DK149893B - Analogifremgangsmaade til fremstilling af thiazolderivater eller farmaceutisk acceptable salte deraf - Google Patents
Analogifremgangsmaade til fremstilling af thiazolderivater eller farmaceutisk acceptable salte deraf Download PDFInfo
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- DK149893B DK149893B DK452273AA DK452273A DK149893B DK 149893 B DK149893 B DK 149893B DK 452273A A DK452273A A DK 452273AA DK 452273 A DK452273 A DK 452273A DK 149893 B DK149893 B DK 149893B
- Authority
- DK
- Denmark
- Prior art keywords
- tert
- hydrochloride
- thienyl
- thiazole
- butylamino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 title description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 150000007979 thiazole derivatives Chemical class 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- -1 C 1 -C 4 alkyl Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 2
- 238000003756 stirring Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 27
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- OCVLSHAVSIYKLI-UHFFFAOYSA-N 3h-1,3-thiazole-2-thione Chemical class SC1=NC=CS1 OCVLSHAVSIYKLI-UHFFFAOYSA-N 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001414 amino alcohols Chemical class 0.000 description 4
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 4
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- DURULFYMVIFBIR-UHFFFAOYSA-N practolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1 DURULFYMVIFBIR-UHFFFAOYSA-N 0.000 description 4
- 229960003712 propranolol Drugs 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229960001749 practolol Drugs 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 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
- YKPQUSLRUFLVDA-UHFFFAOYSA-N $l^{2}-azanylmethane Chemical compound [NH]C YKPQUSLRUFLVDA-UHFFFAOYSA-N 0.000 description 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- WFQBBOJCEMWSSE-UHFFFAOYSA-N 1,3-thiazole 2,4,6-trinitrophenol Chemical compound C1=CSC=N1.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O WFQBBOJCEMWSSE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- MQTAPBGEGTZNBJ-UHFFFAOYSA-N 3-(tert-butylamino)-1-chloropropan-1-ol Chemical compound CC(C)(C)NCCC(O)Cl MQTAPBGEGTZNBJ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical class [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 230000002057 chronotropic effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 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
- 239000000203 mixture Substances 0.000 description 1
- 230000002107 myocardial effect Effects 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/36—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
i 149893
Opfindelsen angår en analogifremgangsmåde til fremstilling af • hidtil ukendte thiazolderivater med formlen R2 R3 \_/
I J--N OH
,As/ | || I
Rx ^ y-SCH2CHCH2NH-R4 (I) hvori R^, R2 og R^ hver er hydrogen, C^_4-alkyl, halogen, 5 cyano, nitro, phenyl, -C-R,., hvori R,. er hydroxy, C1_4~alkyl, 0 C1_4~alkoxy eller allyloxy, eller -C-N-Rg, hvori Rg og Ry hver 0 Ry er hydrogen, amino, cyclohexyl, C^_4~alkyl eller sammen med 10 det tilstødende, nitrogenatom danner morpholinyl, piperidinyl eller pyrrolidinyl, og R4 er C^_4~alkyl, eller farmaceutisk acceptable salte deraf.
C^_4“Alkyl er f.eks. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sek-butyl eller tert-butyl, idet methyl, ethyl, iso-15 propyl eller tert-butyl foretrækkes.
C^_4~Alkoxy er f.eks. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy eller tert-butoxy.
Halogen er f.eks. iod, chlor, brom eller fluor.
Thiazolderivaterne med formlen I har værdifulde farmakologiske 20 egenskaber, såsom en blokerende effekt på β-adrenergiske receptorer, og kan anvendes til forebyggelse og behandling af hjertesygdomme, såsom arrhythmi og coronare hjertesygdomme.
Den blokerende effekt på β-adrenergiske receptorer og den akutte toksicitet af thiazolderivaterne med formlen I er blevet sammen-25 lignet med de tilsvarende egenskaber hos propranolol (1-iso-propylamino-3-(a-naphthyloxy)-2-propanol) og practolol (1-iso-propylamino-3-(4-acetylaminophenoxy)-2-propanol), som er kom- 149893 2 mercielt tilgængelige forbindelser og er kendt som de mest effektive stoffer på dette område. Som det vil ses af de følgende tabeller, har thiazolderivaterne med formlen I en stærkere eller lige så stor β-adrenergisk receptorblokerende akti-5 vitet, men er mindre toksiske end propranolol og practolol.
Tabel 1.
Forbindelse β-Adrenergisk receptorblokerende aktivitet ved åbnet bryst hos hunde
_DPC_DPI_DDE
10 Forbindelse ifølge eksempel 1 2 1,5 4
Forbindelse ifølge eksempel 15 15 15 8
Forbindelse ifølge 15 eksempel 13 2 3 0,8
Forbindelse ifølge eksempel 21 4 5 3
Forbindelse ifølge eksempel 25 3 3 1 20 Forbindelse ifølge eksempel 27 6 46
Forbindelse ifølge eksempel 29 9 93
Propranolol 1 11 25 Practolol 0,5 0,7 0,08
Bemærkning: Bestemmelsen af 3-adrenergisk receptorblokerende aktivitet af forsøgsforbindelserne ved åbnet bryst hos hunde foregik på følgende måde. Hundene blev bedøvet med pento-barbital-natrium (indgivet 30-40 mg/kg intravenøst). Hjerte-30' slagsfrekvensen, den myocardiale sammentrækningskraft og blodtrykket blev registreret med NIHON KODEN RM-150-polygraph. Man bestemte en depressiv virkning af forsøgsforbindelserne på den positive chronotrope virkning (DPC), den positive inotrope virkning (DPI) og depressor-virkningen (DDE), fremkaldt af 35 isoproterenol, som blev injiceret intravenøst med et kvarters interval.
3 149693
Tabel 2.
Forbindelse Akut toksicitet LD^ (mg/kg)
Forbindelse ifølge eksempel 1 46 5 Forbindelse ifølge eksempel 15 86
Forbindelse ifølge eksempel 13 60
Forbindelse ifølge 10 eksempel 21 34
Forbindelse ifølge eksempel 25 28
Forbindelse ifølge eksempel 27 37 15 Forbindelse ifølge eksempel 29 23
Propranolol 23
Bemærkning: Til bestemmelse af den intravenøse LDr_ anvendtes
bU
10 hanmus, og op- og ned-metoden. blev anvendt til beregning af 20 LD50.
Ved fremgangsmåden ifølge opfindelsen, der er ejendommelig ved det i kravets kendetegnende del anførte, omsætter man en amino-alkohol med formlen X - ch2 - CH - ch2 - NH - r4 (II)
OH
25 hvor R4 har den ovenfor angivne betydning, og X er halogen, med et 2-mercaptothiazolderivat med. formlen R2 R3
Yjf - (iii>
Ei (j-SH
149893 4 hvori R-jy R2 og R3 har den ovenfor angivne betydning.
Nærmere betegnet fremstilles thiazolderivaterne med formlen I ved, at man omsætter et 2-mercaptothiazolderivat med formlen III i nærværelse af yand, et organisk opløsningsmiddel (f.eks.
5 alkohol, dioxan) eller et vandigt-organisk opløsningsmiddel (f.eks. vand-alkohol, vand-dioxan) med en ækvimolær mængde af aminoalkoholen med formlen II.
I dette tilfælde udføres reaktionen fortrinsvis i nærværelse af en organisk eller uorganisk base, såsom natriumhydroxid, 10 kaliumhydroxid, natriumcarbonat, kaliumcarbonat, pyridin eller en tertiær amin.
For at undgå oxidation og polymerisation af aminoalkoholen (II) udføres denne reaktion fortrinsvis under en nitrogenatmosfære ved en temperatur under 25°C.
15 Alternativt kan thiazolderivaterne (I) fremstilles kvantitativt ved, at man behandler et 2-mercaptothiazolderivat (III) med en uorganisk base, såsom kaliumhydroxid, natriumhydroxid, kaliumcarbonat eller natriumcarbonat, i vand-alkohol til dannelse af et salt og derpå omsætter saltet med en aminoalkohol (II), og 20 denne metode er særlig fordelagtig til kommerciel produktion af thiazolderivaterne (I), idet de således opnåede thiazolderi-vater og salte deraf kan isoleres og renses ved konventionelle procedurer, såsom ekstraktion, omkrystallisation, genudfældning, søjlekromatografi eller behandling med aktivt·kulpulver, og 25 forbindelserne kan omdannes til farmaceutisk acceptable salte med uorganiske eller organiske syrer (f.eks. saltsyre, svovlsyre, phosphorsyre, vinsyre) ved konventionelle procedurer.
2-Mercaptothiazolderivaterne (III) kan fremstilles efter konventionelle metoder. Et eksempel er angivet nedenfor.
30 (Journal of The Organic Chemistry, 6^, 764 (1941) , Journal of
The Chemical Society, 1945, 925, USA-patentskrift nr. 2.186.421).
149893 5 R2 R3 R2 R3 \~/0 y-/
' [ -C-CH0X + H0NCSNH . -> } J-,- N
^ (IV) (V) (III)
Ved denne reaktion fremstilles mercaptothiazolderivaterne (III) ved, at man omsætter forbindelsen (IV) med samme antal mol af forbindelsen (V). Når forbindelsen (IV) er ustabil i fri-amin-5 form, udføres denne reaktion fortrinsvis ved, at man omsætter saltet af forbindelsen (IV) (f.eks. det saltsure salt) med to mol af forbindelsen (V).
Thiazolderivaterne (I) og salte deraf kan bringes på en egnet indgiftsform, f.eks. som tablet, pulver, opløsning, kapsel, 10 injektionsvæske eller emulsion, til indgift ifølge konventionelle metoder og kan indgives oralt eller parenteralt.
Den almindelige dosis af thiazolderivaterne (I) ligger fra 1 mg/kg til 1000 mg/dag.
Til illustration af den omhandlede fremgangsmåde bringes de følgende eksempler. 15 Eksempel 1.
2-(3’-t-Butylamino-2'-hydroxypropylthio)-4-(2'-thienyl)-thiazol-picrat.
Til en opløsning af 2,0 g 2-mercapto-4-(2'-thienyl)-thiazol i 50 ml af en 1%'s vandig natriumhydroxidopløsning sættes 1,6 g 20 l-chlor-3-t-butylamino-2-propanol i 50 ml methanol, og blandingen henstilles ved stuetemperatur i 20 timer og koncentreres derefter i vakuum til ca. halvdelen af det oprindelige volumen. Remanensen ekstraheres med chloroform, og det organiske lag vaskes med vand, tørres over vandfrit magnesiumsulfat og 25 koncentreres til tørhed. Den resulterende remanens renses ved søjlekromatografi på aluminiumoxid under anvendelse af chloroform som elueringsmiddel, hvorved der fås 1,9 g 2-(3'-t-butyl- 149893 6 amino-2'-hydroxypropylthio)-4-(21-thienyl)thiazol som en viskos olie, nj1 2 3 1,5970.
Behandling af den ovenfor opnåede frie base med en ækvimolær mængde picrinsyre i ethanol og efterfølgende omkrystallisation 5 fra chloroform giver 2-(3'-t-butylamino-2,-hydroxypropylthio)-4-(2'-thienyl)thiazol-picrat, smp. 153-154°C.
Elementaranalyse for ci4H20N24 5 6 73-CgH3N307
Beregnet: C 43,08, H 4,16, N 12,56, S 17,25 (%)
Fundet: C 42,95, H 4,22, N 12,38, S 16,95 (%) 10 Ifølge eksempel 1 fremstilles følgende forbindelser: R2-Γ f-R3
ΗΠΓ H
I I) \s/\ <j)H CH3 (Type I) SCH2CHCH2NHC - ch3 ch3
Eksempel R3 R2 R3 Isoleret Fysisk form konstant
CH3CH2~ Η H Hydrochlorid Smp. 148-149°C
(acetone-methanol) 2
CH-CHCR,- Η H Hydrochlorid Smp. 145-146°C
CH3 (chloroform-itethanol) 3 Η H Fri base n^7 1,5966 4
CH3 ' Η H Hydrochlorid Smp. 123-124°C
(acetone) 25 5 HH CH3 Fri base nd 1,6030 6
Br CH3 H Hydrochlorid Smp. 176-177°C
(acetone-methanol) 7
CH3 CH3 H Hydrochlorid Smp. 229-230°C
(acetone-methanol) 149893 7
Tabellen fortsat
Eksempel R^ R2 R^ Isoleret Fysisk form konstant
9 Br Η H Hydrochlorid Snip. 173-173,5°C
5 (acetone-methanol)
10 I Η H Hydrochlorid Snip. 165-166°C
(acetone-methanol) 11 CN Η H Fri base n^7^ lf6009
12 Η H CN Hydrochlorid Smp. 160-161°C
10 (acetone-methanol)
13 NO2 Η H Hydrochlorid Smp. 236-237°C
(acetone-methanol)
14 H N02 H Hydrochlorid Smp. 174-175°C
(acetone-methanol) 15 Eksempel 15.
2—(3’-tert-Butylamino-21-hydroxypropylthio)-4-(51-carbamoyl-21-thienyl)-thiazol.
Til en opløsning af 3,2 g 2-mercapto-4-(5’-carbamoyl-2'-thienyl)-thiazol i 20 ml 0,3%'s vandig natriumhydroxidopløsning sættes 20 12,64 g l-chlor-3-tert-butylaminopropanol i 2Q ml methanol, medens temperaturen holdes ved 20°C.
Reaktionsopløsningen omrøres ved stuetemperatur i 4 timer og inddampes derpå til det halve volumen i vakuum.
Til den resterende opløsning sættes 100 ml vand·, og der ekstrahe-25 res med chloroform.
Chloroformekstrakten vaskes med vand, tørres over vandfrit magnesiumsulfat og inddampes i vakuum, hvorved fås 4,8 g remanens, som omkrystalliseres af chloroform-let mineraloliefraktion, hvorved fås 2-(3'-tert-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-30 2'-thienyl)-thiazol, nåle, smp. 148-149°C.
149893 8
Analyse for ci5H21°2N3S3
Beregnet: C 48,52%, H 5,66%, N 11,32%, S 25,88%
Fundet: C 48,31%, H 5,42%, N 11,15%, S 25,00%
Ifølge eksempel 15 fremstilles følgende forbindelser Π—Γ-' R5CO s * Jj OH CH3 (Type II) s^sch2chch2nhc - ch3 ch3
Eksempel R,_ Isoleret form Fysisk konstant
16 CH3NH Hydrochlorid Smp. 142-144°C
(acetone-methanol)
17 CH3(CH2)3NH Hydrochlorid Smp. 106-108°C
(acetone-methanol)
18 ^N Hydrochlorid Smp. 163-165°C
(acetone-methanol)
19 I "^N- Hydrochlorid Smp. 165-166°C
(acetone-methanol
20 θ' 'XN- Hydrochlorid Smp. 178-179°C
(acetone-methanol)
21 H2NNH- Hydrochlorid Smp. 202-207°C
(acetone-methanol)
22 (CH3CH2)2N- Hydrochlorid Smp. 152-153°C
(acetone-methanol)
23 -nh- Fri base Smp. 140-141°C
(let mineralolie-fraktion-benzen)
24 (CH3)3C-0- Hydrochlorid Smp. 251-252°C
(acetone-methanol) 25 CH_- Fri base 1,6032 3 d 149893 9
Eksempel 26 2-(3'-tert-Butylamino-2'-hydroxypropylthio)-4-(5'-ethoxy-carbonyl-2'-thienyl)-thiazol-hydrochlorid.
En opløsning af 1,0 g 2-(31-tert-butylamino-2'-hydroxypropyl-5 thio)-4-(5'-tert-butoxycarbonyl-2,-thienyl)-thiazol i 50 ml 3%'s H2SO^-ethanolisk opløsning tilbagesvales i 3 1/2 time.
Efter afkøling neutraliseres opløsningen med natriUmhydrogen-carbonat (fast), filtreres og inddampes i vakuum, hvorved fås en remanens, som ekstraheres med chloroform. Chloroformekstrak-10 ten vaskes med mættet vandig NaHCOg-opløsning, tørres og inddampes til en remanens, som omdannes til hydrochloridet. Hydro-chloridet omkrystalliseres af acetone, hvorved fås 0,3 g 2-(31-tert-butylamino-2'-hydroxypropylthio)-4-(5'-ethoxy-carbonyl-2'-thienyl)-thiazol-hydrochlorid, smp. 118-119°C.
15 Analyse for ci7H25°3N2S3C^
Beregnet: C 46,73%, H 5,72%, N 6,41%, S 21,99%, Cl 8,13%
Fundet: C 46,73%, H 5,61%, N 6,46%, S 21,78%, Cl 8,42%
De følgende to estere fremstilles ifølge eksempel 26.
ri_ nf R.OOC II i V 3 ° SCH2CHCH2NHC - CH3 (Type III) ch3 20 Eksempel Rg Isoleret form Fysisk konstant
27 CHg Hydrochlorid Smp. 124-126°C
(acetone)
28 CH2CH=CH2- Hydrochlorid Smp. 135-136°C
(acetone)
Claims (3)
149893 ίο Eksempel 29. 2-(3'-tert-Butylamino-2-hydroxypropylthio)-4-(5'-carboxyl-2 *-thienyl)-thiazol-hydrochlorid. En opløsning af 0,34 g 2-(3'-tert-butylamino-2'-hydroxypropyl-5 thio)-4-(51-tert-butoxycarbonyl-2'-thienyl)-thiazol-hydrochlorid i 20 ml Si's methanolisk hydrogenchloridopløsning henstilles ved stuetemperatur i 30 minutter og tørres derpå i vakuum* Omkrystallisation af remanensen af acetone giver 2-(3'-tert-10 butylamino-21-hydroxypropylthio)-4-(5r-carboxy-2'-thienyl)-thiazol-hydrochlorid, nåle, smp. 251-252°C. Analyse for *HC1 Beregnet: C 44,06%, H 5,14%, N 6,85%, S 23,50%, Cl 8,69% Fundet: C 43,88%, H 5,32%, N 6,90%, S 22,85%, Cl 8,43%.
15 PATENTKRAV. Analogifremgangsmåde til fremstilling af thiazolderivater med den almene formel R2 *3 \_/
1 J-1— ? m (D εΛ=/ I I ?h Λ1 J. -SCH2CHCH2NH“R4 hvori R^, R2 og R^ hver er hydrogen, C-L_4-alkyl, halogen, 20 cyano, nitro, phenyl, -C-R^, hvori Rg er hydroxy, C^_4-alkyl, 0 C^_4~alkoxy eller allyloxy, eller -C-N-Rg, hvori Rg og R^ O R? hver er hydrogen, amino, cyclohexyl eller C^_4-alkyl, eller sammen med det tilstødende nitrogenatom danner morpholinyl,
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP47082574A JPS5238559B2 (da) | 1972-08-17 | 1972-08-17 | |
| JP8257472 | 1972-08-17 | ||
| JP3935473 | 1973-04-05 | ||
| JP48039354A JPS49125359A (da) | 1973-04-05 | 1973-04-05 | |
| ZA7401280 | 1974-02-26 | ||
| ZA00741280A ZA741280B (en) | 1972-08-17 | 1974-02-26 | Thiazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK149893B true DK149893B (da) | 1986-10-20 |
| DK149893C DK149893C (da) | 1987-04-21 |
Family
ID=27290112
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK452273A DK149893C (da) | 1972-08-17 | 1973-08-16 | Analogifremgangsmaade til fremstilling af thiazolderivater eller farmaceutisk acceptable salte deraf |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US3932400A (da) |
| CA (1) | CA991640A (da) |
| CH (1) | CH581640A5 (da) |
| DE (1) | DE2341753C2 (da) |
| DK (1) | DK149893C (da) |
| FR (1) | FR2196162B1 (da) |
| GB (1) | GB1435139A (da) |
| NL (1) | NL179733C (da) |
| SE (1) | SE421615B (da) |
| ZA (1) | ZA741280B (da) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4001421A (en) * | 1971-10-27 | 1977-01-04 | Syntex (U.S.A.) Inc. | Thiazole cardiovascular agents |
| US4119718A (en) * | 1977-05-02 | 1978-10-10 | Merck & Co., Inc. | 3-Amino-2-oxy-propoxy-substituted isothiazoles |
| US4259341A (en) * | 1977-06-01 | 1981-03-31 | Merck & Co., Inc. | Di- and tri-substituted thiazoles |
| US4260609A (en) * | 1977-06-01 | 1981-04-07 | Merck & Co., Inc. | Di- and tri- substituted thiazoles |
| US4396625A (en) * | 1980-05-13 | 1983-08-02 | Sumitomo Chemical Company, Limited | Treatment of glaucoma or ocular hypertension and ophthalmic composition |
| US4670450A (en) * | 1985-11-13 | 1987-06-02 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic thiazolones |
| AU2003250483A1 (en) | 2002-08-19 | 2004-03-11 | Pfizer Products Inc. | Combination therapy for hyperproliferative diseases |
| EA009646B1 (ru) * | 2003-05-30 | 2008-02-28 | Рэнбакси Лабораториз Лтд. | Замещённые производные пиррола и их применение в качестве ингибиторов hmg-coa |
| US20050037063A1 (en) * | 2003-07-21 | 2005-02-17 | Bolton Anthony E. | Combined therapies |
| US20060063803A1 (en) * | 2004-09-23 | 2006-03-23 | Pfizer Inc | 4-Amino substituted-2-substituted-1,2,3,4-tetrahydroquinoline compounds |
| AP2007003979A0 (en) * | 2004-11-23 | 2007-06-30 | Warner Lambert Co | 7-(2h-pyrazol-3-yl)-3,5-dihyroxy-heptanoic acid derivatives as hmg co-a reductase inhibitors for thetreatment of lipidemia |
| GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
| US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
| JP2009514851A (ja) * | 2005-11-08 | 2009-04-09 | ランバクシー ラボラトリーズ リミテッド | （３ｒ，５ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−［（４−ヒドロキシメチルフェニルアミノ）カルボニル］−ピロール−１−イル］−３，５−ジヒドロキシ−ヘプタン酸ヘミカルシウム塩の製法 |
| US20090226420A1 (en) * | 2005-11-10 | 2009-09-10 | Elizabeth Hauser | Methods of Determining the Risk of Developing Coronary Artery Disease |
| US7888376B2 (en) | 2005-11-23 | 2011-02-15 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
| WO2007084391A2 (en) * | 2006-01-18 | 2007-07-26 | Amgen Inc. | Thiazole compounds as protein kinase b ( pkb) inhibitors |
| US8383660B2 (en) | 2006-03-10 | 2013-02-26 | Pfizer Inc. | Dibenzyl amine compounds and derivatives |
| US7919506B2 (en) | 2006-03-10 | 2011-04-05 | Pfizer Inc. | Dibenzyl amine compounds and derivatives |
| TW200744583A (en) * | 2006-03-14 | 2007-12-16 | Ranbaxy Lab Ltd | Statin stabilizing dosage formulations |
| BRPI0714361A2 (pt) * | 2006-07-14 | 2013-03-26 | Ranbaxy Lab Ltd | polimorfo cristalino, composiÇço farmacÊutica contendo o mesmo, mÉtodo para sua preparaÇço e mÉtodo de tratamento |
| CN101663262B (zh) | 2006-12-01 | 2014-03-26 | 百时美施贵宝公司 | 用于治疗动脉粥样硬化和心血管疾病的作为cetp抑制剂的n-(3-苄基)-2,2-(二苯基)-丙-1胺衍生物 |
| US7919504B2 (en) * | 2007-07-17 | 2011-04-05 | Amgen Inc. | Thiadiazole modulators of PKB |
| EP2986599A1 (en) | 2013-04-17 | 2016-02-24 | Pfizer Inc. | N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases |
| WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
| CN104530033B (zh) * | 2014-12-26 | 2017-07-07 | 江西百神药业股份有限公司 | 一种盐酸阿罗洛尔的制备工艺新方法 |
| CN105646472A (zh) * | 2016-02-29 | 2016-06-08 | 山东齐都药业有限公司 | 一种盐酸阿罗洛尔的制备方法 |
| BR112021013807A2 (pt) | 2019-01-18 | 2021-11-30 | Astrazeneca Ab | Inibidores de pcsk9 e seus métodos de uso |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA599475A (en) * | 1960-06-07 | W. Harman Marion | Aminoethylthiazoles | |
| US2221147A (en) * | 1938-11-18 | 1940-11-12 | Goodrich Co B F | Preparation of aminated esters of sulphydryl compounds |
| US3228952A (en) * | 1962-06-27 | 1966-01-11 | Dow Chemical Co | Thiazole thioethers |
| US3158623A (en) * | 1963-03-01 | 1964-11-24 | Abbott Lab | 5-nitro-2-furylthioamide |
| BE790569A (fr) * | 1971-10-27 | 1973-04-26 | Syntex Corp | Agents cardiovasculaires a base de thiazoles |
-
1973
- 1973-08-14 GB GB3950573A patent/GB1435139A/en not_active Expired
- 1973-08-15 NL NLAANVRAGE7311248,A patent/NL179733C/xx not_active IP Right Cessation
- 1973-08-16 CH CH1182373A patent/CH581640A5/xx not_active IP Right Cessation
- 1973-08-16 DK DK452273A patent/DK149893C/da not_active IP Right Cessation
- 1973-08-16 US US05/389,517 patent/US3932400A/en not_active Expired - Lifetime
- 1973-08-16 SE SE7311181A patent/SE421615B/xx unknown
- 1973-08-16 CA CA178,970A patent/CA991640A/en not_active Expired
- 1973-08-16 FR FR7329860A patent/FR2196162B1/fr not_active Expired
- 1973-08-17 DE DE2341753A patent/DE2341753C2/de not_active Expired
-
1974
- 1974-02-26 ZA ZA00741280A patent/ZA741280B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2341753C2 (de) | 1982-12-09 |
| FR2196162B1 (da) | 1977-01-28 |
| GB1435139A (en) | 1976-05-12 |
| FR2196162A1 (da) | 1974-03-15 |
| AU5928173A (en) | 1975-02-20 |
| DE2341753A1 (de) | 1974-02-21 |
| NL179733C (nl) | 1986-11-03 |
| CH581640A5 (da) | 1976-11-15 |
| NL7311248A (da) | 1974-02-19 |
| SE421615B (sv) | 1982-01-18 |
| US3932400A (en) | 1976-01-13 |
| CA991640A (en) | 1976-06-22 |
| DK149893C (da) | 1987-04-21 |
| NL179733B (nl) | 1986-06-02 |
| ZA741280B (en) | 1975-03-26 |
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