CS200248B2 - Process for preparing new quinazolondiurethanes - Google Patents

Abstract

1333284 Quinazoline derived biscarbamates BAYER AG 11 Oct 1971 [13 Oct 1970] 47212/71 Heading C2C The invention comprises compounds of formula wherein X is O or S, R is alkyl (optionally with its C chain interrupted by O or S), cycloalkyl, aralkyl or aryl, R<SP>1</SP> is alkyl, cycloalkyl or Ph, and any hydrocarbon radicals mentioned may be substituted. In examples, these compounds are prepared by reacting (1) the corresponding diisocyanate or diisothiocyanate with ROH, or (2) the corresponding diamine with ClCO 2 R, or (to obtain a product where R is 2-hydroxyethyl) glycol carbonate. Therapeutic compositions having cytostatic activity comprise compounds of the above formula, and may be administered orally, parenterally or rectally.

Description

The present invention relates to novel quinazolone diurethanes, to a process for their preparation and to their use as cytostatics.

Numerous quinazoline derivatives are already known to have hypnotic, soothing properties or cause muscle relaxation [see Angew. Chemie 74 (1962), 855-861]. .On the opposite. there were no known derivatives of the class of these substances which were effective against malignant growth.

It has now been found that the novel quinazolone diurethanes of the general formula I

(I) where,

R 'is cyclohexyl optionally substituted with 1 to 5 carbon atoms or alkyl with 1 to 5 carbon atoms optionally substituted with hydroxy,

R ¹ předsta U is ⁱⁿ the alk ^yl Kupino ^having 1 to 4 carbon uhHku ⁴ or ^{phenyl group,} the pop ^{of manufacture} pa ^ ^ga subs substituted alkyls having from 1 to 4 carbon atoms and / or methoxy, exhibit strong cytostatic properties.

20Q248

According to the invention, the quinazolondiurethanes of the formula I are obtained by quinazolondiamines of the formula I! '(II)

II R ¹

wherein ^R1 has the previously listed Eny ^d, are reacted with acid derivatives of formula III

where

R is as defined above, optionally in the presence of acid binders.

When 2- (1'-aminophenyl-4-phenyl-b-amirio-N-3H) -quinazolone and methyl formate are used as starting materials, the reaction scheme may be illustrated as follows:

2HCI

O

II H

H ₃ CO-CN

The quinazolondiamines of the general formula II which serve as starting materials in the process according to the invention can be obtained in a manner known per se by catalytic hydrogenation of the corresponding dinitro compounds.

These dinitro compounds can be prepared by the previously described process (German Published Applications No. 1,809,174 and DOS 1,809,175) by reacting nitroanthranilic acids and N-substituted nitrobenzimide chlorides in a polar solvent such as acetone in the presence of an aliphatic tertiary amine such as triethylamine, at a temperature ranging from 0 to 50 ° C nebo.tak that nitroanthranilic acid reacted with nitrobenzoyl chlorides ^yl. for MMN ^also tells uo ^{d d d} and ^h benzoxazinonii CIC 'and these intermediates, ^d uct ^Y' is ^H and NEC ^s rea ^g ovata · s' · primary aliphatic or aromatic amines. In both cases, a first part intermediates which 'may be thermally in an organic solvent such as glycerine, p ^s heat ^you. above ¹⁰⁰ DEG C. or by dehydrating ^T and ^H --N ^{No No} INID ^l, e.g. ^IKL and ^d ^ ⁵ ° in ^{N-Met hy} pyrrolidone, cyclized to a dinitro compound.

Alkyl or cycloalkyl radicals H · optionally contain one or more, preferably one or two substituents. · ¹

The starting compounds of the formula III are known substances.

^J as ⁱⁿ c zřeSovadla ^hook zejí ^at from ^para uso ^b u ^{d p} o le ^y n and ^l in the UVA cut ^hr for any extended Oust ^{d p} Ia which do not react with the compounds of the formulas II and III.'Přednostně however. using . such solvents in which both the starting materials and the end products are well soluble. As solvents, for example, aliphatic ketones, such as acetone, aromatic hydrocarbons, such as benzene, toluene or chlorobenzene may be used, but Ν, Ν-dialkylamides · lower aliphatic carboxylic acids, such as dimethylformamide or dimethylacetamide, or N-alkyl lactams, such as N -methylpyrrolidone.

All conventional acid-binding agents can be used as acid binders.

In all cases in which the solvent itself does not bind acids, it is recommended to bind the resulting hydrochloric acid with inorganic or organic bases, preferably tertiary organic bases, such as alkaline earth or alkali metal carbonates, and their hydroxides such as sodium hydroxide. potassium carbonate, calcium carbonate, sodium bicarbonate, triethylamine, or pyridine.

The reaction temperatures may be within a wide range in the reaction of the compounds of formulas II and III. Q »in ^gamma, E is ^{P s} RAC ranging from about -10 ° C to about 100 ° C, ^eg e ^d in preference in the range ^of 0-50 ° C.

Preferably, at least about 2 moles of the compound of formula (III) is used per mole of the compound of formula (II) in the process of the present invention. to about 1: 3 «

The reaction of the compounds of the formula II with the compounds of the formula III can be carried out not only in solution. but optionally also in suspension or emulsion, for example in water. In these cases, however, it is recommended to use a larger excess of the compounds of formula (III). . .

Non-limiting examples of compounds of the present invention which can be used as therapeutic agents include, but are not limited to:

Table '1

6.

HOr — CHn — CHn — o — C— ² II o

NH-C-O-CH ₂ CH ₂ OH o

In the following examples, parts by weight (parts by weight) have k parts by volume (vol.

parts) as kilograms per liter or grams per milliliter.

Example 1

From 2- (3'-aminophenyl) -3-phenyl-6-amino-4- (3H) -quinazolone and methyl chloroformate, 32.8 parts by weight of 2- (3-aminophenyl) -3-phenyl-6-amino -4- (3H) -quinazolone was dissolved in 150 parts by volume of N-methylpyrrolidone. At 25 ° C, 25 parts by weight of ethyl chloroformate were added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for a further 4 hours. The mixture is then poured into water, filtered off with suction and. product - recrystallizes from. addition of activated carbon from ethanol.

Yield of 2- [3 '- (methoxycarbonylamino) phenyl] -3-phenyl-6-methoxycarbonylamino-4- (3H) -quinazolone with 34 parts by weight (76.5% of theory)

Mp 248-251 ° C

The melting point depends very strongly on the crystallinity of the product. When the product is precipitated vv ^and amorphous form MME yt ^{b b} a a ^d point to ⁰ to 5 ° C lower napříktáčl and 198 ^{of the 200} ° C and ^{characterized} kd product was determined by infrared spectroscopy no impurities.

Analysis:

calculated: 64.86% C, 4.54% H, 18,0% 0, 12.61 % - N found: 64.8% C, .4,6% H, 18,4% 0, 12.6 % N Example 1 a d y 2 to 10

In a manner analogous to that described in Example 1, the quinazoline bisurethanes summarized in Table 2 are obtained from the corresponding diamines and corresponding chloroformic acid esters.

Table 2

Example

Formula

2.

3.

4.

5 <

O

Thawing temperature. % Theory

204-206. 86

262-265 79

252-254 71

195-198 68

Example

Formula

Melting point

H 3 C-O-C-NH

б.

234-235

266-268

7.

8.

143-145

267-270

9.

H ₃ COC-NH

NH-C-O-CH 3

C-O-CH 3

NH - C - O - CH 2 - CH 2 - OH o

The yield of the theory was added. methanol, the mixture is cooled with ice and the product is filtered off with suction.

32.8 pbw of 2- (3'-aminophenyl) -3-phenyl-6-amino-4- (3H) -chinazolonuse spo ¹⁰⁰ hraotnostn ^s Saying ^ly glyco Arbon ^ ^ u 3 ^{H d} in the ^{y also} play V ^{and 100} ° C. ^p o oc ^Capital Assignment

Yield of 2- 3 ' - [(3-hydroxy-ethoxycarbonylamino) -phenyl] -3-phenyl-6- (beta-hydroxyethoxycarbonylamino) -4- (3H) -quinazolone: 26 parts by weight (53% of theory)

Melting point 232 to 230 ° C. 235 ° C

As already mentioned, the novel compounds have good cytostatic efficacy, making it possible for them to be used in medicine, particularly in the control of lymphatic leukemia. The new compounds therefore represent an enrichment of the current technique.

The good activity of the compounds of the invention was tested in a model of transplanted lymphatic leukemia L 1210 in mice (Table 5), and the experiments were performed as follows:

t

M ^y S ^and MO weight. 18 to ²² . g ^(strain B6 D2 ^{F1) and} NTRA lo ^{p p} eritone ^and adheres ODAN 2x10 ^ cells of leukemia L 1210 in 0.2 ml of 'ascites fluid.

Treatment was initiated 24 hours after transplantation of leukemia cells and a 4X intraperitoneal dose was administered every subsequent day.

The experiment time was 2 to 3 weeks.

To evaluate the outcome, the survival index was determined as follows:

If the survival time of the 50 control group is considered to be 100%, it may be as follows. survival pattern 50 treated group x 100 survival index = ^-1 . .......... - Survival time of the 50 control group to determine the value that serves as a measure of the change in survival time of the treated animals *

Assessment:

Values <100% indicate a reduced survival time of the treated group of animals, i.e., the toxic effects of the preparation.

Values <100% indicate an increase in survival time of 50 and height. index can be compared to tumor growth suppression.

Table 5

The compound of Example no.

Leukemia L 1210-optimal dose mg / kg body weight 4. x intraper.

Survival Index%

100 1,047

350913

700187

200113,3

The novel compounds are preferably administered orally or intraperitoneally.

The novel compounds can be used either as such or in combination with non-toxic inert pharmaceutically acceptable carriers. Suitable dosage forms for the administration of the active compounds in combination with various inert carriers include tablets, dragees, capsules, granules of aqueous suspension and emulsion, non-aqueous emulsion and suspension, syrups, and the like. non-toxic organic diluents and the like. Of course, sweeteners and the like may be added to tablets and other dosage forms. The therapeutically active compound should be present in the above forms at a concentration of about 0.1 to 99%, preferably 0.5 to 90% by weight of the total composition.

The formulations are manufactured. by known methods, for example by mixing the active compounds with diluents and / or carriers, optionally using emulsifiers and / or dispersants.

Carriers and / or auxiliary agents include, for example, the following substances:

200248 8

Water, non-toxic. Organic solvents or diluents, such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut and sesame oil), alcohols (e.g., ethyl alcohol, glycerin), glycols (e.g., propylene glycol, polyethylene glycol); solid carriers such as natural mineral meals (for example kaolins, clays, talc, chalk), synthetic mineral meals (for example highly disperse silicic acid, silicates), sugar (for example raw, lactic and grape sugar), emulsifiers such as non-ionic and anionic emulsifiers (for example polyoxyethylated fatty acid esters, polyoxyethylated fatty alcohol ethers, alkylsulfonates and erylsulfonates), dispersants. (e.g., lignin, methylcellulose, starches and polyvinylpyrrolidone), glidants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate). Tablets can. of course, as already mentioned, in addition to the aforesaid carriers, also additives such as sodium citrate, calcium carbonate and middle calcium phosphate, together with various others. admixtures ,. glidants such as magnesium stearate, sodium lauryl sulfate and talc. . V. In the case of suspensions and emulsions, the active compounds can be mixed not only with the active ingredient. above-described adjuvants, but you ^out with rčiznýml. ^ ttami. ^PS badly uj ^í The more ^even flavor and dyes. ₄

The active ingredients may be contained in capsules, tablets, lozenges, dragees, and ampoules. etc., also in unit amounts, each dosage unit being formed to contain a single unit dose of the active ingredient.

The novel compounds may also be present in the formulations in the form of mixtures with others. known active substances. .

In general, about 50 to 300 mg / kg body weight per day has been found to be advantageous for achieving good results. Nevertheless, it may be necessary to reduce the amount, depending on the type and body weight of the object to be treated, its individual tolerability of the medicament, the type of preparation and the administration of the medicament, as well as the time or interval of administration. . So can be in some. cases sufficient and less than the abovementioned lowest quantity, while. in other cases the upper limit of this range must be exceeded. In the case of administration of larger amounts, it is sometimes recommended to divide. total daily dose into multiple individual doses.

Claims (11)

A process for the preparation of novel quinazolone diurethanes of the general formula I wherein R is cyclohexyl optionally substituted with 1 to 5 carbon atoms; alkyl. p. 1 to 5 carbon atoms optionally substituted by hydroxy; ^{R p} pose a and a ^{plurality of projections} ls ^k u ^pi comprising ¹ to ⁴ and ^t om ^y u ^hlík at or phenylsulfanyl ^to in ^p-well, after ^P of ^IP, and ^d of a substituted alkyl group having 1 to 4 carbon atoms and / or methoxy, characterized by quinazolondiamines of formula II (II) NH ₂ R &lt; ¹ & gt ^; is as defined above, and reacted with the acid derivatives of formula III Cl-C-O-R (III) wherein R is as defined above. 2. A process according to claim 1, wherein the compound of formula II is 2- (3'-aminophenyl) -3-phenyl-6-amino-4- (3H) -quinazolone and the compound of formula III is methyl ester. chlormravenčí. / 3. A process according to claim 1, wherein the compound of formula II is 2- (3'-aminophenyl) -3-phenyl-6-amino-4- (3H) -quinazolone and the compound of formula III is ethyl ester. chlormravenčí. 4. A process according to claim 1, wherein 2- (3'-aminophenyl) -3- (4'-methoxyphenyl) -6-amino-4- (3H) -quinazolone is used as the compound of formula II and of formula (III) methyl chloroformate. 5. A process according to claim 1, wherein 2- (3-aminophenyl) -3- (2-tolyl) -6-amino-4- (3H) -quinazolone is used as the compound of formula II and of formula III of methyl chloroformate. 6. A process according to claim 1, wherein 2- (3'-aminophenyl) -3- (3'-methoxyphenyl) -6-amino-4- (3H) -quinazolone is used as the compound of formula II and of formula (III) methyl chloroformate. 7. The process of claim 1, wherein the compound of formula (II) is used. 2- (3-aminophenyl) -3-methyl-6-amino-4- (3H) -quinazolone and as the compound of formula III methyl chloroformate. 8. A process according to claim 1, wherein the compound of formula II is 2- (4'-aminophenyl) -3-phenyl-6-amino-4- (3H) -quinazolone and the compound of formula III is methyl ester. chlormravenčí. 9. A process according to claim 1, wherein the compound of formula II is 2- (3'-aminophenyl) -3-phenyl-7-amino-4- (3H) -quinazolone and the compound of formula III is methyl ester. chlormravenčí. 10. The method of claim 1, wherein as the compound of formula II is 2- (4-aminophenyl ^from) -3-phenyl-7-amino-4- (3H) -quinazolones, and as compounds of formula III Methyl chlorniravenčí. 11. A process according to claim 1, wherein 2- (3'-aminophenyl) -3-phenyl-6-amino-4- (3H) -quinazolone is used as the compound of formula II and tert. butylhexyl chloroformate.