DE2237832A1 - PROCESS FOR THE PREPARATION OF 4HYDROXYMETHYL-1-KETO-1,2-DIHYDROPHTHALAZINE - Google Patents

Description

TATEKTAtIWXLTE

DR. E. WIEGAND DIPL-ING. W. NIEMANN

DR. M. KÖHLER DIPL-ING. C. GERNHARDT 2237832

MÖNCHEN HAMBURG TELEPHONE: 55547 «8000 MÖNCHEN 15, TELEGRAMS: KARPATENT NUSSBAUMSTRASSE 10

August 1, 1972 W 41 236/72 Ko / Yes

Michiro Inoue, Kokuryo-cho, Chofu-shi, Tokyo (Japan)

and _x

Masayuki Ishikawa,

Akazutsumi ,. Setagaya-ku, Tokyo (Japan) and

Takashi Tsuchiya,

Minamikoiwa, Edogawa-ku, Tokyo (Japan)

and ^

Takio Shimamoto ,. * ·· '' Kitamachi, Shinjükü-ku, Tokyo (Japan)

Process for the preparation of 4-hydroxymethyl ~ 1-keto-1,2-dihydrophthalazine

The invention relates to a new process for the preparation of the known 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine, as well as a process for the production of its acid salts, pharmaceutical compositions containing the dihydrophthalazine 'or pharmaceutically acceptable salts thereof and a method for the treatment of hemorrhage

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rhage, thrombosis, or atherosclerosis.

The 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine of the following formula

CH ₂ OH

(D

is a known compound with a melting point of 204 ° C (Annual Report of Department of Pharmacy, Kanazawa University, Japan, Volume 12, Pages 1 to 6 (1961)). However, this compound is not known to be pharmaceutical Shows effects. In the above paper it is stated that the compound of formula (i) can be obtained by bromination of o-acetylbenzoic acid, hydrolysis of the product with a Acid and reaction of the hydrolyzate with hydrazine according to the method according to Ber., Volume 40, 72 (1907) became.

The report does not contain any information about the pharmaceutical effects of the compound obtained, nor about a possible usability. It is also stated that the compound of the formula (I) was obtained in a very low yield of a few % to 10 % , since the disadvantageous procedure there involves numerous stages.

It has now been found that the compound of formula (i) is a substance with valuable pharmaceutical effects, especially for treatment including prevention and cure of hemorrhage, thrombosis and atherosclerosis and a low toxicity (e.g. more than LDc ₀ 4500 mg / kg at the mouse).

Further research led to the finding that

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the compound of formula (I) easily in high yield above 90 % by simply reacting a compound of formula (II)

COR

(II) '

wherein R is an alkoxy group having 1 to 5 carbon atoms or is a halogen atom, can be prepared with an alkali borohydride in a solvent and that the Compound of formula (I) forms new addition salts with organic or inorganic acids, the addition salts having the same or superior effects as the compound of formula (I) show.

It is known that, in general, lithium aluminum hydride is used to obtain a primary alcohol by reducing a carboxylic acid ester and that the reaction practically does not run off with sodium borohydride (Angewandte Chemie Volume 73, 81 (1961 j H.C. Brown "Hydroboration" 242 (1963)). It is also known that when a nitrogen-containing heterocyclic compound, particularly a diazine compound like phthalazine or a quinoxaline is treated with lithium aluminum hydride, the nitrogen-containing hetero ring is slightly reduced ("Jikken Kagaku Koza"

or Lectures on Experimental Chemistry, Volume 17, page 61).

Surprisingly, in contrast to Er ~ found maintenance based on the knowledge listed above that in the implementation of the compound of formula (II) with an alkali borohydride, the compound of the formula (I) can be formed in high yields.

According to the invention, a connection of the

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Formula (I) in high yield from an inexpensive material can be obtained by a simple reaction operation, the reaction steps being greatly abbreviated.

A main object of the invention is therefore a new pharmaceutical composition, in particular for the treatment of hemorrhage, thrombosis and atherosclerosis is valuable.

A second object of the invention is a process for the preparation of the compound of formula (I) with the above-mentioned pharmaceutical effects in an advantageous manner.

A third object of the invention is a method of treating hemorrhage, thrombosis and Atherosclerosis Using Pharmaceutical Effects Now Established.

Numerous other objects of the invention together with their advantages emerge from the following description.

The compound of the formula used according to the invention (II) can be easily obtained by a known method. For example, it can easily correspond to the on page 1316, volume 68, Journal of The American Chemical Society, methods by oxidation of naphthalene with potassium permangant, reaction of the oxidized product with hydrazine and esterification of the 4-carboxy-1-keto-1,2-dihydrophthalazine obtained in the usual way or during treatment with thionyl chloride for conversion into the Acid chloride are produced.

Examples of compounds of the formula (II) are 4-methoxycarbonyl-1-keto-1,2-dihydrophthalazine, 4-ethoxycarbonyl-1-keto-1, 2-dih3rdrophthalazine, 4-propoxycarbonyl-1-keto-1,2-dihydrophthalazine, 4-butoxycarbonyl-1-keto-1,2-dihydrophthalazine, 4-amyloxycarbonyl-1-keto-1,2dihydrophthalazine, 4-chlorocarbonyl-1-keto-1,2-dihydrophthalin

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and ^ -Bromocarbonyl-i-ketQ-ijSdihydrophthalazine.

As alkali borohydride, for example, lithium borohydride, sodium borohydride, potassium borohydride or sodium trimethoxyborohydride can be used be used. ,

In preparing the compound of formula (i), the alkali borohydride is used in an amount of, for example 0.8 to 20 moles, preferably 1 to 3 moles per mole of Compound of formula (II) used and the implementation in run a solvent. It is advantageous to carry out the reaction in the presence of a metal halide such as calcium chloride, Magnesium bromide, lithium chloride, lithium bromide. or lithium iodide. If R in the formula (II) is an alkoxy group, water or an aliphatic alcohol with 1 to 5 carbon atoms such as methanol, Itlia-

Use nol, propanol or amyl alcohol as solvents

The use of alcohol with 1 to 5 carbon atoms is preferred.

If R is a halogen atom in the formula (II) -, customary inert solvents such as benzene, ethyl ether, dioxane or tetrahydrofuran or mixtures thereof can be used as solvents. If R is a halogen atom, it is sufficient that the alkali borohydride is used in an amount of about 1 to 5 moles per mole of the phthalazine derivative. The reaction can usually be carried out at JD to 250RC, preferably 0 Ms 20O ⁰ C, more preferably 0 to 100 ⁵ C. If R is an alkoxy group in the formula (II), it is preferred that the reaction is carried out at 0 to 10O ⁰ C. The reaction is usually complete in 0.5 to 3 hours, but the reaction can also be carried out at lower temperatures for longer periods of time. The product is easy to isolate and clean.

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

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or a pharmaceutically acceptable acid addition salt thereof and a diluent.

These masses have excellent pharmaceutical effects, especially for the treatment of hemorrhage, thrombosis and atherosclerosis. Such thromboses include for example cerebral thrombosis, coronary thrombosis and peripheral thrombosis. Examples of atherosclerosis include Cerebral atherosclerosis, coronary atherosclerosis, arteriosclerosis fobliterans, ThromboangitiSjObliterans, thrombophlebitis, angiopathy of diabetes mellitus or nephropathy of diabetes mellitus. .

The effective amount of the compound of formula (I) can be varied freely in accordance with the particular intended dose, however, is usually about 0 ₉ 1 to 80%, based on the combined amount of the diluent and the compound of formula (I). Any desired concentration required for administration can thus be used at a dosage of 1 to 100 mg / kg body weight / day.

The diluent can be liquid or solid and the term diluent here also includes adjuvants. Examples of liquid diluents are distilled water for injection, 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, polyvinyl

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pyrrolidone, lactose, starch, methyl cellulose, sucrose, Polyethylene glycol, white petrolatum, cetyl alcohol, cocoa butter and spermaceti.

The masses according to the invention can be in various forms such as injections, infusions, powders, tablets, Granules, capsules, suppositories, solutions, elixirs, suspensions, alcoholic solutions, syrups, lemonades, ointments, Eye drops and suppositories are available.

The compositions according to the invention can be used in can be administered in various ways, for example by parenteral administration for example injection including intravenous injection, intra-arterial Injection, intracutaneous injection and infusion, coating, as eye drops and inserts, and by oral administration.

The following examples serve to further explain the invention.

example 1

To a solution of NaBH ^ in ethanol, which had been prepared by dissolving 19 g of NaBIL ₄ in 120 ml of ethanol at 0 to ICH), 12 g of 4-ethoxycarbonyl-i-keto-1,2-dihydrophthalazine were added at 0 to 10 ⁰ C added with stirring. A solution of 3 U calcium chloride in 36 ml of ethanol was added to the suspension obtained, and the reaction mixture was then stirred for a further 5 hours at room temperature. The ethanol was distilled off under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 6 to 7 with acetic acid and dried under reduced pressure. The residue was continuously extracted with chloroform using a Soxlet device. The chloroform extract was distilled off and the residue was recrystallized from methanol, so that 4-hydroxymethyl-1-keto-1,2-dihydro-

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phthalazin were obtained with a melting point of 206 to 20EPC. The yield of the product was 8.6 g (90%).

UV spectrum: λ XtOH, 225 mm (ε = 16,100), 245 m / u (E =

Max ' '

7 700), 253 myu (£ = 8 200), 281 nyu (E = 6 400), 300 m / u (E = 4 500), 312 m / u (L = 2 800).

Example 2

A mixture of 3 g of 4-carboxy-1-keto-1,2-dihydrophthalazin and 40 ml of thionyl chloride was moderately heated at 70 to 80 ⁰ C for 1 hour on a water bath to reflux. The excess of thionyl chloride was then distilled off and the residue was dissolved in 30 ml of dioxane. To the dioxane solution portionwise 2 g of sodium borohydride was added at 0 to 10 ⁰ C with stirring. The reaction mixture was further stirred for 1 hour and then the solvent was distilled off. The residue was recrystallized from water and gave 1.2 g of 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine with a melting point of 201 to 202 ^° C.

Example 5

"Examples of pharmaceutical preparations are given below:
In.iection and infusion:

1 g of compound B, 0.9 g of sodium chloride and distilled water for injection 100 ml,

1 g of compound B, 5 g of glucose and distilled water for injection 100 ml.

1 g of compound B, 10 g of polyvinylpyrrolidone and 90 ml of distilled water,

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1 g of compound B, 20 ml of propylene glycol and distilled water for injection 80 ml.
Powder;

1 g of compound A and 1 g of lactose,
10 g compound A and 90 g lactose, 1 g compound A and 99 g lactose, 1 g compound A and 99 g starch,

1 g of compound 1 and 98.99 g of lactose or starch or their mixture ' and 0.01 g of a yellow dye.

Tablets; · ■ -.

50 mg of compound A, 100 g of lactose, 43 mg of starch, 5 mg of methyl cellulose and 2 mg of magnesium stearate. Granules;

25 % Compound A, 50 % lactose, 22.5 % starch and 2.5 % methyl cellulose.
Capsules;

50 mg of compound A, 100 mg of glucose, 48 mg of starch, 1 mg of magnesium stearate, and 1 mg of talc;
50 mg of compound A and 50 mg of vegetable oil. Lozenges;

50 mg of compound A, 898 mg of sucrose, 50 mg of magnesium stearate, 2 mg of yellow dye. · Solution;

10 % compound B and purified water 90 %. Elixir;

10 g of compound B, 10 ml of ethanol, 20 ml of glycerin, 35 g of sucrose and 30 ml of purified water. Suspension;

10 g of compound A, 1 g of sodium methylcullulose carboxylate, 0.02 g of a yellow dye and purified water 90 ml.

Alcoholic solution;
10 % compound A, 10 % purified water and 80 % ethanol.

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Syrup :

10 g of compound B, 50 g of sucrose, 2 ml of ethanol and 40 ml of purified water.
Lemonadeι

10 g of compound B, 0.3 g of citric acid, 5 g of sucrose and purified water 85 ml.
Ointment;

1 % Compound A, 94 % white petrolatum and 5 % liquid paraffin;

1 g of Compound A, 39 g of white petrolatum, 18 g of cetyl alcohol, 5 g of sesquioleinic acid sorbitol, 0.5 g of lauromagrogol, 0.2 g of boric acid and 40 ml of purified water; 1 g of compound A, 54 g of polyethylene glycol-400, 45 g of polyethylene glycol-4000.
Eye drop:

1 g of compound B, isotonic agent (boric acid or sodium chloride) in a suitable amount and 100 ml of distilled water.
Suppsitories:

0.1 g Compound A, 1.6 g cocoa butter, 0.3 g Spermaceti; 0.1 g of compound A, 0.3 g of polyethylene glycol 4000 and 1.6 g Polyethylene glycol-15000.

Compound A and compound B become 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine or 4-hydroxymethyl-1 -ke; to-1, 2dihydrophthalazine hydrochloride understood.

Example 4

Influence of 4-hydroxymethyl-1-keto-1. 2 -dihvdrophtha l azin on the change in experimental atherosclerosis

4-hydroxymethyl-1-keto-1,2-dihydrophthalazine a pronounced effect for the change of athero-

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223783?

sclerosis, with the deposition of cholesterol on the arterial walls in experimental atherosclerosis inhibited v.oirde _e The test results are given below «. 95 healthy male rabbits were each fed with 150 grams of pellets per day, which contained 1% cholesterol _for a period of 15 weeks. Then 5 of the above rabbits were slaughtered. The remaining 90 rabbits were divided into 6 groups. While all groups were fed a standardized feed, 5 groups were given 10 mg per kg of 4-hydroxymethyl ~ 1-keto-1,2-dihydrophthalazine, while the rest of the group was fed a placebo, which consisted of potato starch. After 6, 10 and 20 weeks, 5 rabbits from each of the 6 groups were sacrificed and the total content of cholesterol in the arterial wall was estimated by gas chromatography. The results are given in Table I below.

(1) The total cholesterol at the end of the first 15 weeks was 40.6 to 12.1 / µg / mg per dry weight.

(2) The total cholesterol content of the 6 groups is in .der given in the following table. The salary is in / Ug units per 1 mg of the dried arterial wall indicated. The values given below show the average value of 5 rabbits each. .. *

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Table I.

Group fed with Time Cholesterol content space (/ ^u ß) (Weeks) placebo 6th 29.3 ± 1.6 10 31.7 + 2.5 20th 24.91 + 8.1 placebo 6th 30.6 + 2.4 10 21.2 + 2.3 20th 23.8 + 6.2 2,6-bis (hydroxymethyl-
pyridine
di-N-methyl carbamate 6th 26.0 + 5.6 (Pyridinol carbamate) 10 17.8 + 2.3 Pyridinol carbamate 20th 10.6 + 2.4 6th 27.3 ± 2.6 10 16.0 + 2.6 4-hydroxymethyl-1,2- ' 20th 9.8 + 2.4 dihydro 6th 28.1 ± 3.4 phthalazine 10 13.2 + 2.1 4-hydroxymethyl-1,2- 20th 6.3 ± 2.5 dihydrophthalazine 6th 26.5 + 4.1 10 12.2 + 2.2 20th 6.7 + 2.0

example 5

4 ~ hydroxymethyl-1-keto-1,2-dihydrophthalazine showed a prevention effect for the increase in coagulability and the thrombogenicity in a Schöck treatment

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- IJ -

treatment of the animals with cholesterol or adrenaline.

After oral administration of 10 mg / kg of the compound according to the invention to a rabbit, the adenosine diphosphate induced intensity of platelet aggregation according to the Born method (Born, J.Physiol, Volume 162, P. 67, 1962, see also O'Brien, J. Clin. Path. Volume 15, Page 452, 1962, Lancet, 1, page 779, 1968).

One rabbit was given adrenaline (1 / ug / kg) for 3 hours injected after the oral administration of the sample. Five minutes after the injection, 4.5 ml of blood was drawn from the carotid artery removed and then with 0 "5 ml of a 3.8% Lo- * solution of sodium citrate. After centrifuging the blood at 100Og for 30 minutes, 0.9 ml aliquots removed from the supernatant liquid. 0.1 ml of a was added to each aliquot

-5-4

3 x 10 molar or 10 molar solution of adenosine diphosphate added. Thus the molar concentrations of ADP in the serum were 3 × 10 and 10 ×, respectively. The intensity platelet aggregation was measured using a platelet aggregation meter (Model 169, Evans Elect Ltd. England). The intensities of the ADP-induced Platelet aggregation are · as a% ~ rate of value given before injection. As can be seen from Table II., The compounds showed lower values of the by ADP-J induced platelet aggregation, causing an increase the coagulability and the thrombogenicity was prevented.

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Table II

link Increasing the intensity of the
due to ADP-induced platelet
aggregation Saline solution (comparison)
Dibenzyline (comparison)
Pyridinol carbamate
(Comparison)
Aspirin (comparison)
4-hydroxymethyl-1-keto-
1,2-dihydrophthalazine
Hydrochloride 3 χ 10 " ⁶ M 10" ⁵ M. 121st, 8 + 7.8 % 115.1 + 4.9 %
101.7 + 8.7 % 106.7 + 7.3 %
109.0 + 5.9 % 100.8 + 6.5 %
106.0 + 3.0 % 111.5 + 2.6 %
86.4 + 2.1 % 78.2 + 3.5 %

Example 6

The effect of the compounds according to the invention on the clinical course and the rate of expiration of the patient after the apopletic attack by cerebral hemorrhage or cerebral thrombosis were examined in a comparative study estimated.

56 patients were diagnosed within 30 days of the stroke subject to investigation. They were divided uniformly into a group A (comparison group) and a group B (group which was treated with the compound according to the invention) at their entry and also according to gender, Age, symptoms and the like distributed. As can be seen from Table III, there were 27 patients in the group A and 29 patients in group B. There were 9 patients with hemorrhages and 18 with thromboses in group A and 9 patients with hemorrhages and 20 with thrombosis were in the B group. There were no significant differences

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differences between the two groups in terms of gender, age, symptoms, complications, history, Use of observation and period of observation. The diagnosis was made mainly according to the criterion according to Dr. Milikan and employees.

1 g of the compound according to the invention was administered orally daily to the patients of group B. All further drug treatment was the same in the two groups. The clinical effect of the compound on the disorder the memory function, language function and motor functions were examined. The extent of the deterioration each symptom was scored for each patient on entry and 10 days later. 5 grades were used

which ranged from no incapacity to total incapacity. A marked improvement of 1 ° or even an improvement of the same degree in any of the three symptoms during this 10 day period was considered a clinical improvement ₀

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Table III

Group A 13th Group B Number of cases: 27 8.7 - 1.6
Days 29 Hemorrhage 9 8 days
until 6
months 9 thrombosis 18th 20th Gender: masculine 21 23 Female 6th 6th Age: 38-86 years, 37-86 years Symptoms: Disturbance of memory (Cima) 10 (2) 13 (1) of language (aphasis) 21 (3) 22 (3) the motor function
(Haemiglegia) 27 (10) 29 (9) complications: Hypertension 17th 15th Diabetes mellitus 1 2 Hypercholesterolemia 7th 5 abnormal ECG 9 11 Prehistory: apoplexy 4th "3 ■. Atherosclerosis deficiencies 7 5 Hypertension 15th start of observation: 9.7-1.6
Days Period of observation: 8 days
until 6
months

In group A, 15 of 27 cases or 55.6? a clinical improvement. On the other hand, the
Group B showed clinical improvement in 25 out of 29 cases

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or observed in 86.2 %. This difference is statistically significant at the 5% value «

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Claims (3)

- IO claims 1) A pharmaceutical composition consisting of an effective compound of the following formula CH ₀ OH or a pharmaceutically acceptable salt thereof and optionally a diluent. 2) Pharmaceutical composition for use in the treatment of hemorrhage, thrombosis or arterosclerosis, consisting of from 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 the diluent from a liquid or a solid. 4) mass according to claim 1 or 2, characterized in that 4ass them in the form of an injection, an infusion, a powder, granules, a capsule, Lozenge, a solution, an elixir, a suspension 309807/133 1 an alcoholic solution, lemonade, ointment, eye drops or as a suppository. and atherosclerosis, characterized by ge kjfe η η that in the patient jfit hemorrhage, thrombosis or atherosclerosis a connection of the following formula or a pharmaceutically acceptable acid salt in one Dose of 1 to 100 mg / kg body weight / day administered will. 6) Method according to J & nspruch 5, "thereby ge ~ indicates that the thrombosis from cere bral thrombosis, coronary thrombosis or peripheral thrombosis consists. 7) Verfahret according to claim 5, characterized g e kejinz / ichnet that atherosclerosis from cerebral icherosclerosis, coronary atherosclerosis, arteriosclerosis / bliterans, thromboangitis obliterans, angiopathy from DiapeteEJmellitus or nephropathy from diabetes mellitus best 8) Method according to claim, characterized thereby e / n n indicates that the administration is through payenteral administration, intravernous injection, intra-aiperial Injection, intracutaneous injection or infusion - follows. 3 0 9 8 0 7/1331 Process for the preparation of 4-hydroxymethyl-i-keto-1,2-dihydrophthalazine of the following formula or its acid addi ons salts CH ₂ OH (D characterized in that a compound of the formula COR (ID wherein R represents an alkoxy group having 1 to 5 carbon atoms or a halogen atom, with an alkali borohydride is reacted in a solvent and, if appropriate, the product is converted into the acid addition salt. Method according to claim 9, characterized in that that as a solvent water, aliphatic alcohols with 1 to 5 carbon atoms, dioxane, Pyridine, benzene, ethyl ether, tetrahydrofuran and mixtures thereof can be used. Process according to Claim 9 or 10, characterized in that the reaction is carried out ^{at 0 to 10O 0 C.} 309807/1331 Process according to claim 9 to 11 ₉ daiii ^ ch characterized _g ■ that an amount of alkali borohydride of at least 0.8 mol per mol of the compound of formula (II) is used » The method of claim 9 in up to 12 _"9 characterized in that the reaction Ge ~ genwart a metal halide is performed _o 309807/1331