NO159384B - Analogi-fremgangsmaate for fremstilling av terapeutisk aktive n6-(1-indanyl) adenosin-derivater. - Google Patents
Analogi-fremgangsmaate for fremstilling av terapeutisk aktive n6-(1-indanyl) adenosin-derivater. Download PDFInfo
- Publication number
- NO159384B NO159384B NO844830A NO844830A NO159384B NO 159384 B NO159384 B NO 159384B NO 844830 A NO844830 A NO 844830A NO 844830 A NO844830 A NO 844830A NO 159384 B NO159384 B NO 159384B
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- Norway
- Prior art keywords
- formula
- indanyl
- preparation
- dibenzo
- acid addition
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 4
- 230000001225 therapeutic effect Effects 0.000 title description 3
- FSKMJUWPFLDDRS-XTMLTMLVSA-N (2r,3r,4s,5r)-2-[6-(2,3-dihydro-1h-inden-1-ylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(NC3C4=CC=CC=C4CC3)=C2N=C1 FSKMJUWPFLDDRS-XTMLTMLVSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- -1 oxalic Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 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 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- XUDMFUCJNFYMRZ-UHFFFAOYSA-N 11-chloro-11h-dibenzo[1,2-a:1',2'-e][7]annulene Chemical compound C1=CC2=CC=CC=C2C(Cl)C2=CC=CC=C21 XUDMFUCJNFYMRZ-UHFFFAOYSA-N 0.000 description 1
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- VNWKTOKETHGBQD-YPZZEJLDSA-N carbane Chemical compound [10CH4] VNWKTOKETHGBQD-YPZZEJLDSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- WWBGONGKRSWMGE-UHFFFAOYSA-N cycloheptene Chemical compound [CH]1CCCC=CC1 WWBGONGKRSWMGE-UHFFFAOYSA-N 0.000 description 1
- PJQCANLCUDUPRF-UHFFFAOYSA-N dibenzocycloheptene Chemical compound C1CC2=CC=CC=C2CC2=CC=CC=C12 PJQCANLCUDUPRF-UHFFFAOYSA-N 0.000 description 1
- 150000008508 dibenzocycloheptenes Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P9/08—Vasodilators for multiple indications
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
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Description
Fremgangsmåte til fremstilling av dibenzocykloheptenylaminer med vesikatorisk virkning.
Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av nye vesikatorisk virksomme dibenzocykloheptenylaminer og deres syreaddisjonssalter.
Ifolge foreliggende oppfinnelse fremstilles nye N-(5H-di-benzo/a,d7cyklohepten-5-yl)-aminer med den generelle formel hvor R <1> betyr en lavere alkylgruppe, '<R>2- betyr en lavere alkylgruppe, RJ r> betyr et hydrogenatom eller R 2 og RJ ? sammen betyr et -CH2-CH2-radikal og n betyr 1 eller 2, samt deres syreaddisjonssalter. Med ut-trykket lavere alkyl menes uforgrenede eller forgrenede alkylgrupper som har hoyst fire karbonatomer.
De nye N-(5H-dibenzo/a,d7cyklohepten-5-yl)-aminer har helt uventet sterk vesikator-aktivitet, endog i lave konsentrasjoner, som kan tilskrives det faktum at de lett spaltes til radikaler ved brudd på bindingen mellom i dibenzocyklohepten-kjernene og tilstotende nitrogenatom. Denne egenskap deles ikke av de analoge forbindelser som har en enkeltbinding mellom karbon 10 og 11 i dibenzocyklohepten-kjernen, kfr. belgisk patent nr. 633 454- De siste har helt forskjel-lig farmasøytisk anvendelse. Forbindelsene som fremstilles ifolge foreliggende oppfinnelse kan også anvendes for fremstilling (ved re-duksjon av dobbeltbindingen mellom karbonatomene 10 og 11 i dibenzocyklohepten-k jernen) av de tilsvarende N-(lp,ll-dihydro-5H-dibenzo /a,d/cyklohepten-5-yl)-aminer, som, som angitt ovenfor, er kjent for å ha nyttige terapeutiske egenskaper.
Blant de fremstilte forbindelser, har forbindelser hvor grupperingen
i
betyr et 4-R^-piperazin-radikal på den ene side og forbindelser hvor den samme gruppering betyr en N', N'-dialkylalkylendiaminrest på den annen side, mest utpreget aktivitet.
For terapeutiske formål kan forbindelsen ifolge foreliggende oppfinnelse anvendes som sådan, men fortrinnsvis omdannes disse til ikke-giftige syreaddisjonssalter for sammensetning med faste eller flytende fortynningsmidler ifolge vanlig farmasøytisk praksis. Eksempler på ikke-giftige syreaddisjonssalter, dvs. salter som ikke er skadelige like overfor den animalske organisme, når de anvendes i terapeutiske doser, er salter avledet fra uorganiske syrer, slik som hydrohalogen-syrer (f.eks. hydroklor- og hydrobromsyrer), svovelsyre, salpetersyre og fosforsyre, og organiske syrer, slik som oksalsyre, maleinsyre, vinsyre, sitronsyre, eddiksyre, fumarsyre, ravsyre og pa-moinsyrer.
Ifolge foreliggende oppfinnelse fremstilles dibenzocyklohep-tenylaminene ned formel I ved at en forbindelse med formelen: hvor X betyr et halogen, fortrinnsvis klor, omsettes med en forbindelse med formelen:
hvori R 1 , R 2 , r 3 og n har den ovenfor angitte betydning.
Reaksjonen utfores fortrinnsvis ved oppvarmning av reaksjons-deltakerne i nærvær eller fravær av et inert organisk opplosningsmiddel, slik som benzen, toluen eller xylen. Det er hensiktsmessig å tilsette et syrebindende middel, f.eks. et alkålimetall (f.eks. natrium eller kalium) eller jordalkalimetallkarbonat, oksyd, hydroksyd eller amid, f. eks. natriurnamid, eller natrium- eller kaliumkarbonat, til reaksjonsblandingen. Et overskudd av forbindelsene med formelen IV kan også tjene som syrebindende middel.
Produktene som oppnås kan renses ved destillasjon av basen eller ved omdannelse av basen på i og for seg kjent måte til et syre-addis jonssalt etterfulgt av krystallisasjon av syreaddisjonssaltet fra et egnet flytende medium.
Utgangsmaterialene med formel III kan oppnås ved å behandle 5H-dibenzo/a,d/cyklohepten-5-ol med formelen:
med en hydrohalogensyre (f.eks. saltsyre eller hydrogenbromid, et tionylhalogenid (f.eks. tionylklorid eller tionylbromid), et fosfor-halogenid (f.eks. fosforpentaklorid), eller et fosforoksyhalogenid (f.eks. fosforoksyklorid).
Folgende eksempler illustrerer oppfinnelsen.
Eksempel 1
22.6 g (0.1 mol) 5H-dibenzo/a,_d7cyklohepten-5-yl-klorid i
200 ml toluen settes dråpevis under omroring til en opplosning som kokes under tilbakelopskjoling av 20.0 g (0.2 mol) N-metylpiperazin i 80 ml toluen. Kokning med tilbakelopskjoling fortsettes i et tidsrom av 5 timer etter fullstendiggjorelse av tilsetningen. Blandingen avkjoles til romtemperatur og vann tilsettes. Toluenlåget skilles fra og torkes med natriumsulfat og filtreres. Toluen avdestilleres. Det tilbakeværende rå 1-(5H-dibenzo/i,d7cyklohepten-5-yl)-4-metylpiperazin kokes med eter. Uopplost stoff frafiltreres og krystalliseres fra petroleter (kokeområde 40°-60°C). Smeltepunktet for det rene stoff som fåes på denne måte er 138°-140°C.
Analyse: Beregnet for C20<H>22<N>2<:> C 82.72$, H 7.64$, N 9.65$
Funnet: C 82.8456, . H'7.8856, N 9.80$.
5H-dibenzo/~a,d7cyklohepten-5-yl-klorid anvendt som utgangs-materiale kan fremstilles som folger: 62.4 g 5H-dibenzo/a,d/cyklohepten-5-ol opploses i 300 ml benzen og hydrogenklorid sendes gjennom oppløsningen i en halv time. Oppløsningen torkes med kalsiumklorid og etter filtrering fordampes til tørrhet for å fjerne alt hydrogenklorid. Resten vaskes med små mengder petroleter (kokeområde 80°-100°C). 5H-dibenzo/a,d7cyklohepten-5-yl-klorid som fåes på denne måte kan anvendes for ovenstående reak-sjon uten videre rensing.
Ved å folge fremgangsmåten som er beskrevet i ovenstående eksempel, men ved å erstatte 5H-dibenzo/~a,d7cykloheptenyl-5-yl-klor-idet med tilsvarende 3-klor- og 3-metyl-forbindelser, fåes l-(3-klor-5H-dibenzo/a,d/cyklohepten-5-yl)-4-metyl-piperazin og 1-(3-metyl-5H-dibenzo/a,d_7 cyklohepten-5-yl)-4-metyl-piperazin.respektive.
Eksempel 2
15.8 g (0.07 mol) 5H-dibenzo/a,d7cyklohepten-5-yl-klorid i 150 mol toluen settes dråpevis under omroring til en opplosning under kokning med tilbakelopskjoler av 12.3 g (0.14 mol) N',N'-dimetyletylen-diamin i 60 ml toluen. Kokning med tilbakelopskjoler fortsettes i et tidsrom av 4 timer, etter fullstendiggjorelse av tilsetningen. Blandingen avkjoles til romtemperatur og vann tilsettes. Toluenlåget skilles fra og torkes med natriumsulfat og filtreres. Toluen avdestilleres. Resterende rå N-(5H-dibenzo/a,d7-cyklohepten-5-yl-N<*>,N<»->di-metyletyléndiamin opploses i petroleter (kokeområde 40°-60°C). Opp-løsningen avkjoles ved hjelp av fast karbondioksyd i aceton og gir 12g
(62$ av det teoretiske utbytte) av fast base som etter isolering viser et smeltepunkt på 46°-49°C. Smeltepunktet kan heves til 49°-52°C ved•videre krystallisasjon fra samme opplosningsmiddel. En ren-hetskontroll ved hjelp av tynns jiktskror.iatograf i viste ingen forurens-ninger.
Farmasøytiske blandinger som inneholder en eller flere av dibenzocykloheptenylaminer mea formel I eller ikke-giftige syreaddisjonssalter av disse i forbindelse med en farmakologisk aksepterbar bærer, kan ha en hvilken som helst av de former som vanligvis anvendes for administrering av terapeutisk aktive stoffer, men de foretrukne typer er slike som er egnet for oral administrering, og særlig tabletter, piller og kapsler som inneholder stoffet. Tablettene og pillene kan sammensettes på i og for seg kjent' måte med en eller flere farmakologisk aksepterbare fortynningsmidler eller hjelpemidler, f.eks. laktose eller stivelse, og omfatte stoffer som har en smorende virkning, f. eks-, kalsiumstearat. Kapsler fremstilt av absorberbart stoff, f.eks. gelatin, kan inneholde det aktive stoff alene, eller i blanding med fast eller flytende fortynningsmiddel. Flytende preparater kan være i form av suspensjoner, emulsjoner, siruper eller eliksirer av det aktive stoff i vann eller annet flytende medium som vanligvis anvendes for fremstilling av oralt aksepterbare farmasøytiske blandinger, f.eks. flytende parafin eller en sirup eller eliksir. Det aktive stoff kan også være fremstilt i en form som er egnet for parenteral administrering, dvs. som en suspensjon eller emulsjon i sterilt vann eller en organisk væske, som vanligvis anvendes for injeserbare preparater, f. eks. en vegetabilsk olje, slik som olivenolje eller en steril opplosning i et organisk opplosningsmiddel.
Claims (1)
- Fremgangsmåte til fremstilling av dibenzocykloheptenylaminer med vesikatorisk virkning og med den generelle formel:hvori R 1 betyr en lavere alkylgruppe, R 2 betyr en lavere alkylgruppe, RJ ? betyr et ■ hydrogenatom eller R 2 og . R 3■ sammén betyr et -CHg-CHg-radikal og n betyr 1 eller 2,.samt deres syreaddisjonssalter, karakterisert ved at en forbindelse med formelen: hvori X betyr et halogenatom, omsettes med en forbindelse:med formelen: hvori R 1 , ■ R 2 , RJ ^og n har den ovenfor angitte betydning og eventuelt omdannes en1 erholdt fri base til et syreaddisjonssalt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/558,144 US4501735A (en) | 1983-12-05 | 1983-12-05 | N6-(1- and 2-benzocycloalkyl) adenosines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO844830L NO844830L (no) | 1985-06-06 |
| NO159384B true NO159384B (no) | 1988-09-12 |
| NO159384C NO159384C (no) | 1988-12-21 |
Family
ID=24228400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO844830A NO159384C (no) | 1983-12-05 | 1984-12-04 | Analogi-fremgangsmaate for fremstilling av terapeutisk aktive n6-(1-indanyl) adenosin-derivater. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4501735A (no) |
| EP (1) | EP0144235A3 (no) |
| JP (1) | JPS60136592A (no) |
| KR (1) | KR850004484A (no) |
| AU (1) | AU562690B2 (no) |
| CA (1) | CA1230595A (no) |
| DK (1) | DK573484A (no) |
| ES (1) | ES538238A0 (no) |
| FI (1) | FI77667C (no) |
| GR (1) | GR81144B (no) |
| HU (1) | HUT36482A (no) |
| IL (1) | IL73700A (no) |
| NO (1) | NO159384C (no) |
| NZ (1) | NZ210428A (no) |
| OA (1) | OA07883A (no) |
| PH (1) | PH21367A (no) |
| PT (1) | PT79613B (no) |
| ZA (1) | ZA849337B (no) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1239397A (en) * | 1983-08-01 | 1988-07-19 | James A. Bristol | N.sup.6-substituted adenosines |
| DE3406533A1 (de) * | 1984-02-23 | 1985-08-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | Verwendung von adenosin-derivaten als antiallergica und arzneimittel, die diese enthalten |
| US4683223A (en) * | 1985-09-09 | 1987-07-28 | Warner-Lambert Company | N6 -Benzopyrano-and benzothiopyrano adenosines and methods of use |
| AU577743B2 (en) * | 1984-10-26 | 1988-09-29 | Warner-Lambert Company | N6-benzopyrano and benzothiopyrano adenosines |
| US4693996A (en) * | 1985-12-23 | 1987-09-15 | Warner-Lambert Company | Method of treating heart failure and medicaments therefor |
| US4833273A (en) * | 1986-02-03 | 1989-05-23 | Warner-Lambert Company | Process for the resolution of 1-aminoindanes |
| NZ222051A (en) * | 1986-10-06 | 1990-07-26 | Univ Virginia | Solution containing adenosine or hypoxanthine and optionally ribose for heart protection during surgery |
| US5063233A (en) * | 1986-11-14 | 1991-11-05 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives useful as adenosine receptor agonists |
| US4954504A (en) * | 1986-11-14 | 1990-09-04 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives having adenosine-2 receptor stimulating activity |
| PT86660B (pt) * | 1987-02-04 | 1992-02-28 | Ciba Geigy Ag | Processo para a preparacao de derivados de adenosina-5'-carboxamida |
| US4968697A (en) * | 1987-02-04 | 1990-11-06 | Ciba-Geigy Corporation | 2-substituted adenosine 5'-carboxamides as antihypertensive agents |
| US4837207A (en) * | 1987-05-13 | 1989-06-06 | Warner-Lambert Company | Diastereoisomers of n6 -endo-bicyclo[2.2.1]heptyladenosine as antihypertensives with selective action |
| US5410019A (en) * | 1987-09-24 | 1995-04-25 | The Administrators Of The Tulane-Educational Fund | Therapeutic peptides |
| US5034381A (en) * | 1988-01-07 | 1991-07-23 | Ciba-Geigy Corporation | 2-(substituted amino) adenosines as antihypertensives |
| JPH0725785B2 (ja) * | 1989-01-11 | 1995-03-22 | 日本臓器製薬株式会社 | アデノシン誘導体及び該化合物を有効成分として含有する医薬組成物 |
| US5561134A (en) * | 1990-09-25 | 1996-10-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
| ATE147074T1 (de) * | 1990-09-25 | 1997-01-15 | Rhone Poulenc Rorer Int | Verbindungen welche antihypertensive und antiischemische eigenschaften besitzen |
| WO2000005234A1 (fr) * | 1998-07-22 | 2000-02-03 | Suntory Limited | INHIBITEURS DE NF-λB CONTENANT DES DERIVES D'INDANE EN TANT QU'INGREDIENT ACTIF |
| JP2015172077A (ja) * | 2015-06-24 | 2015-10-01 | 中国医学科学院葯物研究所 | Ｎ６−置換アデノシン誘導体とｎ６−置換アデニン誘導体の鎮静、催眠、抗うつ、抗痙攣、抗てんかん、抗パーキンソン病と認知証予防・治療の用途 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670175A1 (de) * | 1966-12-21 | 1970-11-05 | Boehringer Mannheim Gmbh | Verfahren zur Herstellung von Adenosin-Derivaten |
| DE1670265A1 (de) * | 1967-08-25 | 1971-01-28 | Boehringer Mannheim Gmbh | 2-Amino-Adenosinderivate und Verfahren zu deren Herstellung |
| JPS4826038B1 (no) * | 1970-09-25 | 1973-08-03 | ||
| DE2059922A1 (de) * | 1970-12-05 | 1972-06-15 | Boehringer Mannheim Gmbh | Neue N(6)-Aralkyl-adenosin-Derivate und Verfahren zur Herstellung derselben |
| DE2136624A1 (de) * | 1971-07-22 | 1973-02-08 | Boehringer Mannheim Gmbh | N (6)-substituierte adenosin-derivate und verfahren zur herstellung derselben |
| BE788958A (fr) * | 1971-09-18 | 1973-03-19 | Schering Ag | Derives d'adenosine et leur procede de preparation |
| US4090021A (en) * | 1971-10-08 | 1978-05-16 | Schering Aktiengesellschaft | Process for the production of N6 -substituted adenosine nucleotides and products resulting therefrom |
| DE2230160A1 (de) * | 1972-06-21 | 1974-01-31 | Merck Patent Gmbh | Adenosinderivat |
| US3922261A (en) * | 1972-06-21 | 1975-11-25 | Merck Patent Gmbh | Adenosine derivative |
| JPS5046689A (no) * | 1972-07-24 | 1975-04-25 | ||
| DE2249397A1 (de) * | 1972-10-09 | 1974-05-02 | Merck Patent Gmbh | Adenosinester und -aether |
| DE2406587A1 (de) * | 1974-02-12 | 1975-08-21 | Klinge Co Chem Pharm Fab | Hypolipaemisch wirksame adenosinderivate |
| DE3019322A1 (de) * | 1980-05-21 | 1981-12-03 | Merck Patent Gmbh, 6100 Darmstadt | Psychopharmakon sowie verwendung von adenosinderivaten |
| US4388308A (en) * | 1980-06-09 | 1983-06-14 | G.D. Searle & Co. | N6 -[(2-Hydroxypropyl)aryl]adenosines |
| JPS57171998A (en) * | 1981-04-15 | 1982-10-22 | Fujisawa Pharmaceut Co Ltd | Adenosine derivative and its salt, preparation thereof and medicinal composition containing the same |
| DE3406533A1 (de) * | 1984-02-23 | 1985-08-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | Verwendung von adenosin-derivaten als antiallergica und arzneimittel, die diese enthalten |
-
1983
- 1983-12-05 US US06/558,144 patent/US4501735A/en not_active Expired - Fee Related
-
1984
- 1984-11-22 CA CA000468430A patent/CA1230595A/en not_active Expired
- 1984-11-29 ZA ZA849337A patent/ZA849337B/xx unknown
- 1984-11-30 IL IL73700A patent/IL73700A/xx unknown
- 1984-12-03 FI FI844750A patent/FI77667C/fi not_active IP Right Cessation
- 1984-12-03 GR GR81144A patent/GR81144B/el unknown
- 1984-12-03 AU AU36216/84A patent/AU562690B2/en not_active Ceased
- 1984-12-03 DK DK573484A patent/DK573484A/da not_active Application Discontinuation
- 1984-12-04 NO NO844830A patent/NO159384C/no unknown
- 1984-12-04 PH PH31527A patent/PH21367A/en unknown
- 1984-12-04 ES ES538238A patent/ES538238A0/es active Granted
- 1984-12-04 NZ NZ210428A patent/NZ210428A/xx unknown
- 1984-12-04 EP EP84308394A patent/EP0144235A3/en not_active Withdrawn
- 1984-12-04 JP JP59255166A patent/JPS60136592A/ja active Pending
- 1984-12-04 HU HU844477A patent/HUT36482A/hu unknown
- 1984-12-05 KR KR1019840007662A patent/KR850004484A/ko not_active IP Right Cessation
- 1984-12-05 OA OA58460A patent/OA07883A/xx unknown
- 1984-12-05 PT PT79613A patent/PT79613B/pt unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0144235A3 (en) | 1986-07-30 |
| OA07883A (en) | 1986-11-20 |
| ES8602033A1 (es) | 1985-11-01 |
| DK573484D0 (da) | 1984-12-03 |
| EP0144235A2 (en) | 1985-06-12 |
| US4501735A (en) | 1985-02-26 |
| NO159384C (no) | 1988-12-21 |
| HUT36482A (en) | 1985-09-30 |
| FI844750L (fi) | 1985-06-06 |
| CA1230595A (en) | 1987-12-22 |
| FI77667B (fi) | 1988-12-30 |
| JPS60136592A (ja) | 1985-07-20 |
| KR850004484A (ko) | 1985-07-15 |
| AU3621684A (en) | 1985-06-13 |
| PT79613B (en) | 1986-12-12 |
| DK573484A (da) | 1985-06-06 |
| PH21367A (en) | 1987-10-15 |
| GR81144B (en) | 1985-04-04 |
| FI77667C (fi) | 1989-04-10 |
| NO844830L (no) | 1985-06-06 |
| PT79613A (en) | 1985-01-01 |
| IL73700A0 (en) | 1985-02-28 |
| FI844750A0 (fi) | 1984-12-03 |
| NZ210428A (en) | 1989-05-29 |
| AU562690B2 (en) | 1987-06-18 |
| ES538238A0 (es) | 1985-11-01 |
| IL73700A (en) | 1988-09-30 |
| ZA849337B (en) | 1986-07-30 |
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