GB2170805A - Process for the preparation of 3, 5-diamino-1,2,4-triazole derivatives - Google Patents
Process for the preparation of 3, 5-diamino-1,2,4-triazole derivatives Download PDFInfo
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- GB2170805A GB2170805A GB08602136A GB8602136A GB2170805A GB 2170805 A GB2170805 A GB 2170805A GB 08602136 A GB08602136 A GB 08602136A GB 8602136 A GB8602136 A GB 8602136A GB 2170805 A GB2170805 A GB 2170805A
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- general formula
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- 238000000034 method Methods 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- PKWIYNIDEDLDCJ-UHFFFAOYSA-N guanazole Chemical class NC1=NNC(N)=N1 PKWIYNIDEDLDCJ-UHFFFAOYSA-N 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- -1 alkaline earth metal salt Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000007858 starting material Substances 0.000 claims abstract description 12
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 150000002989 phenols Chemical class 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 150000002366 halogen compounds Chemical class 0.000 claims abstract description 4
- 150000002440 hydroxy compounds Chemical class 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 229960001340 histamine Drugs 0.000 abstract description 2
- 230000002459 sustained effect Effects 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 5
- 150000003852 triazoles Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 150000002429 hydrazines Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- HXMWGMZZNGHVPQ-UHFFFAOYSA-N 3-[(dimethylamino)methyl]phenol Chemical compound CN(C)CC1=CC=CC(O)=C1 HXMWGMZZNGHVPQ-UHFFFAOYSA-N 0.000 description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 150000002541 isothioureas Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical group CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 125000005359 phenoxyalkyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/14—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Abstract
There is disclosed a process for the preparation of compounds of the general Formula I <IMAGE> wherein R<1> and R<2> are independently hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or R1 and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and R3 is hydrogen or alkyl and pharmaceutically acceptable acid addition salts thereof, which comprises reacting a halogen compound of the general Formula III <IMAGE> [wherein X is halogen, which may be prepared from the hydroxy compound of general formula II, with an alkali metal of alkaline earth metal salt of a phenol derivatives of the general Formula IV <IMAGE> and, if desired, converting the compound of general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof. The compounds of general Formula I have a useful sustained histamine H2 blocking effect. The advantages of the process invention are that it requires readily available starting materials, provides high yields and is readily feasible on an industrial scale.
Description
SPECIFICATION
Process for the preparation of 3,5-diamino-1,2,4-triazole derivatives
This invention relates to a new and improved process for the preparation of 3,5-diamino-1,2,44riazole derivatives.
According to the present invention there is provided a process for the preparation fo 3,5-diamino-1,2,4triazole derivatives of the general Formula I
and pharmaceutically acceptable acid addition salts thereof /wherein
R1 and R2 each stands for hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or R, and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and
R3 stands for hydrogen or alkyl/.
The compounds of the general Formula I are known histamine H2-blockers of sustained effect. These compounds are capable of antagonizing gastric acid secretion stimulated by histamine and are useful in antiulcus therapy.
Several procedures are known for the preparation of the compounds of the general Formula I. According to Belgian patent No. 875,846 an amine of the general Formula V
/wherein R1 and R2 are as stated above is reacted with a cyanoimino derivative of the general Formula VI
/wherein R4 and R5 are alkylthio or alkoxy/. The isourea or isothiourea derivative of the general Formula
VII
thus obtained /wherein R, and R2 are as stated above/ is treated with a substituted hydrazine of the general Formula VIII
R3 - NH - N = Z Nail/ /wherein R3 is as stated above and Z represents two hydrogen atoms/. In the reaction a mixture of the isomeric compounds of the general Formulae I and IX
is obtained /wherein R1, R2 and R3 are as stated above/.The compound of the general Formula I is separated from the mixture by crystallization.
The serious drawback of this process is that the isomers of the general Formulae I and IX - differing from each other in the position of the R3 substituent - are formed only in the last step of the synthesis and for this reason the desired isomer of the general Formula I is obtained with large losses. Moreover the fact that the said losses occur at the very end of the lengthy synthesis, consisting of several steps, makes the process very expensive.
In order to eliminate the formation of the isomeric compounds of the general Formula IX according to a further process described in Belgian patent No. 875,846 the isothiourea of the general Formula VII is reacted with a protected hydrazine derivative of the general Formula VIII /wherein R3 is as stated above and Z represents a protecting group/. From the protected cyano guanidine derivative of the general Formula X
thus obtained /wherein Ri, R2, R3 and Z are as stated above/the protecting group is removed and the cyano guanidine derivative of the general Formula Xl
/wherein R1, R2 and R3 are as stated above/ spontaneously cyclizes to the compound of the general Formula
According to the said Belgian patent the key intermediate of the general Formula X can also be prepared by reacting a protected hydrazine derivative of the general Formula VIII with a cyanimino derivative of the general Formula VI. The protected cyano guanidine derivative of the general Formula XII
/wherein R3 and R4 are as stated above and Z stands for a protecting group/ is coupled with an amine of the general Formula V to yield the desired intermediate of the general Formula X.
The common disadvantage of both of the above processes is the use of the protecting group Z which aims the elimination of the isomeric triazole derivative of the general Formula IX in the ring closure step of the triazole ring. It is namely known [see J.Org.Chem. 39, 1522 /1974/] that an analoguous reaction of dimethyl-N-cyanoimino-dithio carbamate and N-methyl-hydrazine leads to the formation of the isomers of the type of the general Formulae I and IX.
According to a further reaction disclosed in Belgian patent No. 875,846 an isothiourea derivative of the general Formula XIII
/wherein R1 and R2 are as stated above and R8 stands for Cl lO alkyl/ is treated with an amino guanidine, semicarbazide or thiosemicarbazide of the general Formula XIV
/whrein Y is -NH-, oxygen or sulfur and R3 is as stated above/. The compound of the general Formula XV
/wherein R1, R2, R3 and Y are as stated above and Q represents -NH-/ thus obtained is converted into the triazole derivative of the general Formula I by ring-closure.
According to a further procedure disclosed in the said Belgium patent an addition reaction between an isocyanate of the general Formula XVI
/wherein R1 and R2 are as stated above and P is oxygen or sulfur/ and a compound of the general Formula XIV /wherein R3 is as stated above and Y represents -NH-/ is carried out, whereupon the compound of the general Formula XV is cyclized into the desired triazole derivative of the general Formula I.
The common drawback of both of the above processes is that the preparation of the reactants is rather complicated, the last condensation step is very lengthy and energy consuming and the yields are rather moderate.
According to a further reaction described in the said Belgian patent an isothiourea of the general Formula XIII is reacted with a protected hydrazine of the general Formula VIII whereupon the protecting group is removed. The amino guanidine derivative of the general Formula XVII
/wherein R1, R2 and R3 are as stated above/ is reacted with carbamoyl chloride to yield the desired compound of the general Formula I.
The disadvantage of this process is that in order to eliminate the formation of the undesired isomer of the general Formula IX a protected hydrazine derivative of the general Formula VIII is used /wherein Z is a protecting group/, the preparation of the reactants is complicated and the closing condensation step of the synthesis is lengthy and energy consuming.
A further reaction type disclosed in Belgian patent No. 875,846 differs from the reactions disclosed above in the fact that in the place of an amino compound of the general Formula V an acid amide of the general formula XVIII
/wherein R1 and R2 are as stated above/ or an acetale or cyclic acetale of the general Formula XIX
/wherein R, stands for alkyl or the /P6O/2CH- group represents a cyclic acetale/ is used. The last step of the said synthesis is the formation of the group of the general Formula R1R2N-CH2- from the intermediates of the general Formulae XX and XXI
thus obtained /wherein R1, R3, R3 and P6 are as above/ by means of known methods used in the synthesis of the compounds of the general Formula V.
According to a further method disclosed in Belgian patent No. 875,846 a key intermediate of the general Formula XXII
/wherein R3 is as stated above and X stands for halogne/ is condensed withan amine of the general Formula R1R2NH /wherin Ri and R3 are as stated above/.
According to European patent application No. 29,303 the compounds of the general Formula I are prepared by subjecting an aldehyde of the general Formula XXIII
/wherein R3 is as stated above/ and an amine of the general Formula R1R2NH /wherein R1 and R2 are as stated above/ to an amination reaction under reducing conditions.
According to a further reaction of the said European patent application a secondary amine of the gen eral Formula XXIV
/wherein R3 and R3 are as stated above/ is used as starting material which is either subjected to reducing condensation with an aldehyde of the general Formula R7CHO /wherein the R7-CH2- group formed on reducing R7CHO is the R, group/ or alkylated with a compound of the general Formula R7-CH2-X /wherein
R7-CH2- is as stated above and X stands for halogen/ to yield the desired compound of the general Formula I.
In the last four reaction types the same reaction steps are used as in the previously disclosed methods, only the order of sequence of the steps is changed. Consequently, as a matter of fact the said four procedures are accompanied by the same drawbacks as the previously discussed methods.
According to a further process disclosed in Belgian patent No. 875,846 a narrower sub-group of the compounds of the general Formula I is prepared by reacting a phenoxy alkyl derivative of the general
Formula XXV
/wherein R3 is as stated above/ with the ammonium chloride of the Formula XXVI.
Thus a compound of the general Formula I is obtained wherein both R, and R2 represent methyl. The disadvantage of the said process is that it is suitable for the preparation but of a narrow compound group. Moreover the preparation of the compound of the Formula XXVI and also the reaction itself is complicated and labour consuming.
According to a further process disclosed in belgian patent No. 875,846 an amino guanidine of the general Formula XIV /wherein R3 is as stated above and Y stands for imino/ is reacted with a carbamoyl chloride of the general Formula XXVII
/wherein R8 and R8 are suitable protecting groups/, the 3,5-diamino-1H-1,2,4-triazole derivative of the general Formula XXVIII
thus obtained /wherein R3, R8 and R8 are as stated above/ is reacted with an aldehyde of the general
Formula XXIX
/wherein R1 and R2 are as stated above/ and the Schiff-base of the general Formula XXX
/wherein R1, R3, R3 and R8 and R8 are as stated above/ thus obtained is reduced and finally the protecting groups are removed.
According to a modification of the said process the amino triazole of the general Formula XXVIII is reacted with an activated acid derivative of the general Formula XXXI
/wherein R1 and R2 are as stated above and A represents halogen, hydroxy, alkoxy or acyloxy/ whereupon the acid amide of the general Formula XXXII
thus obtained /whereupon Rl, R2, R3, R8 and R8 are as stated above/ is reduced to the desired compound of the general Formula I.
According to a further modification of the above process an amino triazole of the general Formula
XXVIII is reacted with an active ester of the general Formula XXXIII
/wherein R1 and R3 are as stated above and B is mesyloxy or toxyloxy/ to yield the desired compound of the general Formula I.
The above methods are accompanied by the disadvantages that the triazole ring is formed by the complicated methods earlier discussed and the appropriate selection and removal of the protecting groups R8 and P8 cause further problems and inconveniences.
It is the object of the present invention to overcome the above drawbacks of the known procedures and to provide an economical, readily feasible process for the preparation of the compounds of the general Formula I.
According to the present invention there is provided a process for the preparation of compounds of the general Formula I /wherein Rl and R2 each stands for hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or Rl and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and
R3 stands for hydrogen or alkyl/, and pharmaceutically acceptable acid addition salts thereof, which comprises
a/ converting a hydroxy compound of the general formula II
/wherein R3 is as stated above/ into a halogen compound of the general Formula III
/wherein R3 is as stated above and X stands for halogen/ and reacting the compound thus obtained with an alkali metal or alkali earth metal salt of a phenol derivative of the general Formula IV
/wherein Rl and R2 are as stated above/; or b/ reacting a halogen compound of the general Formula lil with an alkali metal or alkali earth metal salt of a phenol derivative of the general Formula IV and, if desired, converting the compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
The hydroxy compound of the general Formula II is converted into the halogen derivative of the general Formula III by methods known per se. It is preferred to react the compound of the general Formula II with a suitable halogenating agent - particularly with a thionyl halide, especially thionyl chloride - in an inert solvent. The excess of thionyl halide may preferably act as reaction medium. As reaction medium aromatic hydrocarbons /e.g. benzene, toluene or xylene/ may also be used. The reaction may be carried out at room temperature or under eating /e.g. between 20 "C and 80 C/.
The halogen derivative of the general Formula Ill is then reacted with an alkali metal /e.g. potassium, sodium or lithium/ or alkali earth metal /e.g. calcium or magnesium/ salt or a phenol compound of the general Formula IV. The reaction may be accomplished in a dipolar aprotic solvent /e.g. dimethyl formamide/.
The alkali or alkali earth metal salt of the compound of the general Formula IV may be formed in the reaction mixture by reacting the phenol derivative of the general Formula IV in a dipolar aprotic solvent / e.g. dimethyl formamide/ with a hydride or alcoholate of the corresponding alkali or alkaline earth metal / e.g. sodium hydride, calcium hydride or potassium tertiary butylate/.
The compound of the general Formula I thus obtained may be isolated by methods known per se.
The salt formation may be carried out in a known manner by reacting the compound of the general
Formula I thus obtained in an organic solvent with the corresponding inorganic or organic acid /e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid, lactic acid etc./.
The starting materials of the general Formulae II and IV are known and readily available compounds.
The compounds of the general Formula III are new, never described in prior art.
The term "alkyl" relates to straight or branched chained saturated aliphatic hydrocarbon groups having 1-5 carbon atoms /e.g. methyl, ethyl, n-propyl, isopropyl etc./. The term "alkenyl" relates to straight or branched chained olephinic hydrocarbon groups having 2-5 carbon atoms /e.g. allyl, propenyl etc./. The term "aralkyl" relates to alkyl groups substituted by an aryl radical /e.g. benzyl, p-phenylethyl etc./. The term "cycloalkyl" relates to saturated cyclic aliphatic hydrocarbon groups having 3-8 carbon atoms /e.g.
cyclobutyl, cyclopentyl, cyclohexyl etc./. The term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms and represents preferably chlorine or bromine, particularly chlorine.
The "heterocyclic group"formed by R1 and R2 and the adjacent nitrogen atom may have 5 or 6 members, may comprise one or two nitrogen, oxygen and/or sulfur atoms and may be optionally substituted.
Preferred heterocyclic groups are the pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl groups.
Rl and R2 may preferably stand for methyl or together with the adjacent nitrogen atom may preferably form a pyrrolidino or piperidino group. R3 may preferably stand for methyl.
The process of the present invention is particularly suitable for the preparation of l-methyi-N5-(3-[3-[/1- piperidinyl/-methyl]-phenoxy]-propyl)-l H-l ,2,4-triazole-3,5-diamine and sa Its thereof.
The advantages of the process of the present invention may be summarized as follows:
a/ The process is readily feasible on industrial scale, too.
b/ No specific apparatus or equipment is required.
c/ The starting materials are readily available in large quantities, too.
d/ Since the formation of the isomeric compounds of the general Formula IX is eliminated and the synthesis of the desired compounds of the general Formula I is carried out not stepwise but by the synthesis of two key intermediates of approximately the same size, the total yield of the synthesis is far superior to the total yields of the hitherto known methods.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examples.
Example 1 Nó-13-Chloropropyll- 1K- 1,2,4-triazole-3, 5-diamin e hydrochloride
5 g /0,032 mole/ of Ns-/3-hydroxypropyl/-1 H-l ,2,4-triazole-3,5-diamine are dissolved in 15 ml of benzene.
To the solution 4.2 g /0,035 mole/ of thionyl chloride are added under stirring and cooling at 10 "C. The reaction mixture is slowly allowed to warm to room temperature. The reaction mixture is stirred for half an hour. The precipitated crystals are filtered off and washed with benzene. Thus 6.3 g of the desired compound are obtained, yield 92.8 %. A strongly hygroscopic white crystalline substance is obtained which liquifies on air. Mp.: 130-132 "C /in a closed tube/.
Example 2 N5-13-chloropropyll- 1K- 1,2,4-triazole-3,5-diamine-hydrochloride One proceeds according to Example 1 except that no benzene is used but 10.6 ml /0,15 ml/ of thionyl chloride are applied and this excess serves as reaction medium. Thus 6.8 g of the desired compound are obtained, yield 94,4 %. The product is identical with the compound prepared according to Example 1.
Example 3 1-Methyl-Nó-13-chloropropyll- 1H- 1,2,4triazole-diamine-hydrochloride One proceeds according to Example 2 except that 8,6 g/0.05 mole/ of 1-methyl-N5-/3-hydroxy-propyl/- 1H-1,2,4-triazole-3,5-diamine are used as starting material and the reaction mixture is heated to 60 "C and stirred at this temperature for 15 minutes. Thus 10.7 g of the desired compound are obtained, yield 94.7 %. Mp.: 170-172 "C /decomposition/.
Example 4 1-Methyl-N6X,3-l3-[l l-piperidinyll-methylJ-phenoxyJ-propyl'J - 1K- 1,2,4-triazo!e-3,5-diamine To a solution of an oily suspension of 1.0 g /0.033 molel of 80 % sodium hydride in 20 ml of an hydros dimethyl formamide 5.7 g /0/03 mole/ of 3-/1-piperidinylmethyl/-phenol are slowly added and the mixture is stirred for half an hour at room temperature. In a separate flask to a solution of 8.1 g /0.036 mole/ or 1 methyl-N5-/3-chloropropyl/-l H-'l ,2,4-triazole-3,5-diamine-hydrochloride in 15 ml of anhydrous dimethyl formamide 3.04 g /0.03 mole/ or triethyl amine are added under stirring at room temperature, the precipitated triethyl amine hydrochloride is filtered off and washed with some an hydros dimethyl formamide.
The solution thus obtained is added to the dimethyl formamide solution of the phenolate prpared above under stirring at room temperature. The reaction mixture is stirred for 72 hours, at room temperature, 30 ml of water are added and it is extracted three times with 20 ml of chloroform each. The united organic phases are extracted three times with 20 ml of water each, the chlorophorm phase is dried over anhydrous magnesium sulfate and the chloroform is distilled off in vacuo. The residual brown oil /9.6 gl becomes slowly crystalline on standing and is recrystallized from a 1:4 mixture of ethyl acetateand cyclohexane. Thus 5.6 g of the desired compound are obtained, yield 54,4 %, mp.: 93-94 "C.
Example 5 1-Methyl- N5-(3-[3-[1 1-piperidinyll-methylj-phenoxyj-propy]} - 1K- 1,2,4-triazole-3,5-diamine-fumarate The oily crude product prepared according to Example 4 is dissolved in 30 ml of ethanol whereupon at 50 "C 3.5 g/0.03 mole/ of fumaric acid are added. After dissolving the reaction mixture is cooled and allowed to stand in a refrigerator overnight. The precipitated crystals are filtered and washed with some ethanol. Thus 7,8 g of the desired compound are obtained, yield 56.4 %, mp.: 142-145 "C.
Example 6 1-Mothy/-N{3-[3-fl 1-piperidinyll-methyl]-phenoxyl-propyl} -1K- 7,24-triazole-3,5-diamine One proceeds according to Example 4 except that 10.2 g /0.045 mole/ of 1 -methyl-NS-/3-chloroprpyl/-l H- 1,2,4-triazole-3,5-diamine-hydrochloride are used. Thus 5.3 g of the desired compound are obtained, yield 51.4 %. The product is identical with the compound prepared according to Example 4.
Example 7 1-Methyl-N5- (3-[3-[1 1-piperidin yl]-meth ylJ-phonoxy]-prop yI\- 1K- 1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 6.8 g /0.03 mole/ or 1-methyl-N5-/3-chloropropyl/-1H- 1,2,4-triazole-3,5-diamine-hydrochloride are used as starting material. Thus 4.9 g of the desired compound are obtained, yield 47.6 %. The product is identical with the compound prepared according to
Example 4.
Example 8 l-Meth yl-N5-{3-[3-[/1 1-piperidinyl]-methyl]-phenoxy]-propyl} - 1H- 1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 1.4 g /0.033 mole/ of calcium hydride are used in the place of sodium hydride. Thus 5.1 g of the desired compound are obtained, yield 49.5 %. The product is identical with the compound prepared according to Example 4.
Examples 9 1-Methyl-N5-{3-[3-[/1-pyrrolidinyl/-methyl]-phenoxy]-propyl}-1H-1,2,4-triazole-3,5-diamine
One proceeds according to Example 4 except that 5.3 g /0.03 mole/ or 3-/1-pyrrolidinyl-methyl/-phenol are used as starting material of the general Formula IV. Thus 4.9 g of the desired compound are obtained, yield 49.4 %, mp.: 94-95 C.
Example 10
1-Methyl-N5-{3-[-[/1 1-pyrrolidinyl]-methyl]-phenoxy]y-propyl}- 1H- 1,2,4triazole-3,5-diamine fumarate
One proceeds according to Example 5 except that as starting material the compound prepared according to Example 9 is used. Thus 7.2 g of the desired compound are obtained, yield 53,7 %, mp.: 140-142 "C.
Example 11 l -Methyl-Ns{3-[3-[ldimethylaminol-methyl7-phenoxyl-propyl}- 1H-1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 4.5 g /0.03 mole/ of 3-dimethylaminomethyl-phenol are used as starting material. Thus 4.1 g of the desired compound are obtained, yield 44.9 %, m.p.: 95-96 "C.
Example 12
N5-{3-[-[/1 [1-Piperidinyl]-methyl]-phenoxy]-propyl}- 1K- 1,2,4triazole-3,5-diamine One proceeds according to Example 4 except that 7.6 g /0.036 mole/ of N5-/3-chloropropyl/-1H-1,2,4- triazole-3,5-diamine-hydrochloride are used as starting material. Thus 4.7 g of the desired compound are obtained, yield 47.4 %, mp.: 100-101 C.
Example 13 Ns-(3-13-[lDimethylaminol-methyl ]-phenoxyl]-propyl}- 111- 7,24-triazole-3,5-diamine One proceeds according to Example 4 except that 4.5 g /0.03 mole/ of 3-dimethylaminomethyl-phenol and 7.6 g /0.036 mole/ or N5-/3-chloropropyl/-1H-1,2,4-triazole-3,5-diamine-hydrochloride are used as starting material. Thus 4.2 g of the desired compound are obtained, yield 48.2 %, mp.: 91-93 "C.
Claims (12)
1. A process for the preparation of 3,5-diamino-1H-1,2,4-triazole derivatives of the general Formula I
/wherein R, and R2 each stands for hydrogen, alkyl, alkenyl, aralkyl or cycloalkyl; or R1 and R2, together with the adjacent nitrogen atom they are attached to, may form a heterocyclic ring; and
R3 stands for hydrogen or alkyl/ and pharmaceutically acceptable acid addition salts thereof, which comprises a/ converting a hydroxy compound of the general Formula II
/wherein R3 is as stated above/ into a halogen compound of the general Formula Ill
/wherein R3 is as stated above and X stands for halogen/ and reacting the compound thus obtained, optionally after having removed the hydrohalide moeity HX, with an alkali metal or alkaline earth metal salt of a phenol derivative of the general Formula IV
(wherein Rl and R2 are as stated above); or (b) reacting a halogeno compound of the general Formula III optionally after having removed the hydrohalide moeity HX, with an alkali metal or alkaline earth metal salt of a phenol derivative of the general Formula IV and, if desired, converting the compound of the general Formula I thus obtained into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to Claim 1, which comprises reacting a compound of the general Formula II with a thionyl halide, preferably with thionyl chloride.
3. A process according to Claim 2, which comprises carrying out the reaction in an excess of thionyl halide or in an inert organic solvent.
4. A process according to Claim 3, which comprises using an aromatic hydrocarbon - preferably toluene, benzene or xylene - as solvent.
5. A process according to Claim 1, which comprises using a sodium, potassium, calcium or magnesium - preferably sodium - salt of a compound of the general Formula IV.
6. A process according to Claim 1 or 5, which comprises preparing in the reaction mixture the alkali or alkaline earth metal salt of the compound of the general Formula IV.
7. A process according to Claim 5 or 6, which comprises carrying out the reaction in an inert dipolar aprotic organic solvent.
8. A process according to Claim 7, which comprises using dimethyl formamide as solvent.
9. A process according to any of Claims 1-8 for the preparation of 1-methyl-N543-[-[/1-piperidinyl/ methyl]-phenoxyl-propyl)-l H-l ,2,4-triazole-3,5-diamine and pharmaceutically acceptable acid addition salts thereof, which comprises using as starting material compounds of the general Formula II and IV, in which R, and P3 together with the adjacent nitrogen atom, they are attached to, form a piperidino ring and R3 represents methyl.
10. A process according to Claim 9 using thiionyl chloride as halogenating agent.
11. Compounds of the general Formula I and salts thereof whenever prepared acccording to the process claimed in any of Claims 1-9.
12. A process as claimed in claim 1 as substantially described herein, with particular reference to the
Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU85315A HU193253B (en) | 1985-01-29 | 1985-01-29 | Process for preparing 3,5-diamino-1,2,4-triazole derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8602136D0 GB8602136D0 (en) | 1986-03-05 |
| GB2170805A true GB2170805A (en) | 1986-08-13 |
| GB2170805B GB2170805B (en) | 1988-04-27 |
Family
ID=10949054
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08602136A Expired GB2170805B (en) | 1985-01-29 | 1986-01-29 | Process for the preparation of 3, 5-diamino-1, 2, 4-triazole derivatives |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS61176576A (en) |
| CN (1) | CN1015456B (en) |
| AR (1) | AR240046A1 (en) |
| AT (1) | AT395149B (en) |
| CA (1) | CA1285568C (en) |
| CS (1) | CS253739B2 (en) |
| DD (1) | DD242807A5 (en) |
| DE (1) | DE3602648A1 (en) |
| DK (1) | DK42986A (en) |
| ES (1) | ES8704910A1 (en) |
| FI (1) | FI860432A7 (en) |
| GB (1) | GB2170805B (en) |
| HU (1) | HU193253B (en) |
| IT (1) | IT1190608B (en) |
| NO (1) | NO167091C (en) |
| PL (1) | PL146491B1 (en) |
| PT (1) | PT81935B (en) |
| SE (1) | SE8600385L (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2023133B (en) * | 1978-04-26 | 1982-09-08 | Glaxo Group Ltd | Heterocyclic derivatives |
| EP0029303B1 (en) * | 1979-10-22 | 1985-01-30 | Glaxo Group Limited | 1,2,4-triazole derivatives, processes for their production and pharmaceutical compositions containing them |
| DK558181A (en) * | 1981-01-30 | 1982-07-31 | Smithkline Corp | METHOD OF PREPARING 3,5-DIAMINO-1,2,4-TRIAZOLES |
| DE3336410A1 (en) * | 1983-10-06 | 1985-04-18 | Ludwig Heumann & Co GmbH, 8500 Nürnberg | SULFEN AMIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DE3341750A1 (en) * | 1983-11-18 | 1985-05-30 | Ludwig Heumann & Co GmbH, 8500 Nürnberg | 1,2,4-Triazole derivatives, process for their preparation and medicaments containing these compounds |
-
1985
- 1985-01-29 HU HU85315A patent/HU193253B/en unknown
-
1986
- 1986-01-19 IT IT19218/86A patent/IT1190608B/en active
- 1986-01-27 CS CS86576A patent/CS253739B2/en unknown
- 1986-01-29 PL PL1986257689A patent/PL146491B1/en unknown
- 1986-01-29 DE DE19863602648 patent/DE3602648A1/en active Granted
- 1986-01-29 GB GB08602136A patent/GB2170805B/en not_active Expired
- 1986-01-29 AT AT0021086A patent/AT395149B/en not_active IP Right Cessation
- 1986-01-29 CA CA000500565A patent/CA1285568C/en not_active Expired - Lifetime
- 1986-01-29 CN CN86100724A patent/CN1015456B/en not_active Expired
- 1986-01-29 DD DD86286590A patent/DD242807A5/en not_active IP Right Cessation
- 1986-01-29 NO NO860324A patent/NO167091C/en unknown
- 1986-01-29 PT PT81935A patent/PT81935B/en not_active IP Right Cessation
- 1986-01-29 FI FI860432A patent/FI860432A7/en not_active Application Discontinuation
- 1986-01-29 AR AR302989A patent/AR240046A1/en active
- 1986-01-29 DK DK42986A patent/DK42986A/en not_active Application Discontinuation
- 1986-01-29 SE SE8600385A patent/SE8600385L/en not_active Application Discontinuation
- 1986-01-29 JP JP61017700A patent/JPS61176576A/en active Granted
- 1986-01-29 ES ES551388A patent/ES8704910A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AR240046A1 (en) | 1990-01-31 |
| PT81935A (en) | 1986-02-01 |
| PT81935B (en) | 1987-11-30 |
| DE3602648A1 (en) | 1986-09-11 |
| DK42986D0 (en) | 1986-01-29 |
| SE8600385L (en) | 1986-07-30 |
| SE8600385D0 (en) | 1986-01-29 |
| HU193253B (en) | 1987-08-28 |
| JPS61176576A (en) | 1986-08-08 |
| CN86100724A (en) | 1986-08-13 |
| FI860432A7 (en) | 1986-07-30 |
| IT8619218A0 (en) | 1986-01-19 |
| GB8602136D0 (en) | 1986-03-05 |
| ATA21086A (en) | 1992-02-15 |
| DE3602648C2 (en) | 1990-09-06 |
| HUT40632A (en) | 1987-01-28 |
| DD242807A5 (en) | 1987-02-11 |
| ES551388A0 (en) | 1987-04-16 |
| CS253739B2 (en) | 1987-12-17 |
| NO167091B (en) | 1991-06-24 |
| PL257689A1 (en) | 1987-02-09 |
| PL146491B1 (en) | 1989-02-28 |
| CA1285568C (en) | 1991-07-02 |
| GB2170805B (en) | 1988-04-27 |
| CN1015456B (en) | 1992-02-12 |
| NO167091C (en) | 1991-10-02 |
| AT395149B (en) | 1992-09-25 |
| JPH0524906B2 (en) | 1993-04-09 |
| IT1190608B (en) | 1988-02-16 |
| FI860432A0 (en) | 1986-01-29 |
| ES8704910A1 (en) | 1987-04-16 |
| DK42986A (en) | 1986-07-30 |
| NO860324L (en) | 1986-07-30 |
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Legal Events
| Date | Code | Title | Description |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940129 |