US3277100A - Novel substituted pyrazoles - Google Patents
Novel substituted pyrazoles Download PDFInfo
- Publication number
- US3277100A US3277100A US284374A US28437463A US3277100A US 3277100 A US3277100 A US 3277100A US 284374 A US284374 A US 284374A US 28437463 A US28437463 A US 28437463A US 3277100 A US3277100 A US 3277100A
- Authority
- US
- United States
- Prior art keywords
- cyano
- carbons
- group
- acetamido
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000003217 pyrazoles Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 36
- -1 3-amino-4-cyano-N-carbamylpyrazoles Chemical class 0.000 description 25
- 125000000217 alkyl group Chemical group 0.000 description 25
- 239000000203 mixture Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 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 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- NUGZBVBZIDWZAD-UHFFFAOYSA-N 1h-pyrazole-4-carbonitrile Chemical compound N#CC=1C=NNC=1 NUGZBVBZIDWZAD-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- YYRHGCUWQUHJFR-UHFFFAOYSA-N n-(4-cyano-1h-pyrazol-5-yl)acetamide Chemical compound CC(=O)NC=1NN=CC=1C#N YYRHGCUWQUHJFR-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XDIYNQZUNSSENW-UUBOPVPUSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XDIYNQZUNSSENW-UUBOPVPUSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- YMJLEPMVGQBLHL-UHFFFAOYSA-N 1h-pyrazole-5-carbonitrile Chemical compound N#CC1=CC=NN1 YMJLEPMVGQBLHL-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000499489 Castor canadensis Species 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000011779 Menyanthes trifoliata Nutrition 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- PQUGCKBLVKJMNT-UHFFFAOYSA-N SC560 Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 PQUGCKBLVKJMNT-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 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
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- NBYQXBYMEUOBON-UHFFFAOYSA-N carbamothioyl chloride Chemical class NC(Cl)=S NBYQXBYMEUOBON-UHFFFAOYSA-N 0.000 description 1
- NMPYTTJSWDQEQM-UHFFFAOYSA-N carbonyl dichloride;1h-pyrazole Chemical compound ClC(Cl)=O.C=1C=NNC=1 NMPYTTJSWDQEQM-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DMIFIPICRBGFTI-UHFFFAOYSA-N n-methyl-1h-pyrazole-5-carboxamide Chemical compound CNC(=O)C=1C=CNN=1 DMIFIPICRBGFTI-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003119 painkilling effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- WLLMAULSQJHANM-UHFFFAOYSA-N piperidin-1-yl(1h-pyrazol-5-yl)methanone Chemical compound C=1C=NNC=1C(=O)N1CCCCC1 WLLMAULSQJHANM-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NJXRORHHSPMXRO-UHFFFAOYSA-N pyrazole-1-carbonyl chloride Chemical compound ClC(=O)N1C=CC=N1 NJXRORHHSPMXRO-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 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
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
Definitions
- R is methyl
- R is alkyl of 1 through 6 carbons Where the alkyl is joined to the carbamyl nitrogen by a primary or secondary carbon of the alkyl group; alken-Z-yl of three through 6 carbons Where the alken-Z-yl group is joined to the carbamyl nitrogen by a primary or secondary carbon of the alken-2-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkyl of 2 through 6 carbons; dimethylamino; or dialkylaminoalkyl where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons with a total of from 3 through 7 in the dialkylaminoalkyl group;
- dehydropiperidyl i.e.--N
- Y is H or CH;;; Y is H, CH C H or COOR where R is alkyl of 1 through 4 carbons; and Y is H, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons, trifluoromethyl, COOR Where R is alkyl of 1 through 4 carbons, dialkylaminoalkyl of 3 through 7 carbons where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinoethyl or arylalkyl of 7 through 9 carbons including such groups as benzyl, phenethyl, and 0-, mand p-tolylethyl;
- R can be hydrogen but it is much more highly preferred that it is an acyl radical of 1 through 3 carbons such as formamido, acetamido and propionamido.
- the alkyl or alken-2-yl group is joined to the carba-myl nitrogen by a secondary carbon of the alkyl or alken-2-yl group.
- the compounds of this invention are generally solids. They can be used as inhibitors for vinyl polymerization but are particularly useful for their physiological characteristics.
- the preferred compounds of Formula 1 are carbamyl pyrazoles where X is oxygen and where R and R are joined to form a piperidino ring and in particular a mono-substituted piperidyl ring where the substituent is in the para position with respect to the carbamyl nitrogen.
- preferred compounds of this invention include the following exemplary ones:
- cyanopyrazole 1-l (4-methylpiperidino) carbonyl-3 (5) -acetamido-4- cyanopyrazole l-N-( 4-methylpiperidino) carb onyl-3 (5 -propionamido- 4-cyan0pyrazole
- R is alkyl of 1 through 4 carbons, such as'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc.
- R is alkyl of 1 through 4 carbons, such as'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc.
- Illustrative of these preferred compounds are the following:
- substituted carbamyl pyrazoles of this invention can be prepared by reaction of the appropriate pyrazole with selected reactants as more fully described below.
- One general method for the preparation of the pyrazoles of this invention can be carried out where the amine N-carboxyl chloride (e.g., N,N-dimethylcarbamoyl chloride) is available.
- the chloride invan unreactive solvent such as ether, ethyl acetate, or benzene
- a base such as sodium hydride or triethylamine.
- the resulting mixture is refluxed for an extended period, say up to about 24 hours or more, .and allowed to cool.
- the insoluble chloride e.g. sodium chloride or triethylamino hydrochloride, is filtered E and the solvent is removed from the filtrate to give the desired carbamyl or thiocarbamyl pyrazole product.
- the same general procedure as just described is used when the pyrazole-l-carbonyl chloride is available (e.g., from pyrazole having hydrogen on nuclear nitrogen and either phosgene or thiophosgene) except that the secondary amine is reacted with the pyrazole carbonyl chloride.
- the first method is preferred if the 3-aminopyrazoles are used since the 3-amino group would react with the phosgene or thiophosgene, whereas the second method is preferred for amines such as N-methyl-N-hydroxyethylamine where the amine substituent can also react with the phosgene or thiophosgene.
- 'Ihe amine carbonyl chlorides such as N-piperidine carboxyl chloride are prepared by placing in a flask fitted with a DryJce condenser, mechanical stirrer and dropping funnel preferably at least 1.2 moles of phosgene in an inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetate or the like.
- an inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetate or the like.
- a solution of 1 mole of the selected amine, e.g., piperidine, and preferably, for increased yields, with 1 mole of tertiary amine such as triethylamine, in the selected solvent is added slowly with stirring and the temperature is kept below 30 C. with occasional cooling.
- the pyrazole can be used in the above procedure in place of the amine (piperidine).
- 3-acetamido-4-cyano-pyrazole one obtains 3'-acetamido-4-cyanopyrazole-1-carbonyl chloride.
- the compounds of this invention have outstanding activity as analgesics, many of them exceeding codeine in potency, as shown by standard animal tests. This analgesic activity inthese compounds is particularly valuable because of significantly favorable therapeutic ratios.
- General painkilling benefits, as well as other physiological remediation associated with aspirin, are 'believed to be obtainable according to this invention based on tests and evaluation thus far carried out.
- the compounds of this invention exhibit outstanding anti-inflammatory and central nervous system activity.
- a compound of this invention will be administered to the body orally, parenterally and by other methods.
- the dosage will vary and will depend on such factors as the condition being treated; age and weight of the recipient; the responsiveness of the recipient; pn'or, concurrent and intended subsequent, medication and treatment, general health of the recipient; frequency of treatment; and of course the purpose and nature of the eifect desired.
- the active compound will be administered in a physiologically beneficial amount. Administration can be in a single dose or in a plurality of doses over an extended period of time. It will furthermore be understood that every compound within this invention does not have an identical level of dosage requirement for therapeutic or prophylactic effectiveness and therefore experts will understand that some dosage variation between compounds can be expected for maximum benefits. It will of course also be understood that an initial dose, or first group of doses, in a course of treatment can bein greater amounts, if appropriate, for a particular medical situation and a rapid response is sought by the early administration of relatively large doses and thereafter the minimally effective dosage, or maintenance dosage, is determined.
- a single dose will rarely exceed about 400 or SOOmilligrams of active compound within this invention, although larger amounts can be used as called for in any given situation. Extremely small doses will effect some benefit but as a practical matter a single dose of less than about 1 or 2 milligrams will seldom be used. Fortreating small animals with high physiological response and using highly active compounds, routine usage can be at much lower dosage levels however. Doses can be repeated in the same or greater or lesser amounts over a period of time as long as improvement in the recipient is observed or as long as needed under the circumstances.
- the active compound will ordinarily be administered with a non-toxic pharmaceutical carrier in a variety of practical dosage forms.
- These dosage forms are noval compositions comprising the non-toxic pharmaceutical carrier and a physiologically beneficial amount of one or more active compounds of this invention.
- These highly useful dosage forms constitute an important aspect of the present invention.
- Suitable non-toxic pharmaceutical carriers or vehicles include liquids such as water, aromatic water, alcohols, syrups, elixirs, pharmaceutical mucilages, such as acacia and tragacanth, oils such as of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, fish oil such as cod liver oil, or the like, for oral administration; water, saline, aqueous propylene glycol, aqueous polyethylene glycol, aqueous lactose, aqueous maltose, aqueous glucose (dextrose), aqueous sucrose, or the like, for administration by injection.
- liquids such as water, aromatic water, alcohols, syrups, elixirs, pharmaceutical mucilages, such as acacia and tragacanth
- oils such as of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, fish oil such as cod liver oil, or the like, for oral administration
- Suitable solid carriers include soft gelatin capsules, hard gelatin capsules, slow or delayed release pills or capsules, powders, tableting vehicles and the like.
- Suitable solid or liquid non-toxic pharmaceutical carriers are well known in the art and the selection of carrier can be from those appropriate and available in accordance with wel known prescription techniques.
- the compositions of this invention therefore include such dosage forms as solution, suspensions, syrups, elixirs, tablets, capsules, powder packets, and the like.
- the active ingredient of Formula 1 or 2 will be present in a physiologically beneficial amount as mentioned above.
- the active ingredient will ordinary constitute at least about 0.01% by weight based on the total weight of the composition;
- the concentration will ordinarily be in the range from about 0.5 to 5.0% by weight of active ingredient.
- -For injection concentrations from 2 to 20% are satisfactory.
- the amount of active ingredient may if desired be as much'as to or more by weight of the total. composition.
- the active compounds of this invention can be formulated if desired with one or more pharmaceutically active materials for combination efieots, treatments and benefits.
- Such materials include but are by no means limited to vitamins, pain killers, tranquilizers, antibiotics, antitussive agents, etc.
- the compositions can of course contain suitable pharmaceutical modifiers such as coloring agents, sweetening or other flavoring agents, solubilizing agents, etc. as will readily occur to persons skilled in this art.
- EXAMPLE 1 3 (5) -amino-4-cyan0-1-N,N-dimethylcarbamylpyrazole A mixture of 20.4 grams of 3-amino-4-cyanopyrazole and 9.2 grams of sodium hydride in 100 milliliters of tetrahydrofuran is stirred minutes. Dimeflhylcarbamoyl chloride (21.4 grams) is added and the mixture refluxed three hours, filtered and the filtrate evaporated to dryness. The solid remaining is recrystallized from ethyl acetate to give 6.8 grams of 3(5)-amino-4-cyano1-N,N-dimethylcarbamylpyrazole, M.P. 134-137 C.
- the compound of this example exhibits excellent analgesic activity and is representative of the compounds of this invention in being characterized -by extremely low acute toxicity as shown in standard animal tests. In combination with its other desirable pharmacological properties, this compound is a :poor cholinesteraseinhibitor and thus can be expected to give rise to little or no undesirable side eifects.
- the compound of this example furthermore exhibits anti-inflammatory activity.
- the compound is formulated conveniently as an injectible solution of 0.5%, 1% and 5% by weight concentration in isotonic saline; as an injectible solution in 0.5%, 1.0% and 5% by weight concentrations in aqueous sugars including in separate solutions lactose, maltose, glucose (dextrose) and sucrose; in water in 1%, 2%, 3% and 4% by weight concentration for oral administration, with and Without a flavoring agent, a coloring agent, an 'antitussive agent, etc.; and in 25, 50, and 100 milligram amounts in standard two-piece sealed hard gelatin capsules, as Well as in soft gelatin capsules, for oral administration.- In pharmacological application it is administered in these dosage forms as dosage levels in the range of -500 milligrams.
- EXAMPLE 2 3-acetamz'd0-4-cyan0-1-N-piperidin0carbonylpyrazole
- a mixture of 15.7 grams (0.1 mole) of 3-acetamido- 4-cyanopyrazole and 4.7 grams of sodium hydride (53% in oil) in 200 milliliters of dimethoxy ethane is stirred and refluxed minutes.
- Pentamethylenecarbarnoyl chloride (15.7 grams, 0.1 mole) is added in portions and the mixture is stirred and refluxed for 6 hours, then. filtered hot.
- the precipitate that forms upon cooling is collected, yield 17.05 grams, MAP. 1-83.5-184.5 C.
- the filtrate is concentrated to about 75 milliliters and the precipitated collected upon cooling is 7.0 grams.
- a portion is recrystallized twice from ethyl acetate to give pure S-acetamido-4-cyano 1 N piperidino carbonylpyrazole, M.P. 183- l84 C.
- the compound is formulated and used in 5, 10, and 25 milligram amounts in standard 2 piece hard gelatin capsules for oral administration.
- Appropriate amounts of corn starch or lactose can be used as a filler in the capsule.
- the compound can also be formulated as a coated or uncoated tablet containing 2.5 to milligram amounts and from 1 to 4% by weight of gelatin, from 0.5 to 1.5%
- magnesium stearate or talc by weight of magnesium stearate or talc and a filler such as lactose or rnannitol.
- Example No. Product 3-tormamido-4cyano-1-N,N-dimethylcarbamylpyrazole. 3-acetam1do- 1-cyano-1-N,N-dlmethylcarbamylpyrazole. 3-prop1onam1do-4-cyano-1-N,N-dimethylcarbamylpyrazole. 3-amino-4-eyano-1-N-methyl-Nethyl-N-ethylcarbarnylpyrazole. 7 3-pr0pi0riamid0-4-cyan0-1-N-methyl-N-ethylcarbamylpyrazo e.
- 3-acetamido-4-cyano-1-N-methyl -N (penten-2-yl) carbarnylpy'razole 3-acetamido-4-cyano-1-N-methyl-N-(2-hydroxyethyl)- carbamylpyrazole. 3-propionamido-4-cyano-l-N-methy1-N-methoxymethylcarbamylpyrazole. 3-for mamido-4-cyano-1-N-methyl-N-methoxypropylthioearbamylpyrazole. 3-acetamido-4-cyano-1-N-methyl-N-diethylaminoethylcarbamylpyrazole.
- 3-acetamido-el-cyano-l-N-pyrrolidino(thiocarbonyl) pyrazole 3-formamid0-4-cyano-l-N-piperidinocarbonylpyrazole. 3-formam1do-4-cyano-1-N-dehydropiperidin0carbonylpyrazole. 3-acetamido-4-cyano-1-N-azabicyelononylcarbonylpyrazole. 3-acetamido-4-cyano-1-N-(3,4-dimethylpiperldino) carbonylpyrazole. 3-acetamido4-eyano-1-N-p-tolylethylpiperidinocarbonylpyrazole.
- 3-t'ormamido-d-cyano-l-N-m-methylpiperidinocarbonylpyrazole 3-acetamido-4-cyano-l-N-ptrifluoromethylpiperidinocarhonylpyrazole. 3-acetamido-4-cyano-l-N-p-ethylpiperidino(thiocarbonyl)pyrazole. 3propionamido-4-cyano-l-N-[p-(n-butyDpiperidino] (thiocarbonyDpyrazole. 3-acetamido-4-cyano-1- -o-methylplperldino(thiocarbonyDpyi-azole.
- 3-torn1aniido-4-cyano-l-N-p-benzylpiperidinocarbonylpyrazo e 3-acetamido-4-cyano-1-N-(m-ethoxycarbonylpiperidino) carbonylpyrazole. 3-tormamido-4-cyano-1-N-(3-methyl-4-ethylpiperidino) carbonylpyrazole. 3-amino4-cyan0-1-N-[p-(n-propyl)piperidino1carbonylpyrazole. 3-acetamido-4-cyano-1-N-phenethylpiperidinocarbonylpyrazo e.
- alkyl of 1 through 6 carbons where the alkyl is joined to the carbamyl nitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alkyl; alken-2-yl of 3 through 6 carbons where the alken-Z-yl is joined to the carbamyl 7.
- X is selected from the group consisting of oxygen and sul-
- 1-N-(4-methylpiperidino) carbonyl-3 (5 -acetamidonitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alken- 2-yl; alkoxyalkyl of 2 through 6 total carbons; dipyrazole. methylamino; and dialkylaminoalkyl where each of the 11; 3 (5)-acetamido-4-cyano-1-N,N-dimethylcarbamylalkyl groups in the dialkyl portion has 1 through 2 pyrazole.
- a substituted piperidino group of the structure 40 References Cited by the Examiner Y3 UNITED STATES PATENTS I 2,476,986 7/1949 Martin 260310 Y1 Y1 2,817,666 12/1957 Beaver 2603 10 3,013,001 12/1961 Lynn 26087.8 wherein Y is selected from the group consisting of hy- 3,060,091 10/1962 Witkin 167-65 drogen and methyl; Y; is selected from the group con- 3,080,287 3/ 1963 Lewenstein 16 7-65 sisting of hydrogenfmethyl, ethyl and COOR where R, is alkyl of 1 through 4 carbons; and Y is selected References Cited y 'Applicant from the group consisting of hydrogen, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 car- UNITED l j PATENTS bons, trifluorornethyl, CO0R where R is alkyl of 255 23333
- each of the alkyl groups in the dialkyl portion has 1 through 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons;
- R is selected from the group consisting of hydrogen
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Description
United States Patent 3,277,100 NOVEL SUBSTITUTED PYRAZOLES Clifiord L. Dickinson, Jr., Wilmington, Del., assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed May 31, 1963, Ser. No. 284,374 15 Claims. (Cl. 260-294) This invention relates to pyrazole derivatives and more particularly refers to 3-amino-4-cyano-N-carbamylpyrazoles and their preparation.
According to this invention I have discovered a narrow class of substituted pyrazoles having a most unusual combination of pharmacological properties.
I have found that this valuable combination of properties is obtained, for reasons which are not understood or yet fully explained, only with a small group of pyrazole compounds where there must be a cyano substituent in the 4-position of the pyrazole ring and also there must be an amino or acylamino substituent of 1 through 3 carbons in the 3-position (or S-position but not both the 3 and the 5; it is critical that one of these positions must be unsubstituted except for hydrogen).
Thus, the compounds ofthis invention have the formvia:
1) NC NHR;
ll if E=X I N R1 R2 which can exist as the isomeric formula 2) NC:NH-R3 NCNR1R1 I! where X is oxygen or sulfur;
R is methyl;
R is alkyl of 1 through 6 carbons Where the alkyl is joined to the carbamyl nitrogen by a primary or secondary carbon of the alkyl group; alken-Z-yl of three through 6 carbons Where the alken-Z-yl group is joined to the carbamyl nitrogen by a primary or secondary carbon of the alken-2-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkyl of 2 through 6 carbons; dimethylamino; or dialkylaminoalkyl where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons with a total of from 3 through 7 in the dialkylaminoalkyl group;
and Where R and R can be joined together and together with the carbamyl nitrogen form a heterocyclic piperidyl, i,e N
dehydropiperidyl, i.e.--N
azabicyclononyl, i.e.
where Y is H or CH;;; Y is H, CH C H or COOR where R is alkyl of 1 through 4 carbons; and Y is H, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons, trifluoromethyl, COOR Where R is alkyl of 1 through 4 carbons, dialkylaminoalkyl of 3 through 7 carbons where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinoethyl or arylalkyl of 7 through 9 carbons including such groups as benzyl, phenethyl, and 0-, mand p-tolylethyl;
and disubstituted piperidyl of the structure Where Y and Y have the same meaning as above; and
R can be hydrogen but it is much more highly preferred that it is an acyl radical of 1 through 3 carbons such as formamido, acetamido and propionamido.
0f the compounds of Formula 1 where R is alkyl or alken-Z-yl, it is preferred that the alkyl or alken-2-yl group is joined to the carba-myl nitrogen by a secondary carbon of the alkyl or alken-2-yl group.
The compounds of this invention are generally solids. They can be used as inhibitors for vinyl polymerization but are particularly useful for their physiological characteristics.
Because of their excellent analgesic activity and other 7 desirable pharmacological properties, the preferred compounds of Formula 1 are carbamyl pyrazoles where X is oxygen and where R and R are joined to form a piperidino ring and in particular a mono-substituted piperidyl ring where the substituent is in the para position with respect to the carbamyl nitrogen. Thus, preferred compounds of this invention include the following exemplary ones:
-l-N'(4-methylpiperidino) carbonyl-3 (5 -formamido-4-.
cyanopyrazole 1-l (4-methylpiperidino) carbonyl-3 (5) -acetamido-4- cyanopyrazole l-N-( 4-methylpiperidino) carb onyl-3 (5 -propionamido- 4-cyan0pyrazole Also preferred are those compounds of Formula 1 where R is alkyl of 1 through 4 carbons, such as'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc. Illustrative of these preferred compounds are the following:
The substituted carbamyl pyrazoles of this invention can be prepared by reaction of the appropriate pyrazole with selected reactants as more fully described below.
One general method for the preparation of the pyrazoles of this invention can be carried out where the amine N-carboxyl chloride (e.g., N,N-dimethylcarbamoyl chloride) is available. In this process there are brought together approximately equirnolar amounts of the pyrazole and the chloride invan unreactive solvent such as ether, ethyl acetate, or benzene, together with an equimolar amount of a base such as sodium hydride or triethylamine. The resulting mixture is refluxed for an extended period, say up to about 24 hours or more, .and allowed to cool. The insoluble chloride e.g. sodium chloride or triethylamino hydrochloride, is filtered E and the solvent is removed from the filtrate to give the desired carbamyl or thiocarbamyl pyrazole product.
The same general procedure as just described is used when the pyrazole-l-carbonyl chloride is available (e.g., from pyrazole having hydrogen on nuclear nitrogen and either phosgene or thiophosgene) except that the secondary amine is reacted with the pyrazole carbonyl chloride. .The first method is preferred if the 3-aminopyrazoles are used since the 3-amino group would react with the phosgene or thiophosgene, whereas the second method is preferred for amines such as N-methyl-N-hydroxyethylamine where the amine substituent can also react with the phosgene or thiophosgene.
'Ihe amine carbonyl chlorides such as N-piperidine carboxyl chloride are prepared by placing in a flask fitted with a DryJce condenser, mechanical stirrer and dropping funnel preferably at least 1.2 moles of phosgene in an inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetate or the like. A solution of 1 mole of the selected amine, e.g., piperidine, and preferably, for increased yields, with 1 mole of tertiary amine such as triethylamine, in the selected solvent is added slowly with stirring and the temperature is kept below 30 C. with occasional cooling. When all of the amine has been added, the mixture is stirred several hours. The mixture is filtered to remove the hydrochloride and the solvent is removed from the filtrate by boiling it off. The remaining amine-N- .carboxyl chloride is distilled under reduced pressure to eifect purification.
' Alternatively, the pyrazole can be used in the above procedure in place of the amine (piperidine). By this procedure, with 3-acetamido-4-cyano-pyrazole, one obtains 3'-acetamido-4-cyanopyrazole-1-carbonyl chloride.
' As mentioned above, the compounds of this invention have outstanding activity as analgesics, many of them exceeding codeine in potency, as shown by standard animal tests. This analgesic activity inthese compounds is particularly valuable because of significantly favorable therapeutic ratios. General painkilling benefits, as well as other physiological benefication associated with aspirin, are 'believed to be obtainable according to this invention based on tests and evaluation thus far carried out.
Furthermore, the compounds of this invention exhibit outstanding anti-inflammatory and central nervous system activity.
In pharmaceutical application a compound of this invention will be administered to the body orally, parenterally and by other methods. The dosage will vary and will depend on such factors as the condition being treated; age and weight of the recipient; the responsiveness of the recipient; pn'or, concurrent and intended subsequent, medication and treatment, general health of the recipient; frequency of treatment; and of course the purpose and nature of the eifect desired.
Generally speaking, the active compound will be administered in a physiologically beneficial amount. Administration can be in a single dose or in a plurality of doses over an extended period of time. It will furthermore be understood that every compound within this invention does not have an identical level of dosage requirement for therapeutic or prophylactic effectiveness and therefore experts will understand that some dosage variation between compounds can be expected for maximum benefits. It will of course also be understood that an initial dose, or first group of doses, in a course of treatment can bein greater amounts, if appropriate, for a particular medical situation and a rapid response is sought by the early administration of relatively large doses and thereafter the minimally effective dosage, or maintenance dosage, is determined.
A single dose will rarely exceed about 400 or SOOmilligrams of active compound within this invention, although larger amounts can be used as called for in any given situation. Extremely small doses will effect some benefit but as a practical matter a single dose of less than about 1 or 2 milligrams will seldom be used. Fortreating small animals with high physiological response and using highly active compounds, routine usage can be at much lower dosage levels however. Doses can be repeated in the same or greater or lesser amounts over a period of time as long as improvement in the recipient is observed or as long as needed under the circumstances.
The active compound will ordinarily be administered with a non-toxic pharmaceutical carrier in a variety of practical dosage forms. These dosage forms are noval compositions comprising the non-toxic pharmaceutical carrier and a physiologically beneficial amount of one or more active compounds of this invention. These highly useful dosage forms constitute an important aspect of the present invention.
Suitable non-toxic pharmaceutical carriers or vehicles include liquids such as water, aromatic water, alcohols, syrups, elixirs, pharmaceutical mucilages, such as acacia and tragacanth, oils such as of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, fish oil such as cod liver oil, or the like, for oral administration; water, saline, aqueous propylene glycol, aqueous polyethylene glycol, aqueous lactose, aqueous maltose, aqueous glucose (dextrose), aqueous sucrose, or the like, for administration by injection. Suitable solid carriers include soft gelatin capsules, hard gelatin capsules, slow or delayed release pills or capsules, powders, tableting vehicles and the like. Suitable solid or liquid non-toxic pharmaceutical carriers are well known in the art and the selection of carrier can be from those appropriate and available in accordance with wel known prescription techniques. The compositions of this invention therefore include such dosage forms as solution, suspensions, syrups, elixirs, tablets, capsules, powder packets, and the like.
A vast number of suitable pharmaceutical carriers are described in Remingtons Practice of Pharmacy edited by E. W. Martin and E. F. Cook, 12th Edition, 1961, published bythe Mack Publishing Company, Easton, Pennsylvania.
, 1n these novel compositions the active ingredient of Formula 1 or 2 will be present in a physiologically beneficial amount as mentioned above. In practice this means that the active ingredient will ordinary constitute at least about 0.01% by weight based on the total weight of the composition; For oral administration in water or other liquid medium, the concentration will ordinarily be in the range from about 0.5 to 5.0% by weight of active ingredient. -For injection concentrations from 2 to 20% are satisfactory. In tablets, powders, capsules and the like the amount of active ingredient may if desired be as much'as to or more by weight of the total. composition.
The active compounds of this invention can be formulated if desired with one or more pharmaceutically active materials for combination efieots, treatments and benefits. Such materials include but are by no means limited to vitamins, pain killers, tranquilizers, antibiotics, antitussive agents, etc. The compositions can of course contain suitable pharmaceutical modifiers such as coloring agents, sweetening or other flavoring agents, solubilizing agents, etc. as will readily occur to persons skilled in this art.
This invention will be better understood by reference to the following illustrative examples in which parts and percentages given are by weight unless otherwise indicated.
EXAMPLE 1 3 (5) -amino-4-cyan0-1-N,N-dimethylcarbamylpyrazole A mixture of 20.4 grams of 3-amino-4-cyanopyrazole and 9.2 grams of sodium hydride in 100 milliliters of tetrahydrofuran is stirred minutes. Dimeflhylcarbamoyl chloride (21.4 grams) is added and the mixture refluxed three hours, filtered and the filtrate evaporated to dryness. The solid remaining is recrystallized from ethyl acetate to give 6.8 grams of 3(5)-amino-4-cyano1-N,N-dimethylcarbamylpyrazole, M.P. 134-137 C.
Analysis.C-alcd. for C- H N O: C, 46.9; H, 5.1; N, 39.1. Found: C, 47.4; H, 5.1, N, 38.8.
The compound of this example exhibits excellent analgesic activity and is representative of the compounds of this invention in being characterized -by extremely low acute toxicity as shown in standard animal tests. In combination with its other desirable pharmacological properties, this compound is a :poor cholinesteraseinhibitor and thus can be expected to give rise to little or no undesirable side eifects.
The compound of this example furthermore exhibits anti-inflammatory activity. The compound is formulated conveniently as an injectible solution of 0.5%, 1% and 5% by weight concentration in isotonic saline; as an injectible solution in 0.5%, 1.0% and 5% by weight concentrations in aqueous sugars including in separate solutions lactose, maltose, glucose (dextrose) and sucrose; in water in 1%, 2%, 3% and 4% by weight concentration for oral administration, with and Without a flavoring agent, a coloring agent, an 'antitussive agent, etc.; and in 25, 50, and 100 milligram amounts in standard two-piece sealed hard gelatin capsules, as Well as in soft gelatin capsules, for oral administration.- In pharmacological application it is administered in these dosage forms as dosage levels in the range of -500 milligrams.
EXAMPLE 2 3-acetamz'd0-4-cyan0-1-N-piperidin0carbonylpyrazole A mixture of 15.7 grams (0.1 mole) of 3-acetamido- 4-cyanopyrazole and 4.7 grams of sodium hydride (53% in oil) in 200 milliliters of dimethoxy ethane is stirred and refluxed minutes. Pentamethylenecarbarnoyl chloride (15.7 grams, 0.1 mole) is added in portions and the mixture is stirred and refluxed for 6 hours, then. filtered hot. The precipitate that forms upon cooling is collected, yield 17.05 grams, MAP. 1-83.5-184.5 C. The filtrate is concentrated to about 75 milliliters and the precipitated collected upon cooling is 7.0 grams. A portion is recrystallized twice from ethyl acetate to give pure S-acetamido-4-cyano 1 N piperidino carbonylpyrazole, M.P. 183- l84 C.
Analysis.Calcd. for C12H15N502: C, H, 5.8. Found: C, 55.2; H, 5.6.
The compound is formulated and used in 5, 10, and 25 milligram amounts in standard 2 piece hard gelatin capsules for oral administration. Appropriate amounts of corn starch or lactose can be used as a filler in the capsule.
The compound can also be formulated as a coated or uncoated tablet containing 2.5 to milligram amounts and from 1 to 4% by weight of gelatin, from 0.5 to 1.5%
6 by weight of magnesium stearate or talc and a filler such as lactose or rnannitol.
The general procedures of the above examples can be repeated using other 3-a-mino and 3-acylamino 4-cyan0 pyrazoles and appropriately substituted carbamoyl and thiocarbamoyl chlorides in place of the reactants of those examples to obtain the following listed exemplary cornpounds of this invention:
Example No. Product 3-tormamido-4cyano-1-N,N-dimethylcarbamylpyrazole. 3-acetam1do- 1-cyano-1-N,N-dlmethylcarbamylpyrazole. 3-prop1onam1do-4-cyano-1-N,N-dimethylcarbamylpyrazole. 3-amino-4-eyano-1-N-methyl-Nethyl-N-ethylcarbarnylpyrazole. 7 3-pr0pi0riamid0-4-cyan0-1-N-methyl-N-ethylcarbamylpyrazo e. 8 3amin0-4 0y8n0-1-N,N-dimethylthiocarbamylpyrazole, 9 3-tormaniido-4-cyano-l-N,N-dimethylthioearbamylpyrazo e. 10 3-acetamido-4-eyano-1-N,N-dimethylth1ocarbamylr pyrazole. 11 S-formamid0-4-cyano1-N-methyl-N-ethylcarbamylpyrazole. 12 3-acetamido-4-cyano-l-N-methyl-N-isopropy1carbamylpyrazole. 13 3-acetamido-4-cyano-l-N-methyl-N-secbutylcarbamylpyrazole. 14 3-formamido4-eyan0-1-N-methyl-N-n-hexylcarbamylpyrazole.
3-acetamido-4-cyano-1-N-methyl -N (penten-2-yl) carbarnylpy'razole. 3-acetamido-4-cyano-1-N-methyl-N-(2-hydroxyethyl)- carbamylpyrazole. 3-propionamido-4-cyano-l-N-methy1-N-methoxymethylcarbamylpyrazole. 3-for mamido-4-cyano-1-N-methyl-N-methoxypropylthioearbamylpyrazole. 3-acetamido-4-cyano-1-N-methyl-N-diethylaminoethylcarbamylpyrazole. 3-acetarmdo-Hyano-l-N-methyl-N-allylcarbamylpyrazole. a-ammot-cyano-l-N-methyl-N-(buten-2-yDcarbamylpyrazole. S-formanndoA-eyano-l-N-methyl N-ethoxypropylthiocarban ylpyrazole. 3-acetam1do-4-cyano-1-N-methyl-Ndimethylaminocarbamylpyrazole. 3-formamido-4-cyano-1-N-methyl-N-isobutylcarbamylpyrazole. 3-anuno-t-cyano-1-N-morpholinocarbonylpyrazole. 8-acetam do-4-cyano-1-N-pyrrolidinocarbonylpyrazole.
3-acetamido-el-cyano-l-N-pyrrolidino(thiocarbonyl) pyrazole. 3-formamid0-4-cyano-l-N-piperidinocarbonylpyrazole. 3-formam1do-4-cyano-1-N-dehydropiperidin0carbonylpyrazole. 3-acetamido-4-cyano-1-N-azabicyelononylcarbonylpyrazole. 3-acetamido-4-cyano-1-N-(3,4-dimethylpiperldino) carbonylpyrazole. 3-acetamido4-eyano-1-N-p-tolylethylpiperidinocarbonylpyrazole. 3-t'ormamido-d-cyano-l-N-m-methylpiperidinocarbonylpyrazole. 3-acetamido-4-cyano-l-N-ptrifluoromethylpiperidinocarhonylpyrazole. 3-acetamido-4-cyano-l-N-p-ethylpiperidino(thiocarbonyl)pyrazole. 3propionamido-4-cyano-l-N-[p-(n-butyDpiperidino] (thiocarbonyDpyrazole. 3-acetamido-4-cyano-1- -o-methylplperldino(thiocarbonyDpyi-azole. 3-torn1aniido-4-cyano-l-N-p-benzylpiperidinocarbonylpyrazo e. 3-acetamido-4-cyano-1-N-(m-ethoxycarbonylpiperidino) carbonylpyrazole. 3-tormamido-4-cyano-1-N-(3-methyl-4-ethylpiperidino) carbonylpyrazole. 3-amino4-cyan0-1-N-[p-(n-propyl)piperidino1carbonylpyrazole. 3-acetamido-4-cyano-1-N-phenethylpiperidinocarbonylpyrazo e. 3-formamido-4-cyano-1-N-(p-diethylaminoethylpiperidino)carbony1pyraz0le. 3acetamido-4cyano-1-N-(p-pyrrolidinoethylpiperldino)carbonylpyrazole. 3-acetamid0-4-cyano-l-N-(p-butoxycarbonylpiperidino) carbonylpyrazole. 3-aeetarmdo-4cyano-l-N-[3A-di(2-hydroxyethyl)piperidino]carbonylpyrazole. 3-formarm'do-4-cyano-1-N-o-tolylethylpiperidinocarbonylpyrazole.
The above examples can be repeated to obtain other compounds with the scope of this invention by appropriate selection of reactants as will be readily understood in the art.
consisting of alkyl of 1 through 6 carbons where the alkyl is joined to the carbamyl nitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alkyl; alken-2-yl of 3 through 6 carbons where the alken-Z-yl is joined to the carbamyl 7. 1-N-(4-methy1piperidino) carbonyl-3 -formamido- 4-cyanopyrazole.
4-cyanopyrazole. 25 a 9. l-N-(4-methylpiperidino)carbonyl 3(5) propion- 7 8 The invention claimed is: 2. 'A compound as set forth in claim 1 wherein 1. A compound selected from compounds of the for- R1 mula B 15 -N NC NIP-R l H: 5 R2 1 where R is methyl and R is alkyl of 1 through 6 carbons N/ joined to the carbamyl nitrogen by a secondary carbon of 1 3:}: the alkyl, R is selected from the group consisting of A formyl, acetyl and propionyl, and X is oxygen.
10 3. A compound as set forth in claim 1 wherein A is Where a heterocyclic group as defined in claim 1. X is selected from the group consisting of oxygen and sul- A compound as set f th in claim 1 wherein A is a 4-mono-substituted piperidino group as defined in A is selected from the group consisting of claim r R 5. A compound as set forth in claim 1 wherein Ais piperidino, R is selected from the group consisting of formyl, acetyl and propionyl, and X is oxygen.
6. A compound as set forth in claim 1 wherein A is piperidino, R is selected fromrthe group consisting of wherein R is methyl; and R is selected from the group formyl, acetyl and propionyl, and X is oxygen.
8. 1-N-(4-methylpiperidino) carbonyl-3 (5 -acetamidonitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alken- 2-yl; alkoxyalkyl of 2 through 6 total carbons; dipyrazole. methylamino; and dialkylaminoalkyl where each of the 11; 3 (5)-acetamido-4-cyano-1-N,N-dimethylcarbamylalkyl groups in the dialkyl portion has 1 through 2 pyrazole.
carbons and the remaining alkyl group has 1 through 4 carbons with a total of 3 through 7 in said dialkylaminoalkyl group;
morpholino; carbamylpyrazole. pyrrolidino; .14. 1-N=sec-butyl-N-methylcarbamyl-4 cyano 3(5)- piperidino; formamidopy-razole. dehydropiperidino; 15. 3 (5 )-acetamido-1-N-sec=butyl-N methylcarbamylazabicyclononidino; and 4-cyanopyrazole. a substituted piperidino group of the structure 40 References Cited by the Examiner Y3 UNITED STATES PATENTS I 2,476,986 7/1949 Martin 260310 Y1 Y1 2,817,666 12/1957 Beaver 2603 10 3,013,001 12/1961 Lynn 26087.8 wherein Y is selected from the group consisting of hy- 3,060,091 10/1962 Witkin 167-65 drogen and methyl; Y; is selected from the group con- 3,080,287 3/ 1963 Lewenstein 16 7-65 sisting of hydrogenfmethyl, ethyl and COOR where R, is alkyl of 1 through 4 carbons; and Y is selected References Cited y 'Applicant from the group consisting of hydrogen, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 car- UNITED l j PATENTS bons, trifluorornethyl, CO0R where R is alkyl of 255 23333 et 1 through 4 carbons, dralkylammoalkyl of 3 through 7 2998426 8/1961 Dickinson.
carbons where each of the alkyl groups in the dialkyl portion has 1 through 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons; and
R is selected from the group consisting of hydrogen,
formyl, acetyl and propionyl.
amido-4-cyanopyrazole.
10. 4-cyano-1-N,N-dimethylcarbamyl-3 (5 -formamido- 12. 4-cyano-3 (5 -formamidol-N-isopropyl-N methylcarbamylpyrazole.
13. 3(5 -acetamido-4-cyano-l-N-isopropyl-N methyl- ALEX MAZEL, Primary Examiner.
FRANK CACCIAPAGLIA, JR., Examiner.
PAUL L. SABATINE, JOSE TOVAR,
Assistant Examiners.
Claims (1)
1. A COMPOUND SELECTED FROM COMPOUNDS OF THE FORMULA
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US284323A US3274203A (en) | 1963-05-31 | 1963-05-31 | 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles |
US284374A US3277100A (en) | 1963-05-31 | 1963-05-31 | Novel substituted pyrazoles |
SE6369/64A SE301812B (en) | 1963-05-31 | 1964-05-26 | |
CH696364A CH454883A (en) | 1963-05-31 | 1964-05-28 | Process for the preparation of pyrazole derivatives |
GB22407/64A GB1039963A (en) | 1963-05-31 | 1964-05-29 | Improvements relating to pyrazole derivatives |
DK270564AA DK116443B (en) | 1963-05-31 | 1964-05-29 | Process for the preparation of 3-amino-N-carbamylpyrazole derivatives. |
NL6406077A NL6406077A (en) | 1963-05-31 | 1964-05-29 | |
BE672304A BE672304A (en) | 1963-05-31 | 1965-11-12 | |
US556540A US3362877A (en) | 1963-05-31 | 1966-06-10 | Use of 3-amino-n-carbamylpyrazoles as analgesic agents |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US284323A US3274203A (en) | 1963-05-31 | 1963-05-31 | 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles |
US284374A US3277100A (en) | 1963-05-31 | 1963-05-31 | Novel substituted pyrazoles |
US556540A US3362877A (en) | 1963-05-31 | 1966-06-10 | Use of 3-amino-n-carbamylpyrazoles as analgesic agents |
Publications (1)
Publication Number | Publication Date |
---|---|
US3277100A true US3277100A (en) | 1966-10-04 |
Family
ID=27403460
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US284374A Expired - Lifetime US3277100A (en) | 1963-05-31 | 1963-05-31 | Novel substituted pyrazoles |
US284323A Expired - Lifetime US3274203A (en) | 1963-05-31 | 1963-05-31 | 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles |
US556540A Expired - Lifetime US3362877A (en) | 1963-05-31 | 1966-06-10 | Use of 3-amino-n-carbamylpyrazoles as analgesic agents |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US284323A Expired - Lifetime US3274203A (en) | 1963-05-31 | 1963-05-31 | 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles |
US556540A Expired - Lifetime US3362877A (en) | 1963-05-31 | 1966-06-10 | Use of 3-amino-n-carbamylpyrazoles as analgesic agents |
Country Status (5)
Country | Link |
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US (3) | US3277100A (en) |
CH (1) | CH454883A (en) |
DK (1) | DK116443B (en) |
GB (1) | GB1039963A (en) |
SE (1) | SE301812B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3760084A (en) * | 1972-05-01 | 1973-09-18 | American Cyanamid Co | Method of using 5-amino-1-phenyl or substituted phenyl-4-pyrazolecarbonitriles or carbox-amides |
US3760082A (en) * | 1972-05-01 | 1973-09-18 | American Cyanamid Co | Compositions containing 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamides and methods of using the same |
US3760083A (en) * | 1972-05-01 | 1973-09-18 | American Cyanamid Co | A method for the use of 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3694456A (en) * | 1970-05-08 | 1972-09-26 | Takeda Chemical Industries Ltd | 1-disubstituted aminopyrazoles |
US3940484A (en) * | 1971-12-07 | 1976-02-24 | The Boots Company Limited | Insecticidal compositions and methods of combatting insects using substituted imidazoles |
DE2458965C3 (en) * | 1974-12-13 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | 3-Amino-indazole-N-carboxylic acid derivatives, process for their preparation and pharmaceuticals containing them |
DE102005057894A1 (en) * | 2005-12-02 | 2007-06-06 | Basf Ag | Stabilized polymerizable mixtures |
Citations (8)
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US2476986A (en) * | 1949-07-26 | Elmobe louis martin | ||
US2817666A (en) * | 1956-10-29 | 1957-12-24 | Monsanto Chemicals | N(3-methyl-5-pyrazolone)-halo-carboxanilides |
US2998426A (en) * | 1959-11-02 | 1961-08-29 | Du Pont | Certain amine, cyano pyrazoles |
US2998419A (en) * | 1959-10-30 | 1961-08-29 | Du Pont | Certain amino, dicyano pyrazoles and process |
US2998425A (en) * | 1959-11-02 | 1961-08-29 | Du Pont | Certain aminopyrazole carbonitriles containing a fluoroalkyl substituent |
US3013001A (en) * | 1959-03-26 | 1961-12-12 | Union Carbide Corp | N-substituted pyrazole compounds and polymerization products thereof |
US3060091A (en) * | 1961-02-13 | 1962-10-23 | Ciba Geigy Corp | Analgesic composition consisting of morphines and amino-indanes |
US3080287A (en) * | 1957-08-05 | 1963-03-05 | Lewenstein Mozes Juda | Analgesic compositions |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3308130A (en) * | 1962-04-26 | 1967-03-07 | Du Pont | N-disubstituted carbamyl pyrazoles |
-
1963
- 1963-05-31 US US284374A patent/US3277100A/en not_active Expired - Lifetime
- 1963-05-31 US US284323A patent/US3274203A/en not_active Expired - Lifetime
-
1964
- 1964-05-26 SE SE6369/64A patent/SE301812B/xx unknown
- 1964-05-28 CH CH696364A patent/CH454883A/en unknown
- 1964-05-29 DK DK270564AA patent/DK116443B/en unknown
- 1964-05-29 GB GB22407/64A patent/GB1039963A/en not_active Expired
-
1966
- 1966-06-10 US US556540A patent/US3362877A/en not_active Expired - Lifetime
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2476986A (en) * | 1949-07-26 | Elmobe louis martin | ||
US2817666A (en) * | 1956-10-29 | 1957-12-24 | Monsanto Chemicals | N(3-methyl-5-pyrazolone)-halo-carboxanilides |
US3080287A (en) * | 1957-08-05 | 1963-03-05 | Lewenstein Mozes Juda | Analgesic compositions |
US3013001A (en) * | 1959-03-26 | 1961-12-12 | Union Carbide Corp | N-substituted pyrazole compounds and polymerization products thereof |
US2998419A (en) * | 1959-10-30 | 1961-08-29 | Du Pont | Certain amino, dicyano pyrazoles and process |
US2998426A (en) * | 1959-11-02 | 1961-08-29 | Du Pont | Certain amine, cyano pyrazoles |
US2998425A (en) * | 1959-11-02 | 1961-08-29 | Du Pont | Certain aminopyrazole carbonitriles containing a fluoroalkyl substituent |
US3060091A (en) * | 1961-02-13 | 1962-10-23 | Ciba Geigy Corp | Analgesic composition consisting of morphines and amino-indanes |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3760084A (en) * | 1972-05-01 | 1973-09-18 | American Cyanamid Co | Method of using 5-amino-1-phenyl or substituted phenyl-4-pyrazolecarbonitriles or carbox-amides |
US3760082A (en) * | 1972-05-01 | 1973-09-18 | American Cyanamid Co | Compositions containing 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamides and methods of using the same |
US3760083A (en) * | 1972-05-01 | 1973-09-18 | American Cyanamid Co | A method for the use of 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide |
Also Published As
Publication number | Publication date |
---|---|
GB1039963A (en) | 1966-08-24 |
CH454883A (en) | 1968-04-30 |
DK116443B (en) | 1970-01-12 |
SE301812B (en) | 1968-06-24 |
US3362877A (en) | 1968-01-09 |
US3274203A (en) | 1966-09-20 |
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