloride: Melting point 233 to 235 ° C (recrystallized from acetone)

Hydrobromide: melting point 250 to 252 ° C (recrystallized from acetone)

Oxalate: Melting point 116 to 118 ° C (recrystalline

made from ethyl acetate)

Nicotinate: Melting point 154 to 156 ° C (recrystallized from acetone) j

Tartrate: melting point 162 to 164 ° C (recrystall

made from ethyl acetate)

Maleate: melting point 87 to 89 ° C (recrystalli

made from ethyl acetate)

Acetylsalicylet: Melting point 132 to 134 ° C (recrystallized from benzene / hexane).

Example 2

To a suspension consisting of 21 g of N-chloroacetylanthranilic acid, 11 g of aniline and 500 ml of toluene consisted of

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5 δ PCI in. 50 N »l toluene were added with stirring. The reaction mixture was left on an oil bath for 2 hours heated to reflux and then poured into ice-water. The mixture became alkaline with 10% Na2CO, solution made and the Tqluolschicht separated, dried and distilled under reduced pressure. The residue was recrystallized from acetone / hexane to give 19 g 2-chloromethyl-3-phenyl-4 (3H) -quinazolinone with a melting point of 152 to 155 ° C.

UV spectrum: ^ £ ^t0 , ^H Ufa 228, 276, 285, 505, 316

Mass spectrum: 272 (M ⁺ ), 270, 235, 221 IR spectrum: ¹ ^ f ₁ y 1685, 1600, 1590, 1470, 1425,

₁ y

^Cm 1350, 1315, 1285, 1265, 1085, 940, 783, 765, 755, 690.

A mixture of 5 g of the above obtained 2-chloro methyl-3-phenyl-4 (3H) -quinazolinone and 1 g Fatriumacetat, 0 »5 g of potassium iodide and 150 ml of dimethyl sulfoxide was heated at 100 ⁰ C for 5 hours. The solvent was then distilled off under reduced pressure, and the residue was diluted with water and extracted with ether. The ether was distilled off and 2.7 g of free 2-acetoxymethyl-3-phenyl-4 (3H) ~ quinazolinone were obtained, which was hydrolyzed in the same way as in Example 1, 2) and 2.6 g of 2-hydroxymethyl-3- phenyl 4 (3H) -quinazolinone, which melts at 155 to 57 ° C. and was identical to the product obtained according to Example 1, 2).

Example 3

To a solution of 2.5 U of N-acetoxyacetyleiuino-bensomi 6 in 150 ml of tetrahydrofuran were proportionally 2.2 g

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Dicyclohexylcarbodiimide in 10 ml of tetrahydrofuran added with stirring. The reaction mixture was kept at 60 to 80 ° C. for 12 hours. Working up the reaction mixture in the usual way gave 2,3 6 2-aceto3? Yaethyl-3J-phenyl * -4 (5H) -quinazolinone with a melting point of 103 to 104 ° C ₁ which was identical to the product obtained in Example 1,1).

Example 4

To a solution of 5 δ 2-C8rboxaldehyde-3-pbenyl-4 (3H) “quin83olinone in 300 ml of methanol, 1 g of HaBH4 was added in portions with stirring. The solution was stirred for an additional hour and then dried under reduced pressure. The residue was dissolved in Waecer and the pH value of the solution was adjusted to 6 to 7. The solution was extracted with chloroform and then chloroform was distilled off. Recrystallization of the residue gave 2-V-hydroxyiaethyl-3-phenyl-4 (3H) -quinazolinone with a melting point of 155 to 157 ° ^C. in a yield of 92 % , which was identical to the product obtained in Example 1, 2).

Example 5

Its solution of 2 g of 2-carboxaldehyde, 10 ml of a 58% formaldehyde solution and 100 ml of ethanol with a content of 5 δ KOH was heated on a water bath for 6 hours. The solution was saturated with CCU-G-as and dried under reduced pressure. The residue was extracted with chloroform and the chloroform was dried and distilled off. The residue turned off

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Ethyl ac et at recrystallized and gave 1.6 g of 2-hydroxy- »ethyl-3-phenyl-4 (5H) ~ quinazolinone with a melting point of 155 to 157 ° C, which was obtained with the product obtained according to Example 1, 2) was identical.

Example 6

Examples of pharmaceutical approaches are given below:

Compound A: 2-hydroxymethyl -3-phei ^ y 1-4 (JH) -

chinazoline ^
Compound B: 2-hydroxymethyl-3-phenyl ~ 4 (3E) -

quinazolinone hydrochloride.

Injection and Infusion: Compound Big, Sodium Chloride

0.9 g and distilled water for injection 100 ml.
Compound Big, Glucose 53 and distilled water for injection 100 ml.

Compound Big, polyvinylpyrrolidone. 10 g and distilled water for

Injection 90 ml.

Compound Big, propylene glycol 20 ml and distilled water for injection 80 ml. Powder: Compound A 1g and lactose 1g

Compound A 10 g and lactose 90 g Compound A 1 g and lactose 99 g Compound A 1 g and starch 99 g Compound A 1 g and lactose or starch or '. Mixtures thereof 98.99 g and yellow coloring agent 0.01 g.

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Tablets: Compound A 50 mg, lactose 100 mg, starch ^ 3 mg, methyl cellulose 5 mg and magnesium stearate 2 mg.

Granules: Compound A 25%, lactose 50%, starch 22.5 % and methyl cellulose 2.5%.

Capsules: compound. A 50 mg, glucose 100 mg, starch MQ mg, magnesium stearate 1 mg and talc 3 mg, compound A 59 mg and vegetable oil 50 mg.

Suppositories: Compound A 50 mg, sucrose 898 mg magnesium stearate 50 mg and yellow dye 2 mg.

L. exercise: Compound B 10% and purified water 90%

Elixir: Compound B 10 g, ethanol 10 ml, glycerin 20 ml, sucrose 55 6 and purified water 30 ml

Suspension: compound A 10 g, sodium methyl cellulose carboxylate 1 g, yellow dye 0.02 mg and purified water 90 ml.

Spirit: Compound A 10%, purified water 10 % and ethanol 80%.

Syrup: Compound B 10 g, sucrose 50 g, ethanol 2 ml and purified water 40 ml

Lemonade: Compound B 10 g, citric acid 0.3 g, sucrose 5 g and purified water 85 ml

Ointment: Compound A 1%, white vaseline 94 % and liquid paraffin 5 %

Compound A 1 g, white petrolatum 39 g of cetyl alcohol 18 g, sesquioleinic acid sorbitol 5 g _t

Lauromagrogol 0.5 g, boric acid 0.2 g and purified water 40 ml

Compound A 1 g, polyethylene glycol-400 5 ^ 6 » Polyethylene glycol-4000 45 g

Eye drops: compound big, isotonic agent (boric acid or sodium chloride) in a suitable amount υ? id distilled Weiser 100 ml..

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Example 7

Effect of 2-hydroxymethyl-5-phenyl-4 (5 H) -quinazolinone to the prevention of the induced by stress, hypertension or inflammatory substances veskul ä ä ren Sch ending and to protect against the Vaskularwand chö? Iesterin-induced atherosclerosis

The compound according to the invention did not show a characteristic pronounced effect experimentally only against the prevention of vascular damage induced by stress, hypertension or inflammatory substances, but also for the experimentally induced atherosclerosis, and inhibited the deposition of cholesterol the vascular wall. The test results are shown below.

A) Protection of the arterial wall against vascular damage

27 healthy albino rabbits were used to study the Protective effect of the compound according to the invention against acute vascular damage used. The rabbits were divided into three equal groups. Three different heating means, i. H. intravenous injection of 1 / Ug / kg Angiotensin, co-administration of cholesterol (1 g / kg, p.o.) and adrenaline (1 ug / kg i.v.) and stress the rabbits were killed by a loud noise on the ears of the animals given to each group to initiate the edematous change in the arotic wall. Three rabbits each of the two groups were pretreated with compound (i) (3 mg / kg) or pyridinol carbamate (10 mg / kg). The with the compound (I) and with pyridinol carbamate

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treated rabbits showed no edematous changes de * aorta, compared to those of a control group with placebo * pie states the with the Compound (I) and the one pretreated with pyridinolearbamate Group were observing the aorta practically the same. The results are in the following Table I summarized.

Table I.

Group Placebo- With Associated- With Pyridinol *

Comparative formula (I) be carbamate

Substance group acted

Group group

Angiotensin +++

Cholesterol &

Adrenaline ++

Stress +

the cholesterol-induced

Atheroscle rose %

Thirty healthy albino rabbits were fed pellets containing 1% cholesterol for 15 weeks. During this period, 10 batteries each day were treated with capsules containing potato starch as a placebo, 5 mg / kg d of the present compound (·) or 10 mg / kg pyridinol carbamate. In the placebo control group, 78.8 + 8 »6 % of the surfaces of the aorta were covered with fat streaks. On the other hand, in the group treated with compound (I), it was covered with fat streaks in 32.1 + 5.2% and in the group treated with pyridinol carbamate in 38.7 + 4.6 % .

ORIGINAL INSPECTED 3Q988T / 117 1

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Example 8

Shows 2-hydroxyiaethyl-3-phenyl-4 (3H) -quinazolinone a debris effect to increase the coagulability and of thrombogenicity "in the one-shot treatment of Animals with cholesterol or adrenaline.

After oral administration of 10 mg / kg of the compound according to the invention to a rabbit, the intensity of the platelet aggregation initiated by adenosine diphosphate was determined according to the Born method (Born, J. Physiol, 152,667 (1962), see also O ' Brien, J. Clin. Path. 15, 452 (1962), Lancet, ± _y 779 (1968).

A rabbit was injected with adrenaline (1 uk / kg) 5 hours after the oral administration of the sample. Five minutes after the injection there was 4.5 ml of blood 8US removed from the carotid artery and then with 0.5 ml a 3 * 85% solution of sodium citrate diluted. To centrifugation of the blood at 1000 g for 30 Minutes, 0.9 ml aliquots were withdrawn from the above liquid. The aliquots Parts were 0.1 ml each of 3 x 10 molar resp.

—4
10 molar solutions of adenosine diphosphate added.

Thus, the molar concentrations of ADP in serum were 5 χ 1Q and 10, respectively. The intensity of the platelet aggregation was using the platelet aggregation meter (Model 169, Evans Elect. Ltd. England). The intensity of the ADP induced Platelet aggregation was expressed as a percentage of the pre-injection value specified. As can be seen from Table II, the compound according to the invention showed low levels ADP induced platelet aggregation values,

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so that an increase in coagulability and thrombogenicity was prevented.

Tabel II , 4% 115.5 10 ""% link .7 % 105.2 + 5.0 % , 1 % 98.2 ± 6.3 % Saline solution (control
le) Increase in the intent of the
ADP induced platelet aggregation .6 % 108.4 ± 5.2 % Dibenzyline
(Control) 3 χ 10 , 0 % 90.8 ± 5.7 % Pyridinol carbamate
(Control 120.9 + 7 Example 9 + 4.0 % Aspirin (control) 1033 + 7 2-hydroxymethyl-3-
phenyl-4 (3H) -chi-
nazolinone 104 + 5 105.2 + 4 69.5 + 3

The effect of the compound (I) according to the invention on the clinical course was determined mainly in atherosclerotic diseases.

1) Clinical effect of compound (I) on coronary sclerosis

62 patients, whose age was 58.4 + 6.3 years, were included in the experiments. Everyone suffered of anginal attack and that showed electrocardiogram an STT depression in the best or in the practice test in practically all cases. 500 mg were given to 22 patients of Compound (I) and administered to 20 patients

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OBSGlMAL INSPECTED

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1000 mg pyridinol carbamate were administered and the remainder received placebo capsules. They were observed under double blind conditions. After 3 months, the subjective and objective values were examined, including an ECG and exercise test. 77% of the patients treated with the compound (I) and 70 % of the patients treated with pyridinol carbaniate showed good results which produced a statistically significant difference compared to the placebo control group, although the latter also showed 35% improved cases. The results are summarized in Table III.

Table III

Number of results

Patients Fairly massive

draws

Placebo control group 20 1 6 13

Group treated with pyridinol carbamate 20 8 6 6

With the compound (I) Group 22 10 7 5 treated

2) Clinical effect of the compound (I) on peripheral vascular diseases

28 patients suffering from cyanosis, pain and ulcers due to atherosclerosis obliterans were examined. 15 patients were treated with 400 mg / day

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binding (I) and the other patients were treated with 50 mg / day nicotinic acid. This experiment was carried out under blank conditions. After 4 months of treatment, 13 cases out of 15 patients showed definite improvement in pain, disappearance of cyanosis and continued healing of the ulcer. All of them were able to walk far better than they could before the treatment. Furthermore, about 40 % of the patients who received nicotinic acid showed little improvement in pain or cyanosis, and none of these showed healing of the ulcer in the nicotinic acid-treated group.

3) Clinical effect of compound ( I) on cerebral atherosclerosis

Patient
iljAwit an episode of cerebral vascular seizures,

for example, cerebral hemorrhage and cerebral thrombosis obtained within 3 weeks were included in this study. si _e were uniformly divided into a control group and a treated with the compound (I) group in their access and also by sex, age and symptoms distributed. 23 patients were treated with a daily dose of 600 mg of the compound (I). Another 20 patients received other conservative treatment. There were 11 patients with hemorrhage and 12 with thrombosis in the compound (I) treated group, and 10 with hemorrhage and 10 with thrombosis in the control group. All other drug treatments were identical in both the control group and the group treated with compound (I).

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In the course of the first month since access, 45 % of the patients in the control group showed a clinical improvement in their speech, motor function and behavior · On the other hand, the clinical improvements were observed in 83% of the patients treated with the compound (I), which was a statistically significant difference showed in a value of 5 %. In the course of observation for 6 months, three patients were attacked again with cerebral vascular seizure and two patients died thereby in the control group, but no seizure occurred in the group treated with the compound (I). The results are summarized in Table IV.

Table IV

The number of improvement does not improve

Control group 20 9 (4-5%) 11 (55%)

Compound (I) treated group 23 19 (83%) 4 (17%)

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Claims (1)

Claims A pharmaceutical composition containing an effective amount of a compound of the following formula: CHpOH or a pharmaceutically acceptable acid salt thereof, and optionally a diluent 2. Pharmaceutical composition for use in the treatment of atherosclerosis, thrombosis and hemorrhage, containing an effective amount of a compound of the formula: CH ₂ OH or a pharmaceutically acceptable acid salt thereof, and optionally a diluent. 3 * mass according to claim 1 or 2, characterized in that that the diluent consists of a liquid or a solid. 4. mass according to claim 1 or 2, characterized by 309881 / characterized in that it is in the form of injections, infusions, powders, Cfcanulate, capsules, troches, solutions, elixirs, suspensions, spirits, soft drinks, ointments, eye drops or suppositories. ^ r - e Thrombosis and hemorrhage, characterized in that one of atherosclerosis, thrombosis, or hemoprhagia patients suffering from a compound of the following formula CH ₂ OH or a pharmaceutically acceptable acid salt thereof is administered in a dosage of 1 to 100 mg / kg body weight / day. / ^y 6. The method according to / claim 5 »characterized in that that the thrombosis from cerebral thrombosis, myocardial infarction or arterial or venous thrombosis. 7 · Verfahrerr according to claim 5 »characterized by that the ateros ^ lerosis from cerebral atherosclerosis, Coronary atherosclerosis, atherosclerosis obliterans, thromboangiitis Oyb'literans or diabetic angiopathy. 8. / The method according to claim 5 »characterized in that the administration takes place by parenteral administration, intravenous injection, intra-arterial injection, intra-injection or infusion. 9y Process for the preparation of 2-hydroxymethyl-3- 309881/1171 ORIGINAL INSPECTED