FI56967B - FRAMEWORK FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC KINAZOLONDIURETANER - Google Patents

Description

rz \ ral. ,,. advertisement publication „ä ^ (11) UTLÄGGNINGSSKRIFT 56 967 C Patent granted on 12 05 1930

Patent aeddelnt ^ T ^ (51) Ky.lk.Vint.CI.1 C 07 D 239/9 * 1 FINLAND - FINLAND (21) p »t *" «lh» k «BU * - P * t * ntwwölcnln * 2837/71 (22) Hik «ml * pllvl - An * Oknln {tdt | 11.10.71 * * (23) Starting point — Giltl | h« tidaj 11.10.71 (41) Tullut | ulkit «k * i —Bllvlt off« ntli |

National Board of Patents and Registration Nlhtlvllulpanon |. moon | ulks | Wn pym.-

Patant- oeh registerstyrelsen Antökan utlagd och utl.skrift «n publkerad 31.01.80 (32) (33) (31) Pyydutty ttuolkuut —Byjird priority! 10/13/70

Federal Republic of Germany-Förbunds republiken Tyskland (DE) P 2050092.9 (71) Bayer Aktiengesellschaft, Leverkusen, Federal Republic of Germany-Förbunds-republiken Tyskland (DE) (72) Hans-Egon Kiinzel, Dormagen, Gerhard Dieter Wolf, Dormagen, Wuppert, Robert Bierling, Robert Elberfeld, Siegfried Petersen, Leverkusen, Gunther Nischk, Dormagen, Dieter Steinhoff, Bochum, Federal Republic of Germany Germany (DE) (7 * 0 Oy Kolster Ab (54)

The present invention relates to a process for the preparation of novel quinazolone diurethanes which have utility as medicaments, in particular as cytostats.

It is already known that numerous quinazolone derivatives have hypnotic, sedative or muscle relaxant properties (cf. Angev. Chemie 74 (1962), 885-861). In addition, nitro-, hydroxy-, and hydroxylamino-substituted 2,3-dihydro-2-phenyl-4- (1H) -quinazolines are known to have cytotoxic activity (U.S. Patent 3,455,920).

The invention relates to a process for the preparation of therapeutically useful quinazolone diurethanes of the formula 0

X C

0-J-> h-c-O-r wherein X is oxygen or sulfur, R is an alkyl group having 1 to 5 carbon atoms optionally substituted with NR'g, furyl, tetrahydrofuryl, phenyl, phenoxy, 2

Not 696 with a pyrrolidinyl, piperidinyl, hexahydroazepinyl, imidazolyl, triazolyl or hydroxyl group, and R 'is alkyl of 1 to 3 carbon atoms, or R is cycloalkyl of 5 or 6 carbon atoms optionally substituted with 1 An alkyl group having 1 to 1 carbon atoms, and R 1 is an alkyl group having 1 to 1 carbon atoms or a phenyl group optionally substituted by one or two alkyl groups having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom.

The process according to the invention is characterized in that (a) an amine of the formula 0 "R1 / V / C \ N / v-foT j, in which the formula has the same meaning as above, is reacted, optionally in the presence of an acid-binding agent, with

Y - C - 0 - R III

11 X

wherein X and R are as defined above and Y is halogen, -OcOR 2, -OR 2 or -S-CH 8 -COOH, wherein R 1 is an alkyl group preferably having 1- 1+ carbon atoms, or (b) a diisocyanate or dithioisocyanate of formula 0

"1 C ^ / H

wherein X and R are as defined above, is reacted, optionally in the presence of an inactive solvent, with the formula

R - OH V

in which R in the formula has the same meaning as above.

When 2- (3'-aminophenyl) -3-phenyl-6-amino-k- (3H) -quinazolone and chloroformic acid methyl ester are used as starting materials, the reaction procedure can be shown by the following scheme: 2 3 56967 νΊ @ £ ° "i 0- ^

N 2 C Vy / v ^ / SHp + 2 Cl-C-OCH

w s η ϊ Γο)

H_C0-C-Nv p _ / V

3> ^ V C'N

"TOJ

When 2- (3'-isocyanatophenyl) -3-phenyl-6-isocyanato-β- (3H) -quinazolone and methanol are used as starting materials, the reaction procedure can be shown by the following scheme: 2 (O) OCl, X- ^ sv / ^ C> '» + 2 CH OH -) XPJ 1 3 »^ C 'φ'» tsC '_ «2 N * ν0γ-Ν-Ο-ΟΟΗ3

In formulas I, II and IV, R 1 is most preferably a straight-chain or branched alkyl radical having 1-U carbon atoms. The phenyl radicals R 1 may have one or two substituents. The substituents are most preferably halogen atoms, in particular fluorine, chlorine or bromine atoms, alkyl groups having 1 to 3 carbon atoms, in particular 1 or 2 carbon atoms, or alkoxy groups having 1 to 3 carbon atoms.

The diamines of formula (II) used according to the invention can be prepared by known methods by catalytic hydrogenation of the corresponding dinitro compounds, which in turn can be prepared (cf. DOS 1 809 17 ^ and 1 809 175) from nitroanthranilic acids and N-substituted nitrobenzimide dichlorides in a polar solvent such as e.g. in acetone, in the presence of an aliphatic tertiary amine such as triethylamine at temperatures of 0-50 ° C, or by reacting nitroanthranilic acids and nitrobenzoyl chlorides to the corresponding benzoxazinones, and reacting this intermediate with primary aliphatic or aromatic. In both cases, partially intermediates are first obtained which can be thermally cyclized in an organic solvent, e.g. glycerol, above 100 ° C, or with dehydrating agents, e.g. e.g. P 2 O 2 in N-methylpyrrolidone, to dinitro compounds.

The diisocyanates of the formula IV used according to the invention can be prepared by known methods from the diamines of the formula II, e.g. by phosgenation of the hydrochlorides in chlorobenzene at 80-120 ° C.

The dithioisocyanates of the formula V used according to the invention can also be prepared from the diamines of the formula II by known methods in reaction with thiophosgene, e.g. at 15-35 ° C in the presence of CaCO 3 as an aqueous suspension. β-Hydroxyurethanes can be prepared from diamines by reaction with glycol carbonates.

The compounds of the formula III and the alcohols of the formula V used as starting materials are known.

Suitable diluents for process variant (a) (reaction of compounds of the formula II with compounds of the formula III) are all solvents which do not react with the compounds of the formulas II and III. Preferably, however, solvents are used in which both the starting materials and the final products are highly soluble. As the solvent, for example, aliphatic ketones such as acetone, aromatic hydrocarbons such as benzene, toluene or chlorobenzene are used; -metyylipyrrolidonia.

The solvent used in process variant b) is preferably an excess of hydroxyl compound V. However, the reaction can also be carried out in the presence of inert diluents, such as, for example, dioxane, aromatic hydrocarbons, dimethylformamide, dimethylacetamide or N-methylpyrrolidone.

As the acid-binding agents, all the usual acid-binding agents can be used in process variant (a).

In all cases where the solvent itself is not an acid scavenger, it is preferred to scavenge the resulting hydrochloric acid with inorganic or organic, preferably tertiary, organic bases, e.g. alkaline earth and alkali carbonates and hydroxides, such as NaOH, K 2 CO 2, NaHCO With triethylamine or pyridine.

In the central reaction of the compounds of the formulas II and III (process option (a)), the reaction temperatures can vary within wide limits.

5,56967 p. ..0

Generally, work is between about -10 ° C and about 100 ° C, preferably between 0 ° C and 50 ° C.

In the central reaction of the compounds of formulas IV and V (process option (b)), the reaction temperatures can be varied within wide limits. In general, work is carried out between about 10 and about 120 ° C, preferably between 25 and 80 ° C.

In carrying out process variant (a) according to the invention, at least 2 moles of a compound of the formula III are preferably used per mole of the compound of the formula II, in particular the molar ratio of the compounds of the formulas II and III is about 1: 2.1-1: 3

The reaction of a compound of formula II with a compound of formula III can take place not only in solution but also optionally in suspension or emulsion, e.g. in water. However, in these cases it is recommended to use a larger excess of compound III.

When carrying out process variant (b) according to the invention, it is used, if the hydroxyl compound of the formula V does not act as a solvent, always about 1 to 10 moles, in particular 2.2 to 6 moles, of the hydroxyl compound of the formula V per mole of the compound of the formula IV.

When the free hydroxyl compounds of formula V are reacted with the compounds of formula IV (process variant (b)), it is preferable to add small amounts of a basic catalyst, e.g. triethylamine, pyridine, triethylenediamine or dimethylcyclohexylamine. This catalyst is added in an amount of about 0.1 to about 5% by weight based on the total weight of the reaction charge.

In the following examples, which illustrate the process according to the invention, the ratio of parts by weight to parts by volume is the same as the ratio of kilograms to liters or the ratio of grams to milliliters.

Example 10 from α-C-NH-C-O-CH3 a) 2- (3'-aminophenyl) -3-phenyl-6-amino-U- (3H) -quinazolone and chloroformic acid methyl ester 32 .8 parts by weight of 2- (3, -aminophenyl) -3-phenyl-6-amino-U- (3H) -quinazolone are dissolved in 150 parts by volume of N-methylpyrrolidone. At 2-5 ° C, 25 parts by weight of chloroformic acid methyl ester are added dropwise under ice-cooling. Stirring is then continued for a further U hour at room temperature, the mixture is poured into water, filtered off with suction and recrystallized from ethanol with the addition of activated carbon. Yield of 2- [5 '- (methoxycarbonylamino) phenyl] -3-phenyl-6-methoxycarbonylamino-U- (3H) -quinazolone: 31 * parts by weight (76.5% of theory); mp. 2U8-51 ° C.

b 5696?

The melting point is very much dependent on the crystallinity of the product; if the product is obtained amorphous, the melting point can always be lower than 50 ° C, e.g. 198-200 ° C, although the product does not contain impurities according to analysis and IR studies.

Analysis:

Calculated: C 6 J, 86%, H h, 5b%, O 18.0%, N 12.61% Found: C 6 J, 8%, H 1 *, 6%, O 18, J JS, N 12, 6%.

b) 2- parts by weight of 2- (3'-isocyanatophenyl) -3-phenyl-6-isocyanato-4- (3H) -quinazolone and methanol 2- (3'-isocyanatophenyl) -3-phenyl-6-isocyanato-U - (3H) -quinazolone and 2 volumes of triethylamine are heated in 200 volumes of methanol at reflux for 30 minutes. The mixture is then poured into water and recrystallized from ethanol.

Yield of 2- [2 ', - (methoxycarbonylamino) -phenyl] -3-phenyl-6-methoxycarbonylamino-1 - (3H) -quinazolone: 36 parts by weight (81% of theory); mp. 2 ^ 3-2U5 ° C.

Analysis:

Calculated: C 6bt86%, H% * 0 18.0%, N 12.61% Found: C 6U, 7%, H U, 7%, 0 18.2%, N 12.8%.

2- (3'-Isocyanatophenyl) -3-phenyl-6-isocyanato-U- (3H) -quinazolone is obtained from 2- (3'-aminophenyl) -3-phenyl-6-amino-U- (3H) -quinazolone as follows: : 164 parts by weight of 2- (3'-aminophenyl) -3-phenyl-6-amino-U- (3H) -quinazolone are suspended in 1000 parts by volume of anhydrous chlorobenzene. Dry hydrogen chloride is introduced into the suspension until at least the amount of hydrochloric acid gas required for the formation of the dihydrochloride is bound. Phosgene is then introduced into the mixture until the clear solution is formed at 80-100 ° C. The mixture is then stirred at a further 100 [deg.] C. for 1/2 hour and then nitrogen is blown through the clear solution and evaporated to dryness in vacuo.

The white product obtained as a residue is pure 2- (3'-isocyanatophenyl) -3-phenyl-6-isocyanato-U- (3H) -quinazolone according to IR studies. Sp. 153 ~ 155 ° C.

Other diisocyanates used as starting materials can be prepared in an analogous manner.

Example 2-12

In analogy to Example 1a), quinazolone diurethanes summarized in Table 2 are obtained from the corresponding diamines and the corresponding chloroformic acid esters.

Table 2

Example Formula Melting point ° C. Rule?" from theoretical J Jo) H5C2-0-C-NH-j ^ j / U 20U-206 86 0 'vx ^ N ^ C-vgYNH-C-O-C2H5 0 3. ° C1-XN 250-53 72 H1c-ocm - ^ r'0'f-1 ^ 0. <^ to) - ,, hJ0-ch3 SG967 ί _ * 62-65 79 c V ^)

HjC-OCW. ^ -N ^ 252-5 «71 oe HjC-OO-HH ^ - ^ nJ ^ Lo-CIIj 195-98 68 o kAH« -c-0rifH-so-cHj jj C1Ä «, Ο-Ο- Ο-ΝΗγ ^ Ν ^ ^ S ^ CJ ^ J-NH-CO-CII ^ 166-70 76 o

B

II COC-NH-r ^ v '' 8 · 0 ^ vN- * ° 1 ^ flra "g'0'CH3 2J! |" 35 88 9i K, C-O-C-8H- (liN ^ 0 '' N'® O 1 ^ AkSSC - ^ - NH-C-O-C11j 266-68 72 LNjg) ......

h50-oc-nhJQ ^ -CO-CH, 1 * 3- «: 69 Λγ® 11. H ^ coc-mi 0: 267-70 67 56967 8 en, S fQ] 155-158 58 ^ 0 ·? λ ^ 0 ·? '' Κη'ι6) Γ / - \ i! L5 0 C1I_

Example 13-24

In analogy to Example Ib), the quinazolone diurethanes shown in Table 3 are prepared from the diisocyanate and corresponding alcohols indicated therein.

Table 3

Example Formula Melting point Yield $ theo from retic no 1 (Qj 10e-112 79 13 '> - ° H -CH, -O-C-KH-jÄf Oli

'V i ^ N ^ Clgrml-S-O-CH2-CII2 "Vc„ J

H C. ^. . L JQ) 126-129 6 '*

14. 7 CN-CH2-CH2- ° t'Ml6r // CA

7 3 4 ^ ^ ε-0ΝΗ - = - ° -α, 2-ΟΙ! 2-νο ^ se- ™ S jQ) 127-130 15. H <1 Ϊ-CH -OC-NH-fÄf '° ^ jT ^ HO-CjH 92 H c-ch2 B 189-200 99 16. HC CH-CH -OC-HH-J ^ N ^ 1 ^ C-CH ^ S ^ \ 1 ^ C ^ rKH-C-O-CH2- CH ^ o ^ CH2 17. ^ Vch -ο-ο-ΝΗ- ^ ν0 '' ·} ^ 1i> 5-15 / 95 9 56967 Ο. '•' χ.

18 0OT '"wN' ^ \« 5-150 39 6 ^ N ^ c- [Q) ra, 1-o0 S j [0ί 19 90-95 84 o ^ N ^ c - ^ - m: -co-cii2 .-CH2-o - (^) 2 ° [^ .CH ^ CH ^ OC-NH ^ 0- ^ 161-164 ^ _ ^ 0 V ^ n ^^ nh-Jo-ch2-ch2-i (7 | » j? 3) 21 (^ N “cVCH2 ~ °“ J ”ratQ] / GSs5iX, AV ^ 175-178 96.» ^ N '* i ^ MI-OO-CH2-CH2-i0. - 8 ^ 0t ^ KHT ° "" 2'Cli2 "0 OI? 23. Q- ™ 2-ch2-oJ-kh ^ ·" Λ "1 146-Ί50 95

IQJ g 2 2 \ * rN

,, «= \ F. 160-165 74

24. U ^ 'CH2 "CH2" ° ^ “KKTQT ^ ί T x — H

Example 25 * jdj HO-CII -CII -O-C-mi-r ^ v '' ^ h ^ 0 2 2 li 10) JV j n

0 ^ NN ^ '°' fQrI3n "c - 0 - C: i;> - C] I2.-02I

SG987 32.8 parts by weight of 2- (31-aminophenyl) -3-phenyl-6-amino-4- (3H) -quinateolone are heated together with 100 parts by weight of glycol carbonate for 3 hours at 100 ° C. After cooling, methanol is added, cooled with ice and filtered off with suction. Yield of 2 [3 '- (p-hydroxyethoxycarbonylamino) -phenyl] -3-phenyl-6- (β-hydroxyethoxycarbonylamino) -4- (3H) -quinazolone: 26 parts by weight (53% of theory); mp. 232-235 0 »

Example 26 (o) HO-CH «-CH-CH - O-C -NH-

'' O I

OH ok A. 0 OH

—Nh-c-o-ch2-ch-ch2-oh Dissolve 13 parts by weight of 2- (3 * -isocyanatophenyl) -3-phenyl-6-isocyanato-4- (3H) -quinazolone in 60 parts by volume of anhydrous dimethylformamide. 60 parts by weight of glycerol dissolved in 60 parts by volume of anhydrous dimethylformamide and 5 parts by volume of triethylamine are then added. It is then stirred for 1 hour at room temperature and for 4 hours at 60 [deg.] C., then poured into water, filtered off with suction and dried.

Yield of 2 [3 '- (β, Y-dihydroxypropyloxycarbonylamino] -phenyl] -3-phenyl-6- (β, Y-dihydroxypropylocycarbonylamino) -4- (3Η) -quinazolone: 15 parts by weight (67% of theory) mp 172-74 ° C.

Analysis:

Calculated: C 59.6 #, H 4.96 96, 0 25.55 H $ 9.95> Found: C 59.1 H 5.1 #, 0 24.9 #, H 10.0 56.

According to NMR studies, the product contains only small amounts of isomeric 2- [3 '- (bis-hydroxymethylmethoxycarbonylamino) -phenyl] -3-phenyl-6- (bishydroxymethylmethoxycarbonylamino) -4- (3H) -quinateolone.

HO-H-C. n I O I

HC-O-C-NH- °

HO-H C ^ '' IU I 1 CH2-0H

N 2 -NH-C-O-CH

[OJ ö XCHj-0H

56987 11

Example 27 H5C-T ’(p1

K _NH-C-O-CH

PO I "5 parts by weight of metallic sodium are dissolved in 150 parts by volume of absolute methanol. 34 parts by weight of 2- (3'-isothiocyanatophenyl) -3-phenyl-6-isothiocyanato-4- (3H) -quinazolone are then added and stirring is continued for 1 liter. / 2 hours at room temperature (about 20 ° C) and for a further hour at 40 ° C. The solution is filtered off with suction to remove small amounts of insoluble, the filtrate is mixed with water and acidified with hydrochloric acid, the precipitate is filtered off with suction and dried at 50 ° C. Yield of 2- [3 '- (methoxythiocarbonylamino) phenyl] -3-phenyl-6-methoxythiocarbonylamino-4- (3H) -quinazolone: 30.3 parts by weight ($ 78 of theory); 158 ° C.

Analysis:

Calculated: C 60.5 #, H 4.2 0 10.1 N 11.75 #, S 13.4 1 ° Found: C 60.1 #, H 4.5 #, 0 10.4 N 12, 0 #, S 13.0 56.

The 2- (3'-isothiocyanatophenyl) -3-phenyl-6-isothiocyanato-4- (3H) -quinazolone used as starting material is prepared as follows:

To a mixture of 240 parts by volume of water, 130 parts by volume of ethylene chloride, 60 parts by weight of calcium carbonate and 32 parts by weight of thiophosgene are added portionwise at 0.5 ° C 65.5 parts by weight of 2- (3'-aminophenyl) - 3-phenyl-6-amino-4- (3H) -quinazolone. It is then stirred for a further 18 hours at room temperature. It is then filtered off with suction, the precipitate is taken up in dilute hydrochloric acid, filtered off with suction again, washed until neutral and the residue is mixed with methanol and dried in vacuo. Yield: 67 parts by weight ($ 81.4 theoretical).

Other diisothiocyanates used as starting materials can be prepared analogously.

Example 28-2?

In analogy to Example 27, the quinazolone bistiourethanes shown in Table 4 are prepared from 2- (3'-isothiocyanato) -3-phenyl-6-isothiocyanato-4- (3H) -quinazolone and the corresponding sodium alcoholates.

56967 12

Table 1+

Example Formula Melting point Yield% of theoretical (° C) 28 ° C 91-93 72.5

• Η3α- (0Η2) 3-Ο-0-ΝΗ- ^ C

S-j ^ j-nh-co- (ch2) 3-ch3 H3C \ "/ (^) 128-136 87 29. N-CH2-CH2-O-C-NH-jgv'Cn ^ N ^ CH3 H3c / S ^ ^ L-fgv ^ ra-CO-CHj-CHj-B ^ S CH3

As already mentioned, the new compounds show good cytostatic activity, which allows their use in medicine, especially in the fight against lymphocytic leukemia. In addition, the compounds of the formula I have a specific mechanism of action (arrest of mitosis in metaphase), which makes them suitable for use in the treatment of cancer. The production of new compounds thus enriches the technology.

The effect of the compounds of formula I was tested in mice using an experimental method in which mice were implanted with lymphocytic leukemia L 1210 (Table 5). The experiments were performed as follows: Mice weighing 18-22 g (strain B 6 D 2 F 1) were injected intraperitoneally with 2 x 10 5 leukemia sol (L 1210) in 0.2 ml of ascites fluid.

Treatment was performed on U x consecutive days by intraperitoneal administration, and treatment began 2 h after leukemia cell transplantation. The trial period was 2-3 weeks.

To evaluate the experimental results, the survival time index (HJA index) was calculated as follows: If the survival time 50 of the experimental group is set to 100 #, the formula HJA index = HJA 50 of the treated group 50 x 100 quotient of the control group HJA 50 shows the change in HJA during processing.

Judgment:

Values ^ 100% indicate a shortened lifespan of the treated group of animals and thus the toxic effect of the preparation. Values ^ 100% indicate an extended survival time of 50, which always indicates the inhibition of tumor growth according to the size of the index.

S6967 13

Table 5

Compound from Example Leukemia L 1210 optimal Survival time No. (Tables 2 and 3) dose mg / kg (body weight) index% hx intraperitoneally 1 100 10l + 7 2 350 913 3 100 187 5 700 187 7 175 126.7 9 200 113, 3 22 25 113.3

The use of the new compounds is most preferably carried out orally, possibly also intraperitoneally.

The novel compounds can be used either alone or in combination with non-toxic, inert pharmaceutically acceptable carriers. In the above case, the therapeutically active compound is present in concentrations of about 0.1 to 99%, preferably 0.5 to 90% by weight, based on the total weight of the mixture.

The new compounds can also be in the form of mixtures with other known active ingredients.

In general, it has been found advantageous to administer amounts of from about 50 mg to about 300 mg per kg of body weight per container per day to obtain effective drug results. Nevertheless, it may sometimes be necessary to deviate from these amounts, depending on the condition and weight of the patient being treated, the individual attitude of the patient to the medication, the quality of the composition and the mode of administration, and the time or time of medication. Thus, in some cases it may be sufficient to use lower amounts than the above-mentioned minimum amounts, while in other cases it is necessary to exceed the said upper limit. In the case of administration of larger amounts, it may be advisable to divide them into several single administrations per day.

Claims (2)

56967 1lt Patent Entry: A process for the preparation of therapeutically useful quinazolone diurethanes of the formula O-R-o-c-Hn. IQ II (&) - Μγ ~ * wherein X is acid or sulfur, R is an alkyl group having 1 to 5 carbon atoms optionally substituted with NR ', - furyl, tetrahydrofuryl, phenyl, phenoxy, pyrrolidinyl, piperidinyl, hexahydroazepinyl, imidazolyl, triazolyl or hydroxyl, and R 'is alkyl of 1 to 3 carbon atoms, or R is cycloalkyl of 5 or 6 carbon atoms optionally substituted with 1 to 1 carbon atoms. alkyl group, and R 1 is an alkyl group having 1 to 1 carbon atoms or a phenyl group optionally substituted by one or two alkyl groups having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, characterized in that (a) SR 1 of formula 0 An amine of formula [m - "« a wherein R 1 is as defined above is reacted, optionally in the presence of an acid scavenger, with an acid derivative of formula Y - E - O - R m X wherein X and Rhave the same meaning as above, and Y is a halogen, -O 2 OR 1 group, -OR 2 group or -S-CH -COOH group, in which 2. in the formulas, R is an alkyl group preferably having 1 to 1 carbon atoms, or (b) a diisocyanate or dithioisocyanate of formula 15 56967 xc »- {oT" 0> T ^] q4- wherein X and are as defined above is reacted, optionally in the presence of an inactive solvent, with a compound of formula R - OH V. with an alcohol in which R has the same meaning as above. 16 b 6967 Förfarande för framställning av therapeutiskt användbara kinazolondiuretaner med formeln 0. f? p 'ROC-HN-f ^^ V ^ C'> V'N 1: Τοζ.,. ί -BH-COR color X is a substituent or a moiety, R is an alkyl group having 1-5 cholaters, optionally substituted with en NR 1 -, furyl, tetrahydrofuryl, phenyl, phenoxy, pyrrolidinyl, piperidinyl, hexahydroazepinyl, imidazolyl, triazolyl or hydroxyl, and R 1 is an alkyl group with 1-3 cholaters, or R is a cycloalkyl group having 5 or 6 colaters, optionally substituted with an alkyl group of 1-1 + a colatomer, and an alkyl group having a 1-U colatom having a phenyl group, optionally substituted with an alkyl group having 1-3 cholatomer, alkoxy group with 1-3 cholaters or halogen atoms, turns of which are derived from (a) en Amin with form / r1 y — HD f color R ^ har ovannämnda betydelse, omsättes, eventuellt i närvaro av ett syra-bindande medel, med en syraders with formulas Y - C - 0 - R III 11 X o "2 color X and R are ovalated, and Y is halogen, en -OCOR group, en 2 2 -OR -group or -S-CH 2 -COOH-group, ι vilka formler R is an alkyl group with a 1-1 + cholate atom, or (b) a diisocyanate or dithioisocyanate with a formula