前苏联专利SU1063289A3 Process for preparing derivatives of 2-amino-1,4,5,6-tetrahydropyrimidine

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专利摘要:
Certain 1,4,5,6-tetrahydropyrimidine compounds which are substituted with an amino, amido or carbamate at the 2-position, with an optionally substituted phenyl at the 5-position or at the 4-position when there is no alkyl at the 1-position and optionally a lower alkyl at the 1-position when the phenyl is at the 5-position are useful as CNS agents and as antihypertensives.
公开号:SU1063289A3
申请号:SU802968601
申请日:1980-08-29
公开日:1983-12-23
发明作者:Курт Вейнхардт Клаус；Маркс Майкл
申请人:Синтекс (Ю.С.А.) Инк (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for the preparation of new 2-amino 1,4,5,6-tetrahydropyrimidine derivatives having antidepressant properties, which can be used in medicine.
The known reaction of converting bases into their salts by the action of an acid in a solvent or in the absence of a solvent and the conversion of a salt to a base by the action of alkali. The invention is the preparation of new 2-amino-1,4,5,6 tetrahydropyrimidine derivatives with valuable pharmacological properties.
A goal of 1 is achieved based on a known reaction by producing 2-amino-1, .4,5,6-tetrahydropyrimidine derivatives of the general formula {t
W-A | HB) „
hydrogen, alkylcarbonyl or
where alkoxycar bonil, in which alkyl with 1-6 carbon atoms;
X is hydrogen, fluorine, chlorine, bromine, iodine, hydroxy group, alkoxy with 1-4 carbon atoms, benzyloxy group, alktio, alkylthionyl or alkylsulfonyl group, in which alkyl with 1-4 carbon atoms, or trifluoromethyl;
Hydrogen or has the same meaning as X; hydrogen or alkyl with 1-4
R is carbon atoms and a phenyl substituent containing X and Y is in position 4 or 5 of the tetrahydropyrimidine ring if R is hydrogen, or in position 5 if R is alkyl with 1-4 carbon atoms;
HB p
-acid;
-Oh, or 1,
The method consists in that the base of the compound of the general formula I, where ntO, is converted to an acid addition salt of the general formula I, or the acid additive salt of the compound of general formula I, where ft: 1, is translated into the base of the general formula I, where Preparation of 3-phenylglutaronitride, 3- (2,6-Dichlorophenyl) glutaronitrile, PactBop 31.5 g of 2,6-dichlorobenzaldehyde, 39 g of cyanoacetic acid and 2.5 ml of piperidine in 100 ml of pyridine are heated in a water bath for 7 hours. Initial rapid carbon dioxide release is gradually slowed down. Most solvent
is removed under reduced pressure and the residue is dissolved in 400 ml of benzene. The solution is washed three times with water, three times with dilute sodium bisulfite, again with water, and then with a saturated solution of sodium bicarbonate. The solvent is removed under vacuum, the residue is recrystallized once from 50 ml of methanol and once from 50 ml of isopropanol. Obtain 12.3 g of 3- (2, b-dichlorophenyl) glutaronitride with so pl. 104-106С.
Similarly, by using the corresponding benzaldehyde instead of 2,6-dichlorobenzaldehyde, other 3-phenylglutaronitrileg 3-phenylglutaronitrile is obtained, i.e. 128134 s / 0, 02 mm Hg; 3 (2-chlorophenyl) glutaronitrile, bp 150С / 0,02 mm Hg; 3- (3-chlorophenyl) glutonitrile, 3- (4-chlorophenyl) glutaronitrile; 3- (2-fluorophenium; 1) glutaronitrile; 3- (3-fluorophenyl) glutaroЕ ittryl; 3- (4-fluorophenyl) glutaronitrile, b.p. 130-140-C / 0.005 mm Hg; 3- (2-bromophenyl) glutaronitrile; 3- (3-bromophenyl) glutaronitrile, so pl. 94-9bs;
3- (4-bromophenyl) glutaronitrile; 3- (2-iodophenyl) glutaronitrile; 3- (3-iodophenyl) glutaronitrile; 3- (4-iodophenyl) glutaronitrile; 3- (2,3-dichlorophenyl) glutaronitrile; 3- (2,4-dichlorofensh1) glutaronitrile, T.Sh1. 76-78C;
3- (3,4-dichlorophenyl) glutaronitrile; 3- (3,5-dichlorophenyl) glutaronitrile; 3- (2,5-dichlorophenyl) glutaronitrile; 3- (2,3-difluorophenyl) glutaronitrile; 3- (2,4-difluorophenyl) glutaronitrile; 3- (3,4-difluorophenyl) glutaronitrile; 3- (2,5-difluorophenyl) glutaronitrile; 3- (2,6-difluorophenyl) glutaronitrile; 3- {3,5-difluorophenyl glutaronitrile; 3- (2,6-dibromophenyl) glutaronitrile; 3- (2,4-dibromfevil) glutaronitrile; 3- (3,5-dibromophenyl) glutaronitrile; 3- (2,4-Diodophenyl) glutaronitrile; 3- (2, b-diiodophenyl) glutaronIItryl.
З- (З-Methoxyphenyl) glutaronitrile.
A solution of 25 g of meta-anis aldehyde, 27. g of cyanoacetic acid and 3 ml of piperidine and 120 ml of pyridine are heated in an oil bath at 22 h. The bulk of the solvent is removed under reduced pressure and the remaining oil is dissolved in ml of toluene. The solution is successively washed with equal volumes of water, 10% hydrochloric acid and saturated sodium bicarbonate solution. After this, the solution is concentrated under vacuum, the residue is distilled and 20.7 g of 3- (3methoxyphenyl) glutaronitrile are obtained, t. kip 146-153 C / 0.01 mm Hg. Art. Similarly, using instead of the meta-anisic aldehyde other substituted benalealdehydes, the derivatives of glutaronitrile are obtained: 3- (2-methoxyphenyl) glutaronitrile; 3- {4-methoxyphenyl) glutaronitrile; 3- (2-toxyphenyl) glutaronitrile; 3- (3-ethoxyphenyl) glutaronitrile; . 3- (4-ethoxyphenyl) glutaronitrile; 3- (2g propoxyphenyl) glutaronitrile; H- (3-propoxyphenyl) glutaronitrile; 3-4- (4-propoxyphenyl) glutaronitrile 3- (4-butoicophenyl) glutaronitrile; 3- (2-benzyloxyphenyl) glutaronitrile Z- (Z-benzyloxyphenyl) glutaronitrile 3- (4-benzsh; hydroxyphenyl) glutaronitrile T. square 140-143 C; 3- (2-methylphenyl) glutaronitrile; 3- (Methylphenyl) glutaronitrile; 3- (4-methylphenyl) glutaronitrile, T. KIP. 124-130 with / About, 02 mm of mercury. Art. ; 3- (2-ethylphenyl) glutaronitrile; 3- (3-ethylphenyl) glutaronitrile; 3- (4-ethylphenyl) glutaronitrile; 3- (2-isopropylphenyl) glutaronitrile; H- (W-isopropylphenyl) glutaronitrile; 3- (4-isopropylphenyl) glutaronitrile, kip -180s / 0.05 mm; 3- (2-trifluoromethylphenyl) glutaronitre 3- (3-trifluoromethylphenyl) glutaronitre 3- (4-trifluoromethylphenyl) glutaronitr 3- (2-methylthiophenyl) glutaronitrile; 3- (4-methylthiophenyl) glutaronitrile; 3 - (2-ethylthiophenyl) glutaronitrile; 3- (4-methylthiophenyl) glutaronitrile; 3- (2-butylthiophenyl) glutaronitrile; 3- (3-butylthiophenyl) glutaronitrile; 3- (4-methylthionylphenyl) glutaronitri 3- (4-ethylsulfonylphenyl) glutaronitrile ;. 3- (2,4-dimethoxyphenyl) glutaronitri 3- (2,6-diethoxyphenyl) glutaronitrile 3- (3,4-dibenzoyloxyphenyl) glutaronitrile; 3- (3 ,, 5-diethylthiophenyl) glutaronitri 3- (2,6-dimethylthionylphenyl). glutaronitrile; 3- (2,6-dimethylsulfonylphenyl) gluta ronitrile, etc. P. Obtaining derivatives of Z-phenylgl taramid. 3- (2,6-dichlorophenyl) glutaramide. 12.3 g 3- (2 ,. 6-dichlorophenyl) glutd ronitrile is dissolved in a mixture of 70 lots of concentrated sulfuric acid and 3 ml of water. This solution was allowed to stand for 2 days at room temperature, then poured onto: ground ice and neutralized with ammonium hydroxide. The solid precipitate is collected, washed with water, dried under vacuum, and 13.8 g of 3- (2,6-dichlorophenyl) glutaramide are obtained, T. square 221-225 s. Similarly, using 3-phenylglutaronitriles instead of 3- (2,6-dichlorophenyl) glutaro-nitrile, other 3-phenylglutaramides are obtained:. 3-phenylglutaramide, t. square 183-184 ° C; 3- (2-chlorophenyl) glutaramide, t. square 189 С; 3- (3-hLrrfonil) glutaramide; 3- (4-chlorophenyl) glutaramide; 3- (2-fluorophenyl) glutaramide; 3- (3-fluorophenyl) glutaramide; 13- (4-fluorophenyl) glutaramide, m. square 194196 ° C; 3- (2-b omfenil) glutaramide; 3- (3-yromophenyl) glutaramide, t. square 168-170s; 3- (4-bromophenyl) glutaramide; 3- (2. iodophenyl) glutaramide; 3- (3-iodophenyl) glutaramide; 3- (4-iodophenyl) glutaramide; 3- (2, 3-dichlorf. . enyl) glutaramide; 3- (2,4-dichlorophenyl) glutaramide, t. square 194-196C; 3- (3,4-dichlorophenyl) glutaramide; 3- (3,5-dichloro-phenyl) glutaramide; 3- (2,5-dichlorophenyl) glutars1mid; 3- (2,3-difluorophenyl) glutaramide; 3- (2,4-difluorophenyl) glutaramide; 3- (3,4-difluorophenyl) g. lutaramide 3- (2,5-difluorophenyl) glutaramide; 3- (2, b-difluorophenyl) glutaramide; 3- (3,5-difluorophenyl) glutaramide; 3- (2,6-dibromophenyl) glutaramide; 3- (2,4-dibromophenyl) glutaramide; 3- (3,5-dibromophenyl) glutaramide; 3- (2,4-diiodophenyl) glutaramide; 3- (2,6-diiodophenyl) glutaramide; 3- (3-Methoxyphenyl. a) glutaramide. 18.7 g of 3- (3-methoxyphenyl) glutaronitrile are dissolved in 250 ml of acetone. This solution is stirred in an ice bath and 125 ml of water, 40 ml of 30% hydrogen peroxide and 25 ml of 10% sodium carbonate are added. This mixture is left to stand at room temperature overnight, after which it is concentrated to a volume of 125 ml. The residue is cooled, the resulting crystalline precipitate is collected, washed with water, dried under vacuum, and 17.4 g of 3- (3-me hydroxyphenyl) glutaramide are obtained, t. square 161-1b2s. In a similar way, using other 3-phenyl glutaramides, the following 3- (substituted phenyl) glutaramides are obtained: 3- (2-methoxyphenyl) glutaramide; 3- (4-megoxyphenyl) glutaramide; 3- (2-ethoxyphenyl) glutaramide; 3- (3-etrxyphenyl) glutaramide; 3- {4-ethoxyphenyl) glutaramide; 3- (2-propoxyphenyl) glutaramide; 3- (3-propoxyphenyl) glutaramide; 3- (4-propoxyphenyl glutaramide; 3- (4-butoxyphenyl) glutaramide} 3- {2-benzyloxyphenyl) glutaramide; 3- {3-benzyloxyphenyl) glutaramide; 3- {4-benzyloxyphenyl) glutaramide, m. square 205-207 С; 3- (4-methylphenyl) glutaramide, t. kip 194-19bS; 3- (2-methylphenyl) glutaramide; 3- (3-methylphenite;) glutaramide; 3- (3-ethylphenyl) glutaramide; 3- (4-ethylphenyl) glutaramide; 3- (2-ethylphenyl) glutaramide; 3- (2-isopropylphenyl) glutaramide; 3- (3-isopropylphenyl) glutaramide; 3- (4-isopropylphenyl) glutaramide, t. kip . 192-193 C; 3- (2-trifluoromethylphensh1) glutaramide; 3- (3-trifluoromethylphenyl) glutaramide; 3- (4-trifluoromethylphenyl) glutaramide; 3- (2-methylthiophenyl) glutaramide, 3- (4-methylthiophenyl) glutaramide; 3- (2-ethylthiophenyl) glutaramide; 3- (4-ethylthiophenyl) glutaramide; 3- (2-butylthiophenylO glutaramide; 3- (3-butylthiophenyl) glutaramide; 3- (4-methylthionylphenyl) glutaramide; 3- (4-ethylsulfonolphenyl) glutamide 3 (2,4-dimethoxyphenyl) glutaramide; 3- (2, 2 -die1; hydroxyphenyl) glutaramide; 3- (3,4-dibenzyloxyphenyl) glutara 3- {3,5-diethylphenyl) glutaramide; 3- (3 l5-diethylthiophenyl) glutaramide; J3- (2,6-dimethylthionylphenyl) glutaram 3 (2, b-dimethylsulfonylphenyl) glutamide ,. Method for preparing 2-phenyl-1,3-propanediaminob. . 2- (3-methoxyphenyl-1,3-propanediamine. Prepare sol. Sodium hypobromite by the interaction of 27 g of hydroaceous sodium and 23 g of bromine in 200 ml of water at -3 ° C 15.2 g of 3- (3-methoxyphenyl) glutaramide is gradually (in equal parts) the sodium hypobromite solution. The mixture is stirred at until the solution is clear, then stirred at room temperature for 1 hour and at the end for another 30 minutes at. The mixture is cooled and extracted with two eleven portions of methylene chloride, 70 ml each, and two portions of toluene, 70 ml each. The combined extracts are dried with sodium sulfate, concentrated and distilled. Obtain 5.1 g of 2- / 3-methoxyphenyl) -1,3-prop diamine, t. kip mm Hg Art. A sample of the dihydrochloride of this compound is obtained by dissolving a few drops of the diamine in an ethanolic solution of hydrogen chloride and adding ether to the resulting solution to precipitate 2- (3-methoxy-phenyl) -1,3-propanediamine dihydrochloride, t. square 23,234 "S. In a similar way, using other 2-phenylglutaramides instead of 3- (3-methoxy-phenyl) -glutaramide, the following 2-phenyl-1,3-propanediamines are obtained: 2-phenyl-1,3-propanediamine, -t. kip 8587 0/2 mmHg Art. , the dihydrochloride has it. 258-262 C; 2- {2-chlorophenyl) -1,3-propanediamineN, T. kip 87-92s / 0.05 mm Hg. Art. , its dihydrochloride has t. pl, 253257 0; 2- (3-chlorophenyl) -1,3-propanediamine; 2- (4-chlorophenyl) -1,3-propanediamine; . 2- (2-fluorophenyl) -1,3-propanediamine; 2- (3-fluorophenyl) -1,3-propanediamine; 2- (4-fluorophenyl) -1,3-propane diamine, its dihydrochloride has t, mp, 292.5295 ° C; 2- (2-bromophenyl) -1,3-propanediamine; 2- (3-bromophenyl) -1,3-propanediamine, t, kip, 120-125 0 / 0.02 mm Hg. Art. , its dihydrochloride has t. pl, 260265 С; 2- (4-bromophenyl) -1,3-propanediamine; 2- (2-iodophenyl) -1,3-propanediamine; 2- (3-iodophenyl) 1,3-propanediamine; 2- (4-iodophenyl) -1,3-propandiamine; 2- (2,3-dichlorophenyl) -1,3-propanediamine; 2- (2,4-dich yurphenyl) -1,3-propanediamine, T. kip , 01 mm Hg. St ,, dihydrochloride it has t. square 268-270 ° C; 2- (3,4-dichlorophenyl) -1,. 3-propanediamine; 2- (3,5-dichlorophenyl) -1,3-propanediamine; | 2- (2,5-dichlorophenyl) -1,3-propanediamine; 2- (2,6-dichlorophenyl) -1,3-propanediamine, T. kip G26-128s / 0.5 mm Hg. Art. , dipicrates with t. square 253-255C; 2- (2,3-difluorophenyl) -1,3-propanediamine; 2- (2,4-difluorophenyl) -1,3-propanediamine; 2-- (3,4-difluorofensh1) -1,3-propanediamine; 2- (2,5-difluorophenyl) -1,3-propanediamine; 2- (2,6-difluorophenyl) -1,3-propanediamine; 2- (3,5-difluorophenyl) -1,3-propanediamine; 2- (3,6-dibromophenyl) -1,3-propanediamine; 2- (2,4-dibromophenyl) -1,3-propanediamine; 2- (3,5-dibromophenyl) -1,3-propanediamine; 2- (2,4-diiodophenyl) -1,3-propanediamine; 2- (2,6-diyodo-phenyl). -1,3-propanediamine; 2- (2-methoxyphenyl) -1,3-propanediamine; 2- (3-methoxyphenyl) -1,3-propanediamine; 2- (4-methoxyphenyl) -1,3-propanediamine; 2- (2-ethoxyphenyl) -1,3-propanediamine; 2- (3-ethoxyphenyl) -1,3-propanediamine; 2- (4-ethoxyphenyl) -1,3-propanediamine; 2-g (2-propoxy-1) -1,3-propanediamine; 2- (3-propoxyphenyl) -1,3-propanediamine; 2- (4-propoxyphenyl) -1,3-propanediamine; 2- {4-butoxyphenyl) -1,3-propanediamine; 2- (2-benzyloxyphenyl) -1,3-propanediam n; 2- (3-benzyloxyphenyl) -1,3-propanediamine; 2- (4-benzyloxyphenyl) -1. , 3-propanediamine; 2- {2-methylphenyl) -1,3-propanediamine; 2- (3-methylphenyl) -1,3-pg -) pandiamine; 2- (4-methylphenyl) -1,3-propanediamine; 2t- (2-ethylphenyl) -1,3-propanediamine; 2- (3-eth1phenyl) -1,3-propanediamine; 2- (4-ethylphenyl) -1,3-propanediamine; 2- (2-isopropylphenyl) -1,3-propanediamine; 2- (3-isopropylphenyl) -1, 3-propanediamine 2-C4-isopropylphenyl) -1, 3-propane diamine, t. kip 103 -108 C / 0.01 mm Hg. with dihydrochloride with t, pl. 284-287 with; 2- (2-trifluoromethylphenyl) -1,3-propanediamine; 2- (3-trifluoromethylphenyl) -1, 3-propanediamine; . 2- (4-trifluoromethylphenyl) -1,3-propanediamine; 2- (2-methyltilphenyl) -1,3-propane amine; 2- (4-methylthiophenide) -1, 3-propanediamine 2t (2-ethylthiophenyl) -1, 3-propanediamine 2- (4-ethylthiophenyl) -1, 3-propanediimine 2- (2-butylthiophenyl) -1,3-propidia 2 - (3-butylthiophenyl) -1,3-propanedia 2- (4-methylthionylphenyl) -1,3-propaideI amine; , -. . , . /, , ;; 2- (4 EtylsulfonylPhenyl) -1,3-propane daamine; 2- (2,4-dimethoxyphenyl) -1 / Z-propane amine; 2- (2, b-diethoxyphenyl) -1,3-propan-, amine-; V,. ,, 2- (3,4-dibeneyl-oxo-phenyl) -1,3-prdpanediamine; In 2- (3, 3-diethylthiophenyl) -1,3-propa-diamine; ; 2- {2,6-dimethylthionylphenyl) -, 3-propanediamine; 2- (2,6-dimethylsulfonylfenil) -1.3 propanediamine. Methods for obtaining K-. methyl 2-pheny-1, 3-propanediaminebv. 4/4 g of ethylene glycol a-gropaldehyde is hydrolyzed by the action of 40 ml of water and 250 mg of oxalic acid in 20 ml of ethanol for 1 hour. 1.4 g of N-methylhydrazine are added and the mixture is left to stand for 4 hours at room temperature. The mixture is then concentrated. To lg50 ml, an aqueous solution of sodium bicarbonate and is added. cheating the mixture with methylene chloride. . The extract is concentrated, distilled and. 2.2 g of 4,5-dihydro-1-methi 4-phenyl- (1H) -pyrazole are obtained, t. kip 66-. , 03 mmHg Art. molecular; weight, mass spectroscopically 160 (S) A mixture of 3.8 g of 4,5-dihydro-1-methyl4-phenyl- (1) pyrazole, 50 ml of 1 acetic acid, 10 ml of 10% hydrochloric acid and 1 g of the catalyst (5% platinum on carbon) is stirred under a hydrogen atmosphere for f -6 h until the calculated amount of hydrogen is absorbed. Death is filtered and the filtrate is concentrated under vacuum. The residue is treated with isopropanol and trluolo. and again concentrated to maximize the removal of water. The residue in ether is refluxed for 3 hours to form a nopoigKO-like solid compound, which is collected by filtration. After recrystallization from ethanol, N-methyl-2-phenyl-1, 3-propanediamine hydrochloride, t are obtained. square 2: 64-267 c. In a similar way, using ethylene glycol acetaldehyde found in the phenyl ring of atropaldehydes, N-methyl-2-3-substituted phenol is obtained. nyl-1,3 propanediamine; ; Y-methyl-2- (2-fluorophenyl) -1,3-pnpan | Diamine; N-methyl-2- (3-fluorophenyl) -1, 3-propanediamine; K-methyl-2- (4-fluorophenyl) -1 3-dropanamine; . N-methyl-2- {2-chlorophenyl) -1, D-propaneDiamine; . . ,,. , -; ; l , . N-methyl-2- (3-chlorophenyl) -1, 3-propanediamine; i N-methyl-2- (4-chlorofensh1) -1, Z-propane diamine; : K-methyl-2- (2-bromophenyl} -1, Z-propanediamine; K-methyl-2- (3-bromophenyl) -1, Z-propanediamine; L-methyl-2- {4-bromophenyl) -1 , Z-propanediamine; N-methyl-2- (2-irdphenyl) -1,3-propanediamine; N-methyl-2- (3-iodophenyl) -1, 3-propanediamine; N-methyl-2g (4-iodophenyl) -1.3-1gropanediamine; N-methyl-2- (2,4-dichlorophenyl) -1, 3-propanediamine-; -. N-methyl-2- (3,4-dichlorophenyl) -1, 3-propanediamine; N-methyl-2- (3,5-dichlrrphenyl) -1, 3-propanediamine; N-methyl-2- 2,5-dichlorophenyl) -1,3-pro-. pandiamine ;: N-methyl-2- (2, b-dichlorophenyl) -1,3-propanediamine; N-methyl-2- (2,3-difluorophenyl) -1,3-prprediamine; N-methyl-2- (2 4-diFluorophenyl) -1, 3-propanediamine ;; . N-methyl-2- (3,4-diphthyrphenyl) -1, 3-propane diamine; N-methyl-2- (2,5-difluorophenyl) -1, 3-propanedi-amine; , "-Methyl-2- (2, b-difftrrhenyl) -1, Z-propane diamine; N-methyl-2- (3,5-difluorophenyl) r1, 3-propanediamine; . ; N-methyl-2- (3,6-dibromophenyl) -1, 3-propanediamine; K-methyl-2- (2,4-dibromophenyl) -1, 3-propanediamine; E1-methyl-2- (3,5-dibrRmphenyl) -1,3-propanediamine; N-methyl-2- (2,4-diiodophenyl) -1,3-prprediamine; Cg-methyl-2- (2, b-diiodophenyl) -1, 3-propanediamine N-methyl-2- (3-hydroxyphenyl) -1,3-propanediamine; N-methyl-2- (2-methoxyphenyl) -1,3-pro pandiamine; M-methyl-2- (3-14etoxyphenyl) -1,3-pro pandiamine; M-methyl-2- (4-methoxyphenyl) -1,3-rfpo pandiamine; N-methyl-2- (2-ethoxyphenyl) -i, 3-propanediamine; K methyl 2- {3-ethoxyphenyl) -1,3-propanediamine; . N-methyl-2- (4-ethoxyphenyl) -1,3-propanediamine; N-methyl-; 2- (2-propoxyphenyl) -1,3-ol pandiamine; N-methyl-2- (3-propoxyphenyl) -1,3-ol pandiamine; N-methyl-2- (4-propoxyphenyl) -1,3-ol pandiamine; . . N-methyl-2- (3-isopropoxyphenyl) -1.3 propanediamine; M-methyl-2- (4-butoxyphensh1X-1,3-pro pandiamine; K-methyl-2- (2-benzyloxyphenyl) -1.3pprpiamine; L-methyl-2- (3-benzyloxyphenyl) -1.3-propanediamine; N-methyl-2- (4-benzyloxyphenyl) -1,3-propane diamine; N-methyl-2- (2-meth-Dphenyl) -1,3-propam diamine; C-methyl-2- (3-methylphenyl) -1,3-prop. diamine; N-methyl-2- (4-methylphenyl) -1,3-propa diamine; and 1 | -methyl-2- (2 ethylphenyl) -1,3-propane diamine; M-methyl-2- 3-ethylphenyl) -1,3-propane diamine; . . . N-methyl-2- {4-ethylphenyl) -1,3-propane diamine; N-methyl-2- (3-propylphenyl) -1,3-propanediamine ;: N-methyl-2- (g-isopropylphenyl) -1,3-propanediamine M-metsh-2- (3-propylpheny) -1 f 3- propandiamine; K-methyl-2- (4-isoprpylphenium), 3-propanediamine; No. Methyl-2- (4-0nuch1f vnil) -1,3-prop diamine; N-methyl-2- (2-trifluoroethylphenyl 1f3-propanediamine; N-methyl-2- 3-griffluoromethylphenyl) -1, pronandiamine g N-methyl-2- (4-triformor-FSH1phen1sh) r-l, prop dis1min; N-methyl-2- (2-methylthiofenyl) -1,3-ol pandiamine; N-methyl-2- (3-methylthiophenyl) fl 3 -pr pandiamine; K-1 methyl-2 (2-ethylthiofvil) -1,3-pro pandiamine; K-metsch1-2g (4-ethnylthiophenyl;) -1,3-pro pandiamnn; M-methyl-2- 2-wu (shtiofemil) -1,3-pr pandiamin; N-methyl-2- (3-butylthiophenyl) -1,3-propanediamine; N-methyl-2- (4-methylthionylphenyl) -1,3-propanediamine; N-methyl-2- (4-ethylsulfonylphenyl) -1,3-propanediamine; N-methyl-2- (2,4-dimethoxyphenyl) -1,3-propanediamine; N-methyl-2- (2j b-diethoxyphenyl) -1,3-propanediamine; N-methyl-2- (3,4-dibenzyloxyphenyl) -1.3-propanediamine; . N-methyl-2- (3, 3-diethylthiophenyl) -1,3-propanediamine; M-metsh1-2- (2,6-dimetiLthionylphenyl) 1, 3-propyamine; K-methyl-2- (2, b-dimethylsulfonylphenyl) - 1,3-p1eopanediamine. In a similar way, using : other N-alkyl hydrazines, such as N-ethyl hydrazine, N-propyl hydrazine, N-butyl hydrazine instead of N-methyl hydrazine, the following diamines are obtained: N-ethyl-2-phenyl-1,3-propanediamine; L-propyl-2-fenil-1,3-propanediamine; H-butyl-2-phenyl-1,3-propanediamine. Methods of obtaining 2-Fenshlgidar MIDA. 25 g of 4-fluorobenzyl cyanide and 3.5 ml of freshly distilled acrylonitrile are mixed. In this stirred mixture. A solution of 80 mg of sodium methoxide and 1 ml of methanol is added dropwise. At. an exothermic reaction proceeds by the addition of half sodium methoxide. After all sodium methoxide was added, the mixture was incubated for 2 hours in a water bath, then dissolved in toluene and washed with water. The toluene is removed by evaporation, the residue is separated by fractional distillation and. 18 g of 4-fluorobenzyl cyanide and 2 g of 2- (4-fluorophenyl) glutaroitrile are obtained, t, kip. 118-122s / 0.03 mm Hg. Art. A mixture of 2- (4-fluorofenx) glutaronitrile, 25 ml of concentrated sulfuric acid and 1 ml of water was left overnight at room temperature. The solution is poured onto 300 g of ice and then neutralized with ammonium hydroxide. The product is extracted with chloroform in a permanent extractor. After three days, crystals are formed, the crystals are collected and 3.61 g of 2- (4-fluorophenyl) glutaramide are obtained, t. square 154-157 C. ; In a similar way, using instead of 4-fluorobenzyl cyanide other benzyl cyanides, the following 2-phenylglutaramides, 2-fvnylglutaramide, are obtained; 2- (2-chlorophenyl) glutaramad; 2- (3-chlorophenyl) glutaramide; 2g (4-chlorophenyl) glutaramd; 2- (2-fluorophenyl) glutaramd; 2- (3-ft6phenyl) glutaramide; 2- (2-bromophenyl) glutaramide; 2- (3-bromophenyl) glutaramide; 2- (4-bromoNEF) glutaramide; 2- (2-iodophenyl) glutaramide; 2- (3-iodofenil) glutaramide; 2- (4-iodophenyl) glutaramide; 2- (2,3-dichlorophenyl) glutaramide; 2- (2,4-dichlorophenyl) glutaramide; . 2- (3,4-dichlorophenyl) glutaramide; 2- (3/5-dichlorophenyl) glutaramide; 2- (2,5-dichlorophenyl) glutaramide; 2- (2,3-difluorophenyl) glutaramide; 2- (2,4-difluorophenyl) glutaramide; 2- (3,4-difluorophenyl) glutaramide; 2- (2,5-difluorophenyl) glutaramide; 2- (2,6g-difluorophenyl) glutaramide; 2- (3,3-dif-EOrphenyl) glutaramide; 2- (2, b-dibromophenyl) glutaramide; 2- (2,4-dibromfenium) glutaramide; 2- (3,5-dibromophenyl) glutaramide; 2- (2,4-diiodophenyl) glutaramide; 2- (2, b-diiodophenyl) glutaramide; 2- (3-methoxyphenyl) glutardmid; 2- {2-methoxyphenyl) glutaramide; 2- (4-methoxyphenyl) glutaramide; 2-2-ethoxyphenyl) glutaramide; 2- (3-etofeiphenyl) glutaramide; . 2- (4-ethoxyphenyl) glutaramide 2- (2-propoxyphenyl) glutaramide; 2- (3-propoxyphenyl) glutaramide; 2- (4-propoxyphenyl) glutaramide; 2- (4-butocatel) glutaramide; 2- (2-benzyl-yoxiphenyl) glutaramide 2- (3-benzyloxyfnyl) glutaramide 2- (4-benzyloxyphenyl) glutaramide 2- (2-methylphenyl) glutaramide; 2- (3-met1Shphenyl) glutaramide; 2- (4-methyLfonyl) glutaramide; 2- (2-ethylphenyl) glutaramide; 2- (3-ethylphenyl) glutaramide; 2- (4-ethylphenyl) glutaramide; 2- (2-isopropylphensh1) glutaramide; 2-DZtizopropylphenyl) glutaramide; 2- (4-isopropyl). Nile) Glutaramide; 2- (2-trifluoromethylphenyl) glutaram 2- (3-trifluoromethylphenyl) glutaram 2- (4-trifluoromethylphenyl) glutaram 2- (2-methylthiophenyl) glutamide; 2- (4-methylthirphenyl) glutaramide; 2- (2-ethylthiophenyl) glutaramide; . 2 (4-ethylthiophenyl) glutar amide; 2- (2-butt-thiophenyl) glutaramna; 2- (3-butylthiof1Evil) glutaramide; 2-. (4-methylthionylphenyl) glutaramine 2- (4-Ethylsulfonylphenyl) glutara 2- (2,4-dimethoxyphenyl) glutaramyl 2- (2, b-diethoxyphenyl) glutaramide. 2- (3,5-diethylthiophenyl) glutapa t 2- (2 b-dimethylthionylphenyl) glutamine 2- (2, b-dimethylsulfonylphenide) Zg amide, and so on. P. Method for preparing 1-phenyl-1 propanediamine. 1-Phenyl-1,3-propanediamine. A solution of 27 g of sodium hydroxide 150 ml of water is cooled to -2 ° C and a thin stream. 17 bromine is poured into it. The mixture was stirred for 10 minutes, after which 10 g of 2-phenylglutaramide was added to it. Maintaining the temperature from -3 to -, stirring is continued until a clear solution (min) is formed, then the solution is stirred at a temperature for 30 minutes and at the end - another 90 mph at. The solution is cooled, extracted several times with methylene chloride, the combined extracts are dried with sodium sulfate, filtered and contaminated. center. The residue is distilled and 4.2 g of 1-phenyl-1,3-propanediamine are obtained, t. kip 84-87 ° C / 0.5 mmHg Art. When dissolving 2.2 g of diamine in 25 ml of ethanol, containing 1.3 g of hydrogen chloride, crystalline dihydrochloride is formed, which is collected under vacuum in vacuo to give 2.8 g of 1-phenyl-1 dihydrochloride. 3-propandiamine, t. square 244-24b S. . . l Method of producing nitriles -amino-2-cinnamic acid. Nitrile | 41-amino-2-trifluoromethylcinnamic acid. A mixture containing 9.3 g of 2-trifluoromethylbenzonitrile, 4. , 5 g of nitrile nitrile, 4.3 g of sodium amide and 100 ml of ether, with over-stirring, reflux. zota atmosphere during the night. The resulting solid is collected on a Buchner funnel, washed with ether and dissolved in -10-o-ml of cold ethanol. Crushed ice is added to this solution. . until total n. e will be different 700 ml. THIS mixture is left standing; for a few hours. The resulting solid. Single wasp: the dock is separated by filtration, dissolved in methanol and activated charcoal is added. The mixture is then filtered and water is added to the filtrate until crystallization is confirmed. Crystalline. the solid is collected, dried under vacuum, and 7.75 g of p-amino-2-trifluoromethylcinnaric acid nitrile are obtained, t. square - 101-103 s. In a similar way, using other substituted benzonitriles instead of 2-trifluoromethylphenzonitrile, the following nitriles of (i-amiaocoric acid) are obtained. . nitrile / l-amino 2-fluorocoric acid nitrile-amino-3-fluorocinnamic acid; nitrile; L-amino-4-fluorocinnamic acid; . nitrile / 3-aminocryphal acid; nitrile / i-amino-3-chlorocinnamic acid; . . nitrile / -amino-4-chlorocorine. oh kislotz,
NITRIL / 4.- amino-3-lophoric acid;
nitrile / .- amino-4-ylccritic acid-nitrile of p-amino-2-methylcrric acid; nitrile (i) amino-4-metic acid, i.p. 111-113C; nitrile / 4-amino-2-ethylcinnamic acid;
nitrile / -amino-4-tert-butylbenzoic acid; nitrile / 5.- amino-2-methoxy cinnamic acid;
li-amino-3-methoxy cinnamic acid nitrile, m.p. 74-75 s; nitrile-amino-3-ethoxycortical cells;
nitrile / b-amino-4-isopropoxycinnamic acid;
nitrile / S -amino-2-methyl-lithiocoric acid;
p-amino-4-isobutylthiocoric acid nitrile; nitrile amino 4-methylthiocoric acid;
nitrile / y-amino-4-methylsulphonyl boric acid;
nitro of p-amino-2,4-difluorocinnamic acid;
p-amino-2, b-dichloroboric acid nitrile;
p-amino-2, b-dibromic acid nitrile; . p-amino-2,4-diiodorbitary acid. nitrile;
nitrile / α-amino-2,4-dimethylcinnamic acid;
nitrile D-amino-2, b-diisopropyl cinnamic acid;
nitrile / 4-iino-2,4-dimethoxycinnamic acid;
nitrile / i-amino-2, b-diethoxycinnamic acid;
nitrile / S-amino-2,4-dimethylthiocoric acid;
nitrile; 5 amino-2, b-dimethylthionyl boric acid.
Method for preparing 1-phenyl-1,3-propanediamines.
1- (2-Trifluoromethylphenyl) -1,3-propacy 1min "..:
60 ml of a 1 M solution of borane in tetrahydrbfuran is added to a solution of 7.6 g of amino-nitro-2-trifluoroethiotic-aric acid in 100 MP. The mixture was stirred at room temperature overnight, then treated with 10 ml of water and stirred for 45 minutes.: The resulting mixture was concentrated under reduced pressure and 200 ml of isopropiol 80 ml of 20% hydrochloric acid was added to it. This mixture is heated under reflux for 2 after which it is concentrated d6 of a small volume. The residue is under | They are added by adding an excess of 20% sodium hydroxide and extracting three times.
are methylene chloride. The extracts are combined, concentrated and distilled. 1.7 g of 1- (2-trifluoromethylphenyl) -1, 3-propanediamine, b.p. 73-77 C / 0.1 mm Hg
The hydrochloride salt is obtained by dissolving diginin in an ethanolic solution of hydrogen chloride and adding zfir to this solution, resulting in the formation of dichloride hydrate I (2-trifluoromethylphenyl) -1.3-propanediamine, m.p. 213-127s.
In a similar way, instead of using nitrile-amino-2-trifluoromethyl- boric acid other nitriles of f) -amino- butyric acid, the following propantimines are obtained: 1-phenyl-1,3-propanediamine, mp. 8487С / 0, 5 mm Hg, its dihydrochloride with so pl. 244-24b ° C; 1- (2-fluorophenyl) -.1,3-propanediamine; 1- (3-fluorophenyl) -1,3-propanediamine; 1- (4-fluorophenyl) -1,3-propanediamine, b.p. 84-88s / 0.7 mmHg, its dihydrochloride with mp 2-2-2 bbs; 1- (2-chlorophenyl) -1,2-propanediamine; 1- (3-chlorophenyl) -1,2-propanediamine; 1- (4-chlorophenyl) -1,2-propanediamine; 1- (3-bromophenyl) -1,2-propanediamine; 1- (4-iodophenyl) -1,2-propanediamine; 1- (2-methylphenyl) -1,2-propanediamine; 1- (4-methylphenyl) -1,2-propanediamine; 1- (2-ethylphenyl) -1,2-propanediamine; 1- (4-tert-butylphensh1) -1,2-propanediamine; :
1- (2-methoxyphenyl) -1,2-propanediamine; 1- 3-methoxyphenyl) -1,2-propanediamine, T. b.p., 120-12b s / 1 mm Hg. (di-HCt salt, T..SH1. 225-227 o f 1- (3-ethoxyphenyl) -1,2-propanediamine; 1- (4-isopropoxyphenyl) -1 2-propa-diamine;
1- {2-Methylthiophenyl) -1,2-propanediamine 1- (4-isobutylthioPhenyl) -1,2-propanediamine;
1- (4-methylthionylphene; 1l) -1,2-propanediamine;
1- (4-methylsulfonylfeivyl) -, 2-propaidiamia;
, 4-difluorophenyl) -1,2-propanediamine 1- (2, b-dichlorophenyl) -1,2-propanediamine 1- (2, b-7-di-bromophenyl) -1,2-pro-pandiamine 1- (2,4-diydphenyl) p g2 - iropandiamia; 1- (2f 4-Dimethylphenyl) -1,2-h1ropandi «1IN7; ,,,, . 6-diisopropylphenyl) -1,2-propane2 amine; .
1- (2,4-dimethokskfeiil) -1,2-propanediamine;
1- (2,6-diethoxyphenyl) -1,2-propanediamine;
1- (2,4-dimethylthiophenyl) -1,2-propanediamine; , 1- (2, b-dimethylthionesh1), etc.
Example. 2-amino-5-phenyl, 4,5,6-tetrahydropyrimidine.
A solution of 1.44 g of 2- (3-bromofei171, 3-propandnamine and 0.72 g of cyanogen bromide in 300 ml of methanol is kept at room temperature for 3 days and then boiled under reflux for 6 hours. The solvent is evaporated on a rotary evaporator. dissolved in boiling isopropanol, which is then filtered through a funnel equipped with a water jacket for heating.The crystals formed after cooling the filtrate are collected by filtration, dried under vacuum and get 0.87 g
BrOMISTIC-WATER-SALT Salt of 2-1MINO-5 (3-broMphenyl) -1,4,5, b-tetrahydropyrimidine, m.p. 223-227 ° C.
A mixture of {3.25 g of 2-phenyl-1,3-propanediamine and 3.02 g of sulfate 2.-yethyl-2-thioisourea in a flask is immersed in an oil bath having a temperature of 245 ° C. When the reaction mixture hardens, the temperature is 1 (ovum) T to 265 s. After TorOf, as a reaction mixture, it melts again, stirring it for a minute, after which the bath is removed. Then boil with 50 ml of methanol under reflux until a powder is formed. The mixture is cooled, the solid product is collected on a Nüchner funnel, washed with 30% ether in methanol and dried at the air and 3.7 g of crude product are obtained. After recrystallization from 20 ml of water, 2.25 g of 2-amino-5-phenyl sulfate is obtained. 1,4,5,6-tetrahydropyrimidine, m.p. 264-267s ..
In an analogous manner, using instead of bromophenyl) -1,3-propanediamine and 2-phenyl-1,3-propanediamine, other 2- (substituted phenyl) -1,3-propanediamines, —found the compounds I: 2-amino-5- (2-chlorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-a "inQ-5- (3-chlorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-5- (4-chlorophenyl) -1,4,5,6 tetragidropne rimidium; 2-amino-5- (2-fluorophenyl) -1,4,5 6Fetrahydropyrimidine; 2-amino-5- (3-fluorophenyl) -1,4,5,6 tetrahydropyrimidine; - /
2-amino-5- (4-fluorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-5- (2-bromophenyl) 1,4,5,6 tetrahydropyrimidine; 2-amino-5- (4-bromophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-5- (2-iodophenyl) -1,4,5, b-tetrahydropyr Sidine; 2-amino-5- (3-iodophenyl) -1,4,5, tetrahydropyrimidine; , 2-amino-5- (4-iodophenyl) -1,4,5,6-tetrahydropyrimidine;
2-amnno-5- (2,4-dichlorfei1sh) -1,4; 6 tetrahydropyrimidine; .
2-amino-5- (3,5-dichlorophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2-5-dichlorophenyl) -1., 4,5,6 tetrahydropyrimidine;
2-amino-5- (2,6-dichlorophenyl) -1,4,5,65 tetrahydropyrimidine;
2-amino-5- (2,3-difluorophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2,4-difluorophenyl) -1,4,5,6 tetrahydropyrimidine; 0 2-amino-5- (2,5-difluorophenyl) -1,4,5,6 tetrahydropyrimidineJ
2-amine B-5- (2,6-difluorophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (3,5-difluorophenyl) -1,4,5,65 tetrahydropyrimidine;
2-amino-5- (3, b-dibrcmphenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2,4-dibromophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (3,5-dibromophenyl) -1,4,5,60
tetrahydropyrimidine
2-1mino-5- (2,4-diiodophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2,6-diiodophenyl) -1,4,5,65 tetrahydropyrimidine;
2-amino-5- (2-trifluoromethylfnyl) 1, 4,5,6-tetrahydropyrimidine; , 2-amino-5- (2-methoxyphenyl) -l, 4,5,6 tetrahydropyrimidine;
2-amino-5- (4-methoxyphenyl) -1,4,5, .60
tetrahydropyrimidine;
2-amino-5- (2-ethoxyphenyl) -1,4,5,6 tetrahydropyrimidine;
2-aminr-5- (3-ethoxyphenyl) -1,4,5,6 tetrahydropyrimidine; 5 2-amino-5- (4-ethoxyphenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2-propoxyphenyl) -1,4,5,6 tetrahydropyrimidine;
12-amino-5- (3-propoxyphenyl) -1,4,5,60 tetrahydropyrimidine;
2-amino-5- (4-propoxyphenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (4-butoxyphepi) -1,4,5,6 tetrahydropyrimidine; . 5 2-amino-5- (4-methylphenyl) -1,4,5,6 tetrahydrbpyrimidine; four
2-amino-5- (2-methylphenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (3-methylphenyl) -1,4,5,6 tetrahydropyl "idin;
2-amino-5, - (3-ethylphenyl) -1,4,5,6 tetrahydropyrimidine; f
2-amino-5- {4-ethylphenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2-ethylphenyl) -1,4,5,65
tetrahydropyrimidine;
2-amino-5- (2-isopropylphenyl -1,4,5 6 tetrahydropyrimidine;
2-aMino-5- (3-isopropylphenyl) -1,4,5,6 tetrahydropyrimidine;
0
2-amino-5 (4-isopropylphenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2-trifluoromethyl) -1,4,5,6 tetrapapropyrimidine;
2-amino-5- (3-trifluoromethylphenyl) 5 1 / 4,5,6-tetrahydropyrimidine;
2-amino-5- (4-trif 5 ormethylphenyl) 1, 4,5, b-heterrahydroirimidine;
2-amino-5- (2-methylthiophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (4-methylthiophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (2-ethylthiophenyl 1 -1,4; 5,6 tetrahydropyrimidine;
2-amino-5- (4-ethylthiophenyl) -1,4,5,6 tetragkropropirimidine;
2-amino-5- (2-butyl-iophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amnno-5 (3-butylthiophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (4-methylthiophenyl) -1,4,5,6 tetrahydropyrimidine;
2-amino-5- (4-etylsulfonylphenyl) 1, 4,5,6-tetrahydropyrimidine;
2-amino-5- (2,4-dimethoxyphenyl) 1, 4,5,6-tetracryptrin dine;
2-amino-5- (2,6-diethoxyphenyl) .- 1,4,5
b-tetrahydropyrimidine;
2-amino-5- (2,5-diethylthiophenyl) 1, 4.5, b-tetrahydropyrimidine;
2-amino-5- (2,6-difluorophenyl) - 1,4,
5,6-tetrahydropyrimidine;
2-amino-5- (2,6-di-Methylsulfonyl); 1, 4,5,6-tetrahydropyrimidine.
PRI mme R 2. 1-Alkyl-2-amino5-fennl-1, 4,5,6-tetrahydropyrimidine
1-methyl-2-amino-5-phenyl-1,4,5,6 tetrahydropyrimidine,
A suspension of 0.55 g of G-netil-2-phenyl-1,3-propanediamine dichlorohydrate in 25 ml of ethanol is stirred with 0.3 g of sodium methoxide for 30 minutes. The precipitated sodium chloride is removed by filtration and the Liltrath is concentrated. The residue is mixed with 0.32 g of 2-methyl-2-thioisourea sulfate and the mixture is stirred in oil. Oye at for 10 min. Isopropanol is then added to the reaction product and refluxed for 2 hours under reflux, cooled, the precipitated substance is filtered off, it is recrystallized from 6-7 ml of water and 0.2 g of 1-methyl-2-amino-5-phenyl sulfate is obtained. , 4,5, b-tetrahydropyrimidine, m.p. 254-257 S.
In a similar manner, using instead of K-methyl-2-phenyl-1,3-propanediamine other N-1 "m-2-phenyl-1,3-propanediamines, the following compounds of formula I are prepared: 1-methyl-2-amino-5- ( 2-XYarenyl) 1, 4,5,6 tetrahydropyrimidium; 1-methyl-2-amino-5- (3-chlorophenyl) 1, 4,5, b-tetrahydropyrimidine; 1-methyl-2-amino-5- (4-CHLOrfeiyl) 1, 4,5, b-tetrahydropyrimidium; 1-methyl-2-c "yno-5- (2-fluorophenyl) 1, 4,5,6-tetrahydropyl-imidine; 1-mvtil-2-gi and o-5- (3-fluorophenyl) 1, 4,5, b-tetragndropirimidy; 1-methyl-2-ayi o-5- (4-ft6rphenyl) 1 g 4.5 ,. 6 - tetragndropirimndin;
1-methyl-2-amino-5- {2-bromophenyl) 1, 4,5,6-tetrahydropyrimriccin; 1-methyl-2-amino-5- (4-bromophenyl) i, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2-iodophenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (3-iodophenyl) 1, 4.5, b-tetrahydropyrimidine; 1-methyl-2-amino-5- (4-iodo-enyl) 1, 4.5,. 6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2,4-dichlorophenyl); 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (4,5-dichlorophenyl); 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2,5-dichlorophenyl) 1, 4,5,6-tetrahydropyrimidine, 1-methyl-2-amino-5- (2,6-dichlorophenyl) 1, 4,5, 6-tetrahydropyrimidine; 1-methyl-2-amino-5- (3,3-difluorophenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2,4-difluorophenyl) 1, 4,5,6-tetrahydropyrimindi.n; 1-methyl-2-amino-5- (2,5-difluorophenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methylt-2-amino-5- (2,6-jifluorophenyl) 1, 4,5,6-those grahydropyrimidine; 1-methyl-2 amino-5- (3,5-difluorophenyl) 1, 4,5,6-tetrahydropyrimidine; 1-m-tail-2-amino-5-: (3,6-dibromophenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2,4-dibromofensh1) 1, 4.5 / 6-tetrahydropyrimidine; 1-methyl-2-amino-5- (3,5-dibromofensh1) 1, 4,5,6-tetrahydropyrmymkdine; 1-methyl-2-amino-5- (2,4-diiodophenyl) 1, 4,5,6-tetragipyrimidine; 1-methyl-2-amino-5- (2,6-diiodophenyl); 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2-trifluoromethylphenyl) -1,4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2-methoxyphenyl) 1, 4,5, b-tetrahydropyrimidine; 1-methyl-2-amino-5- (4-methoxyphenyl); 1,4,5,6-tetrahydropyrimvdin; 1-methyl-2-amino-5- (2-totoxyphenyl) 1, 4,5,6-tetrahydropyl 1-imidine; 1-methyl-2-amino-5- (3-toxiflyl) 1 ,, 6-tetrahydropyrimidine; 1-methyl-2-amino-5- {4-ethoxyphenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2-propox (1 phenes1) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (3-propoxy flux1) 1, 4.5, tetrahydropyrimidine; 1-methyl-2-amino-5- (4 propoxyphenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (4-butoxyphenyl) 1, 4,5,6-tetrahydropyrimidine; 1 -methyl-2-amino-5- (4-methylphenyl) 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2-methylphenyl) 1, 4,5,6-tetrahydropyrimidine; 1 -methyl-2-amino-5- (Z-mv.-llfe yl) 1, 4,5,6-tetrahydropyrim1; 1-methyl-2-amino-5- (3-ethylphenyl) 1, 4,5,6 -tetrahydropyrimidine; 1-methyl-2-ami o-5- (4-ethylphenyl) 1, 4,5,6-tetrahydropyrimidine;
1-methyl-2-amino-5- (2-ethylphenyl) 1, 4.5, b-tetrahydropyrimidine; 1-methyl-2-amino-5- {2-isopropylphenyl); 1, 4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (3-isopropylphenyl) 1, 4,5,6-tetrahydropyrimidine 1-methyl-2-amino-5- (4-isopropylphenyl) 1, 4.5, b-tetrahydropyrimidine; 1-methyl-2-amino-5- 2-trifluoromethylenyl) -1,4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (3-trifluoromethyl-0-nylH, b-tetratidropyrimidine; 1-methyl-2-amino-5- (4-trifluoromethylphenyl) -1,4,5,6-tetrahydropyrimidine;
1-methyl-2-amino-5- (2-methylthiophenyl) 1, 4,5,6-tetrahydropyrimidine; 15 1-methyl-2-amino-5- (4-methylthiophenyl) 1, 4,5, b-tetrahydrpyrimidine; 1-meth, yl-2-amino-5- (2-ethylthiophenyl) 1, 4.5, b-gtetrahydropyrimidine; 1-metsh1-2-amino-5- (4-ethylthiophenyl) - 20 1,4,5,6-tetrahydropyrimidine; 1-methyl-2-amino-5- (2-butylthiophenyl) 1, 4.5, b-tetragcropropyrimidine; 1-methyl-2-amino-5- (3-butylthiophenyl) 1, 4.5, b-tetrahydropyrimidine; 25 1-methyl 72-amino-5- (4-methylthionylphenyl) -1,4,5, b-tetrahydropyrimidine; 1-methyl-2-amino-5- (4-ethylsulfonylphenyl) -1,4, b, b-tetrahydropyrimidine; 1-methyl-2-amino-5- (2,4-dimethoxy-JQ phenyl) 1,4, 5, b-tetrahydropyrimidium; 1-methyl 2-amino-5- (2,6-diethoxyphenyl) -1,4,5, b-tetrahydro Opirimidine; 1-methyl-2-amino-5- (3,5-diethylthiophenyl) -1,4,5, b-tetrahydropyrimidine; , 1-methyl-2-c1 Mino- -5- (2, b-dimethylthionylphenyl) -1,4,5, b-tetrahydropyrimidine; 1-methyl-: 2-amino-5- (2, b-dimethylsulfonyl) -1,4,5, b-tetrahydropyrimidine. In a similar way, instead of N-methyl-2-phenyl-1,3-propanediamine other N-alkyl-2-phenyl-1,3 propanediamine, the following compounds of formula I are obtained: 1-ethyl-2-amino-5-phenyl -1, 4,5, b-tetrahydropyridine, 1-propyl-2-amino-5 phenyl-45 1,4,5,6 - tetrahydropyrimidine, 1-butyl-2-amino-5-phenyl-1 , 4,5, b-tetrahydropyrimidine,
Froze 2-Alkylcarbonyl-.,. amino-5-fench1-1,4,5,6-tetrahydropyrimidines.
2-gAcetamido-5-phenyl-1,4,5, b-tetrahydropyrimidine.
Suspension 600 mg (2.67 mmol) of sulphate 2-amino-5-phenyl-1,4,5, b-. tetrahydropyrimidine in 50 ml of ethanol and 145 mg (2.67 mmol) of sodium methylate are stirred for 2 hours. The mixture is filtered to remove losing sodium chloride and under vacuum. UD– 60% of this solvent. The residue (oil) was dissolved in 100 ml of methylene chloride, 415 mg (1.33 mmol) of N, N, N, N -tetraacegyl glycoluril was added and the resulting solution was stirred,
at room temperature overnight The precipitate formed is filtered off and the filtrate is concentrated. The residue is treated with 25 ml of a mixture of acetone and ethyl acetate, the solid product is separated by filtration and 320 mg of product are obtained. having so pl. 241-245 s. After recrystallization from methanol, 2-acetamido-5-fennl-1,4,5,6 tetrahydropyrimidine with m.p., 246-249 is obtained.
In a similar manner, using Texpai propionyl glycoluryl or tetrabutyryl glycoluryl instead of tetraacetyl glycoluryl, other amides of the formula I are obtained; 2-propionamido-5-phenyl-1, 4,5,6-tetrahydropyramidine, 2-butyramido-5 Phenyl-1,4; 5, 6-tetrahydropyrimidine.
In a similar manner, using another 2-amino-5-phenyl-1,4,5, b-tetrahydropyrimidine derivative instead of 2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine, the following derivatives of formula I are obtained: acetamido2-PrO1. ionamido- or 2-butyramido-5phenyl-1., 4,5, b-tetrahydropyrimidines.
Example 4. 1-Alkyl-2-alkyl, carbonylamino-4-feiyl-1,4,5,6-tetrahydropyrimidines.
In analogy to Example 3, but using instead of 2-amino-5-phenyl-1,4,5,6 tetrahydropyrimidine 1-methyl-2-amino-5-phenyl-1, 4,5,6-tetrahydropyrimidine, the following compounds 1-methyl are obtained -2-acetamido-5-phenyl-1,4,5,6 tetrahydropyrimidine, 1-methyl-2-propionamido-5-phenyl 1,4,5,6-tetrahydropyrimidine, 1-methyl-2-butyramido 5-fensh1-1, 4,5,6-tetrahydropyrimidine, etc.
Similarly, from 1-alkyl-2-amino5-phenyl-1, 4,5, b-tetrahydropyrimidine, the corresponding 1-alkyl-2-acetamido-, 2-propiono4ido or 2-butyramido-5-phenyl-1,4,5,6 tetrahydropyrimidine .
PRI me R 5. 2-alkoxycarbonylamino-5-phenyl-1, 4,5, b-tetrahydropyrimidine.
2-Methoxycarbrylamino-5- (3-methoxyphenyl) -1,4,5, b-tetrahydropyramidine. .
A solution of 2.61 g (14.5 mmol) 2 (3-methoxyphenyl) -1, 3-propyadiamine. in 200 ml of methanol are combined with a solution of 3.0 g (14.55 mmol) of 1,3-bis (methoxycarbonyl) -3-methyliso-thiourea in 200 ml of methanol and left to stand at room temperature overnight. The crystalline product which is separated out is collected, washed with methanol, and dried under vacuum at to give g 2-methoxycarbonylamino-5- (3-methoxyphenyl) 1, 4.5, b-tetragnecyropyrimidine with m.p. 218-221 C.
Similarly, using instead of 2 (3-methoxyphenium) -1,3-propanediamine other 2- (phenylethylene) -1,3-propanediamines, the following compounds of formula I are prepared; 2-methoxycarbonylamino-5-; phenyl1, 4,5, b-tetrahydropyrimidine,
t, pl. ZZZZE;
2-methoxycarbonylamino-5- (2-chlorophenyl) -1,4,5, b-tetrahydropyrimidine, m.p., 353-57 C;
2-methoxycarononMino-5- (3-chlorophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (4-chlorophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (2-fluorfemyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (3-fluorophenyl) -1,4,5,6-tetrahydropyrimidine; 2-methoxycarbonyl-Mino-5- (4-fluorophenyl) -1,4,5, b-tetragnepropyrimidine, m.p. 225-235s (decomp.), Hydrochloride with so pl. 179-1B2s; 2-methoxycarbonylamino-5- (2-bromophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (3-bromophenyl) -1,4,5, b-tetrahydropyrimidine, m.p. 213-215С
2-methoxycarbonylamino-5- (4-bromophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (2-iodophenyl) -1,4,5,6-tetrahydropyrimidine; 3-methoxycarbonylamino-B-CH3-iodophenyl) -1,4,5, b-tetrahydropyrimidine 2-methoxycarboxylamino-5- (4-iodophenyl) 4,5, b-tttrypyridpirimidine; 2 Methoxycarbonylamino- 51 (2.4 dichlorophenyl) -11.4, drocyrimidium,. its hydrochloride with m.p. 2g-methoxycarbonylamino-5- (3, B-dichlorophenyl) "1 41.5, b-tetrazhydropyridine; 2-methoxycarbonylamino-5- (2, B-dusor phenyl) - 4,5, b-tetrahydropyrimidine; 2 Methoxycarboyl 1 Mino-5- (2, b-dnlorfensh), 5 f 6-tetra 1IDrO1trimidine, so pl. 231-234s
2-methoxycarbonyl-amino- 5- (2,13-difluorophenyl) -, 4,5, b-tetrahydropyrimide ng. 2 methoxycarvonil1 "1 5 (2,4-difluorophenyl) i, 4,5,6-tetrahydropyl imzepine; 2Methoxycaronyl-amino-5- (2, B-difluorophenyl), 5,6-tetrahida-pyramidine; 2- "et zhysicarbonyl EMino-5- (2, b-difluorophenyl) -1,4,5,6-tetrahydropyrimidine; 2-methoxycarbonylamino-5-: (3,5-difluoro-phenyl) g1,4,5,6-tetrahydropyrimvdin; 2-methoxycarbonylamino-5- (3 6-dibromophenyl) -1,4, B, B-tetrahydropyrimidine;
2-m-toxica1 bonsch1amiyo-5- (2 ;, 4-DI-. Bromophenip) -1,4,5, b-tetragndropyrimidine; .
2-methoxycarbonyl-yvo-5- (3,5-dibromophenyl) - 4, B, 6-tetrag11dropyrimidine; 2 methoxycarbon 11lamino 5- (2,4-diiodophenyl) 1,4,5, b-tetragtsdropirimidin; 2-methoxy {} bonylamino-5 2, b-diiodophenyl) -1,4,5,6-tetrahydropyrimidine;
2-methoxycarbonylamino-B- (2-methoxy-phenyl) -1,4,5,5-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (4-methoxyphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (2-ethoxyphenyl) -1,4,5, b-ts tragidgypyrimncin; 2-methoxycarbonylamino-5- (3-ethoxyphenyl) -1,4, B, b-tetrahydropyrimidine; 2-methoxycarbonylamino-B- {4-ethoxyphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- {2-propoxyphenyl) -, 4,5, b-tetrahydropyrimidine 2-methoxycarbonylamino-5- (3-propoxyphenyl) -1,4, B, b-tetrahydrogryrimidine; 2-1-2 cytoxycarbonylamino-5- (4-propoxyphenyl) -1,4,5, b-tetrahydropyrimidine 2-methoxycarbonylamino-5- (4-butoxyphenyl) -1,4,5, b-tetragy; ropyrimidine; 2-methoxycarbonylamino-5- (2-methylphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-B- (Z-methylphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylmino-5- {4-methylphenyl) -I, 4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (2-ethylphenyl) -1,4,5,6-tetrahydropyrimidine; 2-Methoxncarb6-nylamino-5- (3-ethylphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-B- (4-ethylphenyl) -1,4,5,6-tetrahydropyrimidine; 2-methoxycarbonylamino-5- {2-isopropylphenyl) -1,4, 5, b-1 etrahydropyrimidIN;
2-methoxycarbonylamino-5- (3-isopropyl-Jlphenyl) -1,4,5,6-tetrahydropyrimidine;
2-methoxycarbanilamino-5- (4-isopropyl) -, 4, B, b-tetrahydropyrimidine, mass spectroscopy: 275 (M);
2-methoxycarbonylamino-5- (2-trigormefilfenil) -1,4,5, b-tetrahydropyrimIdin;
2-methoxycarbonylamino-5- (3-three tormethylphenyl) - 4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-5- (4-trifto1 $ methylphenyl) -, 4, B, opyrimidium b-tetrahydr;
2-methoxycarbonylamino-5- (2-methylthiophenyl) -1,4, B, b-tetrahydropi imidine;
2-methoxycarboxy-aminb-B- (4-methylthiophenyl -1,4,5, b-tetrahydropyrimidine;,
2- methoxycarbovsch1amino-5- (2-ethylthiofeNyl) - 4,5, b-tetraghydropyrmidein; 2-methoxycarbonylamino-B- (4-ethylthiophenyl) -1,4,5,6-tetrahydropyrimidine; 2-methoxycarbonylaminoB- (2-butylthiophenyl) -, 4, B, b-tetragapropirimidine; /
2-methoxycarbonylamino-5- (3-butylthiophenyl) -1,4,5, b-tetragchdrystyridine; 2-methoxycarbonylamino-5- (4-metsch1thionifenyl) .-, 4,5, b-tetrahydropyrimidine;
2-methoxycarbonylamino-5- (4-ethylsulfonylphenyl) -1 4,5, b-tetrahydropyrimidine;
2-methoxycarbonylamino-5- (2,4-dimethoxyphenyl) -1,4,5, b-tetrahydropyrimidine;
2-methoxycarbonylamino-5- (2, b-dietrxyphenyl) -1,4,5, b-tetrahydropyrimidmn;
2-methoxycarbonylamino-5- (3,5-diethylthiophenyl) -1,4,5, b-tetrahydropyrimidine; . 2-methoxycarbonylamino-5- (2,6-dimethylthionylphenyl) -1,4,5, b-tetrahydrpyrimidine; .
2-methoxycarbonylamino-5- (2, b-dimethylsulfonylphenyl) -1,4,5, b-tetra. Hydrolirimidine.
In a similar manner, using 1 ethoxycarbonyl-8-methylisothiourea. or 1-butoxycarbonyl-1-propoxy-2b
carbonyl-; S-methylisothiourea, the following 2-alkoxycarbonylamino-5-phenyl-1, 4,5, b-tetrahydropyridimidines are obtained: 2-ethoxycarbonylamino-5phenyl-1, 4,5,6-tetrahydropyridaidin 25 so pl. 338-343 C; 2-isopropoxycarbonylamino-5-phenyl-1, 4,5, b-tetra-. hydropyrimidine, so pl. 335-342 C,
molecular weight (mass spectroscopy) 261 (M); 2-butoxycarbonyl-30 amino-5-phenyl-1,4,5, b-tetrahydropyrimidine; 2-Y-propoxycarbonylam H5-5- (3-bromophenyl) -1,4,5, b-tetrahydropyrimidine, so pl. 205-206 С; 2-isopropoxycarbRnylamino-5- (2,6-dichlorop-55 phenyl) -1,4,5, b-tetrahydrpyrimidine, m.p. 199-201 S.
PRI me R b. 1-Alkyl-2-alkoxyarb: Okilo (mino-5-phenyl-1,4 5, b-thetahydropyrimidines, .40
1-Methyl-2 "metRxycarbonylamino-5-phenyl-1, 4,5, b-tetrahydropyrimidine.
To a solution of 1.5 g of dihydrochloride s-methyl-2-phenyl-1,3-propandiamine, 200 ml of methanol are first added with 0.68 g of sodium methoxide in a small quantity of methanol, and then a solution of 1.3 g of 1,3-bis- (MetRsxycarboni) S-methylisothiophenol in 200 ml of methane. This mixture was left standing. Q for room telesurgery for: 16 hours, refluxed for 1 hour and then concentrated to dry. The residue is dissolved in 50 ml: 3% hydrochloric acid and the resulting solution is washed. by ether. - Then the product is precipitated by the addition of Hact & H of sodium bicarbonate solution,
Solid compound rfnltrovyvaF.
washed with distilled water:: dried after vacuum and obtaining 0.99 g of 6Q product with mp. 177-179C. After recrystallization from ether, t 1-methyl-2-methoxycarboxylamine 5-phenyl-1, 4,5, b-tetrahydropyrimidine with so pl. IVe-lTT C.65
In a similar way, using instead of K-methyl-2-phenyl-1,3-propanediamine other K-methyl-2-phenyl-1,3-propanediamines, the following compounds of the formula I are obtained: 1-methyl-2-methoxycarbonyl 1 Min-5 (2-fluorophenyl ) -1,4,5,6-tetrahydropyrimidine;
1-met-yl-2-methoxycarbRnylamino-5 (3-fluoro-phenyl) -1,4,5, b-tetrahydro-pyrrmkdine;
2-methyl-2-methoxycarb6, nylamino-5 (4-fluorophenyl) -1,4,5, b-tvtrahydropyrimidine;
2-methyl-2-methoxycarbonylamino-5t (2-chlorophenyl) -1,4,5,6-tetrahydropyrimidine;
1-methyl-2 methoxycarbonyl 11gr "inr-5 (3-chlorophenyl) -1,4,5, b-tetrahydropyrimidine
1-metd-2-methoxycarbrylamino-5 (4-chlorophenyl), 4,5,6, -tetrahydropyriyidine;
1-methyl-2-methoxycarbonylamino-5 (3-bromophenyl) -1,4,5, b-tetrahydropyrimidine;
1-methyl-2-methoxycarbonylamino-5 (b-iodophenyl) -1,4,5, b-tetrahydropyrimidine;
1-methyl-2-methoxycarbRnylamino-5 (2g-oxyphenide) -1,4,5, b-tetrahydrpyrimidine
1-motil-2-methoxycarbonylamino-5 (2-methoxyphenyl) -1,4,5, b-tetrahydropyrimidine;
1-methyl-2-metho1 sicarbonylamino-5 (3-methoxyphenyl) -1,4,5 b-tetra hydropyrimidine;
1-methyl-2-methoxycarbonyl and inr-5 (4-methoxyphenyl) -1,4,5, b-tetrahydropyrimidine; -. 1-methyl-2-metxycarbonylamino-5 {2-ethoxyphenyl) -1,4,5, b-tetrahydropyrimidine;
1-methyl-2-meter-xycarbonylamine-5 (3-isro-propoxyphenyl) -1,4,5,6-tetrahydropyrimidine;
1-methyl-2-meter-xycarbPH1: laminar-5 (4-benzylRXyphenyl) -1,4,5, b-tetrahydropyrimidine {
1-methyl-2-metric. Rbonylamin-5 (4-tert-butoxyphenyl) -1,4,5, b tetrabidropyrimidium;
1-methyl-2 methoxycarbonylamine-5 {2-methylphenyl) -1,4,5, bg-tetrahydrr-. rimidine;
1-methyl-2-meter-hydroxycarbonyl-5- (3-methylphenyl) -1,4,5, b-tetrahydrpyrimidine;
1-methyl-2-methoxycarbRnylimine-5 (4-methylphenyl) -1,4,5, b-tetrahydropyrimidine;
1-methyl-2-metRxycarbrynylimine-5 (2-ethylphenyl) -1,4,5, b-tetrahydryrpyrimidine; . .
1-methyl-2-methoxycarbonylamino-5 (3-propylphenyl) -1,4,5, b-tetragndO-pyrimidine; 1-methyl-2-methoxycarbonylamino-5 (4-butylphenyl) -1,4,5, b-tetrahydropyrimidine; 1-methyl-2-methoxycar6onylMinr-5 {2-methylthiophenyl) -1,4,5, b-tetragizd pdimidine; 1-methyl-2 methoxycarbonylamino-5 (2-ethylthiophenyl) -1,4,5, b-those, pyrimidine tragic acid; 1-methyl-2-methoxy; 1-methyl-6-amino-5-(4-butyl-phenyl) -1,4; 5,6-tetrahydropyriglydine; 1-Methyl-2 methoxycar6-aminylamino-5 (4-methylthionylphenyl) -1,4,5, b-tetra hydropyrimidine; 1-methyl-2-methoxycar6-amino-5-l (4-ethylthionylphene L), 4,5, b-tetra. hydropyrimidine; ., 1-methyl-2-methoxycarbonylamino-5 (2,4-trifluorophenyl) -1,4,5,6-tetrahydroirimidine; 1-methyl-2-mutoxycarboxylamino-5 (2, b-dichlorophenyl) -1,4,5, b-tetrahydropyrimidine; 1-methyl-2-methoxycarbonylamino-5 (3,5-di6romfensh1) -1,4,5, b-tetrahydropyrimidine; 1-mvtil-3-methoxycarbonylamino-5 (, 4-diiodophenyl) -1,4,5, b-tetrahydrin pyrimidH; 1 Methyl-2-methoxycarbonylamino-5 (2,6-diokeiphenyl) -1,4,5, b-tetragy pyrimidine; . 1 methyl-2-methokeicar6-nemino-5 (2,4-dimethoxy-phenyl), 5.b-tetro-ridropyrimidine; 1 methyl-2-carbonylamino-5- (3, -5-dibutoxyphenyl) -1,4,5, b-tetrahydropyrimidine; 1-methyl-2 methoxycarbonylamino-5 (2,6-dimethylphenyl) -1,4,5,6-tetrahydropyrimidine; 1 methyl-2-methoxycar6-aminylamino-5 (2, -dibutylphenyl) -1,4,5, b-tetragi ropyrimidine; 1-methyl-2-methoxycarbonylamino-5 (2 b-dimethylthiophenyl) -1,4,5, b-tetrahydrpyrimidine; 1 1-methyl-2-c 1: icarbonylamide-5 (2, 4m-di-imylnonylphenyl) -; 1,4,5, b hetraripyridine f. 1 methyl-2-methoxycarbonylamino-5 {2, 4-Yaethylsofovylphenyl) -1,4,5.6. tetrahydropyrimidn, Example 7, 2-Amino-4-phenyl 1 4 5, b-tetrahydropyrimidine. A solution of 1.32 g of 1-phenyl-1,3-propanediamine dihydrochloride in a small amount of water is alkalinized with an excess of 30% sodium hydroxide and the free diamine is extracted with tr toluene. The combined extracts with toluene were removed by vortex and the residue was dissolved in 250 ml of methanol, a solution of 0.64 g of brushoschia in methanol was added, the mixture was left at-5 at room temperature, and then boiled under reflux for 1 hour. The solvent the oily residue is removed in 25 ml of isopropanol, the product is crystallized and 0.59 g of crystal is obtained: in the form of fine needles, which are hydrobromide D 2-a1Lino-4-phenyl-1,4,5, b- tetrahydropyrimidine, m.p. 192-lS4c, in a similar manner using, instead of phenyl-1,3-propanediamine, the corresponding 1- {substituted phenyl) 1, 3-propa-diamine, other compounds of the formula I: 2-amino-4- {2 chlorophenyl) -1.4, 5,6 tetrahydropyrimidine; 2-amino-4- (3-chlorophenyl) -1,4,5,6 tetrahydropyrimidine; , 2-amino-4- (4-chlorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (2-fluorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (3-fluorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (4-fluorophenyl) -1,4,5,6 tetraridropyrimidine; 2-amino-4- {2-bromophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4, - (4-bromophenyl) -1,4,5,6 tetra. Hydropyrimidine; 2 amino-4- (2-iodophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (3-iodophenyl) -1,4,5,6-tetrahydropyrimidine; 2-amino-4- (4-iodophenyl), 4, -5.6 tetrahydropyrimidine; 2-amino-4- (2,4-dichlorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (3,5-dichlorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (2,5-dichlorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (2, b-dichlorophenyl) -1,4,5,6 tetrahydropyrimidine; . . 2-amino-4- {2,3-difluorophenyl) -1,4,5,6 tetrahydropyrimidine; . 2-amino-4- (2,4-difluorophenyl) -1,4,5,6--. tbtrahydropyrimidine; 2-amino- 4- (g, b-difluorophenyl) -1 ,, 6 tetrahydropyrimidine; , 2-amino-4- (2, b-difluorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (3,5-difluorophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (3, b dibromophenyl) -1,4,5,6-i tetrahydropyrimidine; -. 2-amino-4- (2,4-dibromophen® 1) -1,4,5,6 tetrahydropyrimidine; . 2-amino-4- (3,5-dibromophenyl) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (3,5-dibromophenyl) -1,4,5,6 tetrahydropyrimidine; 2-; amino-4- (2,6-diiodophenyl) -1,4,5,6 tetrahydropyrimidine; , 2-amino-4- (2-trifluoromethylphenyl) -1,4, 5, b-tetrahydropyrimidine; 2-amino-4- (3-methoxyphenyl) -1,4,5, tetrahydropyrimidine, dihydrochloride with so pl. 189-191 C; 2-aminO-4 (4-m methoxyphenyl) -1,4,5, tetrahydropyrimidine; 2-amino-4- (2-ethoxyphenyl) -1,4,5 / 6 tetrahydropyrimidine; 2-amino-4- (-3-ethoxyfeiyl) -1,4,5., 6 tet1-agidropyrimidine; 2-amino-4- (4-ethoxyphenyl) -1,4,5,6 tetrahydropyrimidine; 2-C1-MINO-4- (2-propoxyphenyl) -1,4,5 tetrahydropyrimidine; 2-amino-4- (3-propoxyphenyl) -1,4,5 tetrahydropyrimidine; 2-amino-4-, (4-prypoxyphenyl) -1,4,5 tetrahydropyrimidine; 2-amino-4- (4-butoxyphenyl) -1,4,5, tetrahydropyrim dyne; 2-aminO-4- (4-methylfvnil) -1,4,5,6 tetrahydropyrimidine; 2-amino-4- (2-methylphenyl) -1,4,5,6 tetrahydrpyrimidine; 2-amino-4- (3-methylphenyl) -1,4,5,6 tetrahydropyrimidine; . 12-amino-4- (3-ethylphenyl) -1,4,5,6 tetrahydropyrimidine 2-amino-4- (4-ethylphenyl -1,4,5,6te. Trahydropyrimidine ;, 2-amino-4- (2- ethylphenyl) -1,4,5,6tetrahydropyrimidine; 2-amino-4-2-isopropylphenyl} -1,4, 5,6-tetrahydropyrimidine; 2-amino-4- (W-isopropylphenyl) -1,4, 5, 6-tetrahydropyrimidine; 3-amino-4- (4-isopropylphenyl) -1,4, 5,6-tetrahydropyrimidine; 2-amino-4- (2-trifluoromethylphenyl) 1,4,5, b-tetrahydropyl | eimidine; 2 -amin6-4- (3-trifluoromethylphenyl) 1, 4,5,6-tetrahydropyrimidine; 2-amino-4- (4-trifluoromethylphenyl) 1, 4,5.6 tetrahydropyrimidine; 2-amino-4- (2-methylthyrfensh1 ) -1,4,5 tetrahydroirimidine; 2-amino-4- (4-methylthiafen L) -1, tetrahydropyrimidine; 2-amino-4- (2-ethylthiophenyl-1,4,5,6 tetrahydropyrimidine; -f 2-amino-4- (4-ethylthiophenyl) -1,4,5, tetrahydropyrimidine; 2- amino-4- {2-butylthiophenyl) -1,4,5 tetrahydropyrimidine; 2-amino-4- (Z-butylthiophenyl) H 4, 5 tetrahydrodimycin; 2-iaj HHo-4- (4-methylthionylphenide); 1, 4,5 / 6-tetra, hydropyrimidine; 2-amino-4- (4-ethylsulfrnophenyl-): 1, 4,5,6-tetrahydropyrimidine; 2-amino-4- (2/4-dimethoxyphenyl) -1 , 5,6-tetragndropirimidine; f --.- - - ... . , 27-amino-4- (2,6-diethoxyphenyl) -1.4 5 6-tetrahydropyrimidine; 2-amino-4- (3 5-diethothiophenyl) .1,4,5 / 6-tetrahydropyrimidine; 2-amino-4- (2f6-dimethylthionylphenium J., 4/5/6-tetrahydropyrimidine; 2-amino 4- (2,6-dimethylsulfonylphenyl) -1,4,5,6-tetrahydropyrimidine; PRI me R 8, 2-Alkylcarbonylamino-4-phenyl-1, 4,5,6-tetrahydrpyrimidine U. Ansshogic Example 3, using instead of 2-amino-5-phenyl-1/4 / 5,6-tetrahydropyrmymidine 2-amino-4-phenyl1 , 4/5, т -tetrahydropirimidine, the corresponding 2-acetamido 4phenyl-1, 4,5,6-tetrahydropyrimidine is obtained. Analogs but using instead of tetraacetylglylcololuride tetrapropig | -fe Nil 1/4/5, 6-tetrahydropyrimidine, 2 butyramido-4-phenyl-1/4/5 / b-tetrahydro-pyrimidine .. for example 9. 2-Alkoxycarbonyl amino-4-phenyl-1,4 / 5/6-tetrahydropyrimindines.; I 2-I1-methoxycarbonylamino-4- (4-fluorophenyl) -1,4,5,6-tetrahydrpyrimidine. A solution of 0.93 g 1- (4-fluorophenyl) (1,3-n } opandiamine and 1.2 g of 1/3-bis | methoxycarbRnst) -B-methyl-methyl tibmoyl.paste, in MJ1, boil with methanol and boil for 2 hours / then concentrate before making 1.02 g of product crystals p .pl. 209-214 s. After recrystallization of this product from 75 ml of methanol, 0/8 g of 2-methoxycarbonyl-amino-4-4-fluorophenyl) 1, 4/5/6-tetrahydro-pyrimimine with m.p. 211-212 s. Treatment with ethechol / withstand Hydrated hydrogen / get hydrochloride with m.p. 16b-168 s. Other formulas-compounds I: 2-metRcRicarbonylamino-4-pheny - 1 g, 5 / 6-7 tetrahydropyrimidine /, tll LL 186-: - .: ,,: /, „,,,. : -,,,. 2-methoxycarbonylamino-4- (2-chlorofenil) -1,4 / 5/6-tetrahydrogirimidine; 2-methoxycarbonylamino-4- (3-chlorophenyl) -1,4 / 5 / b-te Trahydropyrimidine; 2-methoxycarbonylamino-4- (4-chlorophenyl) -1,4 / 5,6-tetrahydrpyrimidine; 2-methoxycarbrylamino-4- (2-fluorophenyl) -1,4,5 / y-tetrahydropyrimidine; 2-methoxycarbranyl mino-4- (3-fluoro-phenyl) -1,4,5 / 6-tetrahydropyrimidine; 2-methoxycarbovyl-amino-4- | 2-bromophenyl) -1.4 / 5/6-tetrahydropyrimide; in; 2-metP1; syCDrbrynyl-amino-4t- (3-bromophenyl) -1 -f 4/5/6-tetrahydropyrnmidine; 2-methoxycarbonylamino-4- (4-bromophenyl) -1 / 4,5 / 6-teTrahydropyrimidine; . 2-methoxycarbonylamino-4- (2-iodophenyl) -1 / 4,5,6-tetrahydropyrimidine; 2-methoxycarb6-nylamino-4- (3th 6dphenyl) 1,4,5,6-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (4-iodophenyl) -1 / 4,5 / 6-tetrahydropyrimidine; 2-methoxycarbonyl-amino-4- (2,4-dichlorophenyl) -1,4,5,6-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (3,5-dichloro-phenyl), b-tetrahydropyrimidine; 2-methoxycarbonyl-amino-4- (2,5-dichloro-phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxyncarbonylamino-4- {2, b-dichloro-phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino 4- (2,3-difluoro-phenyl) -1,4,5,6-tetrahydropyrimidine; 2 methoxycarbonylamino-4- (2,4-difluoro-phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino 4- (2,5-difluoro-phenide) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (2, b-difluoro phenyl) -1,4,5,6g tetrahydropyrimidine; 2-methoxycarbonylamino-4- (3,5-difluoro-phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonyl-amino- 4- (3, b-dibrom phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxy.carbonylamino-4- (2,4-dibromo-phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (3,5-dibromine NILE) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (2,4-diiodophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxyCicarbonylamino-4- (2, b-diiodophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarone6-Mino-4- (2-methoxy. Phenyl) -1 / 4,5b-tetrahydropyrimidine; 2-methoxycarbonylamino-: 4- (4-methoxyphenyl) -1,4,5,6-tetrahydro shrimidine; 2-methoxycarbonylamino-4 -. (2-ethoxyphenyl) -1,4,5, b-tetrahydrot1irimidine; 2-methoxycarboylamino-4- (-ethoxyphenyl) -1 ,, b-tetragvdropyridine; 2-methoxycarbonylsminr-4-C4-ethoxyphenyl) -L, 4,5., € -tetrahydropyrimidine; 2-methoxycarbonylamino-4- (2-propoxyphenyl) -1,4,5, b-tetrahydropyrimiDin 2-toxoid |) bonylamino-4 - (3-propoxyphenyl) -1,4,5, b-tetrahydropyrimtststsin; 2-methoxycarbonylamino-4- (4-propoxy phenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (4-butoxy) enyl) -1,4,5, b-tetrag1adropi1 imidium; 2-m; etoxycarbonylamino-4- {2-methylphenyl) -1,4,5, b-tbtrahydropyrimidine) 2-methoxycarbonimide-4-C3-methylphenyl) -1,4,5, b-tetragvdropyrimidin; 2-methoxycarbon lamino-4- (4-methylfe NIL), 5, b-tetrahydropyrimidine, m.p. 198-200C; 2-methoxycarbonylamine-4- (2-Ethylfe-; nyl) -1,4,5, b-tatragchropyr imidine; 2-methoxycarbonylamino-4- (3-ethylphenyl), 5, b-hetrahydropyrch “is one; 2-methoxycarbonylamino-4- {4 these fe NIL), 5,6-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (2-isopropylphenyl) -1 f 4,5 f 6-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (3-isopropylphenyl), 5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (4 -isopropylphenyl) -1,4,5, b-tetrahydropyrimidine; . 2-methoxycarbonylamino-4- (2-trifluoro methylphenyl) -1,4,5, b-tetrahydropyrimidine, m.p. 195- L7C; 2-methoxycarbonylamino-4- (3-trifluoromethylphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (4-trifluoromethylphenyl) -1,4,5, b-tetrahydropyrimidin; 2-methoxycarbonyl-amino-4- (2-methylthiophenyl) -1,4,5, b-tetragi Dropyrimidine; 2-methoxycarbonylamino-4- (4-methylthiophenyl) -1,4,5, b-tetrahydropyrimidine; , 2-methoxycarbonylamino-4- (2-ethyltyphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (4-ethylthiophenyl) r-i, 4y 5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (2-butylthiophenyl) -1,4,5,6-tetrahydropyrimine; 2-methoxycarbonylamino-4- (3-butylthiophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (4-methylthionylphenyl) -.1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4-. {4-etyleulfonyl) -1,4,5, b-tetrahydropyrimidine; 2-methbicarbonylamino-4- (2,4-dimethoxyphenyl) -1,4,5, b-tetrahydropyrmymidine; . 2-methoxycarbonylamino-4- (2, b-diethoxyphenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (3,5-diethylthiophenyl) -1,4,5, b-tetrahydropyrimidine; 2-methoxycarbonylamino-4- (2, b-dimethylthionylphenyl) -1,, b-tetrahydropyrimidine; 2-Methoxycarbonylamino-4- {2, b-dimethylsulfonylphenyl) -1,4,5, b-tetrahydropyrimidine, and the like. Similarly, using instead of 1 (4-fluorophenyl) -1,3-propanediamine. Suitable 1-phenyl-1,3-propanediamine, and instead of bis-1,3- (methoxycarbonyl) -Smethylnopropane, another bis-1,3 ( alkoxycarbonyl) -3-methyl-isothiourea or mono-1-alkoxy: icarbonyl-8-methyl-isohydro-urea, such as 1 ethoxycarbonyl-S-methyl-isothiourea-. Na, 1-propoxycarbonyl-8 methyldimethiourea or 1-butoxycarbonyl-8-b-1-isothiourea, the following 2-ala {pxycarbonyl-but-4-phenyl-1, 4,5, b-tetrastedropyrimidine are prepared: b-gtetrahydropyrimidine, 2-isopropoxy “arbonylamino-4-phenyl-1, 4,5,6 tetrahydropy-phiMidine, 2-n-proproxycarbylnyl-amino-4-phenyl-1, 4,5,6-tetrahydropyrimryedine, m.p. 134-137®C, 2-H-butoxycarbonylamino-4-fench11, 4,5, .b-tetrahydropyrimidine, 2 propoxycarbonylamino-4- (3-bromophenyl) -1,4,5, b-tetrahydropyrimidine, 2- isopropoxycarbonylamino-h- (2,6 dichlorophenyl) -1,4,5,6-tetrahydropyrimidine.
I'll try it on. A two-fold. Stoichiometric amount of a 3% solution of hydrogen chloride in methanol is added to a solution of 1, O g of 2-amino-5-phenyl-1,4,5, b-tetrahydroprrimidine in 20 ml of methanol. Diethyl ether is then added until settling is complete. The precipitated product is filtered off, washed with ether, air-dried and recrystallized. The hydrochloride is 2-amino-5-phenyl-1, -4.5, b-tetr idropyrimidine with m.p. 193-196 ° -C.
The following compounds are prepared analogously: 2-amino-5-phenyl-1- sulfate; 4, 5, b-tetrahydropyrimidine ,. m.p. 264-2B7S; 1-methyl-2-amino-5-phenyl-1, 4,5, b-tetrahydropyrimidine sulfate, m.p. 254-257C; 2-methoxycarbonylamino-5- (4fluorophenyl) -1,4,5 hydrochloride, b-tetrahydropyrimidine, m.p. 179-132C; 2-amino-4-phenyl-1,4,5 hydrobromide, b-tetrahydropyrimidine, m.p. l92-194c; 2-methoxycarbonylamino-4- (4fluorophenyl) -1,4,5 hydrochloride, b-tetrahydropyrimidine, m.p. 1bb-1b8S; hydrochloride 2 - methoxycarbonylamino-5- (2,4-dichlorophenyl) -1,4,5, b-tetrahydropyrimidine, so pl. 209-210 ° C.
I. . Example 11. .1.0 g of 2-methoxycarbonylamio-5- (3-methoxyphenyl) -1,4,5 hydrochloride, tetrahydropyrimidine hydrochloride is suspended in 50 ml of ether and mixed with a two-fold stoichiometric excess of dilute iodine potassium carbonate solution until the salt is completely dissolved . The organic layer, then, is then separated. they are washed with water, dried with magnesium sulphate and evaporated. 1.0 g of 2-methoxycarbonylamino-5- (3methoxyphenyl) -1,4,5, b-tetrahydropyrimidine is obtained in the form of a base of m.p. 2218221 ° C.
. The following compounds are prepared in a similar manner:
2-acetamido-5-phenyl-1,4,5, b-tetragyropyrimidnn, so pl. 24b-249 C7 2-methoxycarbonylamino-5-phenyl-1,4 5, b-tetrahydropyrimidine t so pl. 333 sze; ,
2-methbicarbonylamino-5 -. {2-chlorfe,; nile) -1,4,5, b-tetrahydropyrimidine, pd. 353-357 C;
2-method | {Syka, rbonylamino-5- (4-fts rfenyl) -: 1.4 f 5, b-tetrahydropyrimidine, m.pl. 179-182S;
2-methoxycarbonylamino-5- (3-bromophenyl) -1,4,5, b-tetragi; ropyrimidine, mp 213-215 C;
2-methoxycarb6-nylamino-5- (2,6-di-g chlorophenyl) -1,4,5, b-tetrahydropyrimidine, m.p. 231-234C; 2-methoxycarbonylamino-5- (4-isopropylphenyl) -1,4,5, b-tetrahydropyrimidine;
2-ethoxycarbonylamino-5-phenyl-1,4, 5, b-tetrahydropyrimidine, m.p. 338343 ° C; 12-isopropoxyxycarbonylamino-50 phenyl-1,4,5, b-tetrahydropyrimidine, so pl. 335-342 C;
2-n-prop6xycarbonylamine-5- (3-bromophenyl) -1,4,5, b-tetrahydropyrymidine, so pl. 205-20b “C;
5 2-isopropoxycarbonylamino-5- (2,6 dichlorophenyl) -1,4,5, b-tetrahydropyrimidine, m.p. 199-201 s; . 1-methyl-2-methoxycarboxy-amino-5phenyl-1, 4,5,6-tetrahydropyrimidine,
0 m.p. 176-177 ° C;
2-Methoxycarbonylamino-4- (4-fluorophenyl 1) -1,4,5, b-tetrahydropyrimidine, m.p. 211-212; 2-methoxycarbonylamino-2- (4-methyl5 phenyl / -1 / 4,5,6-tetrahydropyropine midin, mp 198-200s;
2-n-propoxycarbonylamino-4-phenyl .1,4,5, b-tetrahydropyrimidine, t, pl. 134-137 ° C.
Example 12. Discontinuation of a hypothermal state in mice caused by reserpine.
Male mice weighing 18-24 g are used (from the Shveydarsko-Webster
Cancer Research Institute). We are kept in an open-air cage for at least 5 days and placed in Plexiglas cages measuring 17 to 20 cm in size with a sanitary tissue litter. Five groups of
six, when they consist of 10 mice, intraperio1 are injected reserpine in an amount of 5 mg / kg. Reserpine (10 mg) is dissolved in a mixture of 0.06 ml of glacial acetic acid and
20 ml knew. The sixth group is not subjected to such an introduction (control group). After two hours, either water or the test compound was administered to the mice in different doses. Group,.
not previously treated with reserpine, water is also added. Experienced
compounds are administered orally, in
logarithmically increasing doses.,
After 1 h after oral administration, the body temperature of 8 mice from the cyoide group was measured using a Yellow Springs telethermometer cell. The body temperature is measured through 2.3 and 4 hours after taking the medicine.
The percentage of hypothermic withdrawal; The condition caused by reserpine (the percentage of recovery) is determined according to the formula
Present recovery. Medicine X - Reserpine x
my withdrawal of the hypothermic state caused by reserpine is used
l Jl 1 (just as in Table 2, rf, etc., have relation to formula I, and deputy 1 to the current position of the hypergridropyrimidine ring, in which a notice® is made.
Example 13. Anticonvulsant activity (maximum electric shock test),
The determination is carried out for the evaluation of the anticonvulsant activity of the compounds obtained by the proposed method.
For these experiments, groups of 10 male mice of the Hilitop ICR strain were used. Fifteen minutes before the test, the test substance or solvent was injected intraperitoneally. After an appropriate time, mice are subjected to
PRI me R 14. Testing of skeletal muscle relaxants with a central action — obtaining a lingo-mandibular reflex in a cat.
This test is used to evaluate the activity of the compounds as relaxants of the skeletal muscles of central action.
Outbred cats weighing 2-5 kg are anesthetized intraperitoneally with luminyl sodium (180 mg / kg); The anesthetized cat is placed in a stereo-toxic head holder, shaved and cannulas inserted into the femoral vein and artery. A cannula from the femoral arteries is attached to a Statham Model P-23 AC sensor to monitor blood pressure. The femoral vein is used to inject drugs.
The cat is placed in an open posture and from two sides two electrodes are placed on the base of the tongue, which are spiral clamps attached to the wires. These prb
transconeal electroshock caused by an electrostimulator. Shock (50 mA, 0.2 s) causes three types of seizures: tonic distribution, tonic flexion and clonic seizure. Antagonism to the contracture of the tonic razgibatel is used as the end point. To determine ED 50, quantitative data compressed from several doses of the test compound is used. The results are presented in Table. 2..
Table 2
water is then attached to a Grass S 8 stimulator. A Grass FT-03 sensor is placed under the lower jaw. Another sensor 4 cm in diameter overlaps the lower jaw. This sensor transmits the movement of the lower jaw to the upper sensor. Signals from the sensor recorded on a polygraph firm Bzkman,.
0
The stimulator is set to issue a single pulsation of 2.5 MO. The determination of the voltage required to obtain the maximum response is carried out. After
5 of this, the stimulator is set to 1 V higher than this maximum voltage. When determining a supermaximal threshold, the tongue is stimulated every 10 s. When the response is
0 is defined as constant, the solution of the test compound is administered intrahigmatically in log-increasing doses. Multiple doses of the same test compound are administered to each cat. Doses always
five
vaod t in order of buildup. Before; kai: administer the next dose, recovery after the previous dose.
To determine the activity of a drug, use the percentage of reduction: the opening reflex of the lower
Example 15. Testing relaxantoye skeletal muscles with central action. Resistance caused by etonntazenom rigidity in rats.
This test is based on the resistance of rigidity, caused by the pharmacological agent etonitasei.
Rats are pretreated with the test compound, and then injected
Average score for saline. Average score for physiological.-Individual score.
solution
, having a 60% reduction or more, are dissolvated as demonstrated by resistance, and for each test compound, Compound D.6. For the study, b male male groups (ICR-imonsen) were used for 5 MEUs per group. 2 Methoxycar01-amino-5-phenyl-1,4, 5,6-tetrahydropyrimidine as the maleate salt is administered intraperitoneally in
jaws. Comparative evaluations of the relative blocking of the reflex, the steepness of the response curve and the cardiovascular changes are made and the ED is determined.
The results for the corresponding compounds are presented in table. 3
Table3
dt subcutaneously etonitazenG0 1) G25 mg / kg; After 5, 10 and 15 minutes after the administration of etonitazene, they are evaluated for rigidity of the torso (grades 0-3) and hind limbs (grades 0-2). Estimates for the control group are added and the average score is determined for animals injected with saline. To determine the percentage reduction in stiffness, use the sum of the individual for rats.
X 100
The NIN is thus quantified data for calculating ED. ....
The results are presented in table 4.
as an aqueous solution (0.2% w / v and Behavior is observed 2 hours after drug administration.
The observed effect on behavior is expressed in a decrease in motor activity, loss of voluntary control of movements, muscular straightening, hair bristling, shortness of breath (increasing depth and decreasing Respiratory Rate), tearing, Moderate clonic convulsions and death. The effect begins less than 5 minutes after the administration of the drug; peak activity occurs after lO-lS min after administration. Surviving animals externally returned to normal after 90-120 minutes after: introduction. medication. Death of HjaO, 1 as a result of loss of breath. Y (0, calculated according to the Litchfield-GH-Coxon method is equal to 26.5 mg / kg (25V6-28 t);
The results are shown in Table. five.
Table
Other proposed compounds have similar toxicity.

权利要求:
Claims (2)
[1]
METHOD FOR PRODUCING DERIVATIVES
[2]
2-amino-1,4,5,6-tetrahydropyrimidine of the general formula D wherein A is hydrogen, alkylcarbonyl or alkoxycarbonyl, in co-. alkyl groups of 1-6 carbon atoms;
X is hydrogen, fluoro, chloro, bromo, iodo, oxy, alkoxy with 1-4 carbon atoms, benzyloxy, alkyl with 1-4 carbon atoms, alkio-, alkylthionyl or alkylsulfonyl group in which alkyl with 1-4 carbon atoms, or trifluoromethyl Y is hydrogen or has the same meanings as X;
R is hydrogen or alkyl with 1-4 carbon atoms and the phenyl substituent containing X and Y is in position 4 or 5 of the tetrahydropyrimidine ring if R is hydrogen, or in position 5 if R is alkyl with 1-4 carbon atoms HB - acid;
η - 0 or 1, characterized in that the base of the compound of general formula I, where p-0, is converted into an acid-addition salt of a compound of general formula I or the acid addition salt of a compound of general formula I, where η - 1, is converted to a base common; formulas I, where = = 0.
oo

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同族专利:

公开号 | 公开日

US4261995A|1981-04-14|

ZA805384B|1982-04-28|

PL226480A1|1981-10-30|

JPS5636466A|1981-04-09|

FR2464256A1|1981-03-06|

FR2464256B1|1982-09-17|

引用文献:

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CZ280006B6|1989-11-13|1995-09-13|Pfizer Inc.|Process for preparing optically activeor -endobicyclo£2.2.1|hepan-2-ole|

IL100810A|1992-01-30|1996-12-05|Yeda Res & Dev|Pharmaceutical compositions comprising 2-methyl-4-carboxy-5-hydroxy-tetrahydropyrimidine and/or 2-methyl-4-carboxy-tetrahydropyrimidine methods for the isolation and purification of said compounds and substantially pure 2-methyl-4-carboxy-5-hydroxy-3, 4, 5, 6-tetrahydropyrimidine salts 5-ethers and 5-esters thereof|

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DE102006056766A1|2006-12-01|2008-06-05|Bitop Ag|Use of compatible solutes|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

US06/071,442|US4261995A|1979-08-31|1979-08-31|4-Phenyl-and 5-phenyl-1,4,5,6-tetrahydropyrimidine derivatives|

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