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    • 专利摘要:
    The invention relates to guanidine derivatives of imidazoles and thiazoles which are histamine H-2 antogonists and which inhibit the secretion of gastric acid, to methods for their manufacture, to pharmaceutical compositions containing them and to methods of using such guanidine derivatives and compositions. The guanidine derivatives are of the general formula I: <IMAGE> I in which X is S or NH, Y is O, S, or SO, m is 1 to 4 and n is suitably 1 to 4, R1 is hydrogen, halogen or alkyl, R2 is hydrogen, alkyl, alkanoyl or aroyl, A is a 3,4-dioxocyclobuten-1,2-diyl radical or C=Z in which Z is O, S, NCN, NNO2, CHNO2, NCONH2, C(CN)2, NCOR3, NCO2R3, NSO2R3 or NR4 in which R3 is alkyl or aryl and R4 is hydrogen or alkyl, B is alkoxy or alkylthio or NR5R6 in which R5 and R6 are independently hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl; and the salts thereof.
    公开号:SU730299A3
    申请号:SU782607390
    申请日:1978-04-20
    公开日:1980-04-25
    发明作者:Орегон Еллин Тобайес；Джон Джилман Дэвид；Флит Джоунс Деррик；Майкл Вардлеворт Джеймс
    申请人:Империал Кемикал Индастриз Лимитед；Ай-Си-Ай Америказ Инк (Фирма)；
    IPC主号:
    专利说明:

    A method is proposed for the preparation of new guanidine derivatives of the total form S.JV | 1 h I ((. -Agde X is a sulfur atom or the radical NH; Y is a sulfur or oxygen atom, a simple bond, a methylene or sulfyl radical or a cis- or trans-vinylene o.apik n m is 0-4; n is 1-4, and if Y is a sulfur or oxygen atom, or a sulfinyl radical, then m is 1-4, if Y is a sulfur or oxygen atom, or a sulfinyl radical is a radical, then n is 2-4; R represents an atom of a loood or a halogen or alkyl radical with L-6 carbon atoms; P is a hydrogen atom, an alkyl radical Calcium with 1-10 carbon atoms An alkanoyl radical with 1-6 carbon atoms or an aroyl radical with 7-11 carbon atoms A is 3,4-di9-xycyclobutene-1, 2-diyl radical or a radical of the formula C -Z, where Z it is a sulfur or oxygen atom. or a radical of the formula NCN, NNOg, CHNO, NCONHj, .C (CN) 2, NCORs, NCOOR3, C3O3 or NR, where Cs is alkyl with 1-6 carbon atoms or aryl with 6-12 carbon atoms ; R is hydrogen or alkyl with 1-6 carbon atoms: B is an alkoxy-yl alkythio group with 1-6 carbon atoms .. atoms or a radical of the formula NRjRgf where RS and RS are the same or different, are hydrogen, ashkyl with 1-10 carbon atoms, alkenyl with 3-10 carbon atoms, in which the double bond is separated from the nitrogen atom from the N group RgRe s with less than one carbon atom, cycloalkyl with 3-8 carbon atoms, primary oxyalkyl with 2-6 carbon atoms, in which the oxygen atom is separated from the nitrogen atom of the N R5R6 group by at least two carbon atoms, alkoxyalkyl with 3-10 carbon atoms, in which the oxygen atom is separated from the nitrogen volume of the NRjR group less than 1 two atoms, carbon, alkylaminoalkyl adicles with 3-10 carbon atoms in which the nitrogen atom is separated from the nitrogen atom of the NRsRg group with less than two carbon atoms, or dialkylaminoalkyl radicals with 4-10 carbon atoms, in which the nitrogen atom is separated from the nitrogen atom of the NRjRfi group of at least two carbon atoms, or their salts, possessing valuable physiological properties. Compounds with similar properties are known, which are imidazole and thiazole derivatives with a side chain in guide 4, at the end of which is an addition, for example, urea, thiourea, guanidium or N-cyanoganidine 1. The purpose of the invention is to synthesize new, guanidine derivatives with valuable physiological properties The goal has been achieved by the intended method of obtaining compounds of general formula 1, which consists in the fact that they conduct the reaction of interaction of compounds of general formula CP.1, 1 H I ("2) mY- ((2) where RI, R2, X, Y , A, m and p im the indicated values are given; H alkoxy or alkylthio groups with 1-6 carbon atoms, with a compound of the general formula B — H where B has the indicated values. If necessary Prepare the compound of formula 1 as an acid addition salt, then the compound of formula 1 as its free base It is reacted with an acid. Pr Example 1 1. A suspension of 912 2-guanidine-4- (2-amino ethyl) thiomethyl thiazole hydrochloride in 300 ml of methanol was treated with 6.06 g of triethyl and a clear, light-yellow solution was obtained. 4.38 g of dithyl (cyanimide) dithiocarbonate were added and the solution was stirred overnight at room temperature. The mixture was poured into Wo | Tsu, extracted with ethyl acetate and a yellow resin was obtained. After trituration with acetone, 7.3 g of 2-guanidine-4- 2- (3-cyano-2-methyliso-thioureid) ethylthiomethyl thiazole were obtained in a pink solid with a melting point of 200 g. 146-148 ° C. The 2-guanidine-4- {2-ami ethyl) thiomethyl thiazole hydrochloride used as the starting material can be prepared as follows. A suspension of 16.8 g of amidine urea in 75 of acetone was treated with 18 g of 1,3-dich. Poro-acetone in 60 mp of acetone. A slight exothermic reaction took place and the crystalline suspension gradually melted into a fine crystal mass. After stirring overnight at room temperature, the precipitate was filtered and washed with acetone. After crystallization of ethanol, 2-guanidine-4-chloromethylthiazole hydrochloride was obtained with mp. 19 1-193 ° C. A solution of 4.52 g of 2-aminoethanethiol hydrochloride c. 4-0 ml of ethanol was added portionwise with a solution of ethylate. sodium (prepared from 2 g sodium) in 60 ml of ethanol under nitrogen. After stirring at 0 ° C for 2 hours, a solution of 4.54 g of 2-guanidine-4-chloromethylthiazole hydrochloride in 35 ml of ethanol was added dropwise over 15 minutes, while the temperature was kept at 0-2 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours, filtered, the filtrate was acidified with concentrated hydrochloric acid. At. The 2-guanidine-4- (2-aminoethyl) thiomethyl thiazole hydrochloride precipitated as a white crystalline gist (4.56 g) with m.p. 26.8-270 ° C (decomposition), Example 2. A mixture of 1.1 g of 2-guanidine-4- 2- (3-cyan-2-methylisothioureido) ethylthiomethyl thiazole in 25 ml of ethanol was treated with 70% aqueous ethylamine (5 ml ) at room temperature. - The mixture was stirred at room temperature overnight. and the solution was evaporated to dryness. The residue was crystallized from methanol to obtain 0.53 g of 2-guanidine-4- 2- (2-cyan-3-ethylguanidine) ethylthiomethyl) thiazole with mp. 181-182 ° C. Example 3. A mixture of 2 g of 2-guanidine-4- 2- (3-cyano-2-methylisothioureido) ethylthiomethyl thiazole and 5 ml. Of 30% fes / volume) aqueous methylamine in 25 ml of ethanol was stirred for 5 hours at room temperature. temperature, then the solution is evaporated to dryness. The remaining white foam was dissolved in 10 ml of acetone and 1 g of maleic acid was added. In 12 ml of acetone. The precipitated white precipitate was filtered and crystallized from methanol to give the acid maleate 2-guanidine-4- 2- (2-cyano-3.-Methylguanidine) ethylthiomethyl ethazole with mp. 175-177 ° C. A cleaner product was obtained by replacing 30% ethanolic methylamine with aqueous methylamine. The acid addition salts of the above product listed in Table 1 were obtained by the above procedure. Table Found,%: H 5.2, N 30.6 CK Hj ClNgSj HjO Calculated,%: C 33.1; H 5.0; N 30.6. Example 4. A solution of chlorohydrate 2-guanidine-4- (3 aminopropyl) thiomethyl t, azole (1.64 g) and 1.01 g of triethylamine in 20 ml of cold methanol were treated with 0.73 g of dimethyl cyanimidine dithiocarbonate to a solution. stirred for 16 h at room temperature. A 33% (w / v ethanol solution of methylamine (12 ml) was added and the mixture was stirred at natal temperature for 18 h. The solution was evaporated and a brown gum was obtained, which was applied to Merck 60 F, 254 straps and eluted with cr .A whole ethyl acetate / amgliak (, 880) / ethanol 6: 1: 1 by volume. A light yellow oil was converted to an acidic maleate, a product of recrystallization from methanol to give an acidic maleate 2-guanidine 4- | (3- (2-cyano- 3-methylguanidine) propylthiomethyl thiazole with mp 175-17 ° C. The starting material can be obtained as follows: 2.54 g of 3-aminoprop nthiolchloride in 20 ml of ethanol was added to a solution of sodium ethoxide (1 g of sodium in 25 ml) in ethanol at 0 ° C. under a nitrogen atmosphere. The suspension was stirred at 0 ° C for 2 hours, then a solution of 2.27 g of hydrochloride 2 was added -guanidine-4-chloromethyl ± azazole in 25 ml of ethanol. The suspensions allowed to warm to room temperature and stirred for 16 hours. After filtering the suspension and acidifying the filtrate with concentrated hydrochloric acid, 2-guanidine-4 (3-aminoprotein) thiomethyl thiazole hydrochloride was precipitated with m.p. Example 5. The experiment from Example 3 was repeated, using an excess of the corresponding amine instead of methylamine in ethanol, and the compounds shown in Table 2 were obtained. table 2
    Mes N- (CH2) s
    HOCHgCHg
    CHgfCHg)
    Notes:
    42.3; H 5.45;
    . Found: 20.2
    C22 NZZ N9 S2 Oh
    .O, 5 H2O.
    C 42.2; H 5.4;
    Calculated,%:
    N 20.2. C 45.8; H 6.0;
    . Found ,:
    N22,5
    With HaNgSaO
    C 45.6; H 6, O;
    Calculated,%:
    N .22, 1.
    1. The product is isolated thin layer.
    chromatography on plates
    Mepk 60 F 254, using ethyl acetate / ammonia for elution.
    (d Oh, 880) ethanol (6: 1: 1 by volume).
    Example 6. A solution of 1.06 g of 2-guanidine-4-G2- (3-cyan-2-methylisothioureido) ethylthiomethyl thiazole in 25 ml of ethanol was added to a stirred mixture of 0.6 g of silver nitrate,
    5 ml of isopropyl viin and 20 mp of ethanol. The mixture was stirred at room temperature for 4 days, filtered, and the residue npoNSinH 10 included methanol. The combined Filtrates were evaporated to dryness and the remaining crude free basement was converted into the maleate salt. It was recrystallized from a mixture of methanotoluxole and obtained acidic low 2-guanidine-4- 2- (2-cyan-3-isopooylGuanidine) ethylthiomethyl thiazole with m.p. 162-165 C (decomposition). , Example 7, A mixture of 4 g of 2-methoxyethylamine, and 1 g of 2-guanidine-4- 2- (3-cyano-2-methylisothioureido) ethylthiomethyl thiazole in 10 ml of methanol was stirred at room temperature for 3 days The mixture was evaporated, and the remaining raw c-free base was converted into a molaton-uk1 salt, which was recrystallized from ethanol and the acid maleate 2-guachidin-4-- 2- | 2-cyano-3- (2-methoxyethyl) guanidine ethylthi. Tyl thiazole with m.p., 15E 161 ° C. . This procedure was repeated using the appropriate amine instead of the 2-label of sietilamine, and the compounds were obtained in the form of their acid maleates listed in Table 3. Table. NDY sig scHjCHjNHciraR j Temperature- | Solvent melter for sulphide, C. recapitalization 142-144 Ethanol CHgCHjCHj Methanol / CH CHCH2 130-133 ethyl acetate Ethanol HOCHgCHgCHg 148-151 Example 8, Mixture with 4 ml of cyclohexylamine, 6 ml of pyridine and 1 g of 2-guanidine -4- 2- (3-cyan-2-methyliso thioureido) ethylthiomethyl thiazole, kept at room temperature for 2 weeks. The mixture was evaporated to dryness and the remaining wet free base was salified into maleate acids. This salt was recrystallized from methanol / ether and the α-maleate-2-guanidine-4- 2- (2-cyano-3-cyclohexylguanidine) -sulfate maleate of these (thiomethyl1 thiazole with mp 156159 ° C. Example 9. Mixture 0.90 g of dimethyl- (toluene-p-sulphonyl mido) dithi.ocarbonate, 0.69 g of triethylamine, 10 ml of ethanol and 1.0 g of dichloride 2-guanidine-4- (2-aminoethylthiomethyl) thiazole were stirred at room temperature for 2 hours and leave it to stand for 3 days. Add 3 m of a 33% ethanolic solution of methylamine and let the mixture stand for 3 days. The mixture was evaporated until dry, the residue was turned into salt th maleate, which was recrystallized from water to give 2-guanidino-4- 2- {2-a-toluene-sulfonyl-3-methylguanidine) ethylthiomethyl thiazole, m.p. 167-170 ° C. PRI mme R. 10. To a stirring of a solution of 1.59 g of diethyl- (L-cyanimide) carbonate in 15 ml of ethanol, a solution of 2.58 was added at room temperature. g 2-guanidine-4- (2-aminoethylthiomethyl) thiazole in 25 ml of ethanol for 1.5 minutes while cooling, providing. temperature is about. The solution was kneaded at room temperature for another 30 minutes, then another 0.318 g of diethyl-SO-cyanimide.) Carbonate in 3 ml of ethanol was added. The solution was stirred at room temperature for 15 minutes, then evaporated to dryness under reduced pressure and a light yellow pasta. This residue was dissolved in 20 ml of ethyl acetate. The solution was washed with 20 ml of water (10. adl. X 2), dried with magnesium sulfate, and evaporated under reduced pressure to give 2.-guanidine-4- | 2- (3-cyan-2 -ethylisoureido) ethylthiomethyl1 thiazole, containing a small amount of ethyl acetate, NMR spectrum (CDS1, - tetramethylsilane as an internal standard) ... .6 6.5 (54, very wide), 6.4 (1H, singlet), 4- 4.5 (darkened with ethyl acetate). 3.6 (2H, singlet), 3.4 (24, multiplet), 2.7 (.2H, multiplet, 2, .0 (ethyl acetate),., 2-1.5 (darkened, ethyl acetate). P p I. Mer 11. 11.2 g of triethylamine was added to a suspension of 3.04 g of 2-guanidine-4 -. (2-aminoethyl) thiomethyl thiazole dichlorohydrate in 30 ml of methanol and stirred at room temperature. Added 1.14 g of dimethyl-N-cyanimidocarbonate and the mixture was stirred at room temperature for 3 h, then evaporated under reduced pressure. The residue was extracted with 35 ml of ethyl acetate and the solution was washed with 25 ml of water, then 10 ml of water, then dried with sulphate magnesium, evaporate and under reduced pressure yielded 2.16 g of 2-guanidine-4- 2- (3-cyano-2-methylisoureid) ethylthiomethyl thiazole. NMR spectrum (CDS15, DMSO-d, tetramethylsilane-internal standard): $ 7, 7. (1.H., Very broad), 6.7 (4H, broad.), 6.4 (1H, singlet) 3.8 (3N, syn. Gl), 3, .6. (2n, singlet), 3.4 (darkened), 2.7 (2h, .boood triplet), Prémér 12 .. Mixture 1.88 g 2-guanidine-4- 2- (3-cyan-2-methylisojreido a) ethylthiomethyl thiazole and 6, O ml of 30% aqueous methylamine were stirred at room temperature. After 1 h 40 min, 20 ml of water was added and stirring was continued for another 15 min. Example 13. To a stirred mixture of 0.4 g of 2-guanidine-4- (4-aminobutyl) thiazole hydrochloride hydrobromide in 25 ml of ethanol, 0.3 ml of triethylamine and 0.18 g of dimethyl cyanimide dithiothiocarbonate were added at room temperature, then all the mixture was stirred at room temperature for 5 hours. Then 30 ml of a 33% methylamine solution in ethanol was added and the mixture was allowed to stand for 16 hours. A small amount of carbon was added, the mixture was stirred. A few minutes later, filtered and the filtrate was evaporated to dryness. The remaining resin was purified by chromatography on a silica gel column. elution was carried out with chloroform / methanol / ammonia ((, 88) 80: 20: 5 (by volume), 0.25 g of the purified product was recrystallized from acetonitrile, and 2-guanidine-4- 4- (2-cyan-3- methylguanidine) butyl thiazole with t. square 165-187, 5 ° C. The starting 2-guanidin-4- (4-aminobutyl) thiazole hydrochloride hydrobromide was prepared as follows. A mixture of 4.5 g of N (, 6-bromo-5-oxohexyl) phthalimium and 1.65 g of amidinoth ocular in 300 ml of ethanol was heated by reverse distillation for 1 hour. The reaction mixture was allowed to cool and the product was removed by filtering 2- hydrobromide 2- guanidine 4- (4-phthalimidobutyl) thiazole with mp 218-221 ° C. A mixture of 3.43 g of 2-guanium din-4- (4-phthalimidobutyl) thiazole hydrobromide and .1.68 g of potassium hydroxide in 50 ml of water was heated for 15 min. Then the reaction mixture was acidified to pH 2.2 ns acid and the mixture was heated at 100 s for 1. h. The cooled mixture was extracted 3 times with ethyl acetate, the aqueous layer was evaporated to dryness, and toluene was added to the residue, which was then evaporated to dryness. The obtained resinous PRODUCT was dissolved in methanol, the insoluble substances were filtered off and the filtrate was evaporated to dryness and the hydrochloride of 2-guanidine-4- (4-am gnobu tyl) thiazole was obtained. 1.2 g of free bases were obtained by passing through an ion exchange column (Aberlite {, KA-400 OH), in a 50% solution of methanol in water). Example 14, A mixture of 0.203 g of 2-guanidine-4- (4-aminobutyl) thiazole and 0.076 g of methyl isothiocyanate in 5 ml of ethanol was stirred at room temperature for 2 hours. Product 0.2 g of 2-guanidine-4- 4- {3 -methylthiour Ido) butyl thiazole was filtered and dried, t, pl. 189-192 ° C. Example 15. A solution of 0.65 g of 2- (2-methylguanidine) -4- (4-phthalimidobutyl) thiazole hydrobromide in 50 ml of a mixture of ethanol and water (3il by volume) containing sufficient sodium hydroxide to maintain a pH above 12 is heated with reverse distillation within 15 minutes Then the pH was adjusted to 3 with concentrated hydrochloric acid and the solution was heated by refluxing for 15 minutes. The solution was then strongly basified with sodium hydroxide solution and evaporated to dryness. The residue was dissolved in 30 ml of water and the solution was extracted with ethyl acetate (2x40 ml). The combined ethyl acetate extracts were evaporated to dryness and 0.27 g of the residue was dissolved in 10 ml of ethanol and treated with 0.18 g of dimethyl cyanimide cythiocarbonate. The mixture was allowed to stand for a period of time and a solution of 2- (2-methylguaniline) -4-4- (3-cyano-2-methyl-isothioureido) butyl azazole in ethanol was obtained. The initial 2- (3-methylguanidine) -4- (4-phthalimidobutyl) thiazo.v.bromide hydrate can be prepared as follows. To a solution of 0.4 g (L-methylamidine). Thiourea, 20 ml of hot ethanol was added 1.5 g of N - (5-bromo-5-oxohexyl) phthalimide, the mixture was heated by refluxing for 1 h, cooled and evaporated to dryness. The residue was triturated with acetonitrile, filtered and the precipitate was dried. 2- (2-methylguanidine) -4- (4-phthalimido5uyl) thiazole hydrobromide was obtained with a mp. 210-212C. Example 16. To a solution of 0.38 g of 2- (2-methylguanidine) (3-cyan-2-methylisotipeido) butyl thiazole in 10 ml of ethanol was added 40 ml of 33% ethanolic methylamine. The mixture was stirred overnight, evaporated to dryness and the residue was triturated with water, the residue was filtered, dried and 2- (2-methylguanidine) (2-cyano-3-metl-quguanidine) butyl thiazole was obtained with mp 119-122 ° C. Example 17. To a solution of 0.8 g of 2-guanidine-4- (4-aminobutyl) thiazole in 10 ml of ethanol was added p, 6 g of dimethyl cyanimide didethiocarbonate. The mixture was stirred overnight. The white precipitate was filtered off and recrystallized from acetin nitrile, and 2-guanidine-4-4- (3-cyano-2-methylisothioureido) butyl thiazole was obtained with mp. 178-180 ° C. Example 18. A solution of 0.2 g of 2-guanidine-4- 4- (3-cyan-2-methylisothioureid) butyl thiazole in 10 ml of methanol containing 0.005 g of sodium hydride (50% dispersion in oil ), was heated with reverse distillation. After 4 h, the mixture was treated with charcoal, filtered and evaporated to dryness. The residue was dissolved in 10 ml of acetone and an excess of maleic acid in acetone was added to precipitate the salt. Salt fromAilted, dried and obtained acid maleate 2-guanidine-4- {3-gdian-2-methylisourad butyl} thiazole with mp 174-176С. Example 19. A mixture of 0.43 g of 2-guandic-4- (4-aminobutyl) thiazole 0.33 g of 1, (methylthio) -2-nitroethylene in 15 ml of acetonitrile was heated by reverse distillation for 1 h. The mixture was evaporated to dryness and added 200 ml of a 33% solution of methylamine in ethanol. The mixture was stirred for 5 days at room temperature, filtered, the filtrate was evaporated to dryness, the residue was crystallized from ethanol to give 1-4- {2-guanidinothiazol 4-yl), butylamine -1-methylamine-2-nitroethylene with mp. 225 ° C (decomposition). EXAMPLE 20. To a solution of 2-gu anidine-4 -5- (3-cyano-2-methyl-isothioureid) pentne.hlpal in ethanol was added a methanol solution of methylamine (33%, 15 mp). The mixture was allowed to stand overnight, then evaporated to dryness. The residue was crystallized from acetonite. Rila and received 2-guanidine-4-B - (2-cyan-3-methylguanidine) pentyl thiazole with so pl. 109-113 ° C., The initial solution of 2-guanidine-4- 5- (3-cyan-2-methylisothioureid) pentyl thiazole was obtained as follows. A dilute aqueous solution of sodium hydroxide (10 ml) was added to 1.2 g of hydrobromide. 2-guanidine-4- (5-aminopentyl) thiazole hydrochloride. The mixture was stirred briefly and the precipitated white wasp was filtered. doc (0.588 g). This substance was dissolved in 10 ml of ethanol and 0.4 g of dimethyl cyanimidine dithiocarbonate was added. The mixture was stirred for 2.5 h and a solution of 2-guanidine-4-5- (3-Cyan-2-methylisothioureid) pentyl thiisol was obtained. Example 21. To a mixture of g of 2-guanide-4- (4-aminobutyl) -5-methylthiazole dichloride mixed in 15 ml of ethanol, 0.52 mp of triethylamine was added at room temperature, then 0.25 g of dimethyl cyanimididiocarbonate and. the whole mixture was stirred at room temperature for 15 Then a solution of methylamine in ethanol (331, 20 ml) and a mixture of pere were added. ME11iva 1 and at room temperature for 5 hours. The mixture was evaporated to dryness. The mixture was left to -10 ° C and the mixture was purified by chromatography on a column of silica gel, using a mixture of x.porofor meth a-but l / ammonia (, 88) 8: 2: 0.4 by volume Got 2-guanidich 4-f 4 - (. 2-cyan-3 methylgianidine) -butyl-5-methyl thiazol. NMR spectrum (DMS 0-d, tetramethylsilane as an internal standard, (GO J-: 1.5 (4H, multiplet, 2, (ZN, singleton), 2.4 (multiplet, darkened DMS 0), 2, 6 (3N, doublet), 3.1 (2H, multi-flash) 3.3 (single,), 6.8 (6H, m ltiapet). Example 22. A mixture of 0.17 g 2-ruanidine-4- (4 -aminobutyl) thiazole and 0.113 g of 1,2-dimethoxycyclobutene-3,4-dione in 15 1lp of methanol was stirred at room temperature for 6 hours. The product of 0.05 g (2-guanidinothiazol-4-yl) butylamine 2-methoxycyclobutene -3, 4-dione, filtered and dried, mp 179-180 C. Example 23. For a mixture of 0.2 g - (2-guanidinothiazol-4-yl) butyl 2-methoxycyclobu en-3, 4-dione in methanol MP was added methylamine in ethanol (33%, 7 ml). The whole mixture was stirred at room temperature until a clear solution was formed. The mixture was evaporated to dryness and the residue was triturated with methanol. The product (2-guanidinothiazol-4 or a) butyl. amine of 2-methyl winocyclobutene-3, 4-dcon was filtered and dried, mp 184-18 b C. Example 24. A mixture of 0.11 g of 2-guanidine-4- 3- (3-cyan-2-methyl-isothioureid a) prop-1-trans-etyl1-thiazole and 2 ml of 35% ethanol methaiviMHa were stirred at room temperature for 2 hours, then evaporated to dryness, the residue of crista; mixtures of methanol and acetonitrile and obtained 2-guanidine-4-Z- (2-cyano-3-methyl guanidine) -prop-1 -trans-enyl thiazole with so pl. 2 13-2 16 C (decomposition). Example 25. A mixture of 0.5 g of 2-guanidine-4- (4-ftglimidobut 1-trans-enyl) thiazole hydrochloride, 0.2 g of hydrazine hydrate and 15 ml of methanol was heated by reverse distillation for 1.5 hours. The solution was cooled , treated with 0.3 g of N, N, N, N-tetramethylguanidine, evaporated to dryness, the residue was suspended twice in 20 ml of toluene and evaporated to dryness. A solution of the residue in 10 ml of ethanol was treated with 0.175 g of dimethyl cyanimide dithiocarbonate and the solution was kept at room temperature for 2 hours, then evaporated to dryness. Remaining the current was stirred with 10 ml of water for 5 minutes, then the aqueous phase was drained and the residue was washed with another 10 ml of water. The residue was dissolved in 5 ml of 33% methyl methane: vlina in ethanol, then evaporated to dryness. The residue was purified by preparative thin layer chromatography on plates. Merck 60 P 254 with a mixture of ethyl acetate / ethanol / ammonia (d 0.880) 12: 1: 1 by volume and a band with R, 0.3 were neutralized with methanol, 0.08 g of 2-guanidine was obtained. 4- 4- (2-cyan-3-methylguanidine) -but-1-trans-enyl thiazole, characterized as its acidic little eate with mp, 163-165 ° С with decomposition (after crystallization from methanol / acetonitrile ), Original 2-guanidine-4- (4-diethyl-1-trans-enyl) thiazole hydrochloride
    Received as follows. A solution of 8, 6 8g (, 3 - chlorine acetone or den) triphenylphosphine and 5 g of 3-phthalimidogropionaldehyde in 80 ml of chloroform was heated by refluxing for 24 hours. The solution was evaporated to dryness and the residue was dissolved with ethanol, filtered, and 3.4 I was obtained N- (6-hlop-5-oxyc-3-trans-enyl) phthalimide with mp, 132135 C after recrystallization from ethanol),
    A mixture of 0.554 g of N- (b-chloro-5-oxohex-3-trans-enyl) phthalimide, 0.236 g of amH H HCl
    C NNOzNH2
    C-NCN-NHj
    C NCONHsNHCHj
    Free
    About NHCH Base
    Free C NCNNHCHj base
    Free
    C NCNNHCH3 base
    Free SNHCHg base
    C-NCN NHCH3
    .N male at
    . DOWNLOAD
    2H maleate
    C-ONHCHj 1/2 NgO
    H maleate
    With ksnzyasnz
    Product characterized by NMR, Product sulfoxide - SNDC (CH2) 2 Product characterized by elemental analysis.
    Dinothioureas and 30 ml of ethanol were heated under reflux for 3.5 hours, the mixture was allowed to cool, the filter was dissolved and 2-guanidin-4- (4-phthal and 1-trans-enyl) thiazole hydrochloride was obtained with mp 22bc (decomposition).
    Example 26. The method described in Example 3 or 18 should be repeated using the appropriate starting materials and thus
    0 can &amp; get the compounds listed in Tables 4 and 5,
    Table 4
    Methanol / acetone.
    206 181
    Methanol 150
    Methanol
    Acetone / Cyclohexane
    181
    210
    Methanol 170 ethanol

    HAXA
    S

    S (CNJg
    S
    NH
    S c s
    S
    MUCH.
    4 5 5 4 4 4 4
    Sch,
    The product has CH CH-CHj-NH-A-B, side chain. Example 27: A mixture of acidic maleinate 2-guanidino-4- 2- (3-methylthioureido) ethylthiomethyl thiazole (1.0 g methyl iodide (0.56 g) and ethanol (10 Mrt) is heated at the boiling point reflux for 1.5 hours and then cool, the white crystalline precipitate is filtered off, PI is expelled with diethyl ether and dry4 A sample of this salt S-methylisotiouro and. (0.50 g) is stirred overnight with ethanol / methylamine solution ( 33% w / v 10 ml) The mixture is evaporated to dryness and the residual resin is dissolved in methanol (10 ml). This solution is passed through a onc with ion exchange resin (1RA-400 in hydroxyl Lorm) and eluted with methanol. The fractions containing the product are combined and evaporated to a residue and then 5.
    with the art
    The product is characterized by the same. - 1 I
    180-181
    179-180 Methanol 128-131
    Read-H chromatography:

    223-225 Ethanol Residual frothy, the product is a solution of sweat in isopropanol (5 ml) and this solution is treated with a solution of maleic acid (0.31 g) in acetone (5 ml) i The clear solution is diluted with ethyl acetate until it begins to turbid and incubate for nights The white o.grind is filtered by dp p emitting 2-guanidino-4- (2, 3-dimethylguanidine) ethylthiomethyl thiazole dimaleinate containing two atoms of acidic hydrogen, melting at 126-129 ° С. Example 28. A mixture of 2-guanidino-4- (2-aminoethyl) thiomethyl thiazole dihydrochloride (1.0 g), dimethyl- (methyl methyl sulfonyl, and MI to) dithiocarbonate (0.67 g), t.riethylamine (0 , 85 g) and ethanol (15 ml) is stirred at room temperature for 20 hours. Ethanol solution of methylamine (33%, weight / volume, 3 W) is added and the mixture is stirred overnight. After that, the residue is evaporated to dryness and the residual dissolved in a mixture of ace (10 MJi) and isopropanol (10 ml). The solution is lilted and treated with a solution of maleic acid (0.90 g in acetone (10 ml). The clear solution is heated on a steam bath, diluted with ethyl acetate before being cloudy, NIN and left to cool. The precipitate is filtered and recrystallized from ethanol to obtain an acidic maleinate 2-guanidino-4- 2- (2-methylsulfrnyl-3-methylguanidino) ethylthiomethyl thiazole as a white powder, melting at 168-170 ° C. Example 29, Susansion of 2-guanide hydrochloride inin6-4- {2-amino ethyl tso setil thiazole (0.46 g) in acetonitrile (20 ml) is treated with triethylamine ohm (1 mp) to give a yellow solution. 1,1-di- (methyltco) -.2-nitro-9-thylene (0.22) is added (0.22 and the mixture is heated at reflux for 16 h. The mixture is evaporated to x and the residue is stirred with ethanol (30 ml). The mixture is filtered and the filtrate is evaporated to dryness. The residue, 1-2 2-guadino (thiazol-4-yl; methylthioethylamino -1-methylthio-2-nitroethyl, is dissolved in 33% (w / v) solution of meth amine in ethanol (15 ml) and the solution is stirred for 60 hours at room temperature. The mixture was evaporated to dryness, applied to preparative plates 4 Merck 60 F-254 and eluted & coziness with a mixture of clapoform: methanol: ammonia (specific gravity 0.880) in the ratio 8: 2: 0.5 (by volume). The creamy colored material obtained is recrystallized from acetonitrile to obtain 1- (2-guanidinothiazole) -4-yl (methylthioethylamino) -1-methylamino-2 -nitroethylether a, melted at (decomposed), Example 30, K a solution of (2-γ-II-dinothiaz-4-yl) ethylthiomethylamino) -2-methoxycyclobutene-3, 4-dione (0.25 g) in dimethylformamide (2 ml) is added with a methanol solution of ethanol (33%, w / v, 2 ml) . The mixture is entrained at room temperature for 0.5 h and then evaporated to dryness in vacuo .. Ethanol is added to the residue to obtain (2-guanidinothiazol-4-yl) ethylthiomethylamino -2-methylaminocyclobutene-3, 4-dione as a white solid, which is filtered off and dried in air (0.15 g; melted at a temperature of 207–210 ° C) 31. a mixture of hydrochloride-4- (2-aminoethylthiomethyl) thiazole (0.30 g) in methanol (5 ml) is treated with triethylamine (0.276 ml) and the solution is stirred for 5 min at room temperature before adding the solution of 1, 2-di 1e oksitsiklobute -3, 4-dione (0.142 g) in methanol (2 mL). The mixture was stirred at room temperature for 15 minutes, during which time a solid was precipitated from the solution. The product is filtered and dried to obtain (2-guanidino-thiazol-4-yl) ethylthiomethylamino) -2-methoxycyclobutene-3, 4-dione (0.28 g) melting at 186-188 ° C. Example 32. A crude solution of 2-guanidino-4- (3-aminoprop-1-cis-enyl) thiazole in ethanol (10 mp) at 40 ° C is treated with dimethyl (cyanomide) dithiocarbonate (0.18 g), the solution is kept at room temperature for 2 hours, after which it is evaporated to dryness to obtain a mixture containing 2-guanidino-4- {3) -3-cyano-2-methylisothioureido (prop-cc-enyl) thiazole. This residue was dissolved in a methylamine ethanol solution (33%, weight / volume, 5 ml) and the solution was kept at room temperature for 4 hours, then evaporated to dryness. The residue is chromatographed on preparative silica gel by thin layer chromatography on plates in a mixture of ethyl acetate: ethanol: aqueous ammonia (specific gravity 0.88) 12: 1: 1 by volume, and a band whose C value is equal to 0.3 with methanol to obtain 2 -guanidino-4- (2-cyano-3-methylguanidino) -but-cis-1-enyl-thiazole (0.09 g), melting at 224-226 ° C (with decomposition) after crystallization from methanol / acetonitrile. Crude 2-guanidino-4- (3-aminopropyl-1-cis-ecyl) thiazole, used as a starting material, can be attached as follows. A mixture of triphenylphosphine (25 g), 2-guanidino-4-chloromethylthiazole hydrochloride (20 g) and ethanol (500 ml) is heated at reflux for 16 h. The solution is cooled and filtered to obtain chloride hydrochloride- (2-guanidiothiazole A) -4-yl-methyltriphenylphosphonium (38.4 g), melted at a temperature above 300 ° C. A solution of potassium t-butylate (2.04 g) in anhydrous dimethyl sulfoxide (10 Nm) was added to the mixture of hydrochloride chloride within 30 minutes (2-guanidinothiazol-4-yl) methyltriphenylphosphonium (1.76 g) and anhydrous dimethylsuloxide (10 ml), stirred under argon, the mixture was stirred for another 30 minutes, then added to water (100 ml). Smear this mixture
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of obtaining derivatives of guanidine General formula
    K 2 M 1 5- JI
    H 2 U Ν - where X is a sulfur atom or an NH group;
    The Y nitrogen atom is separated from the nitrogen atom of the NRsRg group by at least two carbon atoms or a dialkylaminoalkyl group with 4-10 carbon atoms, in which the nitrogen atom is separated from the nitrogen atom of the NR $ R 6 He group by less than two carbon atoms, or. their salts ; and with the fact that the compound of the general formula is an oxygen or sulfur atom, a single bond, methylene, sulfinyl, cis or trans-vinyl;
    equal to 0.-4; equal to 1-4; .
    m η and, if 1 is a rock or sulfinyl, and if -1 is an atom or sulfinyl, then
    1-4, sulfur atom, cyst m is equal to sulfur, oxygen is equal to 2-4;
    R t is a hydrogen atom, halogen or alkyl with 1-6 carbon atoms;
    'Kg. - a hydrogen atom, alkyl with 1-10 carbon atoms, alkanoyl with 1-6 carbon atoms or aroyl with 7-11 carbon atoms
    A - 3,4-dioxocyclobutene-1,2-dailyl radical 'or a radical of the Formula C = Z, 2. > C = .I
    V * ·.!
    where R), Rj, X, Y, A, w and η have the indicated meanings;
    - alkoxy or alkylthio group with 1-6 carbon atoms, is reacted with a compound of the general formula
    BH, where B - has the indicated meanings, with the isolation of the target product in free form or in the form of salt,
    类似技术:
    公开号 | 公开日 | 专利标题
    SU730299A3|1980-04-25|Method of preparing guanidine derivatives or their salts
    CA1263115A|1989-11-21|Derivatives of 1,2,5-thiadiazole-1-oxides and 1,1-dioxides as histamine h2-antagonists
    EP0003640B1|1982-01-27|Antisecretory guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them
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    EP0040696A2|1981-12-02|Aminothiadiazoles as gastric secretion inhibitors
    NZ206614A|1986-05-09|Dihydropyridine derivatives and pharmaceutical compositions
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    CA1130806A|1982-08-31|1,2,4-oxadiazole derivatives, theirpreparation and pharmaceutical use
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    同族专利:
    公开号 | 公开日
    FR2519341A1|1983-07-08|
    SE7804461L|1978-10-21|
    JPS6156231B2|1986-12-01|
    CS200545B2|1980-09-15|
    DD135824A5|1979-05-30|
    ZA782129B|1979-03-28|
    PT67921A|1978-05-01|
    NO781300L|1978-10-23|
    IL54549D0|1978-07-31|
    DK172778A|1978-10-21|
    IN148903B|1981-07-18|
    GR62452B|1979-04-12|
    FR2387970A1|1978-11-17|
    ES468985A1|1979-09-16|
    FR2519341B1|1984-05-18|
    US4347370A|1982-08-31|
    AT363099B|1981-07-10|
    AR223315A1|1981-08-14|
    JPS53147069A|1978-12-21|
    JPS6335629B2|1988-07-15|
    ES474929A1|1979-04-16|
    AU516297B2|1981-05-28|
    FI781230A|1978-10-21|
    NL7804159A|1978-10-24|
    CS200546B2|1980-09-15|
    IT1094469B|1985-08-02|
    NL190486B|1993-10-18|
    US4234735A|1980-11-18|
    JPS59130277A|1984-07-26|
    CA1097658A|1981-03-17|
    ATA276978A|1980-12-15|
    GB2060607A|1981-05-07|
    IE780728L|1978-10-20|
    US4165377A|1979-08-21|
    PL113054B1|1980-11-29|
    NL190486C|1994-03-16|
    PL206191A1|1979-06-04|
    AU3510678A|1979-10-18|
    JPS625907B2|1987-02-07|
    NZ186965A|1980-02-21|
    GB2060607B|1982-03-31|
    US4262126A|1981-04-14|
    PL113082B1|1980-11-29|
    HU176807B|1981-05-28|
    ES477387A1|1979-10-16|
    IT7822558D0|1978-04-20|
    PT67921B|1979-11-14|
    FR2387970B1|1983-03-25|
    BE866156A|1978-10-19|
    JPS59130276A|1984-07-26|
    IE47044B1|1983-12-14|
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    法律状态:
    优先权:
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