HRP920625A2 - Novel stereoisomers - Google Patents
Novel stereoisomers Download PDFInfo
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- HRP920625A2 HRP920625A2 HR920625A HRP920625A HRP920625A2 HR P920625 A2 HRP920625 A2 HR P920625A2 HR 920625 A HR920625 A HR 920625A HR P920625 A HRP920625 A HR P920625A HR P920625 A2 HRP920625 A2 HR P920625A2
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- Prior art keywords
- ethyl
- propylsulfinyl
- hydroxypropoxy
- propyl
- amino
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 8
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([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
- 238000002360 preparation method Methods 0.000 abstract description 3
- 150000002825 nitriles Chemical class 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZMHOBBKJBYLXFR-BPNWFJGMSA-N 4-[(2r)-3-[ethyl(3-propylsulfinylpropyl)amino]-2-hydroxypropoxy]benzonitrile Chemical compound CCCS(=O)CCCN(CC)C[C@@H](O)COC1=CC=C(C#N)C=C1 ZMHOBBKJBYLXFR-BPNWFJGMSA-N 0.000 description 3
- WREXVDPOLDOXJL-JTQLQIEISA-N 4-[[(2r)-oxiran-2-yl]methoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OC[C@@H]1OC1 WREXVDPOLDOXJL-JTQLQIEISA-N 0.000 description 3
- WREXVDPOLDOXJL-SNVBAGLBSA-N 4-[[(2s)-oxiran-2-yl]methoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OC[C@H]1OC1 WREXVDPOLDOXJL-SNVBAGLBSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-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
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- RJYAVJQLHICYEN-UHFFFAOYSA-N 3-propylsulfinylpropan-1-amine Chemical compound CCCS(=O)CCCN RJYAVJQLHICYEN-UHFFFAOYSA-N 0.000 description 1
- ZMHOBBKJBYLXFR-KEJDIYNNSA-N 4-[(2s)-3-[ethyl(3-propylsulfinylpropyl)amino]-2-hydroxypropoxy]benzonitrile Chemical compound CCCS(=O)CCCN(CC)C[C@H](O)COC1=CC=C(C#N)C=C1 ZMHOBBKJBYLXFR-KEJDIYNNSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- WZMVRBZTVVOICZ-SNVBAGLBSA-N [(2r)-3-(4-cyanophenoxy)-2-hydroxypropyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@H](O)COC1=CC=C(C#N)C=C1 WZMVRBZTVVOICZ-SNVBAGLBSA-N 0.000 description 1
- WZMVRBZTVVOICZ-JTQLQIEISA-N [(2s)-3-(4-cyanophenoxy)-2-hydroxypropyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](O)COC1=CC=C(C#N)C=C1 WZMVRBZTVVOICZ-JTQLQIEISA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000007774 longterm Effects 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
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- IUSOXUFUXZORBF-UHFFFAOYSA-N n,n-dioctyloctan-1-amine;hydrochloride Chemical compound [Cl-].CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC IUSOXUFUXZORBF-UHFFFAOYSA-N 0.000 description 1
- MNZUQICTERRLAY-UHFFFAOYSA-N n-ethyl-3-propylsulfinylpropan-1-amine Chemical compound CCCS(=O)CCCNCC MNZUQICTERRLAY-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Fats And Perfumes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Laminated Bodies (AREA)
- Stereo-Broadcasting Methods (AREA)
- Separation By Low-Temperature Treatments (AREA)
Description
Područje izuma
Ovaj se izum odnosi na stereoizomere 4-[3-[etil[3-(propilsulfinil)propil]amino]-2-hidroksipropoksi]-benzonitrila, njihovo dobivanje i upotrebu.
Osnova izuma
Naša ranija patentna prijava PCT/SE88/00691, podnesena 20. prosinca 1988., objavljena nakon datuma podnošenja ove prijave, se odnosi na skupinu novih spojeva koji su korisni u tretiranju kako akutnih, tako i dugotrajnih kardijalnih aritmija različite etiologije. Među spojevima opisanim u spomenutoj prijavi je spoj 4-[3-[etil[3-(propilsulfinil)propil]amino]-2-hidroksipropoksi]-benzonitril koji ima formulu I
[image]
koji se može dobiti kao stereoizomerna smjesa, kao i u obliku različitih izomera; u spomenutoj prijavi su navedena slijedeća dva stereoizomera:
4-[3-[etil[3-(propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril
4-[3-[etil[3-(propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril.
Izum
Spoj formule I ima dva kiralna centra (*)
[image]
Sada je pronađeno da su stereoizomeri gornje formule I, tj.
4-[3-[etil[3-((R*)-propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril,
4-[3-[etil[3-((S*)-propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril,
4-[3-[etil[3-((R*)-propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril,
4-[3-[etil[3-((S*)-propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril, i
njihove farmaceutski prihvatljive soli, vrijedan novi produkt koristan kod liječenja kako akutnih tako i dugotrajnih srčanih aritmija različite etiologije.
Cilj je da se osiguraju antiaritmici koji izazivaju manje štetnih nuspojava od postojećih antiaritmičkih lijekova. Spojevi trebaju, na primjer, biti oslobođeni negativnog inotropnog djelovanja, a spojevi mogu čak biti pozitivno inotropni. Nadalje, spojevi moraju imati antiaritmično djelovanje koje je razdvojeno od djelovanja na središnji živčani sustav i na crijevno-želučani trakt.
Stereoizomeri ovog izuma se mogu terapeutski upotrijebiti u stereokemijski čistim oblicima.
Ovaj se izum također odnosi na postupke za dobivanje spomenutih izomera prema ovom izumu.
A. Spoj formule
[image]
se može dobiti reakcijom spoja formule
[image]
sa spojem formule
[image]
Reakcija se obično provodi u pogodnom otapalu poput izopropanola ili N,N-dimetilformamida. Smjesu treba zagrijavati u temperaturnom području od 40 - 100°C dok reakcija nije gotova. Nakon toga se produkt može izolirati uobičajenim metodama; ili
B. Spoj formule
[image]
se može dobiti reakcijom spoja formule
[image]
u kojoj je M metil ili 4-metil-fenilni ostatak, sa spojem formule
[image]
Reakcija se obično provodi u pogodnom organskom otapalu poput acetonitrila ili N,N-dimetilformamida. U smjesu se može dodati pogodna organska ili anorganska lužina poput trietilamina ili kalij-karbonata. Smjesa se zatim zagrijava u temperaturnom području od 90 - 100°C dok reakcija nije gotova, nakon čega se produkti mogu izolirati i očistiti primjenom uobičajenih metoda.
Izum se dalje odnosi na postupak za sprječavanje i ublažavanje kardijalnih aritmija kod sisavaca, uključujući čovjeka, koji obuhvaća davanje domaćinu kome je takav postupak potreban, djelotvorne količine spomenutog stereoizomera spoja formule I ili njegove farmaceutski prihvatljive soli.
Izum se dalje odnosi na spomenute stereoizomere spojeva formule I ili njihovih farmaceutski prihvatljivih soli za upotrebu kao lijekova, posebno kao antiaritmičkog sredstva.
Izum se također odnosi na upotrebu stereoizomera spojeva formule I za proizvodnju lijekova s djelovanjem protiv srčanih aritmija.
Slijedeći primjeri objašnjavaju izum bez ograničenja.
Primjer 1
4-[3-[etil[3-((S*)-propi]sulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril
a) Etil (3-(S*)-propilsulfinil)propilamin
Vruća otopina 27,2 g (0,1 mol) (-)-1,3,2-dioksafosforinan-5,5,-dimetil-2-hidroksi-4-(2-metoksifenil)-2-oksida i 17,73 g (0,1 mol) racemičnog etil (3-propilsulfinil)propilamina u 750 mL acetona i 32,5 mL metanola je ostavljena da se ohladi do sobne temperature dajući 23,9 g kristalinične tvari. Pokus je ponovljen s 0,25 mola, pri čemu je dobiveno 53,0 g kristala. Skupljeni produkti su prekristalizirani pet puta iz aceton-metanola dajući 8,95 g soli.
Otopina 15,06 g (0,0392 mola) trioktilamina u diklormetanu je mućkana s 19,6 mL 2M kloridne kiseline. Slojevi su odvojeni i organski sloj je opran vodom. Organski sloj s trioktilamonij-kloridom je miješan 90 min. s otopinom od 8,8 g (0,0196 mola) gore dobivene odvojene soli u vodi. Slojevi su odvojeni i organski sloj opran s vodom. Spojeni vodeni slojevi su isprani diklormetanom i zaluženina pH 11,5 s 10M natrij-hidroksidom. Četiri ekstrakcije s diklormetanom su dale 2,3 g levo-skretajućeg amina, kojem je dodijeljena oznaka S*, [a]D20 = -8,0° (c 1,0, CH3OH).
I3C NMR (kao sol s (-)-1,3,2-dioksafosforinan-5,5,-dimetil-2-hidroksi-4-(2-metoksifenil)-2-oksidom) u CDCl3: 10,80 12,95 15,81 17,55 19,49 19,58 20,41 36,59 36,61 42,37 45,50 48,73 53,67 54,71 76,79 76,83 77,34 109,63 119,69 126,42 126,50 128,33 128,93 155,83.
b) (R)-4-(oksiranilmetoksi)-benzonitril
Otopina 2,71 g (2S)-1-(4-cijanofenoksi)-3-metansulfoniloksi-propan-2-ola u 40 mL 1,2-dimetoksietana je miješana s 1,0 g praškastog natrij-hidroksida na sobnoj temperaturi tokom 22 h. Zatim je dodano 10 mL zasićene otopine natrij-klorida i smjesa je ekstrahirana dvaput s eterom. Eterski sloj je ispran s 5% natrij-hidrogenkarbonatom, sušen na magnezij-sulfatu, filtriran i uparen dajući 1,76 g kristalne tvari, t.t. 67,5°C,
[α]D20 = -14,7° (c 1,0, aceton).
NMR: 13C u CDCl3: 44,40 49,71 69,02 104,59 115,34 118,95 133,98 161,66 ppm.
c) 4-[3-[etil[3-((S*)-propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril
Smjesa 3 g etil (3-(S*)-propilsulfini])propilamina i 3,18 g (R)-4-(oksiranilmetoksi)-benzonitrila je refluktirana 16 h u 25 mL izopropil alkohola. Nakon uparavanja otapala, sirov produkt je otopljen u 2M kloridnoj kiselini, ispran s eterom, vodeni dio je podešen na pH 11,5 s 2M natrij-hidroksidom i ekstrahiran s diklormetanom. Uparavanjem organskog sloja dobiveno je 6,11 g ulja.
13C NMR u CDCl3: 11,23 13,17 16,08 20,46 47,41 49,98 52,41 54,46 56,11 66,05 70,50 103,80 115,13 118,92 133,69 161,92 ppm.
Primjer 2
4-[3-[etil[3-((R*)-propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril
a) Etil (3-(R*)-propilsulfinil)propilamin
Razdvajanjem racemičnog (3-propilsulfinil)propilamina s ( + )-1,3,2-dioksafosforinan-5,5,-dimetil-2-hidroksi-4-(2-metoksifenil)-2-oksidom na analogan način kao u primjeru 1a, dobivena je desno-skretajuća aminska lužina. Ovaj spoj, kojem je dodijeljena oznaka R*, ima slijedeća svojstva: [α]D20 = + 7,6° (c 1,0, CH3OH).
13C NMR (kao sol s (+)-l,3,2-dioksafosforinan-5,5,-dimetil-2-hidroksi-4-(2-metoksifenil)-2-oksidom) u CDCl3: 10,92 13,07 15,93 17,66 19,56 19,70 20,52 36,72 36,73 42,48 45,61 48,85 53,79 54,82 76,92 76,96 77,45 77,49 109,73 119,81 126,54 126,62 128,44 129,06 155,95 ppm.
b) (S)-4-(oksiranilmetoksi)-benzonitril
Iz 2,7 g (2R)-1-(4-cijanofenoksi)-3-metansulfoniloksi-propan-2-ola na analogan način kao u primjeru 1b, dobiveno je 1,75 g kristalne tvari; t.t. 68.0°C,
[α]D20 = +14,5° (c 1,0, aceton).
13C NMR u CDCl3: 44,21 49,58 68,90 104,25 115,20 118,86 133,80 161,53.
c) 4-[3-[etil[3-((R*)-propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril
Smjesa 2,3 g etil (3-(R*)-propilsulfinil)propilamina i 3,18 g (S)-4-(oksiranilmetoksi)-benzonitrila je refluktirana 16 h u 19 mL izopropil alkohola i zatim obrađena na analogan način kao u 1c dajući 4,1 g ulja;
[α]D20 = + 26,5° (c 1,0, CH3OH).
13C NMR u CDCl3: 11,16 13,05 15,96 20,37 47,38 49,87 52,37 54,31 56,05 66,10 70,47 103,65 115,06 118,78 133,55 161,86.
Primjer 3
4-[3-[etil[3-((R*)-propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril
Smjesa 2,3 g etil (3-(R*)-propilsulfinil)propilarnina i 2,5 g (R)-4-(oksiranilmetoksi)-benzonitrila je refluktirana 16 h u 19 mL izopropil alkohola na analogan način kao u primjeru 1c. Uobičajenim načinom obrade dobiveno je 4,27 g ulja; [α]D20 = - 13,4° (c 1,0, CH3OH).
13C NMR u CDCl3: 11,58 13,36 16,29 20,57 47,70 49,96 52,41 54,64 56,36 66,24 70,63 104,18 115,33 119,07 133,91 162,09.
Primjer 4
4-[3-[etil[3-((S*)-propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril
Smjesa 2,3 g etil (3-(S*)-propilsulfinil)propilamina i 2,5 g (S)-4-(oksiranilmetoksi)-benzonitrila je refluktirana 24 h u 19 mL izopropil alkohola na analogan način kao u primjeru 1c. Uobičajenim načinom obrade dobiveno je 3,65 g ulja;
[α]D20 = + 11,1° (c 1,0, CH3OH).
13C NMR u CDCl3: 11,56 13,33 16,25 20,54 47,71 49,92 52,42 54,53 56,31 66,33 70,64 104,03 115,33 119,06 133,86 162,11.
Claims (9)
1. Spoj formule I
[image]
u obliku jednog od stereoizomera:
4-[3-[etil[3-((R*)propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril,
4-[3-[etil[3-((S*)propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril,
4-[3-[etil[3-((R*)-propilsulfinil)propil]amino|-2(S)-hidroksipropoksi]-benzonitril, i
4-[3-[etil[3-((S*)-propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril,
ili njegova farmaceutski prihvatljiva sol.
2. Spoj 4-[3-[etil[3-((R*)propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril, ili njegova farmaceutski prihvatljiva sol.
3. Spoj 4-[3-[etil[3-((S*)propilsulfinil)propil]amino]-2(R)-hidroksipropoksi]-benzonitril, ili njegova farmaceutski prihvatljiva sol.
4. Spoj 4-[3-[etil[3-((R*)propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril, ili njegova farmaceutski prihvatljiva sol.
5. Spoj 4-[3-[etil[3-((S*)propilsulfinil)propil]amino]-2(S)-hidroksipropoksi]-benzonitril, ili njegova farmaceutski prihvatljiva sol.
6. Postupak za dobivanje spoja prema bilo kojem od zahtjeva 1-5, određen time što obuhvaća
a) reakciju spoja formule
[image]
sa spojem formule
[image]
ili
b) reakciju spoja formule
[image]
sa spojem formule
[image]
gdje je M metil ili 4-metil-fenilni ostatak.
7. Postupak za liječenje srčanih aritmija kod sisavaca, uključujući čovjeka, određen time, što se osobi kojoj je potrebno takvo liječenje daje djelotvorna količina spoja prema bilo kojem od zahtjeva 1-5 ili njegova farmaceutski prihvatljiva sol.
8. Spoj prema bilo kojem od zahtjeva 1-5 za upotrebu kao lijek.
9. Upotreba spoja prema bilo kojem od zahtjeva 1-5 za dobivanje lijekova s djelovanjem protiv srčanih aritmija.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8902237A SE8902237D0 (sv) | 1989-06-20 | 1989-06-20 | Novel stereoisomers |
| YU120690A YU120690A (sh) | 1989-06-20 | 1990-06-20 | Novi stereoizomeri jedinjenja 4-3-etil 3-(propilsulfinil)propil)amino-2-hidroksi propoksi-benzonitrila |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP920625A2 true HRP920625A2 (en) | 1994-08-31 |
Family
ID=20376342
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR920625A HRP920625A2 (en) | 1989-06-20 | 1992-09-30 | Novel stereoisomers |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US5055490A (hr) |
| EP (1) | EP0404748B1 (hr) |
| JP (1) | JPH04506076A (hr) |
| KR (1) | KR920702676A (hr) |
| CN (1) | CN1048213A (hr) |
| AT (1) | ATE88698T1 (hr) |
| AU (1) | AU641665B2 (hr) |
| BG (1) | BG60164B2 (hr) |
| CA (1) | CA2058941A1 (hr) |
| CZ (1) | CZ278988B6 (hr) |
| DE (1) | DE69001461T2 (hr) |
| DK (1) | DK0404748T3 (hr) |
| ES (1) | ES2054325T3 (hr) |
| FI (1) | FI915937A0 (hr) |
| HR (1) | HRP920625A2 (hr) |
| HU (1) | HU211024B (hr) |
| IE (1) | IE902161A1 (hr) |
| IL (1) | IL94677A0 (hr) |
| LT (1) | LTIP1727A (hr) |
| LV (1) | LV10248A (hr) |
| MX (1) | MX174254B (hr) |
| NO (1) | NO914929L (hr) |
| NZ (1) | NZ234023A (hr) |
| PH (1) | PH27009A (hr) |
| PL (1) | PL163988B1 (hr) |
| PT (1) | PT94417A (hr) |
| RU (1) | RU2032663C1 (hr) |
| SE (1) | SE8902237D0 (hr) |
| WO (1) | WO1990015794A1 (hr) |
| YU (1) | YU120690A (hr) |
| ZA (1) | ZA904411B (hr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8705150D0 (sv) * | 1987-12-23 | 1987-12-23 | Haessle Ab | Novel antiarrhythmic agents |
| SE8902236D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel polystyrenesulfonate |
| SE8902235D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel cyclodextrin inclusion complexes |
| DE19546159A1 (de) | 1995-12-11 | 1997-06-12 | Liedtke Pharmed Gmbh | Methode und Zusammensetzung einer topisch wirksamen Therapie postoperativer und posttraumatischer Wundschmerzen |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1457876A (en) * | 1972-12-15 | 1976-12-08 | Ici Ltd | Alkanolamine derivatives device for use in |
| GB1433920A (en) * | 1973-10-01 | 1976-04-28 | Ici Ltd | Alkanolamine derivatives |
| SE8705150D0 (sv) * | 1987-12-23 | 1987-12-23 | Haessle Ab | Novel antiarrhythmic agents |
-
1989
- 1989-06-20 SE SE8902237A patent/SE8902237D0/xx unknown
-
1990
- 1990-06-07 ZA ZA904411A patent/ZA904411B/xx unknown
- 1990-06-08 IL IL94677A patent/IL94677A0/xx unknown
- 1990-06-12 NZ NZ234023A patent/NZ234023A/en unknown
- 1990-06-14 PH PH40674A patent/PH27009A/en unknown
- 1990-06-15 CN CN90104476A patent/CN1048213A/zh active Pending
- 1990-06-15 IE IE216190A patent/IE902161A1/en unknown
- 1990-06-18 US US07/539,852 patent/US5055490A/en not_active Expired - Fee Related
- 1990-06-18 MX MX021202A patent/MX174254B/es unknown
- 1990-06-19 ES ES90850243T patent/ES2054325T3/es not_active Expired - Lifetime
- 1990-06-19 AU AU58514/90A patent/AU641665B2/en not_active Ceased
- 1990-06-19 CA CA002058941A patent/CA2058941A1/en not_active Abandoned
- 1990-06-19 HU HU905353A patent/HU211024B/hu not_active IP Right Cessation
- 1990-06-19 AT AT90850243T patent/ATE88698T1/de active
- 1990-06-19 EP EP90850243A patent/EP0404748B1/en not_active Expired - Lifetime
- 1990-06-19 JP JP2509209A patent/JPH04506076A/ja active Pending
- 1990-06-19 KR KR1019910701914A patent/KR920702676A/ko not_active Application Discontinuation
- 1990-06-19 DE DE9090850243T patent/DE69001461T2/de not_active Expired - Fee Related
- 1990-06-19 WO PCT/SE1990/000438 patent/WO1990015794A1/en active Application Filing
- 1990-06-19 PT PT94417A patent/PT94417A/pt not_active Application Discontinuation
- 1990-06-19 DK DK90850243.8T patent/DK0404748T3/da active
- 1990-06-20 PL PL90285701A patent/PL163988B1/pl unknown
- 1990-06-20 CZ CS903071A patent/CZ278988B6/cs unknown
- 1990-06-20 YU YU120690A patent/YU120690A/sh unknown
-
1991
- 1991-12-13 NO NO91914929A patent/NO914929L/no unknown
- 1991-12-17 FI FI915937A patent/FI915937A0/fi not_active Application Discontinuation
- 1991-12-19 RU SU915010868A patent/RU2032663C1/ru active
- 1991-12-20 BG BG095670A patent/BG60164B2/bg unknown
-
1992
- 1992-09-30 HR HR920625A patent/HRP920625A2/hr not_active Application Discontinuation
-
1993
- 1993-06-28 LV LV930690A patent/LV10248A/xx unknown
- 1993-12-30 LT LTIP1727A patent/LTIP1727A/xx not_active Application Discontinuation
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| A1OB | Publication of a patent application | ||
| ODBC | Application rejected |