FI56836C - 4-SUBSTITUTES OF PIPERAZIN-1- (N-ARYL-N'-CYANO) -CARBOXIMIDAMIDER BUTTER OF THE BREAST PREPARATION WITH PHARMACOLOGICAL PROPERTIES 6,7-DIMETOXY-ELLER 6,7,8-TRIMETOXY-2-AMINO -SUBSTITUERADE-Piperazine-1-YL) -KINAZOLINER - Google Patents

Description

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Patent and registration authorities Anaekan utiagd och uti.skriften pubikerad jy -jr · (32) (33) (31) Requested privilege — Begird prlorltet (71) Fermion Oy, Box 28, 02101 Espoo 10, Suomi-Finland (Fl) "( (72) Heinrich Thaler, Espoo, Finland-Finland (FI) (5U) U-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamides, which are intermediates in the preparation of pharmacologically valuable 6,7-dimethoxy or 6 , 7,8-trimethoxy-U-amino-2- (U-substituted-piperazin-1-yl) -quinazolines - U-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamide, som 6-dimethoxy- or 6,7,8-trimethoxy-U-amino-2- (U-substituent-piperazin-1-yl) -quinazoline as a pharmacologically active substance

The invention relates to novel 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamides which are used as starting materials or intermediates in the synthesis of antihypertensive 6,7-dimethoxy 4-amino-2- (4-substituted-piperazine-1 -yl) -quinazolines and 6,7,8-trimethoxy-4-amino-2- (4-substituted-piperazin-1-yl) -quinazolines.

2 S6836 4-Substituted piperazine-1- (1R-aryl-N'-cyano) -carboximide amides of the formula R1 NHCSN_ CH-Dv ^ vN = C - (/ \ - R2 3 TOT V_ / (I ) can be prepared by either 1) administering a compound of formula

r1 T

= c - n; , N - R2 3 Toi w UI) ch3oA / or a salt thereof react with cyanamide or a salt thereof or when Y = NH2 with halocyanide most preferably in the presence of an equivalent amount of an inorganic or tertiary organic base in an inert solvent, or 2) by administering a compound of formula Ϊ / \ 2 N = C- N = C- - R (III) or a salt thereof to react with a compound of formula R1

ChUCK / ^ 'v-NhL · 3 ΊΟΤ 2 (IV) CH3D ^ \ / or a salt thereof in an inert solvent and especially if Y = NH2 with a diazonium salt of formula R1 3 TOJ 2 (V) οη3οΆΛ and the resulting compound is cleaved with nitrogen or 56836 3 3) administering a compound of formula R 1 i

ChUOv ^^ N = C - NH - C Ξ N

3 TO] (VI) CH 3 O 2 or a salt thereof react with a compound of formula f - 2 H - (VII) in an inert solvent and in the case where Z = SH in the presence of a desulfurizing agent and in the case where Z = OH triphenyldichlorophosphorane or triphenylphosphine / In the presence of CCl 4 or 4) administering a compound of formula R 1 NHCN

cHoOv ^^ n = c - n; , N - H

To react with RX in an inert solvent and wherein R 2 is hydrogen or methoxy and R is alkenyl of 3-5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, cyclopentylcarbonyl, alkoxycarbonyl of 2 to 5 carbon atoms, alkenyloxycarbonyl of 4 or 5 carbon atoms, (2-hydroxyalkoxy) carbonyl of 4 or 5 carbon atoms or of formula 0

R JS —rj ^ j — ΟΝ-N

3, wherein R is an alkyl group having 1 to 6 carbon to 3 atoms or a benzyl group, Y is Cl, Br, NH 2, SH, SR and OR ', 3 1 3 wherein R is as defined above, Z is OH, SH, SR or 3 3 2 OR, where R is as defined above and when R = alkenyl, X is Cl, Br, methanesulfonyl or p-toluenesulfonyl, in other cases X is Cl, Br or phenoxy.

S6636 The four processes described herein differ in that in process 1) 4-substituted piperazine-1- (N-aryl) -carboxylic acid amide or thioamide derivatives are first prepared, which are subsequently converted to the desired 4-substituted 1-piperazine-1 (piperazine) with cyanamide or halocyanide. -aryl-N'-cyano) -carboximidamides, the second method uses 4-substituted piperazine-1- (N-cyano) -carboxylic acid amide or thioamide derivatives as starting materials, the latter of which is allowed to react with arylamines or the diazonium salts mentioned above, and the third method aryl N'-cyanoureas or thioureas, preferably converted to the most reactive intermediates, are reacted with R-substituted piperazines.

Method 4) is a modification of method 3) in which, instead of 4-substituted piperazines, piperazine is reacted with intermediates prepared from N-aryl-N'-cyanoureas or similar thioureas and the group R is attached to the compounds by RX . Figure 1 shows these 4 methods.

The methods used are mainly described in Houben Weyl's "Methoden der organischen Chemie" in Part VIII "Carbohydrate Derivatives" and in Part IX "Schwefelhaltige Kohlensaurederivate", hereinafter abbreviated as HW, the number following the abbreviation refers to the page.

Figures 2 to 5 show the synthesis of Compound I from different starting materials, with Figures 2 and 3 showing different alternatives to Method 1, Figure 4 Method 2 and Figure 5 Methods 3 and 4. All variables are the same as listed above.

The starting materials required in Method 1 can be prepared in a number of ways using known reactions. For example, piperazimes in which the nitrogen atom has a substituent R can be converted by means of a chlorocarbonic acid phenyl ester in a known manner (HW VIII / 138) into the corresponding 4-substituted piperazine-1-carbonic acid phenyl esters, which in turn react in a known manner with (HW VIII / 161) aryl form 4-substituted piperazine-1- (N-aryl) carboxylic acid amides. These compounds can also be prepared by converting arylamines with the corresponding N-arylcarbamic acid phenyl esters (HW VIII / 138) with S6836 chloro-carbonic acid phenyl ester and reacting them with another nitrogen R-substituted piperazune in a nitrogen atmosphere or by modifying the arylamines with ] to the corresponding isocyanates, which in turn react with the second nitrogen-substituted piperazines to form 4-substituted piperazine-1- (N-aryl) -carboxylic acid amides (HW VIII / 157) .These 4-substituted piperazine-1- (N-aryl) carboxylic acid amides, which can also be considered as N, N, N'-trisubstituted urea derivatives, are modified in a manner known per se [Review R. Appel, Angew. Chem. 87, 863-874 (1975), also R. Appel et al., Chem. Ber. 106, 2093-2097 (1973], R. Appel et al., Chem. Ber. 107, 698-705 (1974], R. Appel, Chem. Ber 108, 606-617 (1975], R. Appel et al., Chem. Ber. 110, 2382-2384 (1977]] triphenylphosphine with a carbon tetrachloride system or with dihalotriphenylphosphorane and triethylamine (halogen = Cl, Br] in an organic solvent such as methylene chloride, benzene or acetone · trile to 4-substituted piperazine-1- (N-aryl] carboximide halides. These highly reactive and moisture-sensitive compounds are not isolated but are directly converted to the desired 4-substituted piperazine-1- (N-aryl-N'-cyano] -carboximidamides by reacting them with cyanamide. If benzene-separated hydrogen halide salts are used as the solvent or as an oil, which are converted in solution into the free compounds, which are purified by crystallization from a suitable organic solvent, for example toluene, isopropanol or ethyl acetate.

Alternatively, 4-substituted piperazine-1- (N-aryl] carboximide halides can be converted to 4-substituted piperazine-1- (N-aryl) carboxylic acid imido esters with a lower aliphatic alcohol, which in turn react with the cyanamide to liberate the alcohol. however, the method does not offer significant benefits.

The starting materials for the first process can also be obtained by reacting arylamine hydrochlorides with thiophosgene (HW IX / 877] to give aryl isothiocyanates which are converted to 4-substituted by N-monosubstituted piperazines 6 S 6 8 3 6 piperazine-1- ( N-aryl) -carboxylic acid thioamides (HW IX / 891) Such compounds are known (HW IX / 900) to be converted by alkyl halides into S-alkyl derivatives which react with cyanamide in a suitable solvent such as a lower aliphatic alcohol or aqueous alcohol solution - preferably thus that two equivalents of a suitable base are present, such as NaOH, KOH or NaGCH 4, NaOC 2 H 9, etc. - releasing mercaptan to 4-substituted piperazine-1- (N-aryl-N'-cyano) - To isolate the product, the solvent is distilled off in vacuo, the residue is dissolved in a water-insoluble organic solvent such as CH 2 Cl 2, CHCl 3, etc., and the solution is washed with water. an in vacuo and the residue is recrystallized from a suitable solvent.

If desired, arylamines (HW VIII / 180) can be added to the 4-substituted cyanopiperazines in a known manner to give 4-substituted piperazine-1- (N-aryl) -carboximidamides which can be used as starting materials for the desired 4-substituted piperazine-1- ( Na ry in the preparation of over-N'-cyano) -carboximidamides. The starting materials can also be prepared by coupling mercaptans to 4-substituted 1-cyanopiperazines (HN IX / 904) and finally exchanging the mercapto group for arylamine (HW VIII / 184).

Furthermore, 4-substituted piperazine-1- (N-aryl) carboximidamides can be prepared by known reactions (HW VIII / 175, IX 877, 888, 890, 894, 900, 904) starting from aryl cyanamides prepared from arylamines and N-aryl-S alkyl isothiol urea when reacted in a known manner with N-monosubstituted piperazines (HW VIII / 182, 184).

4-Substituted piperazine-1- (N-aryl) carboximidamides obtained by any of the above methods are reacted with a cyanogen halogen to be added in an equivalent amount; the reaction is carried out in a suitable organic solvent such as CH 2 Cl 2, CHCl 3, etc., to which an equivalent amount of triethylamine is preferably added. Further work-up can follow the procedure already described above: the solution is washed with water, the solvent is evaporated off and the residue is recrystallized.

56836 7

Method 2 uses N-monosubstituted piperazines as starting materials. These can be converted in a known manner to (HW VIII / 161) 4-substituted piperazine-1- (N-cyano) carboxylic acid amides. These can be considered as N, N, N'-trisubstituted urea compounds and can be converted in a known manner (R. Appel, loc. Cit.) To 4-substituted piperazine-1- (N-cyanocarboximide halides which can be converted without isolation by arylamines. to the corresponding 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximide amides, which can be isolated as already described above.Again, the 4-substituted piperazine-1- (N-cyano) -carboximide halides can be converted with alcohol first to the corresponding 4-substituted piperazine-1-CN-cyano) -carboxylic acid functional esters, which in turn react with arylamines to liberate the alcohol to give the desired compounds. This method of synthesis also has no significant advantages.

Alternatively, Method 2 can be performed by converting N-mono-substituted piperazines with N-cyanodithiourea esters (HW IX / 895-6) to 4-substituted piperazine-1- (N-cyano) carboxylic acid thioamides, which are converted after alkylation of a sulfur atom. with arylamine to 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamides, while releasing mercaptan.

Further, Method 2 can be performed by reacting N-monosubstituted piperazine salts with sodium dicyanamide in a known manner (FH Curd et al. Soc. 1948, 1630) to give 4-substituted piperazine-1- (N-cyano) carboximidamides which react in a known manner. (FHS Curd et al., Soc. 1946, 729, and HW VIII / 210) with aryldiazonium salts and form triazine derivatives which are not further characterized but which are converted to the desired 4-substituted piperazine-1- (N-aryl) by hydrochloric acid. -N'-cyano) -carboximidamides, the same 11a releases nitrogen.

Method 3 uses the corresponding arylamines as starting materials, which are converted into the corresponding aryl isocyanates or aryl isothiocyanates by means of phosgene (HW VIII / 120) or thiophosgene (HW ΙΧ / Θ77). These give either N-aryl-N'-cyano-ureas (HW VIII / 134) or N-aryl-N'-cyanothiureas (HW IX / 892) with the aid of sodium cyanamide. Cleavage of water from the N-aryl-N'-cyanourea, as described by, for example, R. Appel (loc. Cit.) With triphenylphosphine / carbon tetrachloride or dichlorotriphenylphosphorane gives N-aryl-N'-cyanocarbodiimides having is reacted without isolation with N-monosubstituted piperazines to give 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamides.

In the case of N-aryl-N'-cyanothioureas, they are treated with a desulfurizing agent such as HgO, PbO, Ag2G, etc. (HW VIII / 183) in the presence of N-monosubstituted piperazines, in which case N-aryl However, N'-cyano-carbodiimides which immediately react immediately with N-monosubstituted piperazines to form 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamides.

In a variation of the above method, the N-aryl-N'-cyano-thio-ureas react with the alkyl halides to form N-aryl-N'-cyano-S-alkyl-isothiol ureas (HW IX / 900) which further react with N with monosubstituted piperazines to cleave mercaptan to form 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamides.

To prepare the starting material for Method 4, the N-aryl-N'-cyano-S-alkyl-thiourea substances described in Method 3 above are reacted with an excess of piperazine (HW VIII / 182) to give piperazine-1- (N-aryl-N '- cyano) -karboksimidiamideja.

2 These are converted to 4-substituted piperazine-1- (N-aryl-N'-cyano) -carboximide amides by R X using known methods, e.g. by the method of Schotten-Baumann or Einhorn.

The intermediates in question are very useful substances in the preparation of antihypertensive 6,7-dimethoxy-4-amino-2- (4-substituted-piperazin-1-yl) -quinazolines and 6,7,8-trimethoxy-4-amino- 2- (4-substituted-piperazin-1-yl) -quinazolines, compounds according to Finnish application 773168. The above end products can be prepared directly without isolating these intermediates. The method is very well suited for industrial production of 56836 9, due to its fewer work steps, higher yield and economy.

The following examples further illustrate the invention:

Example 1

To a suspension of 10.8 g of 4- (furo-2-yl) -piperazine-1- (N-3,4-dimethoxyphenyl) carbonamide and 10.2 g of triphenylphosphine in 250 ml of absolute benzene is added dropwise 2.9 ml of carbon tetrachloride, stirred at room temperature overnight and refluxed for another hour. A saturated solution of 1.4 g of cyanamide in absolute benzene is added dropwise to a clear, yellow solution of 4- (furo-2-yl) -piperazine-1- (N-3,4-dimethoxyphenyl) -carboximide chloride at room temperature.

4- (Furo-2-yl) -piperazine-1- [1,1'-cyano-N '- (3,4-dimethoxyphenyl)] -carboximidamide separates as the hydrochloride and is filtered off. Yield: 10.38 g (82.4% of theory), mp 130 ° C (unclear), IR (free base) (KBr): NH 3235 cm -1, OH (OCH 3) 2855 cm -1, C 2185 and 2160 cm 1 (syn / anti), C = O 1660 cm 1, C> N = 1520 cm 1 (broad), OCH 2 1255-1235 cm 1 (double).

Example 2 The procedure of Example 1 is repeated, but the 4- (furo-2-yl) piperazine-1- (N-3,4-dimethoxyphenyl) carboxamide used therein is replaced by an equivalent amount of the following compounds:

4-allyl-A

4-benzoyl-A

4- (furo-3-yl) -N

4- (allyloxycarbonyl) -N-

4- (2-methylprop-2-enyylioksikarbonyyli) -A

4- (5-methylthio-1,3,4-oxadiazole-2-carbonyl) -N

Where A = piperazine-1- (N-3,4-dimethoxyphenyl) carbonamide.

This gives 10,56836 4-allyl-B, yield 67.1%, m.p. 123 ° C (unclear), IR (KBr): NH 3255 cm -1, CH 2925 and 2845 cm -1, C = N 2155 and 2145 cm -1 (syn / anti),> C = N-1535 cm -1 (syn / anti) broad), OCH 2 1260-1235 cm -1 (double) 4-benzoyl-B, yield 78.4%, mp 135 ° C (unclear), IR (KBr): NH 3240 cm -1, CH 2840 cm -1 , C = N 2195 cm-1 (wide), C = 0 1645 cm-1,> C = N-1550 cm-1 (wide), OCHg 1225-1195 cm-1 (double) 4- (furo-3- yl) -B, yield 72.5%, m.p. 127 ° C (unclear), IR (KBr): NH 3230 cm -1, CH 2855 cm -1, CSN 2180 and 2170 cm -1 ** (syn / anti) C = 0 1655 cm 1,> C = N-1510 cm 1 (broad), OCH 2 1250-1225 cm -1 (double) 4- (allyloxycarbonyl) -B, yield 63.2%, mp 120 ° C (unclear), IR (KBr): NH 3190 cm -1, CH 2920 and 2820 cm -1, C = N 2200 and 2175 cm -1, C = 0 1705 cm 1,> C = N-1570 cm 1 (broad), OCH 2 and ester 1275-1170 cm -1, (multiple) 4- ( 2-methylprop-2-enyloxycarbonyl) -B, yield 57.8%, m.p.

118 ° C (unclear), IR (KBr): NH 3205 cm -1, CH 2940 and 2855 cm -1, C = N 2195 and 2185 cm -1, C = 0 1710 cm -1,> C = N-1580 cm'1 (wide) 0CH_

-1 J

and ester 1260-1175 cm (multiple) and 4- (5-methylthio-1,3,4-oxadiazole-2-carbonyl) -B, yield 68.9%, m.p. 132 ° C (unclear), IR (KBr): NH 3215 cm 1, CSN 2160 cm 1 (broad), C = 0 1640 cm 1,> C = N-1535 cm 1 (broad), OCH 2 1260-1230 cm 1 (double) hydrochloride, where B = piperazine-1- [N-cyano-N '- (3,4-dimethoxy-phenyl)] -carboximidamide, each product can be isolated by filtration.

Example 3

To a suspension of 10.3 g of 4- (furo-2-yl) -piperazine-1- [N- (3,4-dimethoxyphenyl) -5-methyl] -imidothiol ester hydroiodide in 100 ml of absolute methanol is first added a solution , containing 0.9 g of cyanamide in 10 ml of methanol and then a solution of 2.2 g of sodium methylate in 20 ml of methanol is stirred under a nitrogen atmosphere at room temperature for 24 hours. The solvent is then evaporated off under reduced pressure and 100 ml of methylene chloride and 50 ml of water are added to the residue, which is stirred briefly. The methylene chloride phase is separated and washed several more times with water until the washings are neutral. The methylene chloride is evaporated in vacuo and the oily residue is crystallized from ethyl acetate. The 4- (furo-2-yl) piperazine-1- [N-cyano-1 '- (3,4-dimethoxyphenyl)] carboximidamide thus obtained is identical to the free base which can be obtained from the product of Example 1. Yield: 6.75 g (88.1% of theory), m.p. 130 ° C (unclear), IR (KBr): similar to Example 1.

Example 4 7.7 g of N-2,3,4-trimethoxyphenyl-5-methylisothiol urea and 6.2 g of 1- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazine is dissolved in 100 ml of methylene chloride and heated under reflux until the evolution of methyl mercaptan ceases. After cooling to 0 [deg.] C., 4.5 ml of triethylamine are added and 3.2 g of bromocyanine dissolved in any methylene chloride are then added dropwise to the solution. The mixture is stirred for 2 hours at 0 ° C and then for 6 hours at room temperature. The solution is washed several times with water to remove the triethylamine hydrobromide formed and then dried over sodium sulfate. The solution thus obtained contains 4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) -piperazine-1- [1N-cyano-N '--- (2,3,4-trimethoxyphenyl)] - carboximidamide, which can be isolated from solution as described in Example 3 by evaporating the solvent and finally crystallizing the compound. Yield: 9.95 g (76.2% of theory), m.p. 115 ° C, IR (KBr): OH 3385 cm -1 N ~ H 3310 cm -1 C = N 2135 and 2120 cm -1 (syn / anti), C = 0 1705 cm -1,> C = N-1580 cm -1 (broad), 0CH 3 and ester 1230-1170 cm (multiple).

Example 5

To a suspension of 9.7 g of 4-allyl-piperazine-1- (N-cyano) -carboxylic acid amide and 17.0 g of triphenylphosphine in 200 ml of benzene are added dropwise 4.9 ml of carbon tetrachloride, stirred for 24 hours at room temperature under protection from moisture. To the resulting yellow solution of 4-allyl-piperazine-1- (N-cyano) -carboximide chloride 12,56836 is added dropwise a saturated solution of 9.2 g of 2,3,4-trimethoxyniline in absolute benzene, stirred for two hours at room temperature and the precipitated 4 -allyl-piperazine-1-O-1-cyano-N '- (2,3,4-trimethoxyphenyl) -carboximidamide hydrochloride is isolated by filtration Yield: 11.97 g (60.5% of theory), mp 114 ° C (unclear), IR (KBr): NH 3210 cm -1 C 21 N 2150 cm -1 (broad),? C = N-1595 cm -1 (broad), OCH 2 1260-1190 cm -1 (multiple) .

Example 6

To a suspension of 15.6 g of 4- (furo-2-yl) -piperazine-1- (N-cyano-5-benzyl) -imidothiol ester hydrochloride in 150 ml of methanol is added a solution of 2.16 g of sodium methylate. In 20 ml of methanol and stir for half an hour. 6.2 g of 3,4-dimethoxyaniline are then added and the mixture is heated under reflux until the evolution of mercaptan ceases. The solvent is evaporated in vacuo and the residue is dissolved in methylene chloride-water. The synthesis is continued as in Example 3. The product gives 4- (furo-2-yl) -piperazine-1- [N-cyano-N'- (3,4-dimethoxyphenyl)] -carboxyimide. Yield: 10.82 g (71.2% of theory), m.p. 130 ° C (unclear), IR (KBr): similar to Example 1.

Example 7 To a cooled aqueous solution of 4-ethoxycarbonyl-piperazine-1- (N-cyano) -carboximidamide, a diazonium salt solution obtained by diazotizing 6.1 g of 3,4-dimethoxyaniline is slowly added; during the addition, a saturated aqueous solution of sodium carbonate is added portionwise to keep the reaction mixture slightly alkaline at all times. After the addition is complete, stir briefly and filter. The precipitate is washed with ice water and added portionwise at room temperature to a mixture of 150 ml of ethoxyethanol and 20 ml of concentrated hydrochloric acid, whereby nitrogen is released. After stirring for a while, the pH of the solution is adjusted to 7 with 5% sodium hydrogen carbonate solution, whereupon the final product 4-ethoxycarbonyl-piperazine-1- [N-cyano-N '- (3,4-dimethoxyphenyl) J-carboximidamide precipitates . The product is filtered and purified by recrystallization from ethyl acetate. Yield: 4.94 g (34.2% of theory), m.p. 115 ° C (unclear).

56836 13 IR (KBr): NH 3260 cm -1, C = N 2145 and 2135 cm -1 (syn / anti), C = 0 1720 cm -1, XN-1565 cm -1 (broad), OCH 2 and ester 1225-1 160 cm -1 (multiple).

Example 8 7.75 g of N-Cyano-N '- (3,4-dimethoxyphenyl) urea and 11.9 g of triphenylphosphine are dissolved in 125 ml of methylene chloride; 5.0 ml of triethylamine are added, followed by dropwise addition of 3.4 ml of carbon tetrachloride. The batch is stirred at room temperature overnight. A solution of 6.4 g of 1- (furo-2-yl) piperazine in 50 ml of methylene chloride is introduced into the N-cyano-N * - (3,4-dimethoxyphenyl) -carbodiimide solution thus obtained, stirred at room temperature. mode for two hours and cook for another hour with reflux. The methylene chloride solution is washed several times with water to remove triethylaminohydrochloride. The solvent is evaporated off under vacuum, the oily residue is taken up in dry benzene and 4- (furo-2-yl) -piperazine-1- [N-cyano-N- * (3,4-dimethoxyphenyl) -3-carboximidamide hydrochloride is precipitated by adding an alcoholic solution of hydrochloric acid. and isolated by filtration. Yield: 9.40% (74.6% of theory), m.p. 130 ° C (unclear), IR (KBr): similar to Example 1.

Example 9

To a solution of 5.35 g of N-cyano-N '- (2,3,4-trimethoxyphenyl) -thiourea and 3.7 g of 1- (furo-2-yl) -piperazine in 100 ml of methylene chloride, mixed with 25 g of mercuric oxide and boiled under reflux using a water separator. Boiling is continued until the separation of the water ceases, which normally takes about 10-15 hours. The resulting mercury sulfide is filtered off. Reaction product 4- (furo-2-yl) -piperazine-1- [N-cyano-N * - (2,3,4-trimethoxy-phenyl)] - carboximidamide can be isolated from a methylene chloride solution by removing the solvent and crystallizing the product as described above. way. Yield: 5.71 g (69.1% of theory), m.p. 121 ° C (unclear), IR (KBr): NH 3230 cm -1, C = H 21-5 and 2170 cm -1 (syn / anti), 0.56 cm -1 5 ° C = N-1525 cm -1 (broad) , OCHg 1270-1215 cm-1 (multiple).

66836 14

Example 10 12.6 g of N-cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiol urea and 12.9 g of piperazine are dissolved in 150 ml of isopropanol and heated under reflux until the evolution of mercaptan ceases.

When the solution thus obtained is cooled to -15 ° C, piperazine-1- [N-cyano-N '- (3,4-dimethoxyphenyl)] carboximidamide crystallizes, which is isolated by filtration. Yield: 10.63 g (73.5% of theory), m.p. 136 ° C (unclear), IR (KBr): NH 3245 and 3230 cm -1, C = N 2105 cm -1 (broad),> C = N-1540 cm -1, (broad), OCH 2 1265-1245 cm -1 (double) ).

Example 11 5, B g of piperazine-1- [N-cyano-N '- (3,4-dimethoxyphenyl)] -carboximidamide and 3.0 ml of triethylamine are dissolved in 75 ml of methylene chloride and a solution of 3.6 g of 5-methylthio-1,3,4-oxadiazole-2-carboxylic acid chloride in 25 ml of methylene chloride and, after the addition, are heated under reflux for 5 hours. The resulting triethylamine hydrochloride is separated by washing with water several times. The methylene chloride is removed and the residue is recrystallized from ethyl acetate. 4- (5-Methylthio-1,3,4-oxadiazole-2-carbonyl) -piperazine-1- [N-cyano-N '- (3,4-dimethoxyphenyl)] -carboximidamide is obtained. Yield: 7.62 g (80.3% of theory), m.p. 132 ° C (unclear), IR (KBr): similar to 4- (5-methylthio-1,3,4-oxadiazole-2-carbonyl) -B in Example 2.

Example 12

By repeating the procedure of Example 11, but using instead of 4-methylthio-1,3,4-oxadiazole-2-carboxylic acid chloride an equivalent amount of p-toluenesulfonic acid 1-yl ester, benzoyl chloride, furan-2-carboxylic acid chloride, carboxylic acid hydrochloride, thiophene-2-carboxylic acid hydrochloride, chloroic acid chloride, chloroic acid chloride, chloroic acid chloride, chloroic acid 15 gives 4-allyl-B, yield 80.1%, IR (KBr): similar to 4-allyl-B in Example 2 4-benzoyl-B, yield 85.6%, IR (KBr): similar to 4-Bent -soyl-B in Example 2, 4-Furan-2-carbonyl-B, yield 90.7%, IR (KBr): similar to Example 1

4-thienyl-2-carbonyl-B, yield 69.3%, m.p. 117 ° C (unclear), IR

(KBr): NH 3305 cm -1, CsN 2155 and 2140 cm -1 (syn / anti), C = 0 1665 cm -1,> C = N-1515 cm -1 (broad), 0CH 3 1270-1235 cm -1 1 (double) 4-propyloxycarbonyl-B, yield 74.2%, mp 127 ° C (unclear), IR (KBr): NH 3270 cm -1, C = N 2140 cm -1 (broad), C = 0 1715 cm -1, -1-1 ° C = N-1575 cm (broad), OCH 2 and ester 1265-1160 cm (multiple) 4-cyclopentylcarbonyl-B, yield 84.0%, mp 113 ° C (unclear ), IR (KBr): NH 3255 cm -1, C = N 2175 and 2165 cm -1 (syn / anti), C = O 1655 cm -1,> ON- 1560 cm -1 (broad), OCH ^ 1255-1200 cm 1 (double) where B = piperazine-1- [N-cyano-N '- (3,4-dimethoxyphenyl)] - carboximidamide, each compound can be isolated as described above.

Example 13 22.1 g of N-Cyano-N '- (3,4-dimethoxyphenyl) urea and 34.1 g of triphenylphosphine are dissolved in 350 ml of methylene chloride. 14.3 ml of triethylamine are added, followed by dropwise addition of 9.7 ml of carbon tetrachloride with stirring. The batch is stirred at room temperature overnight. To the N-cyano-N '- (3,4-dimethoxy-phenyl) -carbodiimide) solution thus formed is added a solution of 18.25 g of 1- (furo-2-yl) -piperazine in 100 ml of methylene chloride. . Stir for two hours at room temperature and heat for another hour at reflux. The ethylene chloride solution is washed a few times

Claims (2)

56836 16 with water to remove triethylaminohydrochloride. The solvent is partially removed by distillation. 300 ml of dimethylformamide are added and 7.3 g of HCl gas are introduced into the solution. After heating at 70 [deg.] C. for 12 hours, 200 ml of dimethylformamide are evaporated off by vacuum distillation. The residue is kept at 0 ° C for 5 hours. The precipitate formed is filtered off and washed with a small amount of cold dimethylformamide and dried at 100 ° C in vacuo to give 28.4 g (67.8% of theory) of 6,7-dimethoxy-4-amino-2- [4- (furo). 2-yl) -piperazin-1-yl] -quinazoline hydrochloride, m.p. 270-273 ° C. A compound which is an intermediate in the preparation of pharmacologically valuable 6,7-dimethoxy or 6,7, β-trimethoxy-4-amino-2- (4-substituted-piperazin-1-yl) -quinazolines, characterized in that the compound is 4-Substituted piperazine-1- (N-aryl-N'-cyano) -carboximidamide of the formula R 1 CH 2 O 5 / vNN. / —V ~ 3 ToT N: - <> -r2 ch3 ° ^ nh 'w cy III N 1 2 wherein R is hydrogen or methoxy and R is alkenyl of 3-5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, cyclopentylcarbonyl, alkoxycarbonyl, having 2 to 5 carbon atoms, alkenyloxycarbonyl having 4 or 5 carbon atoms, (2-hydroxyalkoxy) carbonyl having 4 or 5 carbon atoms or a group of formula 0 R Sf Yc-NN wherein R is an alkyl group having 1 to 6 carbon atoms or a benzyl group.