DE2329815B2 - PHARMACEUTICAL PRODUCT FOR THE TREATMENT OF ATHEROSCLEROSIS, THROMBOSIS AND HAEMORRHAGIA - Google Patents

Description

O ^

or a pharmaceutically acceptable acid salt thereof in amounts of about 0.1 to 80 percent by weight, based on the combined amount of diluents and the specified compound, contains.

Central nervous system activity or cardiovascular system activity.

According to the invention, it has been found for the first time that the compound of formula 1 given above has pharmaceutical activity and particularly for treatment, including prevention and cure, of hemorrhage. Thrombosis and atherosclerosis and that it still has a low toxicity (e.g. LD ₅₀ more than 5000 mg kg in the mouse).

The compound of the above formula 1 can be very easily obtained in high yield by any of the following Working methods are produced:

a) a connection of the general form '

NHCOCH ₁ R ₁

Y
LJ-COOH

(H)

The object of the invention is to provide a new pharmaceutical agent with good effectiveness for the treatment of atherosclerosis, thrombosis and hemorrhage.

This object is achieved according to the invention through the. Production of a pharmaceutical agent for the treatment of atherosclerosis, thrombosis and hemorrhage. characterized in that it is the connection

CH ₁ OH

(Π wherein R represents a halogen atom or an acetoxy, benzoyloxy or benzyloxy group, is reacted with aniline in the presence of a condensing agent, and then the obtained product becomes the general formula

CH ₁ R,

(111)

, N-

.15 wherein R _{1 has} the meaning given for formula II, hydrolyzed or hydrogenated or in a manner known per se

b) connect the general funnel

or a pharmaceutically acceptable acid salt herein in amounts of about 0.1 to 80 percent by weight, based on the combined amount of diluents and the specified compound.

The 2-hydroxymethyl-3-phenyl-4 (3H) -quinazolinone of the above formula is a known compound with a melting point of 180 C (J. Indian Chem. Soc. 1968, 45 [4], pp. 311 to 316). According to this reference, the connection is through 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 produced. There is no suggestion of any pharmaceutical effects nor for the compound possible uses given in the publication.

According to the reference "Progress in Drug Research", Vol. 14, pp. 225 to 245 (1970). Birkhauser Verlag, have 2-methyl-3-phenyI-4 (3 H) -quinazolinone and its derivatives with a substituent in the 3-phenyl group biological effects on the central nervous system act and are useful as hypnotics. Anticonvulsants, analgesics. Antipyretics and anti-inflammatory agents. With regard to 2-hydroxymethyl-3-phenyl-4 (3 H) -quinazolinone there are there is no reference that is any significant indicating pharmaceutical effectiveness, for example

40 NHCOCH ₁ R ₁

45

55

60

CONH

(IV]

in which R, a halogen atom or a hydroxy, acetoxy, benzoyloxy or benzyloxy group is treated with a condensation agent and then, if R _{1 is} not a hydroxyl group, the product of the formula obtained is obtained

CH ₁ R,

(V)

wherein R _{2 has} the same meaning as in formula IV, hydrolyzed or hydrogenated in a manner known per se, or

c) 2-carboxaldehyde-3-phenyl-4 | 3H) -quinazolinone is reduced with an alkali borohydride, aluminum isopropoxide or formaldehyde.

The starting compound (II) of procedure a) can easily by reacting anthranilic acid

with a derivative of acetic acid of the 1-ormel
R ₁ CH ₂ COCl

be prepared in which R _{1 has} the same meaning as in the formula II, in a manner known per se. Examples of compounds of the formula II are N-acetoxyacetylanthranilic acid. N-chloroacetylanthranilic acid, N-benzoyloxyacetylanthranilic acid, and N-benzyloxyacetylanthranilic acid. When carrying out procedure a), the compound of the formula JI is condensed in a solvent with aniline in the presence of a condensing agent. A preferred combination of condensing agent and solvent in this process consists of phosphorus trichloride or phosphorus, phoryl 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 from ^{1 to} 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 (1) in a manner known per se with an acid or an alkali. If R _{1 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 starting compound (IV) in procedure b) can easily be prepared by reacting o-aminobenzamide with a derivative of acetic acid of the formula R ₂ CH ₂ COCl or R ₂ CH ₂ COOC ₂ H ₅ . wherein R _{2 has} the same meaning as in the formula IV. can be produced in a manner known per se. Examples of connections of the form! IV are N-hydroxyacctylaminobenzamide. ο - Chloracetylaminoben / amide. o-benzoyloxyacetylaminobenzamide and o-benzoyloxyacetylaminobenzamide. When carrying out procedure b), the compound of the formula IV is dehydrated using a dehydrating agent. 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 mole ^and a large excess per mole 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 is running! bd <* iner temperature between 30 and 180 ° C, preferably 100 to 150 ° C, and in most cases is completed in 1 to 5 hours. If R ₂ does not represent a hydroxyl group, then the condensation product (V) is hydrolyzed to the product (I) in a manner known per se with an acid or an alkali. When R 1 is a benzyloxy group in the compound (V). it can also be reduced to the product (1) by hydrogenation in a manner known per se.

The 2-carboxaldehyde-3-phenyl-4 (3 H (-quinazo linon) used as the starting compound of procedure c can be obtained by oxidation of 2-methyl-3-phenyI 4 (3H) -quinazolinone with selenium dioxide (J. Indian Cherr Soc, 1968 , 45 [4], pp. 311 to 316). When carrying out procedure c), 2 - carboxaldehyde - 3 - phenyl - 4 (3 H) - quinazolinoi is converted into compound (I) in accordance with the customary alkali borohydride reduction , Meerwein-Pondorf reduction or Cannizzaro reduction. The reduction with the alkali borohydride can be carried out with sodium borohydride in methanol and the Meerwein-Pondorf reduction can be carried out with a Meerwein-Pondorf reduction system such as aluminum isopropoxide and isopropanol. The Cannizzaro reaction can be carried out with formaldehyde in the presence of an alkali hydroxide or alkali carbonate.

In each of the work described above, the desired connection can effortlessly isolated and cleaned.

The pharmaceutical agent according to the invention has excellent pharmaceutical effects, ins special for the treatment of atherosclerosis, thrombosis and hemorrhage. The masses have therapeutic effects on cercbral thrombosis myocardial infarction and venous thrombosis, atherosclero table disorders such as cerebral atherosclerosis. Coro narathcrosclerosis and peripheral atherosclerosis unc various vascular diseases such as thrombo angiitis obliterans and diabetic angiopathy.

The effective amount of the compound of formula i may vary according to the particular dosage desired are varied, but is usually about 0.1 to 80 percent by weight, based on dit Total amount of diluent and compound of the formula. Anyone can wish it « Concentration administered for a Ge A total dosage of 1 to 100 mg / kg body weight per day is required.

The diluent can be liquid or solid and the term diluent includes aud the aids or adjuvants. Examples of liquid * diluents are distilled water for In jection. isotonic sodium chloride solution. Ringer's solution, Locke's solution, polyethylene glycol. ethyl alcohol. Propylene glycol, glycerine, liquid paraffin and vegetable oils. The solid diluents include, for example, sodium chloride. Glucose. Po ^ vinyl pyrrolidone. Lactose, starch, methylcellulose Sucrose. Polyethylene glycol, white petroleum jelly. Cclyl alcohol. Cocoa butter and sperm aceti.

The Mitlei according to the invention can be in various forms, for example for injections Infusions, powder, tablets. Granules, capsules, suppositories. Solutions. Elixirs, suspensions, oil solutions genes, syrups, lemonades, ointments, eye drops and suppositories.

The agents according to the invention can be used in various ways, for example by parenteral * Administration, e.g. injection including intravenous injection, intraarterial injection intracutaneous injection and infusion, by brushing, eye drops or insertion, or by oral administration.

The preparation of the compound ai contained in the agent according to the invention is described below Hand of production examples explained in more detail.

Manufacturing example a)

1. Preparation of I-acetoxymethyl ^ -phenyl-4- (3 H) -quinazolinone

To a solution of 42 g of N-acetoxyacetylanthranilic acid and 22 g of aniline in 200 ml of toluene was added dropwise 9 g of PCI in 50 ml of toluene, and then the reaction mixture was refluxed on an ulbaa for 4 hours. The reaction mixture was poured into ice-water and then made alkaline _{with a 10% Na, CO 3 solution.} The organic layers were separated, dried and distilled under reduced pressure to leave a crystalline residue. The residue was recrystallized from hexane / ether and gave 37 g of 2-acetoxymethyl-3-phenyl-4 (3H) -quinazolinone with a melting point of from 0.3 to 104 C.

Mass spectrum: 294 (M ⁺ ), 251, 221.

IR spectrum: _t ^K _m ^Br , γ 1740, 1680, 1610, 1595, 1470, 1440, 1390, 1360, 1280, 1240, 1.10, 1065, 940, 873, 770, 700.

2. Preparation of: i 2-hydroxymethyl-3-phenyI-4 (3 H) -quinazolinone

A solution of 10 g of the 2-acetoxymethyl-3-phenyl-4 (3 H) -quinazolinone obtained in Example 1 in LöGinl 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 _{neutralized with 10% Na 2} CO ₃ -LOsUiLg. The precipitate was extracted with CHCl, 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 for C ₁₅ H _{12 OiN 1} :

Calculated ... C 71.4), H 4.80. N 11.11%:
found .... C 71.54. H 4.74. N 11.40%.

UV spectrum: / *! I> ^M m _; i 227, 268, 304, 316.

The following acid addition salts were obtained from 2-hydroxymethyl-3-phenyl-4 (3 H) -quinazolinone educated:

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 (umkri

installed from ethyl acetate).

Nicotinate: Melting point 154 to 156 C (umkri

installed from acetone).

Tartrate: Melting point 162 to 164 C

crystallized from ethyl acetate).

Maleate: melting point 87 to 89 C

stallisicrt from ethyl acetate).

Acetyl salicylate: melting point 132 to 134 ° C. (recrystallized from benzene / hexane).

Production example b)

To a suspension composed of 21 g of N-Chloracclylanthranilsiiure. 11 g of aniline and 500 ml of toluene, 5 g of PCI in 50 ml of toluene were added with stirring. The reaction mixture was refluxed on an oil bath for 2 hours and then poured into ice-water. The mixture was made alkaline with 10% Na, CO ₃ solution, and the toluene layer was separated, dried and distilled under reduced pressure. The residue was recrystallized from acetone / hexane and gave 19 g of 2-chloromethyl -3-phenyl-4 (3Hj-quinazolinone with a melting point of 152 to 153 ° C.

UV spectrum: ?. ™ * '- ιημ 228, 276,285, 305, 316.

Mass spectrum: 272 (M ⁺ ), 270.235, 221.

IR spectrum: ™ r, γ 1685, 1600, 1590, 1470, 1425,, ο 1350, 1315, 1285, 1265, 1085, 940, 783, 765, 755, 690.

A mixture of 3 g of the above obtained 2 - chloromethyl - 3 - phenyl - 4 (3H) - quinazolinone and Ig sodium acetate, 0.5 g of potassium iodide and 150 ml Dknethylsuifoxid was the heated to 100 ⁰ C for 5 Stunis. 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 157 ° C. and was identical to the product obtained according to Example 1, 2).

^2;> Preparation example c)

To a solution of 2.5 g of N-acetoxyacetylaminobenzamide in 150 ml of tetrahydrofuran, 2.2 g of dicyclohexylcarbodiimide were partially in 10 ml of tetrazo added hydrofuran with stirring. The reaction mixture was at 60 to 80 C for 12 hours held. Working up the reaction mixture in the usual way gave 2.3 g of 2-acetoxymethyl-3-phenyl-4 (3H) -quinazolinone with a melting point of 103 to 104 C. which with that obtained in Example 1. 1) Product was identical.

Production example d)

To a solution of 5 g of 2-carboxaldehyde-3-phenyl-4 (3 H) -quinazolinone in 300 ml of methanol, 1 g of NaBH ₄ was added in portions with stirring.

The solution was stirred for an additional hour and then dried under reduced pressure. Of the The residue was dissolved in water and the pH of the solution was adjusted to 6-7. The solution was extracted with chloroform, and then the chloroform was distilled off. By recrystallization the residue was 2-hydroxymethyl-3-phenyl-4 (3H) -quinazolinone obtained with a melting point of 155 to 157 C in a yield of 92%, which was identical to the product obtained according to Example I, 2).

Production example e)

A solution of 2 g of 2-carboxaldehyde, 10 ml of a 38% strength formaldehyde solution and KXJmI ethanol containing 5 g of KOH was heated on a water bath for 6 hours. The solution was _{saturated with CO 2} gas and dried under reduced pressure. The residue was extracted with chloroform, and the chloroform was dried and distilled off. The residue was recrystallized from ethyl acetate to give 1.6 g of 2-hydroxymethyl-3-phenyl-4 (3H) -quinazolinone with a melting point

f> s from 155 to 157 C, the same as in example 1. 2) obtained product was identical.

The invention is explained in more detail below with the aid of examples.

B e. λ ρ; e 1 1

The following are examples of pharmaceutical To see the salts:

connection Λ:
ν erbindune ti:

Injection and
Infusion:

Powder:

Tablets:
Granules:
Capsules:

Za pichen:

Solution:
Elixir:

Suspension:

Spirit:
Syrup:

Lemonade:
Ointment:

Polyvinylpyrrolysed water / ur

Propylengiykoi water for

2 - Hydro.wmeinvi - - pnem; -4i.m ι r

chmazoiinon.

2- Hydroxvmeihvl - ■■ - mien \ i - 4i; H ι

quinazolinon-hvümcrilonü.

\ erbindunu B I s.:. Nairnimchloriti (W a and still water for intake H) O ml.

Compound B I and glucose 5 g and distilled water for Iniekiiou KKi ml

Compound B ι μ.
don 10 α and destil
Start 90 mi
Compound BI g
2 (ImI and distillieries
Injection SO ml.

Compound A i> j imil lactose 1 g.
Compound A IO g and lactose 9ti μ Compound AI g and lactose SWg. Connection A! n and strength 9U μ.
Compound A i ·. · And lactose or starch or (a mixture of these 9X.W ν and yellow larbsiofi ii.iil g.
Compound A 5 (Im ¹ J. Lactose 100 mg. Strong 43 mg. Vlethyleelluiosc 5 mg and Magncsiumstcarat 2 mg.
Compound A 25 "". Lactose 50%. Starch 22.5% and Methylcellulose 2.5%.

Compound A 50 mg. Glucose 100mg. Strong 48 mg. Magnesium clearate 1 mg and talc 1 mg. Compound A 59 mg and vegetable oil 50 mg.
Compound A 50 mg. Sucrose X98 mg, Magnesium Stearate 50 mg and Yellow Color 2 mg.
Compound B 10% and purified water 90%.

Compound B 10g. Ethanol 10 ml. Glycerin 20 ml. Sucrose 35 g and purified water 30 ml.
Compound A 10 g, sodium methyl cellulose carboxylate 1 g. yellow dye 0.02 mg and purified water 90 ml.

Compound A 10%, purified water 10% and ethanol 80%.
Compound B 10 g. Sucrose 50 g. Ethanol 2 ml and purified water 40 ml.

Compound B 10 g. Citric acid 0.3 g. Sucrose 5 g and purified Water 85 ml.

Compound A 1%, white petrolatum 94% and liquid paraffin 5%.
Compound A 1 g, white petrolatum 39 g, cetyl alcohol 18 g, sesquioleinic acid sorbitol 5 g, lauromagrogol 0.5 g, boric acid 0.2 g and purified water 40 ml.

Compound A 1 g, polyethylene glycol-400 54g, polyethylene glycol-4000 45g.

• \ ugentropia: compound B 1 g. isotonic agent (Boric acid (here sodium chloride I in a suitable amount and distilled Water K) OmI.

Pii.irmakologiSuhe test results

1. rffckl of 2-Hulio \ ymeliiyl-3-phenyl- -Ji "! ■ li-chiuii.'olinon on preventing the through Sircl. 1 hypertension or inflammatorycs

Substances induced \ 'ascular damage and / to protect the \' askularvvand against the cholesterol-induced atherosclerosis

The compound according to the invention showed a characteristic pronounced effect experimentally not just against the prevention of stress. Induced hypertension or inflammatory substances Vascular damage. but also for the experimentally induced atherosclerosis and inhibited the cholesterol deposition on the vascular wall. The test results are shown below.

A. Protection of the arterial wall against vascular damage

27 healthy albino rabbits were tested for the protective effect of the compound according to of the invention used against acute vascular damage. The rabbits were divided into three equal groups divided up. Three different stimulants, i. H. intravenous injection of 1 µg / kg angiotensin. simultaneous Administration of cholesterol (1 g / kg, p.o.) and adrenaline (1 ij.g / kg, i.v.) and noise stress The rabbits in each group became thick on the ear shell of the animals to induce edematous disease Change in aortic wall given. Three rabbits from each group were exposed to the compound (i) (3 mg / kg) or pyridinolearbamate (10 mg / kg) pretreated. The one with the connection (I] and rabbits pretreated with pyridinolearbamate showed no edematous changes in the Aorta, compared to those of a placebo control group. The states with the Compound (I) and in the pyridinolearbamate pretreated group with aortic observation were practically the same. The results are summarized in Table I below.

Placebo- Mil Ver Mil Pyri-

Comparative bond (Il dinolcarbama

group treated treated

Group group

± h

Table 1

group
substance

Angiotensin
cholesterol
+ Adrenaline
Stress

B. Protective effect against cholesterol-induced atherosclerosis

30 healthy albino rabbits became true Feeded pellets containing 1% cholesterol for 15 weeks. During this period, respectively 10 rats daily with capsules containing potato starch al placebo, 5 mg / kg of the present compound manure (l) or 10 mg / kg pyridinolearbamate contained

609 509/42!

2329 (Part 5

treated. Waicn for the placebo koiilrollgiuppe jic surfaces of the aorta in 7S, 8 ± 8.0% groove fur strips covered. On the other hand, the one with dei Compound (1) treated Uruppe this in 32.1 ± 5.2% and in the group treated with pyridinol carbamal with 38.7 ± 4.6 "/» with fur strips covered.

II. 2-Hydroxymethyl-3-phenyl-4 (3 H) -quina / .olinone shows a whipping effect to increase coagulability and the Thronibogeni / itat in the Onc-Shoi treatment from "fieren with L holestenn odei Adrenaline.

After oral administration of lomg; kg of the Connection to a rabbit showed the intensity of platelet aggregation produced by Adenosindiphosphal was initiated, beslmt according to the Born method (Born, J. Physiol. 162. 67 [1962], see also O'Brien. J.Chn. Path. 15. 452 I 1962], Lancet, 1.779 L1968]).

L. in rabbits was injected with adrenaline (l; jk / kg) 3 hours after oral administration of the sample. 5 minutes after the injection, 4.5 ml of blood was taken from the carotid artery and then diluted with 0.5 ml of a 3.8% solution of sodium citrai. After centrifuging the blood at 1000 g for 30 minutes, aliquots of 0.9 ml each were removed from the above liquid. The aliquots were added to 0.1 ml each of 3 × 10 " ⁵ molar or 1 () ~ ⁴ molar solutions of adenosine diphosphate Platelet aggregation was determined using the platelet aggregation meter (Model 169, Evans Elect. Ltd. England) The intensity of ADP-induced platelet aggregation was expressed as a percentage / of the pre-projection value As shown in tables, the compound according to the invention showed low values platelet aggregation induced by ADP, so that an increase in coagulation ability and thrombogenicity was prevented.

Tabel!!

Vcrhindup:

Increase in the intensity of the ΛΙ) Γ>
Induced PläUchenaggrcgalion

5 * K) "M 10" ^J M

Saline solution 120.9 ± 7.4% 115.5 ± 5.0%

(Control)

Dibenzyline 1033 ± 7.7% 105.2 ± 6.3%

(Control)

Pyndinolcarb- 104 ± 5.1% 98.2 ± 5.2%

amat (control)

Aspirin 105.2 ± 4.6% 108.4 ± 3.7%

(Control)

2-hydroxy 69.5 ± 3.0% 90.8 ± 4.0%

methyl-3-pheny! -

4 (3 H) -chinazo-

linon

III. The effect of the compound (1) according to the invention on the clinical course was determined mainly in atherosclerotic diseases.

Clinical effect of compound (I)
on Koronarsklciosc

whose ages were 58.4 -i 6.3 years were included in the experiments. Everyone suffered angina attack, and the electrocardiogram showed SSI depression in the rest or in the exercise test in practically all cases. 500 mg of the compound (I) were administered to 22 patients, and on 20 patients were given 1000 mg pyndinol carbamate and the remainder received placebo capsules. they were observed under double blind conditions. After 3 months, the subjective and objective Values including EKG and exercise test examined. 77% of those treated with compound (I) Patients and 70% of the patients treated with pyridinol carbamate showed good results that a statistically significant difference compared to the placebo control group, albeit The latter also showed 35% improved cases. The results are summarized in Table III.

Table ill

Placcoo Koniroy Group 20
With pyridinol carbamai 20
Dealt group
With the connection (1)
treated group

At l-.riiehnis , mn IVKI iilg number the aii.-.- IV lien / eii-h- 6th 13th Il Cl 6th 6th 20th 1 7th S. 20th 8th ■ η 10

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

28 patients suffering from cyanosis, pain and ulcer due to Ätherosklcrosis obliterans iitten. were examined, ί 5 patients were with 400mg / day of compound (I) treated, and the other patients were treated with nicotinic acid 50 mg / day. This experiment was carried out under blind conditions executed. After 4 months of treatment, 13 cases out of 15 patients showed one definite improvement in pain, cyanosis disappearing and healing of the continued Ulcer. All of them were able to walk far better than they could before the treatment. Furthermore showed about 40% of patients who received nicotinic acid had only a slight improvement of Pain or cyanosis, none of which showed ulcer healing in those treated with nicotinic acid Group.

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

43 patients with an episode of cerebral vascular seizures, e.g. cerebral haemorrhagi and cerebral thrombosis obtained within 3 weeks were included in this study They were uniformly divided into a control group and a compound (1) -treated group in their case Access divided and also by gender, age

and symptoms spread. 23 patients were with a daily dose of 6 (X) mg of the compound (I) treated. Another 20 patients received other conservative treatment. There were 11 patients with hemorrhage and 12 with thrombosis in the group treated with the compound (I) and 10 with Hemorrhage and 10 with thrombosis in the control groupc. All other drug treatments were in both the control group and the compound (I) treated group identical.

In the course of the first month, 45% of the patients in the control group had a rope access clinical improvement in their speech, motor function and behavior. On the other hand, they were clinical improvements were observed in 83% of the compound (I) treated patients who received a statistically significant difference in a value of

5% / egg. In the course of an observation of 6 months, three patients and two patients had recurrence of cerebral vascular seizure died in the control group, but there was no seizure in that treated with the compound (I) Group up. The results are summarized in Table IV.

Table IV Λη / ahl
.kr
l'alienlen Verbs
sern η j! Not ver
improves 20th
23 9 (45%!
19 (83% I 11 (55%)
.4 (17%) Control group
With connection (1)
treat group

Claims (1)

Claim: Pharmaceutical agent for the treatment of atherosclerosis, thrombosis and hemorrhage, characterized in that it is the link CH ₁ OH