DK160309B - Analogifremgangsmaade til fremstilling af 8-substituerede pyrrolizidinderivater - Google Patents
Analogifremgangsmaade til fremstilling af 8-substituerede pyrrolizidinderivater Download PDFInfo
- Publication number
- DK160309B DK160309B DK121383A DK121383A DK160309B DK 160309 B DK160309 B DK 160309B DK 121383 A DK121383 A DK 121383A DK 121383 A DK121383 A DK 121383A DK 160309 B DK160309 B DK 160309B
- Authority
- DK
- Denmark
- Prior art keywords
- pyrrolizidine
- acetamide
- group
- general formula
- dimethylphenyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical class NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 68
- -1 alkali metal salt Chemical class 0.000 claims description 24
- 150000001448 anilines Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- ADRDEXBBJTUCND-UHFFFAOYSA-N pyrrolizidine Chemical class C1CCN2CCCC21 ADRDEXBBJTUCND-UHFFFAOYSA-N 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 2
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003288 anthiarrhythmic effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 206010003119 arrhythmia Diseases 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000006793 arrhythmia Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- VOWZNBNDMFLQGM-UHFFFAOYSA-N 2,5-dimethylaniline Chemical compound CC1=CC=C(C)C(N)=C1 VOWZNBNDMFLQGM-UHFFFAOYSA-N 0.000 description 2
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical compound CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 2
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 241001465754 Metazoa Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- BFHBAQJJQJPDGF-UHFFFAOYSA-N 1-methyl-2,3,5,6,7,8-hexahydro-1h-pyrrolizine Chemical compound C1CCC2C(C)CCN21 BFHBAQJJQJPDGF-UHFFFAOYSA-N 0.000 description 1
- KWVPRPSXBZNOHS-UHFFFAOYSA-N 2,4,6-Trimethylaniline Chemical compound CC1=CC(C)=C(N)C(C)=C1 KWVPRPSXBZNOHS-UHFFFAOYSA-N 0.000 description 1
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 1
- FOYHNROGBXVLLX-UHFFFAOYSA-N 2,6-diethylaniline Chemical compound CCC1=CC=CC(CC)=C1N FOYHNROGBXVLLX-UHFFFAOYSA-N 0.000 description 1
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 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 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002763 arrhythmic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- JLYXXMFPNIAWKQ-UHFFFAOYSA-N γ Benzene hexachloride Chemical compound ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DK 160309 B
Opfindelsen angår en analogi fremgangsmåde til fremstilling af hidtil ukendte 8-substi tuerede pyrrolizidinderivater med den almene formel (I) R1 5 A-k-R2 CONH-(! 3 / (I) 10 hvori R* er hydrogen eller en Cj-Cø alkylgruppe, R2 er hydrogen, en Cj-Cø alkylgruppe, en Cj-Cø alkoxygruppe eller halogen, og R3 er en C^-Cø alkylgruppe, en Cj-Cø alkoxygruppe, 15 aminogruppe eller halogen.
Fra EP 39.903 Bl kendes beslægtede forbindelser, men disse har ikke antiarytmisk virkning som forbindelserne fremstillet ifølge opfindelsen.
20
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man a) omsætter en 8-halogencarbonylmethylpyrrolizidin med den almene formel (Ila) 25 COHal / / \ (Ha) 30 hvor Hal er et halogenatom, med en anilin med den almene formel (III) 35 2
DK 160309 B
5 hvor Ri, R2 og R3 har den ovennævnte betydning, eller
b) omsætter en 8-alkoxycarbonylmethylpyrrolizidin med den al-10 mene formel II
^co2R
(II) 15 hvor R er en methyl- eller ethylgruppe, med et alkalimetalsalt af en substitueret anilin med den almene formel III ovenfor.
20
Fremgangsmåde a)
En forbindelse med formlen (I) fremstilles ved et underkaste 8-alkoxycarbonylmethylpyrrolizidin (II) hydrolyse med en mi-25 neralsyre, f.eks. saltsyre, til dannelse af fri carboxyl syre, hvorpå man lader et halogeneringsmiddel, f.eks. thio= nylchlorid, indvirke til dannelse af et syrehalogenid, som får lov til at reagere med tilsvarende substitueret anilin. Reaktionen gennemføres fortrinsvis i et opløsningsmiddel, 30 som er i stand til at opløse syrehalogenidet, men som ikke generer reaktionen, idet opløsningsmidlet f.eks. kan være chloroform. Reaktionen kan fremmes ved, at der til reaktionssystemet sættes en uorganisk base, såsom alkalihydroxid eller en organisk base, såsom triethylamin eller pyridin, men 35 reaktionen forløber også uden tilsætning af base.
3
DK 160309 B
Fremgangsmåde b)
En forbindelse med formlen (I) kan også fremstilles ved at g lade en 8-alkoxycarbonylmethylpyrrolizidin (II) reagere med et alkalimetalsalt af tilsvarende substitueret anilin. Alkalimetalsaltet kan dannes ved at tillade, at en alkalimetalforbindelse, såsom natriumhydrid, natriumamid eller butyl= lithium, indvirker på et substitueret anilin i et vandfrit opløsningsmiddel, såsom ether, tetrahydrofuran, dioxan eller benzen.
Ved de ovenfor beskrevne fremgangsmåder a) og b) giver anvendelsen af lavere alkylanilin, lavere alkoxyanilin, halogen= anilin eller aminoanilin som substitueret anilin det tilsvarende 8-(substitueret anilino)carbonylmethylpyrrolizidin.
De således opnåede N-(substitueret phenyl)-8-pyrrolizidin= acetamidderivater er hidtil ukendte forbindelser med anti-2o arytmisk virkning som beskrevet nedenfor.
Antiarytmisk virkning I overensstemmelse med den af J.W. Lawson (Journal of Phar= macology and Experimental Therapeutics, bind 160, side 22, 2 5 1968) beskrevne måde blev ddY-stamme hanmus, der hver vejede 16-30 g, behandlet med chloroform for at frembringe ven-trikulær arytmias. På det tidspunkt hvor de ophørte med at trække vejret, blev der optaget elektrokardiogram for hvert 30 dyr for at se banken og fibrillering af ventriklen.
De i disse dyr observerede ventrikelabnormaliteter kan hindres ved forudgående administration af et stof, som udviser antiarytmisk virkning. En forbindelse ifølge opfindelsen blev i forskellige doser injiceret subcutant til en mussegruppe 3 5 på 29-40. 30 min. senere blev disse mus behandlet med chloroform for at fremkalde arytmia. Profylaksisprocenter af slag
DK 160309 B
i 4 j og fibrillering af ventriklen for hver dosis blev beregnet.
50% effektiv dosis (ED^q) og 90% konfidensgrænse for hver således fundet værdi blev beregnet ved hjælp af Litchfield j og Wilcoxon's metode (Journal of Pharmacology and Experimen- j 5 tal Therapeutics, bind 96, p. 99, 1949) som vist i tabel I.
50% dødelighed (LD^q) blev beregnet under anvendelse af i ddY-stamme hanmus, hver med en vægt på 18-22 g, ved hjælp af "op- og ned-metoden" (Pharmocological Experiment, udarbejdet af Takagi & Ozawa, p. 204, Nanzando, 1972), og værdi-20 erne af LD,_q og ED^q er vist i tabel I ligesom "terapeutisk indeks".
15 20 25 30 35 5
DK 160309 B
Tabel (I)
Antiarytmisk virkning * CONH—R
cd • ' ...... —III—..... ................ IH— .11— — .
Forbin- R Ε0ςη Terapeu- delse , 3υ τη nr> (95% konfidens- ^50 tisk j grænse) mg/kg indeks __I____ CH, * 100 385 “Cy ! 100 !ED4o) 2 _/~Vot n-e· <100) \ / 3 too (ed20> 3 3 !V\ >10° 347 \ / 100 (ed2Q) * (38^1-91,5) 443 7>54 i - ' »— - - _ i. - 1 - · 6 i
DK 160309 B
Forbin- R Ε0ςη Terapeu- delse (95% konfidens-j u50 -tisk nr. grænse) j mg/kg indeks ί i CH^O^ 5 / \ >100 381 \=J 100(ED40) /och3 6 /Λ >100 W 100 (ED40} 7 \_qcu 60 288 4,80 \-/ 5 (21,7-100,2)
H2N
δ ΤΛ 100 633 6,33 \ / (58,5-171) CH3^__ / OH, 9 64 469 7,33 \ / (40,8-103,5) 10 -/\ _„ >100 393 Λ=/ 3 “O (ED40> 7
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Forbin- R ED5Q mg/kg Terapeu- delse (95% konfidens-· LD^q tisk nr. grænse) mg/kg indeks ch3 n 72 400 5,56 \ / (41,1-126) ^ch3 CH3 — 12 v3 <^-51> 410 17,08 /CH3 » .ry™, __^ch3 14 \_/ 52 355 6,83 - ^Η3 (34,9-77,5) ch3o 15 \ 90 203 2,26 >=( (71,4-113,4) och3 16 —/ \ ^100 200 -/ 100 (ed20) 8
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Forbin- R ED5Q m9/kg Terapeu- fielse (95% konfidens LD50 tisk 5 - nr· grænseI mg/kg indeks °2H5 ^ 17 v_7 28 278 9’93 10 (20,1-38,9) C2H5 CH3\ 15 18 34 309 9,09 " \ / (19,4-59,5) 20 Til sammenligning blev der foretaget lignende forsøg med fire forbindelser beskrevet i EP-A 39903. Resultaterne er vist nedenfor 25 30 35 9
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^CONH-R
_ CD _ R ^°50 ros/kg Reference 5 (95% konfidensgrænse) EP-A 39903 —ingen aktivitet side 23, eks. 6 CON^^4 10 /—""Λ ___________\Å-J__ R3 R^ ED50 mg/kg Reference (95% konfidens- EP-A 39903 grænse) 15 ir: ~~~ H / ingen aktivitet side 20, eks. 5(A) /7~\\ ^H—/'N ingen aktivitet side 22 V 2\_/ eks. 5(B) 20____ -/^V-OCH -CH ingen aktivitet side 22 / 3 2Π^_/ eks. 5(c) E ;.følge opfindelsen opnåede forbindelser anvendes som tera-25 peutisk middel mod arytmia i form af fri base eller i form af farmakologisk acceptabelt salt, f.eks. hydrochlorid, der kan administreres oralt eller ikke-oralt alene eller sammen med konventionelle uskadelige hjælpestoffer i form af et egnet middel, såsom et middel i kapselform, tabletform eller bereg-30 net til injektion. Disse midler kan fremstilles f.eks. ved hjælp af følgende fremgangsmåder:
Den aktive komponent pulveriseres fint, blandes med et egnet hjælpestof, f.eks. lactose, stivelse eller et derivat deraf 35 eller cellulosederivat, hvorefter blandingen pakkes i gela tinekapsler , eller til fremstilling af tabletter, idet den aktive bestanddel ud over hjælpestof som nævnt ovenfor æltes sammen 10
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med et bindemiddel, f.eks. natriumcarboxymethylcellulose, algininsyre eller gummi-arabicum og vand, og det således æltede materiale granuleres ved hjælp af en ekstruder, hvorefter der dertil tilsættes et smøringsmiddel, såsom talkum ~ elL· stearLnsyre, inden blandingen tabletteres ved hjælp af en ker*;entionel tabletpresse, eller til fremstilling af in-jicerbare præparater et vandopløseligt salt af en forbindelse ifølge opfindelsen opløses i steriliseret vand eller steriliseret fysiologisk saltvand og med eller uden et egnet stabili-10 seringsmiddel og/eller et egnet puffermiddel bringes på ampulform.
Den effektive dosis af et antiarytmisk middel varierer afhængigt af administrationsmetoden, typer og grad af patienternes 15 arytmiske og fysiske tilstand, men det skal almindeligvis være en mængde, som er tilstrækkelig til at bevirke normalisering af dysrytmi. I tilfældet med en forbindelse ifølge opfindelsen er en praktisk dosis, når den administreres oralt 50-200 mg/dag/voksen, og denne dosis deles i 3-4 portioner, 20 og når der sker administration ved intravenøs infusion anvendes 0,5-5 mg/kg (legemsvægt).
Eksempel 25 Almen fremstillingsmetode 1,5-2 ækvivalenter af hver af forskellige substituerede ani-linderivater opløses i dioxan. Til opløsningen sættes 1,5-2 ækvivalenter natriumhydroxid under omrøring ved stuetemperatur og under nitrogenstrøm. Blandingen opvarmes til 100°C i 30 2 timer, afkøles derpå til stuetemperatur, hvorefter der tildryppes en opløsning af 1 ækvivalent 8-ethoxycarbonyl= methylpyrrolizidin opløst i dioxan. Blandingen opvarmes så igen til 100°C i 2 timer, og reaktionsblandingen afkøles.
Under iskøling tilsættes is og ether dertil. Blandingen un-35 derkastes ekstraktion med 5% saltsyre. Det resulterende saltsure lag neutraliseres med natriumhydrogencarbonat, hvorpå der vaskes med ether. Det resterende vandige lag gøres alka- 11
DK 160309 B
lisk med en 20% vandig opløsning af natriumhydroxid efterfulgt af ekstraktion med chloroform. Det således opnåede chloroformlag vaskes med mættet saltvand, tørres på magnesium= sulfat, hvorefter opløsningsmidlet fjernes under reduceret 5 tryk. Resten omdannes til dets hydrochlorid på sædvanlig måde, og dette omkrystalliseres fra ethanol-ether. I overensstemmelse med den ovennævnte almene metode fås, når der som substituerede anilinderivater anvendes 2-methylanilin, 4-methyl= anilin, 2-chloranilin, 2-bromanilin, 2-methoxyanilin, 3-meth= 10 oxyanilin, 4-methoxyanilin, 2-aminoanilin, 2,3-dimethylamino= anilin, 2,4-dimethylanilin, 2,5-dimethylanilin, 2,6-dimethyl= anilin, 3,4-dimethylanilin, 3,5-dimethylanilin, 2,5-dimethoxy= anilin, 2,6-dichloranilin, 2,6-diethylanilin og 2,4,6-tri= methylanilin, det hertil svarende 15 N-(2-methylphenyl)-8-pyrrolizidinacetamid, N-(4-methylphenyl)-8-pyrrolizidinacetamid, N-(2-chlorphenyl)-8-pyrrolizidinacetamid, N-(2-bromphenyl)-8-pyrrolizidinacetamid, 2o N-(2-methoxyphenyl)-8-pyrrolizidinacetamid, N-(3-methoxyphenyl)-8-pyrrolizidinacetamid, N-(4-methoxyphenyl)-8-pyrrolizidinacetamid, N-(2-aminophenyl)-8-pyrrolizidinacetamid, N-(2,3-dimethylphenyl)-8-pyrrolizidinacetamid, 25 N-(2,4-dimethylphenyl)-8-pyrrolizidinacetamid, N-(2,5-dimethylphenyl)-8-pyrrolizidinacetamid, N-(2,6-dimethylphenyl)-8-pyrrolizidinacetamid, N-(3,4-dimethylphenyl)-8-pyrrolizidinacetamid, N-(3,5-dimethylphenyl)-8-pyrrolizidinacetamid, 30 N-(2,5-dimethoxyphenyl)-8-pyrrolizidinacetamid, N-(2,6-dichlorphenyl)-8-pyrrolizidinacetamid, N-(2,6-diethylphenyl)-8-pyrrolizidinacetamid, og N-(2,4,6-trimethylphenyl)-8-pyrrolizidinacetamid.
De fysisk-kemiske egenskaber af de således opnåede 8-substi-35 tuerede pyrrolizidiner er vist i tabel 2 i ovennævnte rækkefølge.
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Claims (5)
1, Analogifremgangsmåde til fremstilling af 8-substituerede 5 pyrrol izidinderivater med den almene formel (I) λ1 R2 „ ,, 15 hvori R Ver hydrogen eller en C1-c6 alkylgruppe, R2 er hydrogen, en Cx-Cg alkylgruppe, en Cj-Cg alkoxygruppe eller halogen, og R3 er en C^-Cg alkylgruppe, en Ci-Cg alkoxygruppe, aminogruppe eller halogen, kendetegnet ved, at man 20 a) omsætter en 8-halogencarbonylmethylpyrrol izidin - .r-n almene formel (Ila) ^pOHal 25 \^h -v hvor Hal er et halogenatom, med en anilin med den almene formel (III) 30 1 R _/V2 (iii> N“2 35 hvor Ri, R2 og R3 har den ovennævnte betydning, eller b) omsætter en 8-alkoxycarbonylmethylpyrrolizidin med den almene formel II DK 160309 B J^o2r Cl) hvor R er en methyl- eller ethylgruppe, med et alkalimetalsalt af en substitueret anilin med den almene formel III ovenfor. 10
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles derivater med den almene formel (I), hvori Ri og R2 begge er hydrogen, og R3 er en methylgruppe, methoxy- gruppe, aminogruppe, chlor eller brom. 15
3 S N-(2-aminophenyl)-8-pyrrolizidinacetamid, N-(2,3-dimethyIpheny1)-8-pyrrolizidinacetamid, DK 160309 B N-(2,4-dimethylphenyl)-8-pyrrolizidinacetamid, N-(2,5-dimethylphenyl)-8-pyrrolizidinacetamid, N-(2,6-dimethylphenyl)-8-pyrrolizidinacetamid, N- (3,4-dimethylphenyl)-8-pyrrolizidinacetamid,
3. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles derivater med den almene formel (I), hvori Ri er hydrogen, og R2 og R3 hver for sig er en methylgruppe, ethylgruppe, methoxygruppe eller chlor. 20
4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles derivater med en almene formel (I), hvori Ri, R2 og R3 hver er en methylgruppe. 25
5. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der fremstilles N-(2-methyIpheny1)-8-pyrrolizidinacetamid, N-(4-methylphenyl)-8-pyrrolizidinacetamid, 30 N (2 chlorphenyl)-8-pyrrolizidinacetamid, N- ,-broraphenyl) -8-pyrrolizidinacetamid, N-(2-methoxyphenyl)-8-pyrrolizidinacetamid, N-(3-methoxyphenyl)-8-pyrrolizidinacetamid, N~(4-methoxyphenyl)-8-pyrrolizidinacetamid,
5 N-(3,5-dimethylphenyl)-8-pyrrolizidinacetamid, N-(2,5-dimethoxyphenyl)-8-pyrrolizidinacetamid, N-(2,6-dichlorphenyl)-8-pyrrolizidinacetamid, N-(2,6-diethylphenyl)-8-pyrrolizidinacetamid, og N-(2,4,6-trimethylphenyl)-8-pyrrolizidinacetamid. 10 15 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57042297A JPS58159493A (ja) | 1982-03-16 | 1982-03-16 | ８−置換ピロリチジン誘導体およびその用途 |
| JP4229782 | 1982-03-16 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK121383D0 DK121383D0 (da) | 1983-03-16 |
| DK121383A DK121383A (da) | 1983-09-17 |
| DK160309B true DK160309B (da) | 1991-02-25 |
| DK160309C DK160309C (da) | 1991-07-29 |
Family
ID=12632091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK121383A DK160309C (da) | 1982-03-16 | 1983-03-16 | Analogifremgangsmaade til fremstilling af 8-substituerede pyrrolizidinderivater |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US4564624A (da) |
| EP (1) | EP0089061B1 (da) |
| JP (1) | JPS58159493A (da) |
| AT (1) | ATE31414T1 (da) |
| AU (1) | AU554261B2 (da) |
| CA (1) | CA1210401A (da) |
| DE (1) | DE3374934D1 (da) |
| DK (1) | DK160309C (da) |
| ES (2) | ES8500277A1 (da) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60184079A (ja) * | 1984-02-29 | 1985-09-19 | Suntory Ltd | ピロリチジン誘導体 |
| JPS6122084A (ja) * | 1984-07-06 | 1986-01-30 | Suntory Ltd | ピロリチジン化合物、その製造法およびその用途 |
| JPS6222785A (ja) * | 1985-07-23 | 1987-01-30 | Sanwa Kagaku Kenkyusho:Kk | 新規な２−オキソピロリジン化合物及びその塩、その製法並びにこれらを有効成分とする脳機能障害の予防及び治療剤 |
| JPS6256489A (ja) * | 1985-09-04 | 1987-03-12 | Sanwa Kagaku Kenkyusho:Kk | 新規なピロリチジン化合物及びその塩、これらの製法並びにこれらを有効成分とする消化性潰瘍治療剤 |
| US4638006A (en) * | 1985-09-24 | 1987-01-20 | Warner Lambert Company | Amnesia reversal with N,N-dialkylaminoalkyl-hexahydro-5-oxo 1H-pyrrolizine-3-carboxamides |
| CA2082415A1 (en) * | 1991-03-07 | 1992-09-08 | Daniel P. Becker | Meso-azacyclic aromatic acid amides and esters as novel serotonergic agents |
| US5516782A (en) * | 1991-03-07 | 1996-05-14 | G. D. Searle & Co. | New meso-azacyclic aromatic acid amides and esters as novel serotonergic agents |
| JP2706057B2 (ja) * | 1995-06-14 | 1998-01-28 | 勝之 岸 | 自動車用トイレ |
| JP4317693B2 (ja) * | 2001-05-31 | 2009-08-19 | ニプロパッチ株式会社 | 経皮吸収用医薬組成物 |
| US7473407B2 (en) * | 2004-11-19 | 2009-01-06 | Solvay Chemicals | Magnetic separation process for trona |
| CN103864796B (zh) * | 2012-12-18 | 2016-04-27 | 北京嘉林药业股份有限公司 | 一种盐酸吡西卡尼的纯化生产方法 |
| KR102351052B1 (ko) * | 2019-12-26 | 2022-01-14 | 보령제약 주식회사 | 피롤리지딘 화합물 제조 방법 및 피롤리지딘 염산염 1/2 수화물 제조 방법 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56156283A (en) * | 1980-05-07 | 1981-12-02 | Suntory Ltd | 8-substituted pyrrolitidine and its quaternary ammonium salt |
-
1982
- 1982-03-16 JP JP57042297A patent/JPS58159493A/ja active Granted
-
1983
- 1983-03-08 AU AU12140/83A patent/AU554261B2/en not_active Expired
- 1983-03-10 US US06/473,947 patent/US4564624A/en not_active Expired - Lifetime
- 1983-03-15 AT AT83102561T patent/ATE31414T1/de not_active IP Right Cessation
- 1983-03-15 DE DE8383102561T patent/DE3374934D1/de not_active Expired
- 1983-03-15 CA CA000423638A patent/CA1210401A/en not_active Expired
- 1983-03-15 EP EP83102561A patent/EP0089061B1/en not_active Expired
- 1983-03-16 DK DK121383A patent/DK160309C/da not_active IP Right Cessation
- 1983-03-16 ES ES521032A patent/ES8500277A1/es not_active Expired
-
1984
- 1984-06-22 ES ES533620A patent/ES8505683A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK160309C (da) | 1991-07-29 |
| EP0089061A2 (en) | 1983-09-21 |
| DK121383D0 (da) | 1983-03-16 |
| ES521032A0 (es) | 1984-11-01 |
| AU1214083A (en) | 1983-09-22 |
| CA1210401A (en) | 1986-08-26 |
| US4564624A (en) | 1986-01-14 |
| ES8500277A1 (es) | 1984-11-01 |
| ES533620A0 (es) | 1985-06-16 |
| AU554261B2 (en) | 1986-08-14 |
| DE3374934D1 (en) | 1988-01-28 |
| ATE31414T1 (de) | 1988-01-15 |
| ES8505683A1 (es) | 1985-06-16 |
| DK121383A (da) | 1983-09-17 |
| JPH0446956B2 (da) | 1992-07-31 |
| EP0089061A3 (en) | 1984-07-18 |
| EP0089061B1 (en) | 1987-12-16 |
| JPS58159493A (ja) | 1983-09-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |