DK155663B - Analogifremgangsmaade til fremstilling af n-oe6-(fluorsubstitueret phenoxy)-5-indanylaa-methansulfonamidderivater - Google Patents
Analogifremgangsmaade til fremstilling af n-oe6-(fluorsubstitueret phenoxy)-5-indanylaa-methansulfonamidderivater Download PDFInfo
- Publication number
- DK155663B DK155663B DK035882A DK35882A DK155663B DK 155663 B DK155663 B DK 155663B DK 035882 A DK035882 A DK 035882A DK 35882 A DK35882 A DK 35882A DK 155663 B DK155663 B DK 155663B
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- DK
- Denmark
- Prior art keywords
- derivatives
- difluorophenoxy
- preparation
- fluoro
- substituted phenoxy
- Prior art date
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- -1 FLUORO-SUBSTITUTED PHENOXY Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical class CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract 1
- 125000005646 oximino group Chemical group 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SLNHKGRXIDXAHF-UHFFFAOYSA-N 5-amino-6-(2,4-difluorophenoxy)-2,3-dihydroinden-1-one Chemical compound NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1F SLNHKGRXIDXAHF-UHFFFAOYSA-N 0.000 description 3
- FPKWQCUOBUOMPA-UHFFFAOYSA-N 6-(2,4-difluorophenoxy)-2,3-dihydro-1h-inden-5-amine Chemical compound NC1=CC=2CCCC=2C=C1OC1=CC=C(F)C=C1F FPKWQCUOBUOMPA-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- STLAIELUNHAWRT-UHFFFAOYSA-N 5-(2,4-difluorophenoxy)-6-nitro-2,3-dihydro-1h-indene Chemical compound [O-][N+](=O)C1=CC=2CCCC=2C=C1OC1=CC=C(F)C=C1F STLAIELUNHAWRT-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- ZUDBSSVBLLYQTE-UHFFFAOYSA-N n-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]acetamide Chemical compound CC(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1F ZUDBSSVBLLYQTE-UHFFFAOYSA-N 0.000 description 2
- CXJONBHNIJFARE-UHFFFAOYSA-N n-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1F CXJONBHNIJFARE-UHFFFAOYSA-N 0.000 description 2
- VJOLSBZDECMJIR-UHFFFAOYSA-N n-[6-(2,4-difluorophenoxy)-2,3-dihydro-1h-inden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1OC1=CC=C(F)C=C1F VJOLSBZDECMJIR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SVYOXGBINYWSDQ-UHFFFAOYSA-N 1,4-dioxane;ethanol Chemical compound CCO.C1COCCO1 SVYOXGBINYWSDQ-UHFFFAOYSA-N 0.000 description 1
- DUROKJUTAMUPAH-UHFFFAOYSA-N 1-nitro-2,3-dihydro-1h-indene Chemical compound C1=CC=C2C([N+](=O)[O-])CCC2=C1 DUROKJUTAMUPAH-UHFFFAOYSA-N 0.000 description 1
- RPEPGIOVXBBUMJ-UHFFFAOYSA-N 2,3-difluorophenol Chemical compound OC1=CC=CC(F)=C1F RPEPGIOVXBBUMJ-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- OJNRHKOJADOVAE-UHFFFAOYSA-N 5-bromo-6-nitro-2,3-dihydro-1h-indene Chemical compound C1=C(Br)C([N+](=O)[O-])=CC2=C1CCC2 OJNRHKOJADOVAE-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000008822 Ankylosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010023198 Joint ankylosis Diseases 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- TWFZGCMQGLPBSX-UHFFFAOYSA-N carbendazim Chemical compound C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- HXRAMSFGUAOAJR-UHFFFAOYSA-N n,n,n',n'-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine Chemical compound CN(C)C(N(C)C)OC(C)(C)C HXRAMSFGUAOAJR-UHFFFAOYSA-N 0.000 description 1
- RIRLKJARARLWRZ-UHFFFAOYSA-N n-[6-(2,4-difluorophenoxy)-2,3-dihydro-1h-inden-5-yl]-n-methylsulfonylacetamide Chemical compound CC(=O)N(S(C)(=O)=O)C1=CC=2CCCC=2C=C1OC1=CC=C(F)C=C1F RIRLKJARARLWRZ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 155663 B
Den foreliggende opfindelse angår en analogif remgangsmåde til fremstilling af hidtil ukendte N-[6-(f1uorsubsti tueret phe-noxy)-5-indany1]-methansulfonamidderivater med den almene formel I
F U*3
r»—frK
CH.SO--N o Z i i1 hvori R1 betegner et hydrogenatom eller en acetylgruppe, og R2 og R3 tilsammen betegner en oxogruppe eller to hydrogenatomer.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man kondenserer en forbindelse med den almene formel n x=/ I >
HN
R1 hvori Ri, R2 og R3 har den ovenfor anførte betydning, med methansul fonsyrech 1 or i d , hvorefter man eventuelt acetylerer in-danylderivater med den almene formel I med R1 i betydningen hydrogen.
Fremgangsmåden ifølge opfindelsen til fremstilling af de hidtil ukendte indanylderivater kan gennemføres under de betingelser, som er beskrevet i beskrivelsen til europæisk patentansøgning nr. 009 554. I forhold til de i beskrivelsen til
DK 155663 B
2 nævnte ansøgning beskrevne indanyIderivater udmærker de ifølge den foreliggende opfindelse fremstillede forbindelser sig ved en overlegen antiinflammatorisk virkning, således som resultaterne af det i det følgende beskrevne adjuvans Arthritisforsøg 5 viser.
Der anvendes hunlige og hanlige rotter af stammen Lewis (LEW) i vægtområdet 110-190 g. Dyrene modtager drikkevand 10 og altromin-pressefoder ad libitum.
Til hver dosisgruppe anvendes 10 rotter.
Mycobacterium butyricum fra firmaet Difko i Detroit an-1® vendes som pirringsmiddel. En suspension af 0,5 mg Myco= bacterium butyricum i 0,1 ml tyndtflydende parafin (DAB 7) indsprøjtes subplantart i den højre bagpote.
Forsøgsforbindelserne indgives oralt fra den 11. forsøgs-20 dag dagligt i fire dage. Forbindelserne administreres som klar vandig opløsning eller som krystalsuspension under tilsætning af "Myrj 53" (85 mg %) i isotonisk natrium-chloridopløsning.
25 Rotterne bliver i henseende til deres legemsvægt inddelt så vidt muligt ensartet i forskellige grupper. Efter plethysmografisk volumenmåling af den højre bagpote indsprøjtes 0,1 ml adjuvans eller hjælpestof subplantart i denne.
30
De højre bagpoter måles fra den 14. forsøgsdag indtil slut- j ningen af forsøget. Forsøgstiden andrager tre uger.
Helingen af dyrenes højre pote i afhængighed af den admini-35 strerede dosis forsøgsforbindelse bestemmes.
DK 155663 B
3
Den efterfølgende tabel viser de ved dette forsøg opnåede resultater med de ifølge opfindelsen fremstillede forbindelser 3-5 i sammenligning med de fra beskrivelsen til ovennævnte europæiske patentansøgning nr. 0009 554 kendte strukturanaloge 5 indanylderivater 1 og 2. Resultaterne viser, at de ifølge opfindelsen fremstillede forbindelser har en god virkning ved en så lav dosering, ved hvilken sammenligningsforbindelserne 1 og 2 parktisk taget ingen virkning udviser.
10 15 20 25 30 35
DK 155663 B
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DK 155663B
De omhandlede hidtil ukendte forbindelser egner sig således i kombination med de inden for den galeniske farmaci sæd” vanlige bæremidler . til behandling af sygdomme indenfor de rheumatiske lidelser (såsom ostearthritis eller ankylosier= 5 ende spondalitis), bronchial astma og høfeber.
Bemærkelsesværdigt er det endvidere, at indanylderivaterhe med den almene formel I yderligere også egner sig til behandling af migræne og af dysmenorrhoea og formindsker risikoen for thrombose.
10 Overraskende findes der blandt de ifølge opfindelsen fremstillede indanylderivater også sådanne, som foruden anti-inflammatorisk virkning også har en udpræget antiulcerogen samt svulsthæmmende virkning.
Fremstillingen af lægemiddelspecialiteter foregår på sæd-15 vanlig måde, idet man med passende tilsætninger, bærematerialer og smagskorrigerende stoffer bringer de aktive stoffer til at indgå i de ønskede administrationsformer, såsom tabletter, drageer , kapsler, opløsninger.og inhalationsmidler.
20 Til oral anvendelse egner sig især tabletter, drageer og kapsler, der eksempelvis indeholder 1 til 250 mg aktiv forbindelse og 50 mg til 2 g farmakologisk uvirksom bærer, såsom eksempelvis lactose, amylose, talkum, gelatine og aag-nesiumstearat,samt de sædvanlige tilsætninger.
De efterfølgende udførelseseksempler tjener til belysning af fremgangsmåden ifølge opfindelsen.
25
DK 155663B
6 EKSEMPEL· · ·1 a) 10,1 g 5-brom-6-nitroindan, 4,1 g kobber(Ϊ)-chlorid, 7,1 g kaliuro-tert.-butanolat og 8,5 g 2,4-difluorphenol koges i 7 timer i 210 ml tert.-butanol. Køling, fortynding 5 med ether, filtrering, inddampning, optagelse af resten i ether, vaskning af den etheriske opløsning med 1 N saltsyre samt tørring og inddampning resulterer i 10,5 g råprodukt, der ved hjælp af en kiselgelsøjle kromatograferes med hexan-ethylacetat. Udbytte 6,3 g 5-(2,4-difluorphenoxy)-6-10 nitroindan med smeltepunkt 65 til 68 C (fra hexan).
b) 14,6 g 5-(2,4-difluorphenoxy)-6-nitroindan bliver i 300 ml dioxan-ether 1:1 tilsat 10 g Raney-nikkel og derefter 4,86 ml hydrazinhydrat ved 40°C. Efter yderligere 30 minutter ved 50°C og 30 minutter under tilbagesvaling bliver der kølet, filtreret og inddampet. Det opnås et udbytte på 13 g rå 6-(2,4-difluorphenoxy)-5-indanylamin.
c) 13,1 g 6-(2,4-difluorphenoxy)-5-indanylamin i 60 ml pyridin tilsættes 4,0 ml methansulfonylchlorid ved 0°C.
Efter 3 timer ved 0°C og 16 timer ved 20°C bliver der ind- 20 dampet, resten optages i chloroform, og opløsningen vaskes med 1 N saltsyre og inddampes. Omkrystallisation af resten fra ethanol fører til 8,1 g N-[6-(2,4-difluorphenoxy)-5-indanyl]-methansulfonamid med et smeltepunkt på 85 til 87°C.
EKSEMPEL 2 25 3 g N-[6-(2,4-difluorphenoxy)-5-indanyl]-methansulfonamid i 30 ml pyridin tilsættes ved 0°C i løbet af 10 minutter under nitrogen 1,5 ml eddikesyreanhydrid og efteromrøres i 3 timer ved 0°C og i 13 timer ved stuetemperatur. Der inddampes, resten optages i chloroform, rystes 3 gange med 30 IN saltsyre og 1 gang med vand, den organiske fase tørres over calciumsulfat, inddampes, og resten omkrystalli-
DK 155663B
7 seres fra ethanol.
Udbytte: 3,1 g N-acetyl-N-[6-(2,4-difluorphenoxy)-5-in= danyl]-methansulfonamid med smeltepunkt 160°C.
EKSEMPEL 3 2 12,8 g 5-amino-6-(2,4-difluorphenoxy)-1-indanon i 95 ml pyridin tilsættes 8,3 ml methansulfonylchlorid ved 0oC„
Efter 3 timer ved 0°C og 16 timer ved 20°C bliver der inddampet, resten optages i chloroform, opløsningen vaskes med 1 N saltsyre og inddampes. Kromatografering af resten 10 over kiselgel med dichlormethan-ethylacetat resulterer i 1,2 g 6-(2,4-difluorphenoxy)-5-bis(methylsulfonyi)-amino- 1-indanon med smeltepunkt 190eC (fra toluen; biprodukt), og derefter 8,9 g 6-(2,4-dif1uorphenoxy)-5-methylsulfony1a«ino-l-indanon med smeltepunkt 153eC (fra ethanol).
15 Udgangsforbindelsen for disse syntesetrin kan opnås ad to veje:
Ve j · 1 a) 13,9 g 6-(2,4-difluorphenoxy)-5-indanylamin i 93 ml eddikesyre blev ved 30°C tilsat 40 ml eddikesyreanhydrid. Der- 20 efter tildryppedes en opløsning af 11 g chromtrioxid i
27 ml vand og 17 ml eddikesyre ved 50°C„ Efter yderligere 40 minutter ved 50°C blev · der kølet, udhældt på isvand og frasuget. Resten kromatograferes over kiselgel med dichlormethan-ethylacetat. Derved opnås 9 g 5-acetylamino-25 6-(2,4-difluorphenoxy)-1-indanon med smeltepunkt 153°C
og derefter 4 g af den isomere 6-acetylamino-5-(2,4-difluor= phenoxy)-1-indanon med smeltepunkt 199°C.
b) 12,9 g 5-acetylamino-6-(2,4-difluorphenoxy)-1-indanon koges i 210 ml ethanol sammen med 22 ml koncentreret salt- /
DK 155663 B
8 syre i 2 timer. Derefter inddampes, resten tilsættes vand og ammoniakopløsning (pH 8), og det faste stof 5-amino- 6-(2,4-difluorphenoxy)-1-indanon frasuges. Udbytte 11,1 g med smeltepunkt 132°C.
5 Vej 2 a) 4,58 g 5-(2,4-difluorphenoxy)-6-nitroindan og 8,2 g bis-(dimethylamino)-tert.-butoxy-methan omrøres i 5 ml dimethylformamid i 60 minutter ved 140°C. Inddampning i vakuum resulterer i rå l-dimethylaminomethylen-6-(2,4-di= fluorphenoxy)-5-nitroindan.
b) Denne opløses i chloroform, og ved -40°C tilledes ozon (12 minutter, hastighed 4,5 g per time). Efter tilledning af nitrogen udhældes på isvand, indstilles på pH 3 med saltsyre, vaskes med natriumhydrogensulfitopløsning og ind- 15 dampes. Kromatografering af resten over kiselgel med chlo= roform resulterer i 250 mg 6- (2,4-difluorphenoxy)-5-nitro- 1-indanon med smeltepunkt 145°C (fra ethanol).
c) Denne opløses i 5 ml ethanol-dioxan 1:1, 250 mg Raney-nikkel tilsættes, og derefter tilsættes 100 mg hydrazinhydrat 20 ved 45°C. Efter 30 minutter under tilbagesvaling køles, filtreres og inddampes. Udbytte 240 mg 5-amino-6-(2,4-di= fluorphenoxy)-1-indanon med smeltepunkt 153°C (fra ethanol).
EKSEMPEL 4 2,82 g 6-(2,4-difluorphenoxy)-5-methylsulfonylamino-l-indanon 25 bliver i 30 ml pyridin tilsat 1,57 g acetylchlorid. Efter 20 timer ved 20°C inddampes, tilsættes vand, indstilles på pH 6 med saltsyre og ekstraheres med chloroform. Chloroformekstrakten vaskes neutral, inddampes, og resten kromatogra-feres med toluen-ethanol 99:1 over kiselgel.
Udbytte: 2,50 g 5-(N-acetyl-N-methylsulfonylamino)-6-(2,4- 1 · f-X 1 _____\ 1 " J A Ί J. 1 O O ί ·Ρν* Ά 1 \
Claims (1)
- DK 155663B Patentkrav. Analogifremgangsmåde til fremstilling af N-[6-(fluorsubstitueret phenoxy)-5-indanyj|-methansulfonaniidderivater med den almene formel I -R3 S*- 0 (i), CH-SO„-N ^ l· hvori R* betegner et hydrogenatom eller en acetylgruppe, og R2 og R3 tilsammen betegner en oxogruppe eller to hydrogenatomer, kendetegnet ved, at man kondenserer en forbindelse med den almene formel II _2 F R 3 hvori Ri, R2 og R3 har den ovenfor anførte betydning, med me-thansulfonsyrechlorid, hvorefter man eventuelt acetylerer in-danylderivater med den almene formel I med i betydningen hydrogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813103372 DE3103372A1 (de) | 1981-01-27 | 1981-01-27 | Neue indanyl-derivate, ihre herstellung und verwendung |
| DE3103372 | 1981-01-27 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK35882A DK35882A (da) | 1982-07-28 |
| DK155663B true DK155663B (da) | 1989-05-01 |
| DK155663C DK155663C (da) | 1989-09-04 |
Family
ID=6123795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK035882A DK155663C (da) | 1981-01-27 | 1982-01-27 | Analogifremgangsmaade til fremstilling af n-oe6-(fluorsubstitueret phenoxy)-5-indanylaa-methansulfonamidderivater |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4375479A (da) |
| EP (1) | EP0056956B1 (da) |
| JP (1) | JPS57176948A (da) |
| AT (1) | ATE16701T1 (da) |
| AU (1) | AU555252B2 (da) |
| CA (1) | CA1175443A (da) |
| DE (2) | DE3103372A1 (da) |
| DK (1) | DK155663C (da) |
| GB (1) | GB2092144A (da) |
| IE (1) | IE52717B1 (da) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3208079A1 (de) * | 1982-03-04 | 1983-09-08 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue indanyl-derivate, ihre herstellung und verwendung |
| US4555406A (en) * | 1983-09-06 | 1985-11-26 | Schering Aktiengesellschaft | Indanyl derivatives, their preparation and use |
| DE3343331A1 (de) * | 1983-11-28 | 1985-06-05 | Schering AG, 1000 Berlin und 4709 Bergkamen | Verfahren zur herstellung von indanyl-derivaten und deren verwendung |
| US5604260A (en) * | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
| GB9420616D0 (en) * | 1994-10-12 | 1994-11-30 | Merck Sharp & Dohme | Method, compositions and use |
| US5409944A (en) * | 1993-03-12 | 1995-04-25 | Merck Frosst Canada, Inc. | Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase |
| US5840746A (en) * | 1993-06-24 | 1998-11-24 | Merck Frosst Canada, Inc. | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
| WO1996023786A1 (en) * | 1995-01-31 | 1996-08-08 | Merck Frosst Canada Inc. | 5-methanesulfonamido-3h-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2 |
| US5681842A (en) * | 1996-11-08 | 1997-10-28 | Abbott Laboratories | Prostaglandin synthase-2 inhibitors |
| WO1998047509A1 (en) * | 1997-04-18 | 1998-10-29 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors in the prevention of cardiovascular disorders |
| ITMI20010733A1 (it) | 2001-04-05 | 2002-10-05 | Recordati Chem Pharm | Uso di inibitori dell'isoenzina cox-2 per il trattamento dell'incontinenza urinaria |
| DE10142661B4 (de) * | 2001-08-31 | 2004-06-09 | Aventis Pharma Deutschland Gmbh | Mehrfach substituierte Indan-1-ol-Systeme und ihre Verwendung als Arzneimittel |
| DE10142659A1 (de) * | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von mehrfach substituierten Indan-1-ol. Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2965279D1 (en) * | 1978-07-27 | 1983-06-01 | Schering Ag | Indanyl derivatives, process for their preparation and pharmaceutical compositions containing these compounds |
-
1981
- 1981-01-27 DE DE19813103372 patent/DE3103372A1/de not_active Withdrawn
-
1982
- 1982-01-14 AT AT82100238T patent/ATE16701T1/de not_active IP Right Cessation
- 1982-01-14 EP EP82100238A patent/EP0056956B1/de not_active Expired
- 1982-01-14 DE DE8282100238T patent/DE3267634D1/de not_active Expired
- 1982-01-26 CA CA000394947A patent/CA1175443A/en not_active Expired
- 1982-01-26 JP JP57009613A patent/JPS57176948A/ja active Granted
- 1982-01-27 IE IE168/82A patent/IE52717B1/en not_active IP Right Cessation
- 1982-01-27 AU AU79887/82A patent/AU555252B2/en not_active Ceased
- 1982-01-27 DK DK035882A patent/DK155663C/da not_active IP Right Cessation
- 1982-01-27 US US06/343,066 patent/US4375479A/en not_active Expired - Lifetime
- 1982-01-27 GB GB8202248A patent/GB2092144A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DK155663C (da) | 1989-09-04 |
| JPS57176948A (en) | 1982-10-30 |
| GB2092144A (en) | 1982-08-11 |
| AU555252B2 (en) | 1986-09-18 |
| US4375479A (en) | 1983-03-01 |
| ATE16701T1 (de) | 1985-12-15 |
| EP0056956A2 (de) | 1982-08-04 |
| AU7988782A (en) | 1982-08-05 |
| IE52717B1 (en) | 1988-02-03 |
| JPH0150698B2 (da) | 1989-10-31 |
| EP0056956B1 (de) | 1985-11-27 |
| CA1175443A (en) | 1984-10-02 |
| DK35882A (da) | 1982-07-28 |
| DE3267634D1 (en) | 1986-01-09 |
| IE820168L (en) | 1982-07-27 |
| DE3103372A1 (de) | 1982-09-02 |
| EP0056956A3 (en) | 1982-11-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |