Method of producing thieno-(2,3-c)-pyrroles

专利摘要:
Derivatives represented by the formula <IMAGE> in which X1 and X2 denote an oxygen or sulphur atom; R1 denotes a linear or branched alkyl radical containing from 1 to 8 carbon atoms, an alkynyl radical, an alkoxyalkyl radical containing from 3 to 8 carbon atoms or an aromatic residue; R2 denotes a hydrogen atom or a linear or branched alkyl radical; m = 2 or 3, when m = 2, X1 and X2 denote a sulphur atom. U denotes a 3,4-diaminocyclobuten-1,2-dione or aminosulphonylformamidine residue; U may also denote the nitrogenous structures <IMAGE> in which V denotes a nitrogen atom or a CH fragment; W denotes NO2 or CN; R3 denotes a hydrogen atom, a linear or branched alkyl radical containing 1 to 8 carbon atoms, or an alkynyl radical; R4 denotes an alkyl group containing from 1 to 3 carbon atoms. Medication with antagonist action on H2 receptors of histamine and antiulcer action, containing a thieno- or furo[2,3-c]pyrrole as active principle.
公开号:SU1329621A3
申请号:SU853963352
申请日:1985-10-11
公开日:1987-08-07
发明作者:ФЕСТАЛЬ Дидье；Дескур Дени；Депэн Жан-Клод；Кентэн Иветт
申请人:Лифа-Лионнэз Эндюстриель Фармасетик (Фирма)；
IPC主号:

专利说明:

 I}
The invention relates to a process for the preparation of new compounds, namely thio- (2,3-c) -pyrroles, which exhibit cytoprotective and antihistamine Hj action.
The aim of the invention is to obtain new thieno- (2,3-c) pyrrole derivatives, possessing more long-term antisecretory properties,
Example 1. N-UHaHo-N - (2- -ethyl-5,6-dihydro-4H-thieno- (2,3-c) -2 -2-propylyJ-methylthio 5-ethyl) -Y-meth-guanidine ( connection 1)
To a solution of sodium methoxide in methyl nol, obtained by dissolving 0.9 g (0.039 g-at.) Of sodium in 50 cm of methanol, was added with a solution of 5.6 g (0.035 mol) of N-cyano-N - (2- mercapto-methyl) -M-methylguanidine in 40 cm of methanol. The mixture is stirred for 2 hours at, then, at this temperature, 4, 2 g of O, O 176 mol of 2-chloromethyl-5-methyl-5,6-dihydro-4H-thieno (2,3-e) - are added. pyrrol hydrochloride. Stirring continued c. 42 hours at room temperature, after which the mixture is evaporated, the residue is dissolved in a sufficient amount of chloroform. The solution thus obtained is washed with a solution of sodium hydroxide, then with water, the organic phase is dried over sodium sulfate, filtered, the solvent is evaporated, the residue is dispersed in diisopropyl ether, sucked off and dried. Weight 3.3 g. Yield 3%, t. square 129-132 s, T. pl. 142-143 with (isopropanol).
NMR (DMSO-dJ: 1.3 (triplet); 3H (CH5CHj); 2.6-3.3 (multiplet, 7H, CHj-CHjN, CHjN, SCH); 3.8-4.3 (multiplet) 8H , CHjS, N-CHj 6.8-7.3 (multiplet) 3H, (NH, H aromatic).
Calculated,%: C, 51.98; H 6.54; N 2 G, 65; G 19,83.
 (mol. weight. 323.4). Found,%: C 52.02; H 6.55; N 21.81; S 19.53.
Example 2. H- (2- {5-Ethyl- -5,6-dihydro-4H-thieno- (2,3-c) -2-pyrrolyl-methylthio-ethyl) -1-methylthio--2- nitro-ethanolamine (compound 2).
A mixture of 7.8 g (0.032 mol) of 2- {5-ethyl-5-6, dihydro-4H-thieno- - (2, 3-e) -2-pyrrolylmethylthio is boiled under reflux for 12 hours -ethyl-amine and 5.3 g (0.032 mol) of bis-2,2-mrtiltyp-2-11 | 1 mercury NL n 10P cm apetoiitrile, then the reaction mixture is filtered, the filtrate is dried to dryness, the resulting residue is dispersed in the minimum amount of ethyl acetate , sucked off, washed solid with diisopropyl ether, then dried. Weight 7 g. Output 61Z. T. pl. 85-87 0. T. pl. 93-94 ° C (diisopropyl ether-isoprop — nol, 1: 1).
NMR (CDCl1): 1.2 (triplet) 3H (CHjCHj); 1.8 (singlet) IH (NH) .; 2.4 (singlet) GH (CHjS); 2.6 - 3.1 (multiplet) (4H) SCHj, CHjCHjN); 3.33-4.1 (multiplet) 8H (CH N,); 6.6 (singlet) and 6.75 (singlet) 2H, (-CH, H aromatic).
Calculated,%: C 46.77; H 5.89; N I 1.69; S 26, .75.
. (mol. weight. 359.53).
Naida no,%: C 46.52; H 5.90; . N 11.85; S 26.45.
Example 3. N- (2- C5-Ethyl-5,6-dihydro-4H-thieno- (2,3-e) -2-pyrrolyl J-methyl thio-ethyl) -N-methyl-2-nit- ro-ethylene-1,1-diamine (compound 3).
A solution of 5, 3 g (0.0147 mol) of the compound obtained in example 2 in 15 cm of a 33% solution of methylamine in ethanol is boiled under reflux for 11 hours, then the mixture is evaporated and the residue obtained is dispersed in a sufficient amount of ethyl acetate , suck it off and dry. Weight 4.6 g. Yield 92%. T. pl. 96-10l C. T. pl. 99-101 C (ethyl acetateisopropanol, 2: 1).
NMR (CDCl1): 1.2 (triplet) EF (CH, -CH); 2.6-4.08 (multiplet) 15 N (CHj); 6.6-7.3 (multiplet) 3N (CH, NH); 10.1 (broadt singlet), 1H (NH).
Calculated,%: C 49.09; H 6.48; N 16.36; S 18.73.
 (mol. weight. 342.4).
Found,%: C 49.09; H 6.39; N 16, 19; S 18.90.
Example 4. Nt (HaHo-N - (2- (5- -ethyl-5,6-dihydro-4H-thieno- (2,3-e) - -2-pyrrolyl-methylthio-ethyl) -H-iso propylguanidine (compound 4).
To a methanol solution of sodium methylate, obtained by dissolving I g (0.434 g-at.) Of sodium in 50 cm of methanol and cooled to 0, was added 7.2 g (0.0386 mol) of N-cyano-N-isopropyl- N - (2-mercapto-ethyl) guanidine to a solution of 85 cm metattol, and the mixture is stirred for 2 hours at 0–5 ° C, then 4.6 g (0.0193 mol) of 2-chloromethyl hydrochloride -5,6-di1 idro-5-ethyl-4H-thieno- (2,3-c) -pyrrole as a solution in 50 cm of methanol, stirring the mixture for 24 hours at room temperature, then evaporated, the resulting residue dissolved sufficiently to The amount of chloroform obtained is washed with a solution of sodium hydroxide, then with water, the organic phase is dried over sodium sulfate, filtered, the solvent is evaporated and the residue is dispersed: in ethyl acetate, sucked off and dried. Weight 6.8 g. Yield 47%. T. pl. 9 2-9 T. pl, 97-94 C (diisopropyl isopropanode, 5: 1).
Calculated,%: C 54.66; And 7.17; N 19.93; S 18.24.
. (mol. weight. 351.53).
Found,%: C 54.40; H 7.24; N 20, 16; S 18.31.
The compounds of examples 5-7 are prepared according to the method described in example 1 using the corresponding 2-chloromethylthieno (2,3-c) pyrrole.
Example 5. N-Cyano-N - (2-. - 5,6-dihydro-5-methyl-4H-thieno- (2,3-c) -2-pyrrolyl methylthio-ethyl) -N-methyl- guani, in (iande 5). T. pl, 145-147 C (isopropanol).
Calculated,%: C 50.46; H 6.19; N 22.63; S 20.72,
C ,, H, N.S (supposedly, weight 309.45).
Found%: C 50.34; H 6.21; N 22.45; S 20.57.
Example 6. Y-Cyano-H - (2-, 6-dihydro-5-isopropyl-4Y-thieno- (2, 3-e) -2-pyrrolyl-methydithio-ethyl) -N-methyl-guanidine (compound 6), T. pl, 120-12l C (diisopropyl ether-isopropanol, 2: 1),
Calculated,%: C 53.38; H 6.87; N 20.75; S 19.00.
 (supposedly, weight 337.50).
Found,%: C 53.49; H 6.97; N 20.99; S 19.17.
Example 7. N- (2- 5-Benzyl-5,6-dihydro-4H-thieno- (2,3-c) -pyrrol-methylthio-ethyl) -m-cyano-K-methyl- guanidine (compound 7). T, pl. 122-123 ° C (diisoproxy ether - isopropanol, 1: 3).
Calculated,%: C 59.19; H 6.01; N 18.17; S 16.63.
C ,, and, JJ.S. (mol. dog 385,54).
Found,%: C 59.02; P 6.10; N 17.90, S 16.58.
Example 8. 3- (5-These-5,6- -di1 pdro-411-thieno- (2, 3-e) -2-pyrrolylmethylthio jN-sulfamoyl-propane-t jNniaHH (compound eight) ,
In a reactor placed under a nitrogen atmosphere, a mixture of 11.3 g (0.0397 mol) of methyl-3-5-ethyl-5, 6-dihydro-4H-thio-but- (2 , 3-c) -2-pyrrolyl-methylthio-propano-imidate and 7.6 g (0.08 mol) of sulph. 1mide in 100 cm of methanol, evaporated, the residue is treated with chloroform, filtered, the filtrate is evaporated and the residue is crystallized from isog7p1 H; Nola, Weight 3.8 g, B ld 28 /. T. pl, 124-130 with.
This solid was dissolved in chloroform, a little methanol was added thereto, and this chromatographic solution on a silica gel column using 5% solution of MCTaiiojia in chloroform as a 1: 3 solution. Weight 1.1 g. 1. pl. 137-139 4 (isopropanol-etapol, 4: 1),
NQR (DMSO-df.): L (triple (m-) 3N (CH);

0
five
five
0
five
3 (multiplet) Gil (SI.-C, SCH
;
CH; N); 3-4.2 (multiplet) 6H (CH, S, NC l,); 6.4 (singlet) 2H (NH); b, 75 (siglet) 1H (H thiofia); 7-8.2 (multiplet) 2H (NHj),
Calculated,%: C 41.35; H 5.79; N 16.08; S 27.60.
C ,, Hj ,, ,, (supposedly, weight 348.5).
Found,%: C 41.58; H 5.71; N 16.03; S 27.40.
Example 9. N-IUiaHo-N - (2- - 5 - ETHYL-5, 6-dihydro-4H-t1 eno- - (2,3-c) -2-pyrrolyl-methylthio-e gil) - -N -ethyl-guanidine (compound 9).
A solution of 5 g (0.0147 mol) of N-imano-N - (-5, 6-dig11Dro-4H-thieno (2,3-c) -n -ppolyl) is boiled with a condenser for 5.5 h. -methylthio | -ethyl) -8-methyl-isothiourea and 19.9 g (0.441 mol) of ethyl amine in .30 cm of ethanol, then the solution is evaporated and the resulting residue is crystallized from a sufficient amount of ethyl acetate, sucked off and evaporated. . Weight 3.4 g. Yield 68%. T, pl, 91-93 ° C.
This solid is tterecrystal - from a mixture of 20 cm diisopropyl ether and 10 cm isopropanol, then from a mixture of 15 cm diisopropanol
ether and 20 cm of ethyl acetate, Weight 2.4 T. pl. 95-96 C.
Calculated,%: C 53.38; H 6.87; N 20.75; S 19.00.
C, jH ,, jN, fSj (mol. Weight 337.50).
Found,%: C 53.55; H 6.60; N 20.95; S 18.92.
Example 10. N-Cyano-N - (2- - 5-ethyl-5,6-dihydro-4H-thieno- (2,3-c) -2-pyrrolyl} -methylthio J-ethyl) -N-propargil -guanidine (compound 10).
A mixture of 3 g (0.0088 mol N-cyano-c - (2-C5-ethyl-5,6-dihydro-LH-thieno- (2,3-c) -) is heated under reflux for 8 hours 2-pyrrolyl} methylthio-ethyl) -5-methyl-isothiourea and
7.3 g (0.132 mol) of propargylamine in 30 cm of methanol, then the solution is evaporated, after which the residue in the form of a solution in chloroform is chromatographed on a column of silica gel, using chloroform, ethyl acetate, chloroform with 5% methanol successively as eluent agents with ethyl acetate and chloroform mixture
with methanol, the fractions are combined and evaporated to dryness, thus obtaining a solid. Weight 1.7 g. Yield 56%. T. pl. 107-110 S.T. pl. II2-I (diisopropyl ether-ethyl acetate, 1: 3).
NMR (CDC1): 1.2 (triplet) OZ (SI,)
2.4 (multiplet) 1H (C-H); 2.6-3.3 (multiplet) 4И (S-CH,); 3.3 - 3.6 (multiplet) 2H (); 3.6-4.2 (multiplet) 8H (NCH, CHjS); 5.8-6.6 (multiplet) 2H (NH); 6.7 (singlet)
1H (H thiophene).
Calculated,%: C 55.3; H 6.09; N 20, 16; S 18.45.
 (mol. weight 347.50.
Found,%: C 55.35; H 6.15; N 20, 12; S 18, 17.
Example II N- (2- {5-Ethyl- -5,6-digipro-DN-thieno- (2,3-c) -2-pyrrolylmethylthio-ethyl) -1-methyl-1H (1,2, 4) -triazole-3,5-diamine (compound 11) ..
Kip t with reflux,
in a nitrogen atmosphere and within 2 hours a solution of 4.23 g (0.0925 mol) of methylhydrazine and 6.75 g (0.0925 mol) of anhydrous M, K-dimethyl-formamide in 60 cm-toluene, then the solution is cooled - give up to 30 s; and 6.3 g (0.0185 mol) of K-cyano-L - (2-5-ethyl-5,6-dihydro-4H-thieno (2,3-c) -2-pyr rolyl7-methylthioVtil) -S-methyl-isotope is refluxed for 7 hours, then the solvent is evaporated, the residue is washed with water, extracted with chloroform, the chloroform phase is dried over sodium sulfate, concentrated and chromatographed on a silica gel column, The quality of the primer is successively chloroform, ethyl acetate and 5% chloroform solution in methanol. After elution of the fraction with this last mixture after evaporation and crystallization of the residue from diisopropyl ether, to which a few drops of acetone are added, gives a solid which will recrystallize from ethyl acetate. Weight 1.8 g. Yield 28%. T. pl, 109-112 C (diisopropyl sufir-ethyl acetate).
NMR (CDCl1): 1.08 (triplet) MN (); 2, .4-3.1 (multiplet) 4H; 3.1-4.6 (multiplet) 14 N; 6.7 (syn- (singlet) IH (H thiophene).
Calculated,%: C 49.67; H 6.55; N 24.83; S 18.95.
C, H .. (mol. Weight 338.5).
Found,%: C 49.62; H 6.52; N 24.50; S 18,81.
Example 12. N-Cyano-Y - (2- - (C3, 6-dihydro-5-phenyl-4H-thieno- (2,3-e) -2-pyrrolyl methylthio-ethyl) II-
-N-methyl-guanidine (compound 12). A mixture of 2.5 g (0.0064 mol) of N-cyano-N - (, 6-dihydro-5-phenyl-4H-tie-but- (2,3-e) -2-) is heated under reflux. pyrrolyl-methylthioI-α-ethyl) -3-megyl-isothiourea, 30 cm of a 33% methylamine solution in ethanol and 30 cm of DMF and a methylamine current is bubbled into it for 5 hours, then the solvents are passed in, the residue is dispersed in isopropanol and recrystallized from a sufficient amount of water-DMF (2: 3). Weight 1.4 g. T. pl. 164-168 seconds Yield 58%.
NMR (DMSO-d (): 2.85-3 (multiplet) 5H (CH.S, CHjN); 3-3.6 (multiplet) 2H (); 3.8-4.2 (singlet) 2H (CHjS ); 4.2-4.8 (multiplet) 4H () 6.4-7.4 (multiplet) 8H n aromatic, NH).
Calculated Z: C 58.19; H 5.70; N 18.85; S 17.26.
., (mol. weight 371.52).
Found,%: C 58.19; H 5.73; N 19.01; S 17.18.
11 p II m er 1: K N - () - in 1- -5 .b-dr idro- -}} - (2, 1-e) - -pyrro.pit -methyl T 10 I-THESE :) - 1 -о к с id- f 1,, 1, 5) -thiadiol-H, A-bottom min (sog /. Ineiio 13).
To suspensions 1, 7 i- (O, 0089 mop) J, h- -diethoxy- (1, 2.5) - -, nadiazole- 1 - (well g or 20 CNp methanol at D1 and -1: 1 are pacTisop 2 , 15 g (0.0089) J; -ethyl-5, 6-dihydro- | H-hyeno- (2, 1-e; -2 -2-pyrrol l methylthio-pylamine n 20 cm of methanol. The mixture is mixed for S, 5 hours at room temperature, rvrr, then for 10 minutes at iree, blasting ammonia current. Continue heating for hours at room temperature, for- tantly get solid custy iron about; - tt. Weight of 1.4 g. T. ill. 174 g (marriage) i Yield 60%. T. dl. (p; v. (position) (methane (PL-dimethylformag-; -1-1): one).
Calculated,%: C, 51.67; And 5. 1b; N 19.59; S 26.91.
Ci, And, N5 OS, (mol. Carried 357.52).
Found,%: C 48.60; H 5.35; N 19.62; S 26.73.
Example 1A. N- (2-, 6-D: id po-5-methyl-4I-thieo- (2, 3rd)) - lil} -methylthio) -N -methyl-2-} itro-ethylene-1 , I-diamine (co-coupling)
During 11.5 hours, g rastor 2.4 g (0.0105 mol) of bis-2.2-methylthio-nitro-ethylene and 1.75 g (0.0076 mol) of 2-, 2 6-dihydro-5-methyl-4 1-thieno- (2,3-e) -2-pyrrolyl J-methylthio j-ethyl-amia n 10 cm of apetonitrile, then cooled to -5, the obtained solid is sucked off (weight 2.4 g, m.p. (;) and suspended (mch) in 15 cm of a 33% methylamine solution in ethanol, this mixture is heated under reflux for 6.5 h, then the solvents are evaporated. Thus a solid is isolated. Weight 1.9 g. Zkod 72%. T. pl. 108- (ethyl acetate-isopropanol, 5: 1).
Calculated,%: C, 47.54; H 6.14; N 17.06; S 19.52.
C ,,, H,, (mol. Weight 345.5).
Found,%: with 47.65; H 5.98; N 16.89; S 19.78.
Example 15. N- (2- | 5-Ethyl-5,6-dihydro-4H-furo (2,3-c) -2-pyrrolyl methylthio-ethyl) -N-methyl-2-nit- ro-ethylene-1,1-diamine (compound 15).
-, (CHI1G- 9.5 h with first-time chiptcht ;; 1 Ы 1 fridge 1, g (o, o I Ul MiXIlI,)
.-; S - :) TH-i- 5,) -digid11о-.4И-фур1-: (.,, Jc) - -2-ir. (Xrni.ri j-meti.ptio-oh gich. And 2,. 5 : (0, ni4h mol) Pis-2, .- - -ch type- 11 1 - 1Itro: p ylena p 55 L; e e peritrill, oypryriyakp dsi uh ;, the rest of shch sk faba pnayu g 35 c -fv) 7-Horo nacTjiopa gtilamip in - (taHo / re ,, this
rLGGLOR is boiled with (MZraTPI–; COLD, I.P 1pik1L in mc – 8 hours, chat — ;;.n Priri- ngg pochuch (mP1Y11 residue ii in the form of rastran.ora 1 Me-TanoJif chromatography) m; ikke with 40 g of sitskat l, isolz -.ch. and k, 3-I with 11., ti I11 101 what (pt-ncT iT Methano ;;; it turned out pmmy after vikgrppani-it: - t; 1T11 l; ost К K di (pergI) in e 1 il- j; u I lii m O; - (. .5 i. ((11I1: zoropil (; i40iip;: in, 5: -).
:; ычchys:; e; P, /: C 5, 5; li b, 7;
N 17.17; 9 .-- С L, -N / ЛЬ. :) 2b. - /).
Paidrio: C 5 1, 29; f-, N 17.1 L; S 9.63.
1 p and mep 16. K-Tsiapo-x - (.- 5-zti: 1-5, 6-dihydro-i-pyro- - (2, 1-e). (J-Mc gk thio -: thyl -N -1- -; 1 liji-g anig, in (co. 16).
And 1 G iOiiilO 6 h K1P1AGSHT with v- paTlilvM
xygydil com growth 2.1; (0, () 095 can be) 2-1 5-ETIHL-5, 6-di1 1 d-;: h1-4I- (1) uro- (2, 1-с) - 2-pyoro, | : silt -iu-- tpl I il 1-2 - e-1lamine and 1.4 g ((), 005 mo dimgil-iian1; midod1ggio: ar:: o; a ha,: ia leb the solvent is evaporated and remain- I OK dispers on the air, :: elucg-n0
five
P. 1g. ho.igigdi, pm1pr; o -,: og: to -m: they are about to crystallize. ilo; i} -4C: iioc and backwash solid matter: P it is chromatographed in a Bii-solution of a mixture of these mixtures: 1app: gg with methanol on a column with 15 g; i:; in: arc l, used this (; 1ad gat with: -ieTVi iu: iii: M in KaiiecT Be elvied epc: ie, i-; i, nccjif-sharing get tellyug pc-iu.e with gtyu, Weight 1.5 I-, T. Pl. 51-58 g. Then a solution of this solid in 20 CNr ethanol with 11% .-- and boil with inverse ;-) holo,: 1ilm: iko; -1, and then evaporate to dosa: -. a, the residue is dispersed in ether, removed from it and dried. Weight 1.3 g B1 ::, od 44; -,
(ethnyl acetate isopropa g :: l, g: 1).
132962
 NMR (CDCl1): 1.2 (triplet) (CH, CH); 2.6-3.1 (multiplet) (S — CH j, CH, —N, CH j — CH j); 3.5 (quintet) 2H (); 3.8 (singlet) 6H (,); 5.7, (triplet) 1H (NH); 6.1 (multiplet) 1H (NH); 6.2 (singlet) 1H (H furan).
Calculated,%: C 5A, 69; H 6.89; N 22.78; S 10,43.10
C, Hj, N50S (mol. Weight 307.42).
Found,%: C 54, 55; H 6.74; N 22.60; S 10.57.
Example 17. N- (2- (5-EthylC, H, j, (mol. Weight 384.55).
Found,%: with 53.24; H 7.26; N 14.44; S 16.75.
Example 19. N- (2- (G5-Ethyl-5, 6-dihydro-3-methyl-4H-thieno (2,3 -2-pyrpolyl-methylthio-ethyl) -H-me-2-nitro ethylene-1,1-diamine (coupling 19).
Compound according to Example 3 is obtained from N- (2- 5-Ethyl-5,6-dihyd-po-3-methyl-4H-thieno- (2, 3-c) -2-pyrryl-methylthio-ethyl) - 1-methylthio-2- -nitro-ethyleneamine and methylamine.
-5,6-dihydro-4H-fu- (2,3-c) -2-pyrro-15 T. pl. 112-113 C (diisopropyl
lil-methylthio J-ethyl) -1-methylthio-2-nitroethylene (compound 17).
A solution of 2.3 g (0.0095 mol) of 2-5-ethyl-5,6-dihydro-4H-furo (2,3-c) -2-pyrrolyl is boiled under reflux for 6 hours. -methyl-1-ethylamine and 1.6 g (0.0095 mol) of bis-2,2.-methylthio-nitroethylene in 25 cm-acetonitrile, then the solution is evaporated and the residue is recrystallized from 25 cm of ethyl acetate in the presence of Norit and sucked off and the resulting solid is dried. Weight 1.4 g. Yield 43%. T. pl. 77-79 C,
1 o
ether isopropanol).
Calculated,%: C 50.53; H 6.78; N 15.72; S 17.99.
(mol. weight 356.5). 20 Found,%: C 50.48; H 6.72; N 15.84; S 18.22.
Example 20. M- (2- {5-Ethyl-5, 6-dihydro-4H-thieno- (2,3-e) -2-pyrrolyl-methylthio-ethyl) -M-methyl-1-5 -oxide- (1,2,5) -thiadiazole-3,4-diamine (compound 20).
The compound was prepared according to Example 13 using methylamine instead of a miac. T. pl. 144-146 ° C (diisoprop, mp, 80-82 C (chromatography on 10 g of zoyl ester-isopropanol, 1: 4), silica gel, zluent, then NMR (CDClj): 1.16 (triplet), ZN methanol . (CH ,, - CHj); 2.35-3.1 (multiplet) 7H
NMR (CDCl1): 1.1 (triplet) E3 (SCH2, .CH, N,); 3.1-4 (multi- (CHjCH); 2.4 (singlet) 3N (CHjS); lash). NCHj); 6.7 (singlet)
25 (thiophene), 7.6-8.4 (broad singlet) 2H (NH).
Calculated,%: C 45.25; H 5.70; N 18.85; S 15.89.
,, (mol. weight 371.55). 40 Found: C 45.27; H 5.39; N 18.74; S 15.65.
Example 21. N- (2- 5-Ethyl- -5,6-dihydro-4H-thieno- (2,3-c) -2- -pyrrolyl-methylthio-ethyl) -H-pro2, 8 (multiplet) 4H (Sch,); 3.3-3.9 (multiplet) 8H (,) 6.1 (singlet) 1H (CH-NO); 6.5 (syn-Glt) 1H (H furan); 10.5 (singlet) 1H (NH).
Calculated,%: C 48.95; H 6.16; N 12.23; S 18.67.
Cj H NjOjSj (mol. Weight 343.46).
Found,%: C 49.20; H 5.94; N 12.04; S 19.45.
Example 18, K - (, 6-Dihyd-45 pargyl-1-oxide- (1,2,5) -thiadiazolro-5-n-pentyl-4H-thieno (2,3-s) -2- -3,4-diamine (compound 21). -Pyrrolyl-methylthio-ethyl) -s-methyl- At room temperature, in te-2-nitro-ethylene-1,1-diamine (compound 6 h, mixture 1 is passed over , 7 g of 18). (0.0089 mol) 3,4-diethyl- (1,2,5) This compound is obtained according to gg thiadiazol-1-oxyl and 0.5 g (0.0089 mol) / but example 3 of N - (, 6-dihydropropylamine in a solution of 20 cm
methanol, evaporated to dryness, then 2, 15 g (0.0089 mol) of 2-5-ethyl-5,6-dihydro-4H-thieno-gg - (2,3-c) -2-pyrrolylmethylthio are added -ethyl-amine as a solution in 20 cm of meta-5-n-pentyl-4H-thieno- (2,3-c) -2-pyrrolyl-methylthio j-ethyl) -1-methylthio-2- -nitro-ethyleneamine and methylamine. Weight 3.6 g, yield 86%, so pl. 90-93 ° C, t, gsh, 93-95 ° C (diisopropyl ether-isopropanol, 1: 2).
Calculated,%: C 53.09; H 7.34; N 14.57; S 16.68.
The solution is stirred at room temperature for 17 hours, then the resulting precipitate is sucked With, H, j, (mol. Weight 384.55).
Found,%: with 53.24; H 7.26; N 14.44; S 16.75.
Example 19. N- (2- (G5-Ethyl- -5, 6-dihydro-3-methyl-4H-thieno- (2,3-c-2-pyrpolyl-methylthio-ethyl) -H-methyl- 2-nitro-ethylene-1,1-diamine (compound 19).
Get the compound according to example 3 of N- (2- 5-ETHYL-5,6-dihyd-po-3-methyl-4H-thieno- (2, 3-s) -2-pyrrolylmethylthio-ethyl) - 1-methylthio-2- -nitro-ethyleneamine and methylamine.
nola, the solution is stirred at room temperature for 17 h, then the resulting precipitate is sucked I 13
yut. Weight 1.8 g. Yield 51%. T. pl. 164- (decomposition). Mp 165-166 ° C (methanol-DMF, 8: 1).
Calculated,%: C A8,58; H 5.35; N 17.71; S 24.32.
C, H, NjOS (mol. Weight 395.57).
Found 7.: C 48.58; H 5.41; N 17.63; S 24.40.
Example 22. N - (, 6-Dihydro-5-n-propyl-4H-thieno- (2,3-c) -2-pyrrolyl-methylthio-ethyl) -1-oxide- (1,2 , 5) thiadiazole-3,4-diamine (compound 22).
To a solution of 2.4 g (0.0216 mol) of 3,4-diethoxy- (1,2,5) -thiadiazole-1-oxide in 25 cm of methanol was added a solution of 3.25 g (0.0216 mol), 6-dihydro-5-n-propyl-4H-thieno- (2,3-c) -pyroylmethylthio J-ethylamine in 25 cm of methanol, the mixture is stirred for 20 hours at room temperature, then bubbled into it for 10 minutes under an ammonia flow, stirring is continued for 4 hours at room temperature, then cooled to and the precipitate formed is filtered off with suction. Weight 2.4 g Yield 51%. T. pl, 178 С (decomposition) T. pl. 179 C (methanol-DMF, 1: 1).
Calculated,%: C 45.25; H 5.70; N 18.85; S 25.89.
C.H.NyOSj.
Found,%: C 45.41; H 5.75; N 18.70; S 25.64.
The compounds of examples 23 and 24 were prepared according to the method described in example 2 from the corresponding 2-, 6-dihydro-4H thieno (2,3-c) -2-β-pyrrolyl methylthio-ethylamines.
Example 23. N- (2- 5-Ethyl- -5,6-dihydro-3-methyl-4H-thieno- (2,3-c) -2-pyrrole-1-methylthio-1-methyl) -1-methyl-thio- 2-nitro-ethyleamine (compound 23).
 .Sj (mol. Weight 373.55), t. Pl. 74-77 C (days 3 propyl ether-isopropanol).
NMR (CEC): 2.46 (singlet) OZ (CHjS).
Example 24. N - (, 6-Dihydro-5-and-pentyl-4H-thieno- (2,3-c) -2-pyrrolyl-methylthio-ethyl) -1-methylthio--2-nitro ethyleneamine (compound 24).
, N ,, OjS5 (mol. Weight 401.61), t. Pl. 72-74 C (isopropanol).
NMR (CDCl1): 2.46 (singlet) CH ,, S)
Example 25. Y-Cyano-Y - (2 - - and 5,6-dihydro-5-phenyl-4H-thieno
5 o
about
five

five
i12
- (2, 3-e) -2-pyrrolyl 1 -methyl hyo - :) tyl) - -S-methyl-isothiomine spin (compound 25).
C, gH ,, (mol. Weight 388.57).
A mixture of 2.6 g (0.0094 mol), 6-di-hydro-5-phenyl-4H-thieno (2,3-c) -2-pyrrolylmethylthio-ethylamine and 1.4 g (0.0094 mol) of dimethyl cyanoinidodiothiocarbonate in 50 cm of acetonitrile, the resulting solid is sucked off, washed with diisopropyl ether and dried. Weight 3 g. Output 82%. T. pl. 189-193 ° C. T. pl. 195-197 ° C (H O-DMF, 4:15).
IR spectrum (KBG): VCN 2180 cm: Example 26. L-Cyano-H - (2- {5-EHYL-5, 6-dig1 {dro-4H-thieno- (2,3-e) -2- pyrrolyl-methylthio J-ethyl) -S-methyl-isothiourea (compound 26).
 (mol. weight 340.53).
The compound is prepared as in example 25 from 2-g 5-ethyl-5,6-dihydro-4H-thieno (2,3-c) -2-pyrrolyl methyl thio ethylamine. T. pl. 112-114 C.
IR spectrum (KVg): VCN 2170 cm
Example 27. K- (2- 5-Ethyl- -5,6-dihydro-4H-thieno- (2,3-c) -2-pyrrolyl-methoxy-ethyl -1-oxide- (1,2, 5) -diadiazole-3,4-diamine (compound 27).
To a solution of 3.2 g (0,0168 mol) of 3,4-diethoxy- (1,2,5) -thiadiazole-1-oxide in 30 cm of methanol was added a solution of 3.8 g (0,0168 mol) 2-C5-ethyl-5,6-dihydro-4H-thieno- (2,3-e) -2-pyrrolyl-methoxy-ethyl-amine in 20 cm of methanol, the mixture is stirred for 9 hours at room temperature, then bubbling into it at 0.5 ° C for 10 min. flow of ammonia, continue stirring at room temperature for 5 hours, then evaporated to dryness, the residue is treated with water and chloroform, the organic phase is dried over sodium sulfate, chloroform is evaporated, the residue is dispersed full body, isopropanol, sucked off, washed with diisopropyl ether and dried. Weight 1.5 g. Vbgkhod 267 ,, T. PL4 144-146 C (decomposition). T. pl. 149-150 ° C (methanol).
Calculated,%: 45.73; H 5.61; N 20.51; S 18.78.
C ,, H „NjOjSj (mol. Weight ZA1.45).
13
Found,%: C 46.01; H 5.49; N 20.25; S 18.68.
Example 28. N- (2- 5-n-Butyl-5, 6-dihydro-4H-thieno (2, 3-c) -2-pyrrolylmethylthio-ethyl) -I-oxide- (1 , 2, 5) -thiadiazole-3,4-diamine (compound 28).
To a solution of 4.1 g (0.0214 mol)
lil-methylthio} -ethyl) -1-oxide- (1,2,5) - -thiadiazole-3,4-diamine (compound 31). M.p. -172-173 C (ethanol). Output
60%.
Calculated, I: C 48.08; H 6.31;
7.53; S 24.07.
C HjjNjOS, (mol. Weight 399.60).
Found 7; C From 48.15; H 6.33; 3,4-dystoxy- (1,2,5) -thiadiazole-1-ox N, 17.32; S 23.80.
40 ml of methanol at Example 32. N- (3- 5-Ethyl- added solution of 5.8 g (0.0214 mol) of 2- 5-n-butyl-5,6-dihydro-4H-thieno - - (2,3-c) -2-pyrrolyl-methylthio-ethyl-5,6-dihydro-4H-thieno- (2,3-c) -2-pyrrolyl-methylthio-propyl) -1-oxide, - (I, 2,5) -thiadiazole-3,4-diamine (soyamine in 40 cm of methanol, perenodine mixture 32). T. pl. 157-158 ° C (is stirred for I7 hours at room temperature, then it is bubbled into the flow of ammonia for 10 minutes, then stirred for 4 hours at room temperature, 20 the solid is filtered off with suction and dried. Weight 5.1 g. Yield: 62%. T. pl. 183-1844: (S. DMF, 2: 1).
Calculated,%: C 46.72; H 6.01; N 18.17; S 24.95.
C jHjjN OSj (mol. Weight 285.57).
Found,%: C 46.88; H 5.67; N 18.08; S 24.49.
The compounds of examples 29-33 were prepared according to example 28 from the corresponding, 6-dihydro-4H-thieno- (2, 3-c) -2-pyrrolyl-methylthio J-alkyl-amines and 3,4-diethoxy- ( 1,2,5) -thiadiazole-1-oxide. 25 - (2,3-c) -2-pyrrolyl-methylthio-ethyl. Example 29. N- (2- {5-Iso-amino) -cyclobutene-1 , 2-dione (soyedil-5,6-dihydro-4H-thieno- (2,3-c) -2- -pyrrolyl-methylthio-1-ethyl) -1-oxide- - (I, 2,5) -thiadiazole- 3,4-diamine (soydipropanol). Yield 27%.
Calculated,%: C 45.25; H 5.70; N 18.88; S 25.89.
C74Hj, NjOSj (mol. Weight 371.55).
Naida no,%: C, 44.94; H 5.60; N 18.98; S 24.60.
Example 33 N - (, 6-Digdro-5- (2-methoxy-ethyl) -4H-thieno- (2,3-c) -2-pyrrolylmethylthio - 25-ethyl) -1-oxide - (1,2,5) -thiadiazole-3,4-diamine (compound 33). M.p. 174-17b with (ethanol). Yield 64%.
Calculated,%: C 43.39; H 5.46;
8.07; S 24.82.
, (mol. weight 387.55).
Found,%: C 43.19; H 5.38;
8.18; S 24.84.
PRI me R 34. 3-Amino-4- (2-, 6-dihydro-5-n-propyl-4H-thienoN
N
34).
2.6 g (0.01 mol) N-2-40, 6-dihydro-5-n-propyl-4H-thieno- (2,3-c) -2-pyrrolyl methylthio ethyl amine in the 20 cm of methanol are added with a solution of 1.4 g (0.01 mol) of 3,4-dimethoxy-cyclobutene-1,2-dione 45 in 20 cm of methanol, the mixture is stirred at room temperature for 48 hours, then it is bubbled at 5-10 ° C for 15 min. Ammonia flow.
Decision 29). Yield 57%. T. pl. 178-1794 (ethanol-DMF, 7: 4).
Calculated,%: C 46.72; H 6.01; N 18.17; S 24.95.
C, Hj NyOSj (mol. Weight 385.57).
Found,%: From 46.91; H 6.06; N 17.93; S 24.67.
Example 30. N- (2- {5-n-Hexyl-5,6-dihydro-4H-thieno- (2,3-e) -2- -pyrrolyl-methylthio-ethyl) -1-oxide Solution: 6 g (0.01 mol) N-2-40, 6-dihydro-5-n-propyl-4H-thieno- (2,3-c) -2-pyrrolyl methylthio-ethyl amine in 20 cm of methanol while adding a solution of 1.4 g (0.01 mol) of 3,4-dimethoxy-cyclobutene-1,2-dione 45 in 20 cm of methanol, the mixture is stirred at room temperature for 48 hours, then it is bubbled at 5-10 ° C for 15 min the current of ammonia.
then continue mixing
- (I, 2,5) -thiadiazole-3,4-diamine (co-50 for 4 hours at room temperature 30). T. pl. 180-1 (з1 ° С (to the stage, the obtained solid is sol-DMF 7: 4). The yield is 73%. It is filtered, washed with ether and dried, then it is recrystallized from a mixture of 20 ml of ethanol and 20 ml
Calculated,%: C 49.36; H 6.58; N 16.93; S 23.26.
С „Н2тН5ОЯЗ (mol. Weight 413.63).
Found,%: C 49.41; H 6.59; N 16.63; S 22.95.
SC DMF, Weight 0.9 g. Yield 25%. T. pl. 320H
Calculated,%: C 54.67; H 6.02;
Example 31. C. - (, 6-Dihydrin-N 11.96; S 18.25. Ro-5-n-pentyl-4H-thieno- (2, 3-c) -pyrro-C j H ,,, S, (mol. Weight 351.48).

14
lil-methylthio} -ethyl) -1-oxide- (1,2,5) - -thiadiazole-3,4-diamine (compound 31). T. pl. -172-173 C (ethanol). Output
60%.
sharing 32). T. pl. 157-158 ° С (iso-
- (2,3-c) -2-pyrrolyl-methylthio-ethylpropanol). Yield 27%.
Calculated,%: C 45.25; H 5.70; N 18.88; S 25.89.
C74Hj, NjOSj (mol. Weight 371.55).
Naida no,%: C, 44.94; H 5.60; N 18.98; S 24.60.
Example 33. N - (, 6-Digdro-5- (2-methoxy-ethyl) -4H-thieno- (2,3-c) -2-pyrrolyl methylthio-ethyl) -1-oxide (1,2,5) -thiadiazole- -3,4-diamine (compound 33). M.p. 174-17b with (ethanol). Yield 64%.
Calculated,%: C 43.39; H 5.46;
8.07; S 24.82.
, (mol. weight 387.55).
Found,%: C 43.19; H 5.38;
8.18; S 24.84.
PRI me R 34. 3-Amino-4- (2-, 6-dihydro-5-n-propyl-4H-thienoN
N
amino) -cycle
34).
amino) -cyclobutene-1,2-dione (compounds
2.6 g (0.01 mol) N-2-, 6-dihydro-5-n-propyl-4H-thieno- (2,3-c) -2-pyrrolyl methylthio-ethyl amine in a 20 g cm of methanol; a solution of 1.4 g (0.01 mol) of 3,4-dimethoxy-cyclobutene-1,2-dione in 20 cm of methanol is added, the mixture is stirred at room temperature for 48 hours, then it is bubbled at 5- 10 ° C for 15 minutes the flow of ammonia.
SC DMF, Weight 0.9 g. Yield 25%. T. pl. 320H
15
Found,%: C 54.59; H 5.92; N I 1.94; S 18,52.
In connection with their ability to INHIBATE the secretion of gastric acid in the body, the compounds of formula (I) possess anti-ulcer activity. This particularly intensive and long-lasting effect makes it interesting to use in the treatment of peptic ulcers and other similar pathological symptoms. The length and intensity of the antisecretory and antiulcer effects of the compounds of formula (I) depends on the nature of the substituent R.
The method used to study gastric antisecretory activities is based on the use of rats with associated pylori according to N. Stay et al., Gastrochterology,
In female rats weighing about 200 g, staying on an empty stomach for 72 hours, tie the pylor under light ethereal
anesthesia. After the animals have been killed, 25 are tested in three geometrically and the contents of the stomachs are taken to measure the acidity. The compound is injected intraperitoneally, just after the ligature of the pylorus (pylorus). A dose reducing gastric acidity by 50% (ED p) is calculated for each compound relative to the untreated batch. Each compound is tested in three geometrically divided doses. Each party includes 10 rats.
The blocking of histamine N. receptors involved in the secretion of gastric acid is studied in vitro on an isolated atrium of a guinea pig and in vivo by the method of gastric hyperacidity to histamine in an anesthetized rat.
Isolated guinea pig atrium. White guinea pigs weighing 300-400 g kill and release blood. After opening the chest, the right atrium is quickly released and placed in a bath for an isolated organ containing 100 ml of CGER (composition, g / l: NaCl 6.9; KC1 0.35; CaCl 0.28 MgSO 0.14; NaHCOj 2.09; 0.16; glucose 2), kept at 32 ° C and highly oxygenated (95% QI and 5% COj).
The atrium is connected with the device dp to determine the capacity of an isometric trough under pressure (tension) I g. Spontaneous pulsations
; yu 15
20
sixteen
recorded on a galvanometer recorder.
After a period of stabilization of 1 hour, cumulated doses of histamine are added to the survival medium (all for 5 minutes), which causes the acceleration of pulsations by stimulation of the histamine receptor, which, in cardiac tissues, are of the nature H. as long as the atrial rhythm no longer rises (maximum effect). Then you can draw a curve that reproduces the change in rhythm depending on the concentration of histamine in the bath. After rinsing and quiescence for 30 minutes, the same experimentation is continued for 30 minutes, the same experimentation is continued 30 minutes after the H antagonist is introduced into the bath (proposed compound or standard product).
Each connection in this way
0
five
0
increasing concentrations, which, in case of blocking of the Hj receptors, shift histamine concentration curves to the right / chronotropic effect. For each active compound, we determine pA |, i.e. solo arithms of the concentration of the test compound, for which it is necessary to double the concentration of histamine to find this chronotropic effect. The calculation is carried out according to the method 0. Arunlakshana and N. O. Shild, Br. J. Pharmae. A minimum of 3 atria are used for each test compound.
This preparation also makes it possible to understand the nature (reversible or not) of the inhibition. In the first case, one can always move the receptors using repetitive rinsing or using a higher concentration of histamine, which is expressed by histamine concentration curves (chronotropic effect), parallel, not coincident.
On the contrary, in the second case (inhibition is difficult to reversible) H antagonism cannot be completely eliminated either by rinsing or by increasing histamine concentrations, which is expressed by mismatching dose / effect curves (the maximum chronotropic effect is all the more weak when the antagonist concentration increases H).
0
five
1713
ZH.gudochna g inercidity to gistl mine in anestheshironoy rat (Black et al., Nature). Rats anesthetized with ethylurethane receive a continuous perfusion of histamine (25 µg / kg / day) into the strap vein. The stomach is continuously perfused with physiological serum at 37 ° C with a constant flow rate of 3 ml / mi
The pyloric cannula collects perfusate, the acidity of which is continuously measured. Each test compound is administered intravenously (one dose per rat). Inhibition of acidity is measured at the appropriate time at the maximum exposure (variable time from one compound to another). A minimum of 3 rats are used for each dose tested. For each active proposed compound, a dose is reduced by 50% (ED hyperacidity Caused by histamine. In addition, the duration of action resulting from intravenous injection of one dose corresponding to rounded JP has been measured for the most active compounds.
The compounds of formula (I) are usually very little toxic. For example, the compound of Example 22 has no toxic effect when it is administered intravenously to mice or rats at a dose 100 times its ED in the test of gastric hyperacidity to histamine in an anesthetized rat.
Table I, A-A shows the activities of compounds of Formula (I), as well as standard products, while A denotes H-methyl-L (2-methyl-1,2,3,4-tetrahydro-5-isoquinoline) -propio. -2-nitro-ethylene-1,1-diamine
In tab. 3 shows the gastric hyperacidity to histamine in an anesthetized rat.
In tab. gastric hyperacidity to histamine in anesthetized rat is given.
In tab. 5 shows the data on toxicity in mice when compounds of formula (I) and control products (cimetidine and ranitidine) are injected into a vein,
Drugs (drugs can be administered according to a wide variety of different dosage forms, such as tablets, gelatin capsules, granules, and







etc. R ECHNKH OF COMMUNICATION OF L - ISTPUK1CHR (
The starter is mixed with one or T1 of several inert diluents, such as lactose or starch, in addition, these compositions may include other substances, such as diluents, for example, lubricants, such as talc or magnesium stearate.
When preparing aqueous suspensions, elixirs or syrups for oral administration, the main active ingredient may be associated with various sweetening and / or flavoring agents, if necessary with emulsifiers and / or suspending agents, as well as with diluents, for example water, ethanol, propylene - glycol, and various similar associations.
A pharmaceutical composition suitable for oral administration and administered as a unitary dose containing 5-500 mg of active principle is considered interesting.
Example. A composition of the following composition is prepared, mg: active principle 10; lactose 100; grain bread starch 30; talc 6; peristone, excipient 3; Magnesium Stearate I.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining thieno (2,3-c) -pyrroles of general formula
 V
CH2S- (CH2H- (;
and R is a linear or branched C-Cg-alkyl or Cj-Cg-alkoxyalkyl group; the residue of 3,4-diaminocyclobutene-1, 2-dione or aminosulfonylformamidine or and - nitrogen-containing structure of the general formula
HN /
Ng
 -N
or
R3
ABOUT
t
S
LL
mn: NHR 132962
where R is hydrogen, linear, -alkyl or C —C-alkynyl; V is a nitrogen or CH group; W is a nitro or cyano group; Rj-C, -Cj alkyl,
characterized in that the compound of the general formula
R ROGr sn) w
where R has the indicated meanings, is reacted with a compound of the formula
v-w
or
S
LL
 OS2N5
Table 1 Rats with a boned pylori
19 (9-40) 8 (4.4-14) 50
18 (7.5-43)
8 (4-16)
1.5 (0.9-2.4)
15 (8.3-27)
50
20 (9.5-42)
32 (18-58)
0.5 (0.3-0.8)
1 (0.3-3)
0.9 (0.3-2.5)
20 NCSO
or
about
 about ,
where V and W have the indicated values, in the medium of an organic solvent at a temperature ranging from 0 ° C to the boiling point of the reaction medium, followed by treatment of the reaction mass with an amine of the general formula
,
where Rj has the indicated meanings, or hydrazine of the formula
RjNHj-Mj,
where Rj has the indicated value, in the medium of an organic solvent at a temperature ranging from 0 ° C to the boiling point of the reaction medium.
Bound pylori rats
300.5 (0.2-1.2)
313.6 (1.9-6.8)
330.7 (0.3-1.6)
3411 (6-20
Ranidin14 (6-32.2)
Cimeticin42 (24.7-71 .4)
Table 2 Selected guinea pig atria
32962i
22 Continuation tlbl. one
28 3.9 20 1.3
I
0.3
 Inhibition is difficult to reversible.
one
3
eight
I I
13
18
20
21
22
Continuation of table 2
Table 3
0.6 (0.25-1.5) 0.3 (0. 1-0.9)
five
0.5 (0.18-1.4) 0.4 (0.15-1) 0.03 (0.02-0.05) 0.5 (0.17-1.5)
five
0.1 (0.03-0.3) 0.6 (0.3-1.2) 0.05 (0.02-0.11) 0.2 (0.08-0.5)
Table 4
27

0.1 (0.04-0.25) 4
0.2 (0.07-0.6) 2
0.15 (0.07-0.3) 2.7
0.2 (0.08-0.5) 2
0.25 (0.12-0.5) 1.6
0.09 (0.05-0.17) 4.4
0.4 (0.18-0.9) 1 5
Table 5
I50 325 670 8140
II150
1355
18,100
1945
2025
Edaktor C, Baker
Compiled by I. D chenko Tehred M. Khodanych
Order 3499/58 Circulation 371
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab, 4/5
Production Polygraphic Enterprise, Uzhgorod, ul. Project, 4
28 Continuation of table 4
0.9
0.45
0.6
0.45
0.36
1 0.22
Continuation of table.5
Proofreader A. T sko
Subscription

类似技术:

---

公开号 | 公开日 | 专利标题

---

AU731055B2|2001-03-22|1-phenylpyrazole compounds and pharmaceutical use thereof

---

US3995039A|1976-11-30|Pyrazolo [1,5-a] [1,3,5] triazines

---

SU1400508A3|1988-05-30|Method of producing derivatives of arylthiazole

---

CZ290737B6|2002-10-16|Use of hydroxyalkylidenecyanacetic acid amides for preparing medicaments

---

AU2003257300A1|2004-02-25|Amino benzothiazole compounds with nos inhibitory activity

---

PL118387B1|1981-09-30|Process for preparing novel derivatives of thiadiazole

---

BRPI0615939A2|2012-12-18|compound, pharmaceutical formulation, use of a compound, and method for treating a disease

---

SU1329621A3|1987-08-07|Method of producing thieno-|-pyrroles

---

US4921856A|1990-05-01|Dihydropyridazinone derivatives, a process for their preparation and pharmaceutical preparations containing these compounds

---

EA002037B1|2001-12-24|Cyanoguanidines as cell prolifiration inhibitors

---

US4406897A|1983-09-27|6-Aryl-4-hydrazinyl-s-triazin-2-ones

---

EP0548680B1|1998-02-25|Beta-oxo-beta-benzenepropanethioamide derivatives

---

US4678801A|1987-07-07|Novel 2-oxopyrrolidine compounds, salts thereof process for the preparation thereof as well as pharmaceutical agent comprising the compound

---

US4157340A|1979-06-05|N,N&#39;-[Bis|]cystamine derivatives

---

US4137326A|1979-01-30|Use of magnesium monospartate hydrochloride complex

---

SU1364240A3|1987-12-30|Method of obtaining derivatives of 4,5,6,7-tetrahydrothiazolo-|-pyridine or pharmaceutically acceptable salts thereof

---

US4681888A|1987-07-21|Thienopyridine derivatives and anti-thrombotic compositions containing the same

---

SU1322979A3|1987-07-07|Method of producing imidazolylphenylamidine derivatives or acid-additive salts thereof

---

CA1336516C|1995-08-01|Acyl derivatives of 2-amino-4-substituted-5-hydroxy pyrimidines

---

US8202997B2|2012-06-19|Compositions and methods for treating or preventing hypoxic or ischemic injury

---

PL92078B1|1977-03-31|

---

KR890001151B1|1989-04-25|Preparation method of imidazole carboxylic acid derivatives

---

US4477449A|1984-10-16|Certain 1,8-naphthyridine compounds useful as antibacterial agents

---

US5240918A|1993-08-31|2-|-thiazolidines and process for the preparation thereof

---

US5686452A|1997-11-11|Indane derivative and processes for preparing the same

同族专利:

---

公开号 | 公开日

---

ES547789A0|1986-03-16|

---

DK465685D0|1985-10-11|

---

NO854051L|1986-04-14|

---

CS714485A2|1988-08-16|

---

NO161917B|1989-07-03|

---

FR2571723B1|1988-08-26|

---

YU162485A|1987-12-31|

---

JPS6197286A|1986-05-15|

---

NO161917C|1989-10-11|

---

HUT40133A|1986-11-28|

---

CA1250847A|1989-03-07|

---

ES8605524A1|1986-03-16|

---

IL76619D0|1986-02-28|

---

FR2571723A1|1986-04-18|

---

EP0180500A1|1986-05-07|

---

CS265211B2|1989-10-13|

---

AU593776B2|1990-02-22|

---

AU4852885A|1986-04-17|

---

MA20543A1|1986-07-01|

---

DD237662A5|1986-07-23|

---

ZA857809B|1986-05-28|

---

IN169684B|1991-12-07|

---

PT81282A|1985-11-01|

---

PT81282B|1988-02-17|

---

IL76619A|1990-07-12|

---

HU193827B|1987-12-28|

---

OA08119A|1987-03-31|

---

DK465685A|1986-04-13|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

RU2473551C2|2006-11-15|2013-01-27|Тяньзинь Хемэй Био-Тек Ко., Лтд|Therapeutic agent on pyrroline derivates for prevention of tumorous cell death, method for preparing it and method for using it|GB1565966A|1976-08-04|1980-04-23|Allen & Hanburys Ltd|Aminoalkyl furan derivatives|

---

GB1601459A|1977-05-17|1981-10-28|Allen & Hanburys Ltd|Aminoalkyl thiophene derivatives|

---

US4390701A|1981-05-18|1983-06-28|Bristol-Myers Company|1-Amino-2-[3-propylamino]cyclobutene-3,4-dione|

---

US4520025A|1982-07-21|1985-05-28|William H. Rorer, Inc.|Bicyclic nitrogen heterocyclic ethers and thioethers, and their pharmaceutical uses|JPH058183B2|1984-06-01|1993-02-01|Ikeda Mohando Co|

---

FR2733750B1|1995-05-03|1997-06-13|Synthelabo|DERIVATIVES OF GAMMA-OXO-ALPHA--5,6- DIHYDRO-4H-THIENOPYRROLE-5-BUTANOIQUE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|

---

JP4596915B2|2002-09-06|2010-12-15|ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ|Thienopyrrolyl and furanopyrrolyl compounds and their use as histamine H4 receptor ligands|

---

WO2022034121A1|2020-08-11|2022-02-17|Université De Strasbourg|H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

FR8415658A|FR2571723B1|1984-10-12|1984-10-12|THIENO AND FURO-PYRROLES DERIVATIVES, METHODS OF PREPARATION AND MEDICAMENTS CONTAINING THEM|

---