FI97384B - Förfarande för framställning av terapeutiskt användbara N-cykloalkylalkylaminer - Google Patents
Förfarande för framställning av terapeutiskt användbara N-cykloalkylalkylaminer Download PDFInfo
- Publication number
- FI97384B FI97384B FI910894A FI910894A FI97384B FI 97384 B FI97384 B FI 97384B FI 910894 A FI910894 A FI 910894A FI 910894 A FI910894 A FI 910894A FI 97384 B FI97384 B FI 97384B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- thienyl
- compound
- phenyl
- cyclopropane
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 49
- 238000002360 preparation method Methods 0.000 title claims description 29
- -1 1,2-cyclopropanediyl group Chemical group 0.000 claims abstract description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 150000001412 amines Chemical class 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 74
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000005219 aminonitrile group Chemical group 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 19
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 150000004681 metal hydrides Chemical class 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 229910052987 metal hydride Inorganic materials 0.000 claims description 11
- 125000002734 organomagnesium group Chemical group 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 8
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 7
- 150000001350 alkyl halides Chemical class 0.000 claims description 7
- 229910052796 boron Inorganic materials 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 229910052782 aluminium Inorganic materials 0.000 claims description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 6
- 150000004678 hydrides Chemical class 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 230000000737 periodic effect Effects 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 7
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 229940001470 psychoactive drug Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 54
- 239000000047 product Substances 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 14
- 108010085082 sigma receptors Proteins 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 238000005292 vacuum distillation Methods 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000029936 alkylation Effects 0.000 description 9
- 238000005804 alkylation reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 208000025865 Ulcer Diseases 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 7
- 150000008064 anhydrides Chemical class 0.000 description 7
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 108020001588 κ-opioid receptors Proteins 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000010933 acylation Effects 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 5
- 150000003857 carboxamides Chemical class 0.000 description 5
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 5
- 108700023159 delta Opioid Receptors Proteins 0.000 description 5
- 102000048124 delta Opioid Receptors Human genes 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229960003151 mercaptamine Drugs 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
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- 208000035475 disorder Diseases 0.000 description 4
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- 238000011065 in-situ storage Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- 231100000397 ulcer Toxicity 0.000 description 4
- BFPMCZWKUSUMKE-UHFFFAOYSA-N 1-cyclopropyl-n-methylmethanamine Chemical compound CNCC1CC1 BFPMCZWKUSUMKE-UHFFFAOYSA-N 0.000 description 3
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
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- 230000002265 prevention Effects 0.000 description 3
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- XGLKPPHCLTWSOD-NKWVEPMBSA-N 2-[(1r,2r)-2-(chloromethyl)cyclopropyl]thiophene Chemical compound ClC[C@@H]1C[C@H]1C1=CC=CS1 XGLKPPHCLTWSOD-NKWVEPMBSA-N 0.000 description 2
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 description 2
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
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- 208000020016 psychiatric disease Diseases 0.000 description 2
- 230000000506 psychotropic effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
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- 238000005303 weighing Methods 0.000 description 2
- HQFGNFFBFNVEOQ-UHFFFAOYSA-N 1-(furan-2-yl)-4-phenylbut-3-en-1-amine Chemical compound NC(CC=CC1=CC=CC=C1)C=1OC=CC=1 HQFGNFFBFNVEOQ-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- YYPZNASNKFYKRA-UHFFFAOYSA-N 2-(3-chloroprop-1-enyl)thiophene Chemical compound ClCC=CC1=CC=CS1 YYPZNASNKFYKRA-UHFFFAOYSA-N 0.000 description 1
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- LWKSZBQHSQBVAE-UHFFFAOYSA-N 2-thiophen-3-ylprop-2-enoic acid Chemical compound OC(=O)C(=C)C=1C=CSC=1 LWKSZBQHSQBVAE-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- AKXNSCAUPMPGMZ-UHFFFAOYSA-N 3-(3-chloroprop-1-enyl)thiophene Chemical compound ClCC=CC=1C=CSC=1 AKXNSCAUPMPGMZ-UHFFFAOYSA-N 0.000 description 1
- UQTOFZUKDDYETJ-YUMQZZPRSA-N 3-[(1r,2r)-2-(chloromethyl)cyclopropyl]thiophene Chemical compound ClC[C@@H]1C[C@H]1C1=CSC=C1 UQTOFZUKDDYETJ-YUMQZZPRSA-N 0.000 description 1
- ZXMZAFMNGMMUFA-UHFFFAOYSA-N 3-thiophen-2-ylprop-2-en-1-ol Chemical compound OCC=CC1=CC=CS1 ZXMZAFMNGMMUFA-UHFFFAOYSA-N 0.000 description 1
- KKMZQOIASVGJQE-UHFFFAOYSA-N 3-thiophen-2-ylprop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CS1 KKMZQOIASVGJQE-UHFFFAOYSA-N 0.000 description 1
- JHBVVETVSPASKG-UHFFFAOYSA-N 3-thiophen-3-ylprop-2-en-1-ol Chemical compound OCC=CC=1C=CSC=1 JHBVVETVSPASKG-UHFFFAOYSA-N 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
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- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- SWPRYIDABUXSIR-YUMQZZPRSA-N [(1R,2R)-2-thiophen-3-ylcyclopropyl]methanol Chemical compound OC[C@H]1[C@@H](C1)C1=CSC=C1 SWPRYIDABUXSIR-YUMQZZPRSA-N 0.000 description 1
- NPQDVSAYSKRJPN-NKWVEPMBSA-N [(1r,2r)-2-thiophen-2-ylcyclopropyl]methanol Chemical compound OC[C@@H]1C[C@H]1C1=CC=CS1 NPQDVSAYSKRJPN-NKWVEPMBSA-N 0.000 description 1
- AYLIEDQYYJIGDP-UHFFFAOYSA-N [C]1=CC=CS1 Chemical group [C]1=CC=CS1 AYLIEDQYYJIGDP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- GEAXLHPORCRESC-UHFFFAOYSA-N chlorocyclohexatriene Chemical compound ClC1=CC=C=C[CH]1 GEAXLHPORCRESC-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000003873 derivative thermogravimetry Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002555 ionophore Substances 0.000 description 1
- 230000000236 ionophoric effect Effects 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N isonitrile group Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UMBICWSYOPEZIA-UHFFFAOYSA-N methyl 2-thiophen-3-ylprop-2-enoate Chemical compound COC(=O)C(=C)C=1C=CSC=1 UMBICWSYOPEZIA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000002151 myoclonic effect Effects 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940096717 pamine Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- CXYRUNPLKGGUJF-RAFJPFSSSA-M scopolamine methobromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 CXYRUNPLKGGUJF-RAFJPFSSSA-M 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- AHDDRJBFJBDEPW-DTWKUNHWSA-N trans-2-Phenylcyclopropanecarboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=CC=C1 AHDDRJBFJBDEPW-DTWKUNHWSA-N 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Furan Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (9)
1. Förfarande för framställning av terapeutiskt användbara N-cykloalkylalkylarainer med formeln (I) och 5 syraadditionssalter därav, Rl CH2 R5 \ / \ / /cx Q R2 /N (I)
10 R3 CH2)m R4 där Rl är en furylradikal eller en tienylradikal, eller 15 förutsatt, att Q är en cyklopropan-1,2-diylgrupp (-CH-CH-), CH2 är Rl en fenylradikal,
20 R2 är lägre alkyl, R3 är väte eller lägre alkyl, m har ett värde 1 eller
2, R4 är cykloalkyl-(-CH(CH2)n), där n har ett värde 2-5,
25 R5 är fenyl, som kan vara monosubstituerad, disub- stltuerad eller trlsubstltuerad med halogenatomer eller lika eller olika lägre alkyl- eller alkoxiradikaler, eller R5 är tienyl, Q är en etylen-1,2-diylgrupp (-CH=CH-) eller en 30 cyklopropan-1,2-diylgrupp (-CH-CH), CH2/ kännetecknat därav att (A) för framställning av en förening med formeln 35 (I), där R3 är väte, vilken förening har formeln (II), 48 97384 (i) reduceras en N-karboxamidmellanprodukt med for-meln (IV) Rl CH2 R5 5 > Q R2 NH (IV) CO (CH2)m-l R4 10 med en metallhydrid (Hm) med formeln Ml(t) M2H(r) Rx (S) (Hm) 15 där Ml är en alkallmetallatom, säsom t.ex. litium eller natrium, och index (t) har värdet 0 eller 1, M2 är ett element som hör till grupp III i det pe-20 riodiska systemet, företrädesvis bor eller aluminium, (r) är ett index, som beskriver antalet väteatomer i hydriden och som har värdet 1, 2, 3 eller 4, och Rx är en karbonitrilgrupp eller en lägre alkyl-eller alkoxigrupp, där index (s) har värdet 0, 1, 2 eller 25 3, varvid förhällandet mellan indexen, som ovan an-förts för hydriderna, är (r) + (s) - (t) * 3, och varvid föreningarna (IV) företrädesvis reduceras med hydriderna (Hm.2), där M2 är aluminium eller den är bor, ifall värdet 30 för (r) är 3 och värdet för (s) och (t) är 0, (ii) en amin med formeln (V) Rl CH2 R5 \ / \ / /c Q (V)
35 R2 NH2 li 97384 49 alkyleras med en alkylhalogenid R4-(CH2)m-Z2, där R4 och m betecknar sanuna som ovan och Z2 är halogen, säsom t.ex. klor, brom eller jod, (B) för framställning av en cykloalkylalkylamin med 5 den allmänna formeln (I), där R3 är lägre alkyl, vilken förening har formeln (III), (i) alkyleras förening (II) reduktivt genom att den omsätts med en aldehyd R6-CH0, där R6 är en kolhomolog, som är en närmast lägre homolog i förhällande till R3 som 10 skall kopplas (R3 = CH2-R6), och med ett reducerande me-del, säsom t.ex. en metallhydrid eller organometallhydrid med formeln (Hm) som defierats ovan, där M2 är företrädes-vis bor och Rx är företrädesvis en karbonitrilgrupp, vilken förening har formeln (Hm.3), eller 15 (ii) en N-karboxamidmellanprodukt med formeln (VIII) Rl CH2 R5 \ / \ / C Q / \
20 R2 N v / \ R3 CO (VIII) (CH2)m-l R4 25 reduceras med en metallhydrid (Hm.2) som definierats ovan, eller iii) en aminonitrilmellanprodukt (IX) Rl CH2 R5 \ / \ / Λ 0
30 NC N. (IX) ·: R3 (CH2 )m R4 omsätts med ett organomagnesiumreagens R2M9Z3, där Z3 är 35 halogen, säsom t.ex. klor, brom eller jod, eller 50 97384 (iv) en amin med formeln (VII) Rl CH2 R5 \ / \ / A Q
3. Förfarande enligt patentkrav 1 eller 2, k ä n-netecknat därav, att R5 är fenyl.
4. Förfarande enligt nägot av patentkrav 1 - 3, 15 kännetecknat därav, att R2 är etyl.
5. Förfarande enligt nägot av patentkrav 1-4, kännetecknat därav, att R3 är metyl.
5 R2 ^NH (VII) R3 alkyleras med en alkylhalogenid R4-(CH2)m-Z2, där Z2 är halogen, säsom t.ex. klor, brom eller jod. 10 2. Förfarande enligt patentkrav 1, känne- t e c k n a t därav, att Rl är tienyl.
6. Förfarande enligt nägot av patentkrav 1 - 5, kännetecknat därav, att m är 1 och R4 är cyk- 20 lopropyl.
7. Förfarande enligt patentkrav 1, kännetecknat därav, att Rl är 2-tienyl, R2 är etyl, R3 är metyl, m är 1, R4 är cyklopropyl, R5 är fenyl och Q är cyklopropan-1,2-diyl. 25
8. Förfarande enligt patentkrav 1, känne- » t e c k n a t därav, att Rl är 2-tienyl, R2 är etyl, R3 är metyl, m är 1, R4 är cyklopropyl, R5 är fenyl och Q är etylen-1,2-diyl.
. 9 < ii
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/484,403 US5034419A (en) | 1988-09-01 | 1990-02-26 | N-cycloalkylalkylamines, process for their preparation, their use as medicament and their synthesis intermediates |
| US48440390 | 1990-02-26 | ||
| FR9002494 | 1990-02-28 | ||
| FR9002494A FR2658822A1 (fr) | 1990-02-28 | 1990-02-28 | N-cycloalkylalkylamines, leur procede de preparation, leur utilisation comme medicament et leurs intermediaires de synthese. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI910894A0 FI910894A0 (sv) | 1991-02-25 |
| FI910894L FI910894L (sv) | 1991-08-27 |
| FI97384B true FI97384B (sv) | 1996-08-30 |
| FI97384C FI97384C (sv) | 1996-12-10 |
Family
ID=26227891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI910894A FI97384C (sv) | 1990-02-26 | 1991-02-25 | Förfarande för framställning av terapeutiskt användbara N-cykloalkylalkylaminer |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0445013B1 (sv) |
| JP (1) | JP2899429B2 (sv) |
| AT (1) | ATE106879T1 (sv) |
| AU (1) | AU633695B2 (sv) |
| CA (1) | CA2037114C (sv) |
| DE (1) | DE69102309T2 (sv) |
| DK (1) | DK0445013T3 (sv) |
| ES (1) | ES2054452T3 (sv) |
| FI (1) | FI97384C (sv) |
| HU (1) | HU215430B (sv) |
| IE (1) | IE66180B1 (sv) |
| IL (1) | IL97354A (sv) |
| NZ (1) | NZ237224A (sv) |
| PT (1) | PT96885B (sv) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5849760A (en) * | 1993-12-09 | 1998-12-15 | Institut De Recherche Jouveinal | 2-(arylalkenyl)azacycloalkane derivatives as ligands for sigma receptors |
| GB9405392D0 (en) * | 1994-03-18 | 1994-05-04 | Secr Defence | Microorganism detection apparatus and method |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS584748A (ja) * | 1981-06-30 | 1983-01-11 | Takasago Corp | エナミンまたはイミンの製造方法 |
| IL86740A (en) * | 1987-06-30 | 1992-11-15 | Tanabe Seiyaku Co | Thiphene derivatives,their preparation and pharmaceutical compositions containing them |
| JPS6416778A (en) * | 1987-07-09 | 1989-01-20 | Tanabe Seiyaku Co | Thiophene derivative |
-
1991
- 1991-02-25 EP EP91400497A patent/EP0445013B1/fr not_active Expired - Lifetime
- 1991-02-25 AU AU71340/91A patent/AU633695B2/en not_active Ceased
- 1991-02-25 DE DE69102309T patent/DE69102309T2/de not_active Expired - Fee Related
- 1991-02-25 CA CA002037114A patent/CA2037114C/en not_active Expired - Fee Related
- 1991-02-25 ES ES91400497T patent/ES2054452T3/es not_active Expired - Lifetime
- 1991-02-25 HU HU91625A patent/HU215430B/hu not_active IP Right Cessation
- 1991-02-25 IL IL9735491A patent/IL97354A/en not_active IP Right Cessation
- 1991-02-25 DK DK91400497.3T patent/DK0445013T3/da active
- 1991-02-25 FI FI910894A patent/FI97384C/sv active
- 1991-02-25 AT AT91400497T patent/ATE106879T1/de not_active IP Right Cessation
- 1991-02-25 IE IE62091A patent/IE66180B1/en not_active IP Right Cessation
- 1991-02-26 JP JP3031059A patent/JP2899429B2/ja not_active Expired - Fee Related
- 1991-02-26 NZ NZ237224A patent/NZ237224A/en unknown
- 1991-02-26 PT PT96885A patent/PT96885B/pt not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE69102309T2 (de) | 1994-09-15 |
| HUT62284A (en) | 1993-04-28 |
| PT96885B (pt) | 1998-07-31 |
| FI910894A0 (sv) | 1991-02-25 |
| AU7134091A (en) | 1991-08-29 |
| HU215430B (hu) | 1999-09-28 |
| IE66180B1 (en) | 1995-12-13 |
| HU910625D0 (en) | 1991-09-30 |
| DK0445013T3 (da) | 1994-07-11 |
| FI910894L (sv) | 1991-08-27 |
| IL97354A0 (en) | 1992-05-25 |
| ATE106879T1 (de) | 1994-06-15 |
| IL97354A (en) | 1995-12-08 |
| DE69102309D1 (de) | 1994-07-14 |
| CA2037114C (en) | 2003-09-09 |
| ES2054452T3 (es) | 1994-08-01 |
| CA2037114A1 (en) | 1991-08-27 |
| AU633695B2 (en) | 1993-02-04 |
| JPH0616598A (ja) | 1994-01-25 |
| EP0445013B1 (fr) | 1994-06-08 |
| JP2899429B2 (ja) | 1999-06-02 |
| PT96885A (pt) | 1991-10-31 |
| IE910620A1 (en) | 1991-08-28 |
| EP0445013A1 (fr) | 1991-09-04 |
| NZ237224A (en) | 1992-05-26 |
| FI97384C (sv) | 1996-12-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| BB | Publication of examined application |