HUT74562A - Optically active benzothiepin derivatives, their preparation and use - Google Patents
Optically active benzothiepin derivatives, their preparation and use Download PDFInfo
- Publication number
- HUT74562A HUT74562A HU9503802A HU9503802A HUT74562A HU T74562 A HUT74562 A HU T74562A HU 9503802 A HU9503802 A HU 9503802A HU 9503802 A HU9503802 A HU 9503802A HU T74562 A HUT74562 A HU T74562A
- Authority
- HU
- Hungary
- Prior art keywords
- formula
- optically active
- compound
- active compound
- oxo
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 8
- NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
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- 206010017076 Fracture Diseases 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000010392 Bone Fractures Diseases 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- 239000013003 healing agent Substances 0.000 claims description 2
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 50
- -1 phosphorylmethyl Chemical group 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655363—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring
- C07F9/655372—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
Optikailag aktĂv benzotiepin-szĂĄrmazĂ©k; elĆĂĄllĂtĂĄs^ Ă©s alkalmazĂĄsa
A talĂĄlmĂĄny tĂĄrgya oszteogenezis elĆsegĂtĆ hatĂĄsĂș, csontfelszĂvĂłdĂĄst elnyomĂł hatĂĄsĂș Ă©s mĂĄs hatĂĄsokkal rendelkezĆ optikailag aktĂv benzotiepin-szĂĄrmazĂ©k Ă©s a hatĂłanyagot tartalmazĂł csontbetegsĂ©g megelĆzĆ vagy gyĂłgyĂtĂł kĂ©szĂtmĂ©ny.
A csontbetegsĂ©g patolĂłgiai ĂĄllapot vagy olyan betegsĂ©g, amely a csont kvantitatĂv csökkenĂ©sĂ©nek bizonyos fokon tĂșl törtĂ©nĆ bekövetkezĂ©sĂ©nek következmĂ©nyekĂ©ppen elĆĂĄllĂł tĂŒnettel vagy rizikĂłval jĂĄr. Az oszteoporĂłzis fĆ tĂŒnetei gerinc pĂșpossĂĄg, a hĂĄt derĂ©kcsontok törĂ©sei, csigolya központ törĂ©s, combnyaktörĂ©s, orsĂłcsont, borda Ă©s a felkarcsont felsĆ vĂ©gĂ©nek törĂ©se Ă©s egyĂ©b törĂ©sek. Az egĂ©szsĂ©ges csontszövetben a csontromlĂĄs folyamatosan törtĂ©nik, miközben a csontkĂ©pzĆdĂ©s Ă©s a csontfelszĂvĂłdĂĄs egyensĂșlyban van; a csontkĂ©pzö sejt Ă©s a csontfalĂł sejt kulcsszerepet jĂĄtszik a csontkĂ©pzödĂ©sben illetve -felszĂvĂłdĂĄsban. Ennek az egyensĂșlynak a megromlĂĄsa eredmĂ©nyezi a csont kvantitatĂv csökkenĂ©sĂ©t. TradicionĂĄlisan a csontritkulĂĄs megelĆzĂ©sĂ©re Ă©s kezelĂ©sĂ©re fĆleg csontfelszĂvĂłdĂĄs csökkentĆket hasznĂĄltak, pĂ©ldĂĄul ösztrogĂ©nt, kalcitonint Ă©s
Aktaszåm: 83093-5372-KY/KmO ⹠· ⹠· · · *· ⹠· · · · ···· ·· ··· ···· ··
- 2 bifoszfonĂĄtokat. Ezek a csontfelszĂvĂłdĂĄst csökkentĆk azonban bizonyos esetekben nem Ă©rik el a kielĂ©gĂtĆ hatĂĄst az egyĂ©n korlĂĄtĂĄi Ă©s bizonytalan hatĂ©konysĂĄg következtĂ©ben.
Ugyanakkor a jelen talĂĄlmĂĄny feltalĂĄlĂłi mĂĄr felfedeztĂ©k, hogy egy kĂ©ntartalmĂș heterociklusos vegyĂŒlet kivĂĄlĂł csontfelszĂvĂłdĂĄst elnyomĂł hatĂĄssal rendelkezik, mĂ©gpedig az (A) vagy (B) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet, vagy ennek sĂłja (nem vizsgĂĄlt közzĂ©tett japĂĄn szabadalmi bejelentĂ©s: 232880/1991 Ă©s 364179/1992), ahol A jelentĂ©se adott esetben szubsztituĂĄlt benzilgyĂșrƱ, R jelentĂ©se hidrogĂ©natom vagy adott esetben szubsztituĂĄlt szĂ©nhidrogĂ©ncsoport, B jelentĂ©se adott esetben Ă©szterezett vagy amidĂĄlt karboxilcsoport, X jelentĂ©se -CH(OH)vagy -CO-; k jelentĂ©se 0 vagy 1, k' Ă©s n jelentĂ©se 0, 1 vagy 2.
Ilyen vegyĂŒlet pĂ©ldĂĄul a (C) kĂ©pletƱ vegyĂŒlet.
SzĂŒksĂ©ges tehĂĄt olyan jobb tulajdonsĂĄgokkal rendelkezĆ, megelĆzĆ vagy gyĂłgyĂĄszati szer kifejlesztĂ©se, amely jobb stabilitĂĄst, abszorbeĂĄlhatĂłsĂĄgot Ă©s biohozzĂĄfĂ©rhetĆsĂ©get mutat klinikailag hasznos gyĂłgyszerkĂ©nt, kĂŒlönösen orĂĄlis kĂ©szĂtmĂ©nykĂ©nt.
A jelen talĂĄlmĂĄny feltalĂĄlĂłi intenzĂv kutatĂĄst vĂ©geztek klinikailag hasznosabb gyĂłgyszer kidolgozĂĄsĂĄra, amely közvetlenĂŒl hat a csontra, a csontfelszĂvĂłdĂĄs megakadĂĄlyozĂĄsĂĄra Ă©s a csontkĂ©pzĆdĂ©s elĆsegĂtĂ©sĂ©re, melyet elĆször szintetizĂĄltunk, Ă©s a kapott optikailag aktĂv benzotiepin-szĂĄrmazĂ©kot az (I) ĂĄltalĂĄnos kĂ©plet mutatja, ahol
R jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport;
R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl rövidszĂ©nlĂĄncĂș alkilcsoportot jelent, vagy egyĂŒtt gyƱrƱt kĂ©pez, »· ····
- 3 Ă©s azt talĂĄltuk, hogy ez a vegyĂŒlet vĂĄratlanul hasznos klinikailag az (A) vagy (B) kĂ©pletƱ vegyĂŒletek közĂŒl, kĂŒlönösen kivĂĄlĂł oszteogenezis elĆsegĂtĆ hatĂĄsĂș Ă©s orĂĄlisan abszorbeĂĄlhatĂł. PĂ©ldĂĄul az (I) kĂ©pletƱ optikailag aktĂv benzotiepin-szĂĄrmazĂ©k orĂĄlis abszorbeĂĄlhatĂłsĂĄg szempontjĂĄbĂłl felĂŒlmĂșlja a (C) kĂ©pletƱ vegyĂŒletet.
A jelen talålmåny feltalålói tovåbbi kutatåsokat végeztek ennek az ismeretnek az alapjån, és kifejlesztették a jelen talålmånyt.
A jelen talĂĄlmĂĄny tehĂĄt (1) (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletre vonatkozik, ahol R jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport; R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl rövidszĂ©nlĂĄncĂș alkilcsoportot vagy egyĂŒtt rövidszĂ©nlĂĄncĂș alkilĂ©ncsoportot jelent;
(2) a fentiek szerinti vegyĂŒlet, ahol R, R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl 1-4 szĂ©natomos alkilcsoport, (3) a fentiek szerinti vegyĂŒlet, amely (2R,4S)-(-)-N-[4-(dietoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamid, (4) a talĂĄlmĂĄny kiterjed tovĂĄbbĂĄ az (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet - ahol R jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport; R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl rövidszĂ©nlĂĄncĂș alkilcsoport; vagy egyĂŒtt rövidszĂ©nlĂĄncĂș alkilĂ©ncsoportot kĂ©pez - elĆĂĄllĂtĂĄsĂĄra, oly mĂłdon, hogy egy (II) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletet - ahol R jelentĂ©se a fenti - vagy reakciĂłkĂ©pes szĂĄrmazĂ©kĂĄt vagy a karboxilcsoporton kĂ©pezett sĂłjĂĄt (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlettel reagĂĄltatunk, ahol R1 Ă©s R2
.. . .. · .· . ·. : ·· .·*.
.... .· ··· ···· ··
- 4 jelentése a fenti, vagy ennek reakcióképes szårmazékåval vagy az aminocsoporton képezett sójåval reagåltatunk;
(5) a talĂĄlmĂĄny kiterjed tovĂĄbbĂĄ a (II) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletre, ahol R jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport vagy reakciĂłkĂ©pes szĂĄrmazĂ©ka vagy a karboxilcsoporton kĂ©pezett sĂłja;
(6) a talĂĄlmĂĄny kiterjed tovĂĄbbĂĄ oszteogenezist elĆsegĂtĆ szerre, amely a fentiek szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletet tartalmazza;
(7) a fentiekben leĂrt oszteogenezist elĆsegĂtĆ szer orĂĄlisan abszorbeĂĄlhatĂł;
(8) a talĂĄlmĂĄny kiterjed tovĂĄbbĂĄ csontbetegsĂ©geket megelĆzĆ vagy gyĂłgyĂtĂł szerre, amely hatĂłanyagkĂ©nt a fenti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletet tartalmazza, (9) Ă©s egy olyan csonttörĂ©st gyĂłgyĂtĂł szerre, amely a fenti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletet tartalmazza, Ă©s (10) a fenti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet alkalmazĂĄsĂĄra oszteogenezis elĆsegĂtĆ szer gyĂĄrtĂĄsĂĄhoz;
(11) valamint az (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet alkalmazĂĄsĂĄra csontbetegsĂ©gek megelĆzĂ©sĂ©re vagy gyĂłgyĂtĂĄsĂĄra szolgĂĄlĂł szer elĆĂĄllĂtĂĄsĂĄra, Ă©s (12) a fenti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet alkalmazĂĄsĂĄra csonttörĂ©sek gyĂłgyĂtĂĄsĂĄnak elĆsegĂtĂ©sĂ©t szolgĂĄlĂł szer elĆĂĄllĂtĂĄsĂĄra.
A fentiekben a rövidszĂ©nlĂĄncĂș alkilcsoport R, R1 vagy R2 jelentĂ©sĂ©ben egyenes vagy elĂĄgazĂł lĂĄncĂș Ă©s 1 - 6 szĂ©natomos, pĂ©ldĂĄul metil-, etil-, propil-, izopropil-, butil-, izobutil-, szek-butil-, terc-butil-, pentil-, izopentil-, neopentil- vagy ⹠· ⹠· · · · · ⹠· · hexilcsoport. R1 Ă©s R2 egyĂŒtt rövidszĂ©nlĂĄncĂș alkilĂ©ncsoportot jelent, ahol
jelentése lehet
(CH2)n (ahol n 2 - 4 közötti egész szåm).
R, R1 Ă©s R2 jelentĂ©se elĆnyösen 1 - 4 szĂ©natomos alkil-, pĂ©ldĂĄul metil- vagy etilcsoport.
Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet (2R,4S) konfigurĂĄciĂłjĂș optikailag aktĂv vegyĂŒlet Ă©s elĆnyösen nem tartalmaz (2S.4R) konfigurĂĄciĂłjĂș vegyĂŒletet Ă©s optikai tisztasĂĄga közel 100 %-os.
Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletek közĂŒl elĆnyösek a (2R,4S)-(-)-N-[4-(dietoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamid stb.
Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet Ășgy ĂĄllĂtjuk elĆ, hogy egy (II) kĂ©pletƱ optikailag aktĂv vegyĂŒletet vagy reakciĂłkĂ©pes szĂĄrmazĂ©kĂĄt vagy a karboxilcsoporton kialakĂtott sĂłjĂĄt (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlettel, vagy szĂĄrmazĂ©kĂĄval vagy az aminocsoporton kĂ©pezett sĂłjĂĄval reagĂĄltatjuk.
A (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet elĆnyös szĂĄrmazĂ©kai, melyek az aminocsoporton reakciĂłkĂ©pesek, magukban foglaljĂĄk a Schiff-bĂĄzis tĂpusĂș imino- vagy enamin formĂĄjĂș tautomer izomereket, amelyeket Ășgy kapunk, hogy egy (Ilii) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet reagĂĄltatunk egy karbonil-vegyĂŒlettel, pĂ©ldĂĄul aldehiddel, pĂ©ldĂĄul acetaldehiddel vagy ketonnal, pĂ©ldĂĄul acetonnal; vagy ezek a szĂĄrmazĂ©kok lehetnek a (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet Ă©s egy szililvegyĂŒlet, pĂ©ldĂĄul bisz(trimetiI
- 6 -szil i l)-acetam i d, mono(trimetil-szilil)-acetamid vagy bisz(trimetil-szilil)-karbamid reakciĂłjĂĄbĂłl szĂĄrmazĂł szilil-szĂĄrmazĂ©k, tovĂĄbbĂĄ a (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet Ă©s foszfor-tri ki Ćri d vagy foszgĂ©n reakciĂłjĂĄbĂłl szĂĄrmazĂł vegyĂŒletek.
A (II) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet karboxilcsoporton reakciĂłkĂ©pes szĂĄrmazĂ©kai lehetnek pĂ©ldĂĄul a savhalogenidek, savanhidridek, aktivĂĄlt amidok Ă©s aktivĂĄlt Ă©szterek, elĆĂĄllĂtĂĄsuk ismert mĂłdon törtĂ©nik. KözelebbrĆl, az ilyen elĆnyös reakciĂłkĂ©pes szĂĄrmazĂ©kok lehetnek savkloridok, savazidok, vegyes savanhidridek, pĂ©ldĂĄul szubsztituĂĄlt foszforsavval, pĂ©ldĂĄul dialkil-foszforsavval, fenil-foszforsavval, difenil-foszforsavval, dibenzil-foszforsavval vagy halogĂ©nezett foszforsavval kĂ©pezett vegyes savanhidridek vagy kĂ©nsavval, tiokĂ©nsavval vagy kĂ©nessavval kĂ©pezett anhidridek, vagy szulfonsavval, pĂ©ldĂĄul metĂĄnszulfonsavval vagy alifĂĄs karbonsavval, pĂ©ldĂĄul ecetsavval, propionsavval, vajsavval, izovajsavval, pivĂĄlsavval, pentĂĄnsavval, izopentĂĄnsavval vagy triklĂłr-ecetsavval kĂ©pezett anhidridek vagy aromĂĄs karbonsavval, pĂ©ldĂĄul benzoesavval kĂ©pezett savanhidridek; szimmetrikus savanhidridek; imidazollal, 4-szubsztituĂĄlt imidazoilal, dimetil-pirazollal, triazollal vagy tetrazollal kĂ©pezett aktivĂĄlt amidok; aktivĂĄlt Ă©szterek, pĂ©ldĂĄul ciano-metilĂ©szter, metoxi-metil-Ă©szter, dimetil-imino-metil-Ă©szter, vinil-Ă©szter, propargil-Ă©szter, p-nitro-fenil-Ă©szter, triklĂłr-fenil-Ă©szter, pentaklĂłr-fenil-Ă©szter, mezil-fenil-Ă©szter, fenilazo-fenil-Ă©szter, feniltio-Ă©szter, p-nitro-fenil-Ă©szter, p-krezil-tio-Ă©szter, karboxi-metil-tio-Ă©szter, piranil-Ă©szter, piridil-Ă©szter, piperidil-Ă©szter Ă©s 8-kinolil-tio-Ă©szter; tovĂĄbbĂĄ N-hidroxi-vegyĂŒletekkel kĂ©pezett Ă©szterek, pĂ©ldĂĄul N,N-d i met i I-h idroxi I-a m i η, 1 -hidroxi-2-(1 H)-piridon, N-hidroxi-szukcinimid, N-hidroxi-ftĂĄlimid, 1 -hidroxi-1 H-benzotriazol, N-hidroxi-5-norbornĂĄn-2,3-dikarboximid. Ezeket a reakciĂłkĂ©pes szĂĄrmazĂ©kokat tetszĆlegesen vĂĄlaszthatjuk meg a hasznĂĄlt (II) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet tĂpusĂĄnak fĂŒggvĂ©nyĂ©ben.
A (II) vagy (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletek elĆnyös reakciĂłkĂ©pes szĂĄrmazĂ©kainak sĂłi lehetnek bĂĄzisokkal kĂ©pezett sĂłk, pĂ©ldĂĄul alkĂĄlifĂ©msĂłk, pĂ©ldĂĄul nĂĄtrium- Ă©s kĂĄliumsĂł, alkĂĄliföldfĂ©msĂłk, pĂ©ldĂĄul kalciumsĂł Ă©s magnĂ©ziumsĂł, ammĂłniumsĂł, tovĂĄbbĂĄ szerves bĂĄzissal kĂ©pezett sĂłk, pĂ©ldĂĄul trimetil-amin-sĂł, trieti l-amin-sĂł, piridin, pikolin, diciklohexil-amin-sĂł Ă©s N,N-dibenzil-etilĂ©n-diamin-sĂł.
Ezt a reakciĂłt rendszerint szokĂĄsos oldĂłszerben, pĂ©ldĂĄul vĂzben, alkoholban, pĂ©ldĂĄul metanolban vagy etanolban, acetonban, dioxĂĄnban, acetonitrilben, kloroformban, metilĂ©n-kloridban, etilĂ©n-kloridban, tetrahidrofurĂĄnban, etil-acetĂĄtban, Î,Î-dimetil-formamidban vagy piridinben vĂ©gezzĂŒk, de bĂĄrmilyen mĂĄs szerves oldĂłszerben is vĂ©gezhetĆ, hogyha nem reagĂĄl a reakciĂł egyĂ©b rĂ©sztvevĆivel. Ezek a szokĂĄsos oldĂłszerek vĂzzel elegyĂtve is hasznĂĄlhatĂłk. Ha a (II) vagy (III) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet szabad sav vagy sĂłja formĂĄjĂĄban alkalmazzuk, akkor a reakciĂłt elĆnyösen a szokĂĄsos kondenzĂĄlĂłszer jelenlĂ©tĂ©ben hajtjuk vĂ©gre. Ilyen lehet pĂ©ldĂĄul: N.Nâ-diciklohexil-karbodiimid; N-ciklohexil-N'-morfolino-etil-karbodiimid; N-ciklohexil-N'-(4-dietil-amino-ciklohexil)-karbodiimid; Î,Î'-dietil-karbodiimid; Î,Î'-diizopropil-karbodiimid; N-etil-N'-(3-dimetil-amino-propil)-karbodiimid; N,N'-karbonil-bisz(2-metil-imidazol); pentametilĂ©n-ketĂ©n-N-ciklohexil-imin; difenil-ketĂ©n-N-ciklohexil⹠· · ·
- 8 -imin; etoxi-acetilĂ©n; 1 -alkoxi-1 -klĂłr-etilĂ©n; trialkil-foszfit; etil-polifoszfĂĄt; izopropil-polifoszfĂĄt; foszforoxi-klorid; difenil-foszforil-azid; tionil-klorid; oxalil-klorid; vagy rövidszĂ©nlĂĄncĂș halogĂ©n-hangyasav-alkil-Ă©szter, pĂ©ldĂĄul klĂłr-hangyasav-etil-Ă©szter vagy klĂłr-hangyasav-izopropil-Ă©szter; valamint trifenil-foszfin; 2-etil-7-hidroxi-benzizoxazĂłlium-sĂł, 2-etil-5-(m-szulfofenil)-izoxazolium-hidroxid- intramolekulĂĄris sĂł; N-hidroxi-benzotriazol; 1 -(p-klĂłr-benzolszulfonil-oxi)-6-klĂłr-1 H-benzotriazol; vagy Ășgynevezett Vilsmeier-reagens, melynek elĆĂĄllĂtĂĄsa N,N'-dimetil-formamid Ă©s tionil-klorid, foszgĂ©n, klĂłr-hangyasav, trikiĂłr-metil-Ă©szter vagy foszforoxi-klorid reagĂĄltatĂĄsĂĄval törtĂ©nik. ElĆnyös tovĂĄbbĂĄ kondenzĂĄlĂłszer, pĂ©ldĂĄul N,N'-diciklohexil-karbodiimid alkalmazĂĄsa N-hidroxi-benzotriazol vagy N-hidroxi-5-norbornĂĄn-endo-2,3-dikarboximid jelenlĂ©tĂ©ben. Ezt a reakciĂłt elvĂ©gezhetjĂŒk szervetlen vagy szerves bĂĄzis, pĂ©ldĂĄul alkĂĄlifĂ©m-hidrogĂ©n-karbonĂĄt tri(rövidszĂ©nlĂĄncĂș)alkil-amin, piridin, N-(rövidszĂ©nlĂĄncĂș)-alkil-morfolin vagy N,N-di(rövidszĂ©nlĂĄncĂș alkil)-benzil-amin jelenlĂ©tĂ©ben is. BĂĄr a reakciĂł hĆmĂ©rsĂ©klete nem döntĆ, a reakciĂłt rendszerint hƱtĂ©s vagy melegĂtĂ©s (-10 - 120 °C közötti) körĂŒlmĂ©nyek között hajtjuk vĂ©gre. A reakciĂłidĆ rendszerint fĂ©l ĂłrĂĄtĂłl 100 ĂłrĂĄig, elĆnyösen
1-tĆl 50 ĂłrĂĄig terjed. Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒleteket ismert mĂłdon izolĂĄlhatjuk Ă©s tisztĂthatjuk elvĂĄlasztĂĄssal vagy tisztĂtĂĄsi mĂłdszerrel, pĂ©ldĂĄul bepĂĄrlĂĄssal, csökkentett nyomĂĄson vĂ©gzett bepĂĄrlĂĄssal, oldĂłszer extrahĂĄlĂĄssal, kristĂĄlyosĂtĂĄssal, ĂĄtkristĂĄlyosĂtĂĄssal, Ășjra oldĂĄssal Ă©s kromatografĂĄlĂĄssal.
A (II) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet elĆĂĄllĂthatjuk pĂ©ldĂĄul Ășgy, hogy a (II) ĂĄltalĂĄnos kĂ©pletƱ racemĂĄtot optikailag ⹠· · · rezolvĂĄljuk a 364179/1992 szĂĄmĂș nem vizsgĂĄlt közzĂ©tett japĂĄn szabadalmi bejelentĂ©s szerint. KözelebbrĆl, az optikailag aktĂv vegyĂŒlet elĆĂĄllĂthatĂł Ășgy, hogy elĆĂĄllĂtjuk a (II) ĂĄltalĂĄnos kĂ©pletĂŒ vegyĂŒlet racemĂĄt sĂłjĂĄt, amelyet egy optikailag aktĂv bĂĄzissal, pĂ©ldĂĄul optikailag aktĂv α-metil-benzil-aminnal, brucinnal, kininnel vagy cinkoninnal kĂ©pez, majd a kapott diasztereomerek oldĂ©konysĂĄgĂĄnak kĂŒlönbözĆsĂ©gĂ©n alapulĂł frakcionĂĄlt kristĂĄlyosĂtĂĄst vĂ©gzĂŒnk ismĂ©telten, Ă©s Ăgy egy tiszta formĂĄjĂș, enyhĂ©n oldĂłdĂł sĂłt kapunk, majd savval kezeljĂŒk. Egy mĂĄsik mĂłdszer szerint az optikailag aktĂv vegyĂŒletet elĆĂĄllĂthatjuk Ășgy, hogy a (II) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet racemĂĄtjĂĄt optikailag aktĂv alkohollal, pĂ©ldĂĄul optikailag aktĂv metil-laktĂĄttal vagy metil-mandelĂĄttal Ă©szterezzĂŒk, Ă©s elĆĂĄllĂtjuk az Ă©szter diasztereomerjei közĂŒl az egyiket tiszta formĂĄban annak alapjĂĄn, hogy a kĂ©t diasztereomer fizikai tulajdonsĂĄgai eltĂ©rĆek, majd hidrolĂzist vĂ©gzĂŒnk.
A talĂĄlmĂĄny szerinti kĂvĂĄnt (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet szilĂĄrd kĂ©szĂtmĂ©ny formĂĄjĂĄban is elĆĂĄllĂthatjuk, pĂ©ldĂĄul tabletta, kapszula, granulĂĄtum Ă©s por formĂĄjĂĄban, vagy elĆĂĄllĂthatunk folyĂ©kony kĂ©szĂtmĂ©nyt, pĂ©ldĂĄul szirupot Ă©s injektĂĄlhatĂł kĂ©szĂtmĂ©nyeket a gyĂłgyĂĄszatilag elfogadhatĂł hordozĂłk segĂtsĂ©gĂ©vel, Ă©s adagolĂĄsuk orĂĄlisan vagy nem orĂĄlisan törtĂ©nhet. Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet arĂĄnya a kĂ©szĂtmĂ©nyben ĂĄltalĂĄban 0,01 - 95 tömeg%, elĆnyösen 0,1 - 20 tömeg% az egĂ©sz kĂ©szĂtmĂ©nyre vonatkoztatva. Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet elĆnyösen orĂĄlis kĂ©szĂtmĂ©ny formĂĄjĂĄban hasznĂĄljuk.
GyĂłgyĂĄszatilag elfogadhatĂł hordozĂłk lehetnek kĂŒlönbözĆ szerves vagy szervetlen anyagok, melyeket ĂĄltalĂĄban hasznĂĄ-
lĂŒnk gyĂłgyszerekben, ilyenek a segĂ©danyagok, kenĆanyagok, kötĆanyagok, szĂ©tesĂ©st elĆsegĂtĆ szerek a szilĂĄrd kĂ©szĂtmĂ©nyekben, tovĂĄbbĂĄ oldĂłszerek, oldĂĄst elĆsegĂtĆ szerek, szuszpendĂĄlĂłszerek, izotĂłniĂĄs oldatot elĆĂĄllĂtĂł szerek, pufferek Ă©s folyĂ©kony kĂ©szĂtmĂ©nyekben hasznĂĄlatos nyugtatĂłszerek. MĂĄs adalĂ©kok lehetnek konzervĂĄlĂłszerek, antioxidĂĄnsok, szĂnezĆk Ă©s Ă©desĂtĆszerek, ha szĂŒksĂ©ges. ElĆnyös segĂ©danyagok mĂ©g a laktĂłz, szacharĂłz, D-mannit, kemĂ©nyĂtĆ, kristĂĄlyos cellulĂłz Ă©s könnyƱ kovasav-anhidrid. ElĆnyös kenĆanyagok pĂ©ldĂĄul a magnĂ©zium-sztearĂĄt, kalcium-sztearĂĄt, talkum Ă©s kolloid szilĂcium-dioxid. ElĆnyös kötĆanyagok a kristĂĄlyos cellulĂłz, szacharĂłz, D-mannit, dextrin, hidroxi-propil-cellulĂłz, hidroxi-propil-metil-cellulĂłz Ă©s polivinil-pirrolidon. ElĆnyös szĂ©tesĂ©st elĆsegĂtĆ szerek pĂ©ldĂĄul a kemĂ©nyĂtĆ, karboxi-metil-cellulĂłz, karboxi-metil-cellulĂłz kalcium, crosscarmelloz, nĂĄtrium Ă©s karboxi-metil-kemĂ©nyĂtĆ nĂĄtrium. ElĆnyös oldĂłszerek az injekciĂłs vĂz, alkohol, propilĂ©nglikol, makrogol, szezĂĄmolaj Ă©s kukoricaolaj. ElĆnyös oldĂĄst elĆsegĂtĆ szerek a polietilĂ©nglikol, propilĂ©nglikol, D-mannit, benzil, benzoĂĄt, etanol, trisz-amino-metĂĄn, koleszterin, trietanol-amin, nĂĄtrium-karbonĂĄt Ă©s nĂĄtrium-citrĂĄt. ElĆnyös szuszpendĂĄlĂłszerek a felĂŒletaktĂv anyagok, pĂ©ldĂĄul sztearil-trietanol-amin, nĂĄtrium-lauril-szulfĂĄt, lauril-amino-propionsav, lecitin, benzalkĂłnium-klorid, benzetonium-klorid Ă©s monosztearin glicerin; Ă©s hidrofil polimerek, pĂ©ldĂĄul polivinil-alkohol, polivinil-pirrolidon, karboxi-metil-cellulĂłz-nĂĄtrium; metil-cellulĂłz, hidroxi-metil-cellulĂłz, hidroxi-eti I-cellulĂłz Ă©s hidroxi-propil-cellulĂłz. izotĂłniĂĄs oldatot elĆsegĂtĆ szerek közĂŒl elĆnyösek a nĂĄtrium-klorid, glicerin Ă©s D-mannit.
- 11 ElĆnyös pufferek a foszfĂĄtok, acetĂĄtok, karbonĂĄtok Ă©s citrĂĄtok puffer-oldatai. ElĆnyös nyugtatĂłszer a benzil-alkohol. ElĆnyös konzervĂĄlĂłszer a para-oxi-benzoesav-Ă©szter, klĂłr-butanol, benzil-alkohol, fenetil-alkohol, dehidroecetsav Ă©s szorbinsav. ElĆnyös antioxidĂĄnsok a szulfitek Ă©s aszkorbinsav.
Minthogy az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet hatĂĄsos csontfelszĂvĂłdĂĄst elnyomĂł Ă©s oszteogenezist elĆsegĂtĆ szer, Ă©s kivĂĄlĂł olyan tulajdonsĂĄgokkal rendelkezik, amelyek a klinikai hasznossĂĄgot elĆsegĂtik, ilyen pĂ©ldĂĄul a stabilitĂĄs, abszorbeĂĄlhatĂłsĂĄg Ă©s bio-hozzĂĄfĂ©rhetĆsĂ©g, hasznĂĄlhatĂł oszteogenezis elĆsegĂtĆkĂ©nt, Ă©s alkalmazhatĂł kĂŒlönbözĆ csontbetegsĂ©gek megelĆzĂ©sĂ©re Ă©s kezelĂ©sĂ©re. Ilyen betegsĂ©gek pĂ©ldĂĄul az oszteoporĂłzis Ă©s csonttörĂ©s emlĆsöknĂ©l, pĂ©ldĂĄul embernĂ©l, patkĂĄnynĂĄl, egĂ©rnĂ©l, kutyĂĄnĂĄl, macskĂĄnĂĄl, nyĂșlnĂĄl, szarvasmarhĂĄnĂĄl Ă©s sertĂ©snĂ©l. A talĂĄlmĂĄny szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet alacsony toxicitĂĄsa miatt biztonsĂĄgosan alkalmazhatĂł. Ăgy pĂ©ldĂĄul orĂĄlis adagolĂĄsnĂĄl az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒletet patkĂĄnynak 500 mg/kg/nap dĂłzisban adagolhatjuk 2 hĂ©tig, anĂ©lkĂŒl, hogy abnormĂĄlis tĂŒnetre bukkannĂĄnk.
Az (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet kĂŒlönösen jobban megfelelĆ a racĂ©m vegyĂŒlethez viszonyĂtva abszorbeĂĄlhatĂłsĂĄg tekintetĂ©ben orĂĄlis adagolĂĄs esetĂ©n, Ă©s ezĂ©rt orĂĄlisan adagolhatĂł kĂ©szĂtmĂ©ny. KözelebbrĆl, az optikailag aktĂv benzotiepin-szĂĄrmazĂ©k, melyet az (I) ĂĄltalĂĄnos kĂ©plettel jellemzĂŒnk, kivĂĄlĂł alkĂĄli-foszfatĂĄz indukĂĄlĂł hatĂĄssal rendelkezik, ennek következmĂ©nye a kivĂĄlĂł oszteogenezis elĆsegĂtĆ hatĂĄs, Ă©s ezĂ©rt gyĂłgyszerkĂ©nt hasznĂĄlhatĂł metabolikus csontbetegsĂ©gek megelĆzĂ©sĂ©re vagy kezelĂ©sĂ©re, beleĂ©rtve az oszteoporĂłzist is. BĂĄrmilyen
- 12 (I) ĂĄltalĂĄnos kĂ©pletĂŒ vegyĂŒletet tartalmazĂł oszteogenezis elĆsegĂtĆ ilyen hatĂĄsĂș szer alkalmazhatĂł csonttörĂ©sek kezelĂ©sĂ©re, csontkĂĄrosodĂĄsok kezelĂ©sĂ©re Ă©s olyan csontbetegsĂ©gek esetĂ©n, mint amilyen az oszteo-artritisz, ortopĂ©dia Ă©s periodontĂĄlis betegsĂ©gek terĂŒletĂ©n. Ilyen elĆsegĂtĆ szer vĂĄrhatĂłan a fogĂĄszat terĂŒletĂ©n is hatĂ©kony, a fogĂĄtgyulladĂĄs szövetkĂĄrosĂtĂł hatĂĄsĂĄnak javĂtĂĄsĂĄra, a mestersĂ©ges foggyökerek stabilizĂĄlĂĄsĂĄra Ă©s gerinckĂ©pzĆdĂ©s elĆsegĂtĂ©sĂ©re Ă©s farkastorok gyĂłgyĂtĂĄsĂĄra.
Ha oszteoporĂłzis megelĆzĂ©sĂ©re vagy gyĂłgyĂtĂĄsĂĄra hasznĂĄljuk pĂ©ldĂĄul, akkor az (I) ĂĄltalĂĄnos kĂ©pletĂŒ vegyĂŒletet napi 5 - 1000 mg, elĆnyösen 30 - 600 mg dĂłzisban adagoljuk, attĂłl fĂŒggĆen, hogy a beteg milyen ĂĄllapotban van, milyen a testsĂșlya Ă©s milyen az adagolĂĄs mĂłdja, minden felnĆtt esetĂ©ben, aki 50 kg-os, naponta 1-3 adagban adagoljuk orĂĄlis adagolĂĄs esetĂ©n.
Az (I) ĂĄltalĂĄnos kĂ©pletĂŒ vegyĂŒletet mĂĄs csontfelszĂvĂłdĂĄs visszaszorĂtĂł Ă©s oszteogenezis elĆsegĂtĆ anyaggal kombinĂĄlva is adagolhatjuk, mint amilyenek pĂ©ldĂĄul a DiffrakciĂłs spektrum vitamin (pĂ©ldĂĄul 1a-hidroxi Vitamin D31 1 a,25-dihidroxi Vitamin D3, Flocalcitriol, Secalciferol, stb.), kalcitoninok (pĂ©ldĂĄul kalcitonin angolna, kalcitonin lazac, kalcitonin sertĂ©s, Avicatonin, stb.), biszfoszfonsav-szĂĄrmazĂ©kok (pĂ©ldĂĄul etidronĂĄt, kimadronĂĄt, alendronĂĄt, tiludronĂĄt, rizedronĂĄt, klodronĂĄt, YH-529, stb.), szex hormon-szerƱ vegyĂŒletek (pĂ©ldĂĄul tibolon, ösztradiol, osateron, raloxifen, droloxifen, ormeloxifen, tamoxifen, mifepriszton, stb), Ipriflavon, K2 vitamin (pĂ©ldĂĄul Menatetron), nĂĄtrium-fluorid Ă©s PTH szĂĄrmazĂ©kok (pĂ©ldĂĄul PTH(1-34), PTH(1-84), PTH(1-36) stb.).
··· ·
- 13 A talĂĄlmĂĄny tovĂĄbbi rĂ©szleteit az alĂĄbbi teszt pĂ©ldĂĄval, referencia pĂ©ldĂĄval Ă©s kiviteli pĂ©ldĂĄval vilĂĄgĂtjuk meg anĂ©lkĂŒl, hogy a pĂ©ldĂĄk korlĂĄtozĂł jellegƱek lennĂ©nek.
1. Teszt példa
Oszteogenezis elĆsegĂtĆ hatĂĄs
NormĂĄlis patkĂĄny combcsontvelöjĂ©böl elĆĂĄllĂtott vĂĄz sejtek alkalmazĂĄsĂĄval hatĂĄroztuk meg az alkĂĄli-foszfatĂĄz hatĂĄst, mint az oszteogenezis mutatĂłjĂĄt. KözelebbrĆl, egy 7-hetes hĂmnemĂŒ Sprague Dawley patkĂĄny comb csontvelĆjĂ©bĆl Maniatopoulos Ă©s munkatĂĄrsai [Cell Tissue Research, 254. kötet, 317. oldal (1988)] mĂłdszerĂ©vel elĆĂĄllĂtott vĂĄz sejteket 10â7 mĂłl dexametazont Ă©s 10'2 mĂłl ÎČ-glicerofoszforsavat tartalmazĂł a-MEM (minimĂĄlis esszenciĂĄlis közeg) oldatban tenyĂ©sztettĂŒk, Ă©s Ăgy ĂĄsvĂĄnyi anyagban dĂșs csontszerƱ szövetet kaptunk. 1 hĂ©ttel kĂ©sĆbb a 10'6 mĂłl vagy 10'5 mĂłl tesztvegyĂŒletet hozzĂĄadtuk az összefolyĂł sejtekhez, majd 10-14 tovĂĄbbi nap tenyĂ©sztĂ©s következett a fenti tĂĄptalajban. FoszfĂĄtpufferrel mostuk, majd a sejteket 0,2 % Nonidet ÎĄ-40-nel homogenizĂĄltuk Ă©s 3000 rpm mellett 10 percig centrifugĂĄltuk. A kapott felĂŒlĂșszĂłt megvizsgĂĄltuk alkĂĄlikus foszfatĂĄz hatĂĄsra Lowry Ă©s munkatĂĄrsai mĂłdszerĂ©vel [Journal of Biological Chemistry, 207. kötet, 19. oldal (1954)]. A kapott Ă©rtĂ©keket ĂĄtlag ± SE-kĂ©nt adtuk meg az 1. tĂĄblĂĄzatban. Az adatokat Student-fĂ©le t-teszttel statisztikailag analizĂĄltuk.
- 14 1. tĂĄblĂĄzat
| VegyĂŒlet | KoncentrĂĄciĂł (M) | AlkĂĄli-foszfatĂĄz hatĂĄs (nmol p-nitrofenol/perc/ĂŒreg ) |
| kontroll | nem adtunk hozzå | 113,7 ± 8,1 |
| 1. pĂ©lda szerinti vegyĂŒlet | 10â5 | 1635,5 ± 169,7â |
| 1. pĂ©lda szerinti vegyĂŒlet | 10â6 | 682,5 ± 123,2â |
p<0,05; â p<0,01 versus kontrol
Az 1. tĂĄblĂĄzatbĂłl kitƱnik, hogy a talĂĄlmĂĄny szerinti optikailag aktĂv benzotiepin-szĂĄrmazĂ©k kivĂĄlĂł alkĂĄli-foszfatĂĄz indukĂĄlĂł hatĂĄssal rendelkezik, ezĂ©rt kivĂĄlĂł oszteogenezis elĆsegĂtĆ hatĂĄsĂș Ă©s ezĂ©rt gyĂłgyszerkĂ©nt alkalmazhatĂł csont anyagcsere betegsĂ©gek, beleĂ©rtve az oszteoporĂłzis kezelĂ©sĂ©re vagy megelĆzĂ©sĂ©re.
1. referencia példa
4,18 g (2R,4S)-(-)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsav (R)-a-metoxi-karbonil-benzil-Ă©szter, 45 ml ecetsav Ă©s 30 ml koncentrĂĄlt sĂłsav elegyĂ©t 30 percig keverjĂŒk visszafolyatĂł hƱtĆ alatt. A reakciĂłelegyet 800 ml vĂzbe öntjĂŒk, a kapott kristĂĄlyokat leszƱrjĂŒk Ă©s feloldjuk 150 ml etil-acetĂĄtban. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk, a maradĂ©k kristĂĄlyt leszƱrjĂŒk Ă©s hexĂĄnnal mossuk, majd etil-acetĂĄt Ă©s hexĂĄn elegyĂ©bĆl ĂĄtkristĂĄlyosĂtjuk. 1,62 g (59 %)
⹠· · · ⹠· · ·
- 15 (2 R, 4 S)-(-)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsavat kapunk szĂntelen tƱk formĂĄjĂĄban. OlvadĂĄspont: 194-195 °C.
Optikai forgatóképesség [a]D (23 °C) -210,8° (c = 0,50, metanol).
2. referencia példa
12,59 g 1 -etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 200 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk 15,34 g (±)-transz-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsav Ă©s 18,19 g (R)-(-)-mandulasav-metil-Ă©szter 200 ml dimetil-formamiddal kĂ©szĂtett oldatĂĄhoz, majd hozzĂĄadunk 0 °C-on 3,34 g 4-dimetil-amino-piridint (DMAP). Ezt az elegyet 1 Ăłra hosszat keverjĂŒk 0 °C-on, majd 15 Ăłra hosszat szobahĆmĂ©rsĂ©kleten, Ă©s ezutĂĄn vĂzbe öntjĂŒk Ă©s etil-acetĂĄttal extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt fölött szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk. A maradĂ©k kristĂĄlyokat leszƱrjĂŒk, Ă©ter Ă©s hexĂĄn elegyĂ©vel mossuk majd kĂ©tszer ĂĄtkristĂĄlyosĂtjuk etil-acetĂĄt Ă©s hexĂĄn elegyĂ©bĆl. 4,09 g (17 %) (2R,4S)-(-)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsav (R)-a-metoxi-karbonil-benzil-Ă©szterĂ©t kapjuk szĂntelen tƱk formĂĄjĂĄban. OlvadĂĄspont: 140-141 °C.
Optikai forgatóképesség [a]D (23 °C) -244,2° (c = 0,50, kloroform).
1. pĂ©lda (2R,4S)-(-)-N-[4-(Dietoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamid (1) kĂ©pletƱ vegyĂŒlet
0,39 g 1 -etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 7 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk 0,47 g (2R,4S)-(-)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsav Ă©s 0,41 g 4-amino-benzil-dietil-foszfonĂĄt 7 ml dimetil-formamiddal kĂ©szĂtett oldatĂĄhoz, majd hozzĂĄadunk 0,28 g 1-hidroxi-benzo-triazolt (HOBt). Ezt az elegyet 0 °C-on 1 Ăłra hosszat keverjĂŒk, majd 25 °C-on, azaz szobahĆmĂ©rsĂ©kleten mĂ©g 15 Ăłra hosszat keverjĂŒk, Ă©s ezutĂĄn vĂzbe öntjĂŒk, etil-acetĂĄttal extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄton szĂĄrĂtjuk. EzutĂĄn az oldĂłszert ledesztillĂĄljuk, Ă©s a maradĂ©k kristĂĄlyokat leszƱrjĂŒk, etil-acetĂĄt Ă©s hexĂĄn elegyĂ©böl ĂĄtkristĂĄlyosĂtjuk, majd metanol Ă©s hexĂĄnbĂłl Ășjra ĂĄtkristĂĄlyosĂtva 0,37 g (44 %) (2R,4S)-(-)-N-[4-(dietoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamidot kapunk. A termĂ©k szĂntelen prizmĂĄk formĂĄjĂĄban keletkezik.
Olvadåspont: 181-182 °C.
Optikai forgatóképesség [a]D (23 °C) -187,4° (c = 0,50, kloroform).
2. pĂ©lda (2R,4S)-(-)-N-[4-(dimetoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepi η-2-karboxamid (2) kĂ©pletƱ vegyĂŒlet
0,51 g 1-hidroxi-benzotriazolt (HOBt) Ă©s 0,69 g 1 -etil-3-(3-dimetil-amino-propil)-karbodiimid-hidrokloridot hozzĂĄadunk 0,84 g (2R,4S)-(-)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepĂ©n-2-karbonsav Ă©s 0,65 g 4-amino-benzil-dimetil-foszfonĂĄt 10 ml dimetil-formamiddal kĂ©szĂtett oldatĂĄhoz 0 °C-on. Ezt az elegyet 0 °C-on 1 Ăłra hosszat, majd szobahĆmĂ©rsĂ©kleten 15 Ăłra hosszat keverjĂŒk, ezutĂĄn vĂzbe öntjĂŒk Ă©s etil-acetĂĄt Ă©s tetrahidrofurĂĄn 3:1 arĂĄnyĂș elegyĂ©vel extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist egymĂĄs utĂĄn 1 n sĂłsavval, vĂzzel, majd telĂtett nĂĄtrium-hidrogĂ©n-karbonĂĄt-oldattal, vĂzzel, majd telĂtett konyhasĂł-oldattal mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk Ă©s az oldĂłszert ledesztillĂĄljuk. A visszamaradĂł szilĂĄrd anyagot leszƱrjĂŒk, etanol Ă©s hexĂĄn elegyĂ©bĆl ĂĄtkristĂĄlyosĂtva 0,92 g (64 %) (2R,4S)-(-)-N-[4-(dimetoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepĂ©n-2-karboxamidot kapunk szĂntelen tƱk formĂĄjĂĄban.
Olvadåspont: 198-199 °C.
Optikai forgatóképesség [cx]d (23 °C) -198,8° (c = 0,50, kloroform).
3. pĂ©lda (2R,4S)-(-)-N-[4-(tetrametilĂ©n-dioxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamid (3) kĂ©pletĂș vegyĂŒlet
A 2. pĂ©ldĂĄban leĂrt eljĂĄrĂĄssal (2R,4S)-(-)-N-[4-(tetrametilĂ©n-diox8i-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamidot kapunk szĂntelen prizmĂĄk formĂĄjĂĄban.
Olvadåspont: 149-140 °C.
Optikai forgatóképesség [a]D (23 °C) -176,2° (c = 0,50, kloroform).
ElĆĂĄllĂtĂĄsi pĂ©ldĂĄk
HatĂłanyagkĂ©nt (I) kĂ©pletĂŒ optikailag aktĂv vegyĂŒletet tartalmazĂł oszteogenezis elĆsegĂtĆ szert ĂĄllĂthatunk elĆ a következĆ kiszerelĂ©ssel:
1. Kapszula (1) (2R,4S)-(-)-N-[4-(dietoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilén-dioxi-5-oxo-3-benzotiepin-2-karboxamid (2) Laktóz (3) Mikrokristålyos cellulóz mg mg mg (4) Magnézium-sztearåt mg
Ăsszesen: kapszulĂĄnkĂ©nt 180 mg
Az (1), (2) Ă©s (3) komponenst Ă©s fĂ©l adag (4) komponenst összekeverĂŒnk Ă©s granulĂĄlunk. A granulĂĄtumokhoz hozzĂĄadjuk a
maradĂ©k (4) komponenst Ă©s az egĂ©sz elegyet zselatin kapszulĂĄba töltjĂŒk.
2. Tabletta (1) (2R,4S)-(-)-N-[4-(dietoxi-foszforil-metil)-fenil]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamid 10mg (2) LaktĂłz 35mg (3) KukoricakemĂ©nyĂtö 150mg (4) MikrokristĂĄlyos cellulĂłz 30mg (5) MagnĂ©zium-sztearĂĄt 5mg
Ăsszesen: tablettĂĄnkĂ©nt 230 mg
Az (1), (2) Ă©s (3) komponenst, Ă©s a (4) komponens 2/3 rĂ©szĂ©t Ă©s az (5) komponens felĂ©t összekeverjĂŒk Ă©s granulĂĄljuk. A granulĂĄtumokhoz hozzĂĄadjuk a (4) Ă©s (5) komponens maradĂ©k rĂ©szĂ©t, Ă©s az egĂ©szet tablettĂĄzzuk.
3. InjektĂĄlhatĂł kĂ©szĂtmĂ©ny (1) (2R,4S)-(-)-N-[4-(dietoxi-foszforil-metil)-fenil]-1,2,4,5-
-tetrahidro-4-metil-7,8-metilén-dioxi-5-oxo-3-benzotiepin-2-karboxamid 10 mg (2) Inozit 100 mg (3) Benzil-alkohol 20 mg
Ăsszesen: 130 mg ampullĂĄnkĂ©nt
Az (1), (2) Ă©s (3) komponenst injekciĂłs desztillĂĄlt vĂzben feloldjuk Ă©s a kapott vĂ©gleges 2 ml mennyisĂ©get ampullĂĄkba csomagoljuk. Az egĂ©sz eljĂĄrĂĄst aszeptikusĂĄn vĂ©gezzĂŒk.
3. referencia példa
27,5 g (±)-3,4-dihidro-6,7-dimetil-4-oxo-1 Î-2-benzotiopirĂĄn-1-karbonsav 200 ml kloroformmal kĂ©szĂtett szuszpenziĂłjĂĄhoz
14,1 g (S)-(-)-a-metil-benzil-amint adunk. SzobahĆmĂ©rsĂ©kleten 30 percig keverjĂŒk, majd a reakciĂłelegyet csökkentett nyomĂĄson bepĂĄroljuk. A kapott maradĂ©kot feloldjuk 200 ml etil-acetĂĄtban Ă©s szobahĆmĂ©rsĂ©kleten 2 Ăłra hosszat ĂĄllni hagyjuk. A kapott kristĂĄlyokat leszƱrjĂŒk, kloroform Ă©s etil-acetĂĄt elegyĂ©böl ĂĄtkristĂĄlyosĂtjuk, majd ezt követĆen kloroform Ă©s hexĂĄnbĂłl ĂĄtkristĂĄlyosĂtva 15,5 g (37 %) (-)-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-benzotiopirĂĄn-1 -karbonsav (S)-(-)-a-metil-benzil-am in-sĂłjĂĄt kapjuk szĂntelen prizmĂĄk formĂĄjĂĄban.
Olvadåspont: 162-163 °C.
Optikai forgatóképesség [a]D (23 °C) -43° (c = 0,50, kloroform).
4. referencia pĂ©lda g (±)-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-benzotiopirĂĄn-1 -karbonsav 300 ml kloroformmal kĂ©szĂtett szuszpenziĂłjĂĄhoz
17,9 g (R)-(+)-a-metil-benzil-amint adunk. SzobahĆmĂ©rsĂ©kleten 30 percig keverjĂŒk, majd a reakciĂłelegyet csökkentett nyomĂĄson bepĂĄroljuk. A kapott maradĂ©kot 200 ml etil-acetĂĄtban feloldjuk Ă©s szobahĆmĂ©rsĂ©kleten 2 Ăłra hosszat ĂĄllni hagyjuk. A kapott kristĂĄlyokat leszƱrjĂŒk, kloroform Ă©s etil-acetĂĄt elegyĂ©böl, majd kloroform Ă©s hexĂĄn elegyĂ©böl ĂĄtkristĂĄlyosĂtjuk, Ă©s Ăgy 17,9 g (34 %) (+)-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-benzotiopirĂĄn-1 -
-karbonsav (R)-(+)-a-metil-benzil-amin-sĂłt kapunk szĂntelen prizmĂĄk formĂĄjĂĄban.
Olvadåspont: 162-163 °C.
- 21 Optikai forgatóképesség [oc]d (23 °C) +42,2° (c = 0,51, kloroform).
5. referencia példa
14,5 g (-)-3,4-dihidro-6,7-dimetil-4-oxo-1 Î-2-benzotiopirĂĄn-1-karbonsav (S)-(-)-a-metil-benzil-amin-sĂł 100 ml etil-acetĂĄttal kĂ©szĂtett szuszpenziĂłjĂĄhoz hozzĂĄadunk 100 ml 2 n sĂłsavat. MiutĂĄn az elegyet szobahĆmĂ©rsĂ©kleten 30 percig kevertĂŒk, az etil-acetĂĄtos fĂĄzist izolĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk majd az oldĂłszert ledesztillĂĄljuk Ă©s etil-acetĂĄt Ă©s hexĂĄn elegyĂ©böl ĂĄtkristĂĄlyosĂtjuk.
9,1 g (95 %) (-)-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-
-benzotiopirĂĄn-1-karbonsavat kapunk szĂntelen prizmĂĄk formĂĄjĂĄban.
Olvadåspont: 177-178 °C.
Optikai forgatóképesség [a]D (23 °C) -135,0° (c = 0,50, kloroform).
6. referencia példa
8,0 9 (+)-3,4-dihidro-6,7-dimetil-4-oxo-1 Î-2-benzotiopirĂĄn-1-karbonsav (R)-(+)-a-metil-benzil-amin-sĂł 100 ml etil-acetĂĄttal kĂ©szĂtett szuszpenziĂłjĂĄhoz 50 ml 2 n sĂłsavat adunk. Az elegyet szobahĆmĂ©rsĂ©kleten 30 percig keverjĂŒk, majd az etil-acetĂĄtos fĂĄzist izolĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄttal szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk Ă©s etil-acetĂĄt Ă©s hexĂĄn elegyĂ©böl ĂĄtkristĂĄlyosĂtjuk az elegyet. Ăgy 4,55 g (86 %) (+)-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-benzotiopirĂĄn-1 -karbonsavat kapunk szĂntelen prizmĂĄk formĂĄjĂĄban. OlvadĂĄspont: 177-178 °C.
- 22 Optikai forgatóképesség [a]D (23 °C) +136° (c = 0,50, kloroform).
7. referencia példa
4,89 g 1-etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 80 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk 6 g (±)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsav Ă©s 4,43 g (R)-(+)-metil-laktĂĄt 80 ml dimetil-formamiddal kĂ©szĂtett oldatĂĄhoz 0 °C-on, majd hozzĂĄadunk 1,3 g 4-dimetil-amino-piridint. Az elegyet 0 °C-on 1 Ăłra hosszat Ă©s szobahĆmĂ©rsĂ©kleten 15 Ăłra hosszat keverjĂŒk, majd csökkentett nyomĂĄson bepĂĄroljuk. A maradĂ©khoz 500 ml etil-acetĂĄtot Ă©s 500 ml vizet adunk, majd a szerves fĂĄzist izolĂĄljuk Ă©s vĂzzel mossuk, magnĂ©zium-szulfĂĄton szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk Ă©s a visszamaradĂł szilĂĄrd anyagot leszƱrjĂŒk, Ă©terrel mossuk Ă©s etil-acetĂĄt Ă©s hexĂĄn elegyĂ©bĆl kĂ©tszer ĂĄtkristĂĄlyosĂtjuk. 2,2 g (28 %) (2R)-(-)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-
-benzotiepin-2-karbonsav (R)-1-metoxi-karbonil-etil-Ă©sztert kapunk szĂntelen tƱk formĂĄjĂĄban.
Olvadåspont: 161-162 °C.
Optikai forgatóképesség [a]D (16 °C) -194,1° (c = 0,50, kloroform).
A fent emlĂtett szilĂĄrd anyag szƱrletĂ©t bepĂĄroljuk, Ă©s a kapott kristĂĄlyokat leszƱrjĂŒk, Ă©ter Ă©s hexĂĄnnal kristĂĄlyosĂtjuk, majd kĂ©tszer ĂĄtkristĂĄlyosĂtjuk etil-acetĂĄt Ă©s hexĂĄn elegyĂ©bĆl. Ily mĂłdon 1,6 g (20 %) (28)-(+)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsav (R) -1 -metoxi-karbonil-etil-Ă©sztert kapunk szĂntelen lemezek formĂĄjĂĄban.
Olvadåspont: 121-122 °C.
⹠· 9 9 9 9 ·· · ······ ···· ·· ··· ···· ··
- 23 Optikai forgatĂłkĂ©pessĂ©g [a]D (16 âC) +234,3° (c = 0,50, kloroform).
8. referencia példa
0,5 g (2R)-(-)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsav (R)-1-metoxi-karbonil-etil-Ă©szter, 2,5 ml ecetsav Ă©s 2,5 ml koncentrĂĄlt sĂłsav elegyĂ©t 30 percig viszszafolyatĂł hƱtĆ alatt keverjĂŒk. A reakciĂłelegyet 50 ml vĂzbe öntjĂŒk, a kapott kristĂĄlyokat leszƱrjĂŒk, majd vĂzzel, etanollal, vĂ©gĂŒl Ă©terrel mossuk. 0,2 g (53 %) (2R)-(-)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsavat kapunk szĂntelen por formĂĄjĂĄban, amely 223-224 °C-on olvad.
Optikai forgatóképesség [<x]d (23 °C) -190,0° (c = 0,50, dimetil-szulfoxid).
9. referencia példa
0,7 g (2S)-(+)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsav (R)-1-metoxi-karbonil-etil-Ă©szter, 3,5 ml ecetsav Ă©s 3,5 ml koncentrĂĄlt sĂłsav elegyĂ©t 30 percig viszszafolyatĂł hƱtĆ alatt keverjĂŒk. A reakciĂłelegyet 70 ml vĂzbe öntjĂŒk, a kapott kristĂĄlyokat leszƱrjĂŒk, vĂzzel, etanollal majd Ă©terrel mossuk. 0,3 g (56 %) (2S)-(+)-1,2,4,5-tetrahidro-7,8-dimetoxi-65-oxo-3-benzotiepin-2-karbonsavat kapunk szĂntelen por formĂĄjĂĄban, amely 223-224 °C-on olvad.
Optikai forgatóképesség [a]D (22 °C) +196,7° (c = 0,50, dimetil-szulfoxid).
10. referencia példa
12,5 g 1 -etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 200 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk 15,34 ⹠· ···· · · · ⹠· · · · · g (±)-transz-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsav Ă©s 18,19 g (S)-(+)-mandulasav-metil-Ă©szter 200 ml dimetil-formamiddal 0 °C-on kĂ©szĂtett oldatĂĄhoz, majd hozzĂĄadunk 3,34 g 4-dimetil-amino-piridint. Ezt az elegyet 0 °C-on 1 Ăłra hosszat Ă©s szobahĆmĂ©rsĂ©kleten 15 Ăłra hosszat keverjĂŒk, ezutĂĄn vĂzbe öntjĂŒk Ă©s etil-acetĂĄttal extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk Ă©s a visszamaradĂł kristĂĄlyokat leszƱrjĂŒk, Ă©ter Ă©s hexĂĄn elegyĂ©vel mossuk Ă©s kĂ©tszer ĂĄtkristĂĄlyosĂtjuk etil-acetĂĄt Ă©s hexĂĄn elegyĂ©böl. Ily mĂłdon 4,57 g (19 %) (2S,4R)-(+)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-kar bonsav (S)-a-metoxi-karbonil-benzil-Ă©sztert kapunk szĂntelen tƱk formĂĄjĂĄban.
OlvadĂĄspont: 141-142 âC.
Optikai forgatĂłkĂ©pessĂ©g [a]D (23 âC) +239,7° (c = 0,50, kloroform).
11. referencia példa
4,37 g (2S,4R)-(+)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsav, 45 ml ecetsav Ă©s 30 ml koncentrĂĄlt sĂłsav elegyĂ©t 30 percig visszafolyatĂł hƱtĆ alatt keverjĂŒk. Az elegyet 800 ml vĂzbe öntjĂŒk, a kapott kristĂĄlyokat leszƱrjĂŒk Ă©s feloldjuk 150 ml etil-acetĂĄtban. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk Ă©s a maradĂ©k kristĂĄlyokat leszƱrjĂŒk, hexĂĄnnal mossuk Ă©s etil-acetĂĄt - hexĂĄn elegyĂ©böl ĂĄtkristĂĄlyosĂtjuk.
1,38 g (48 %) (2S,4R)-(+)-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karbonsavat kapunk szĂntelen tƱk formĂĄjĂĄban.
- 25 Olvadåspont: 192-193 °C.
Optikai forgatóképesség [a]D (23 °C) +212,9° (c = 0,50, metanol).
12. referencia példa
8,6 g (-)-3,4-dihidro-6,7-dimetil-4-oxo-1 Î-2-benzotiopirĂĄn-1-karbonsavat feloldunk 100 ml tetrahidrofurĂĄnban, hozzĂĄadunk 5 g oxalil-kloridot az oldathoz, vĂ©gĂŒl 1 csepp dimetil-formamidot. SzobahĆmĂ©rsĂ©kleten 3 ĂłrĂĄt keverjĂŒk, a reakciĂłelegyet csökkentett nyomĂĄson bepĂĄroljuk. A maradĂ©kot feloldjuk 30 ml diklĂłr-metĂĄnban, Ă©s ezt az oldatot hozzĂĄcsepegtetjĂŒk 8,8 g
4-amino-benzil-foszfonsav-dietil-Ă©szter, 10 g nĂĄtrium-hidrogĂ©n-karbonĂĄt Ă©s 100 ml diklĂłr-metĂĄn elegyĂ©hez jeges hƱtĂ©s közben. 30 percig jeges hƱtĂ©s közben keverjĂŒk, majd az elegyet vĂzzel mossuk Ă©s magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk, majd az oldĂłszer ledesztillĂĄljuk, kloroform Ă©s hexĂĄn elegyĂ©böl ĂĄtkristĂĄlyosĂtva 15,4 g (92 %) (-)-N-[4-(dietoxi-foszforil-metil)-fenil]-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-benzotiopirĂĄn-1 -karboxamidot kapunk szĂntelen tƱk formĂĄjĂĄban.
Olvadåspont: 175-176 °C.
Optikai forgatóképesség [a]D (23 °C) -152,0° (c = 1,0, metanol).
13. referencia példa
Ξ.4 g (+)-3,4-dihidro-6,7-dimetil-4-oxo-1 Î-2-benzotiopirĂĄn-1-karbonsavat feloldunk 100 ml tetrahidrofurĂĄnban, Ă©s az oldathoz hozzĂĄadunk 5 g oxalil-kloridot majd 1 csepp dimetil-formamidot. SzobahĆmĂ©rsĂ©kleten 3 Ăłra hosszat keverjĂŒk, majd csökkentett nyomĂĄson bepĂĄroljuk. A maradĂ©kot feloldjuk 30 ml diklĂłr-metĂĄnban, Ă©s ezt az oldatot hozzĂĄcsepegtetjĂŒk 8,6 g 4-amino-benzil-dietil-foszfonĂĄt, 8,0 g nĂĄtrium-hidrogĂ©n-karbonĂĄt
- 26 Ă©s 100 ml diklĂłr-metĂĄn elegyĂ©hez, miközben jeges hƱtĂ©st alkalmazunk. 30 percig jeges hƱtĂ©s közben keverjĂŒk, a reakciĂłelegyet vĂzzel mossuk, magnĂ©zium-szulfĂĄttal szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk Ă©s kloroform Ă©s hexĂĄn elegyĂ©bĆl ĂĄtkristĂĄlyosĂtjuk. 15,8 g (96 %) (+)-N-[4-(dietoxi-foszforil-metil)-fenilj-3,4-dihidro-6,7-dimetil-4-oxo-1 H-2-benzotiopirĂĄn-1 -karboxamidot kapunk szĂntelen tƱk formĂĄjĂĄban.
Olvadåspont: 175-176 °C.
Optikai forgatóképesség [a]o (23 °C) +155,0° (c = 1,0, metanol).
14. referencia példa
0,149 g 1 -etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 3 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk 0,183 g (R)-(-)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsav Ă©s 0,158 g 4-amino-benzil-dietil-foszfonĂĄt 3 ml dimetil-formamiddal kĂ©szĂtett oldatĂĄhoz 0 °C-on, majd hozzĂĄadunk 0,109 g 1-hidroxi-benzotriazolt. Ezt az elegyet 0 °C-on 1 Ăłra hosszat, szobahĆmĂ©rsĂ©kleten 15 Ăłra hosszat keverjĂŒk, majd vĂzbe öntjĂŒk Ă©s etil-acetĂĄttal extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄttal szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk, Ă©s a maradĂ©kot etanol Ă©s izopropil-Ă©ter elegyĂ©vel kezeljĂŒk. A szilĂĄrd anyagot leszƱrjĂŒk. A szĂșrletet bepĂĄroljuk, a maradĂ©k olajat szilikagĂ©len oszlopkromatografĂĄljuk. Az etil-acetĂĄt, kloroform, metanol 15:15:1 tĂ©rfogatarĂĄnyĂș elegyĂ©vel eluĂĄlt frakciĂłkbĂłl 0,136 g (41 %) (2R)-(-)-N-[4-(dietoxi-f oszf Ćri I-met i l)-fen i I]-1,2)4l5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karboxamidot kapunk szĂntelen amorf szilĂĄrd anyag formĂĄjĂĄban.
Olvadåspont: 96-98 °C.
⹠· ⹠· ⹠· ⹠· ⹠· · ·
- 27 Optikai forgatóképesség [a]D (23 °C) -155,0° (c = 0,50, kloroform).
15. referencia példa
0,228 g 1-etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 5 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk 0,28 g (S)-(+)-1,2,4,5-tetrahidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karbonsav Ă©s 0,241 g 4-amino-benzil-dietil-foszfonĂĄt 5 ml dimetil-formamiddal 0 °C-on kĂ©szĂtett oldatĂĄhoz, majd hozzĂĄadunk 0,167 g 1-hidroxi-benzotriazolt. Az elegyet 0 °C-on 1 Ăłra hosszat Ă©s szobahĆmĂ©rsĂ©kleten 15 Ăłra hosszat ke verjĂŒk, majd vĂzbe öntjĂŒk Ă©s etil-acetĂĄttal extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂt-
| juk majd az oldószert | ledesztillåljuk. A maradékot etanol és |
| izopropil-Ă©ter elegyĂ©vel | kezeljĂŒk, a szilĂĄrd anyagot leszƱrjĂŒk. A |
| szƱrletet bepåroljuk, | a maradék olajat szilikagélen |
| oszlopkromatograf ĂĄljuk. | Az etil-acetĂĄt, kloroform Ă©s metanol |
| 15:15:1 tĂ©rfogatarĂĄnyĂș | elegyĂ©vel eluĂĄlt frakciĂłbĂłl kapjuk a |
0,202 g (40 %) (2S)-(+)-N-[4-(dietoxi-foszforil-metil)-fenilj-1,2,4,5-tetrhidro-7,8-dimetoxi-5-oxo-3-benzotiepin-2-karboxamidot szĂntelen amorf szilĂĄrd anyag formĂĄjĂĄban. OlvadĂĄspont: 97-99 °C.
Optikai forgatóképesség [a]D (23 °C) +155,3° (c = 0,50, kloroform).
16. referencia példa
0,69 g 1 -etil-3-(3-dimetil-amino-propil)-karbodiimid-hidroklorid 12 ml diklĂłr-metĂĄnnal kĂ©szĂtett oldatĂĄt hozzĂĄadjuk
0.84 g (2S,4R)-(+)-1,2,4,5-tetrahidro-4-metil-7,8-metilén-dioxi-5-oxo-3-benzotiepin-2-karbonsav és 0,73 g 4-amino-benzil⹠· · · ···· · · · · ⹠· · · · · · ⹠· · · · ⹠· ··· ···· ··
- 28 -dietil-foszfonĂĄt 12 ml dimetil-formamiddal kĂ©szĂtett oldatĂĄhoz 0 °C-on, majd hozzĂĄadunk 0,51 g 1-hidroxi-benzotriazolt. Ezt az elegyet 0 âC-on 1 Ăłra hosszat, majd szobahĆmĂ©rsĂ©kleten 15 Ăłra hosszat keverjĂŒk. EzutĂĄn vĂzbe öntjĂŒk, Ă©til-acetĂĄttal extrahĂĄljuk. Az etil-acetĂĄtos fĂĄzist vĂzzel mossuk, magnĂ©zium-szulfĂĄt felett szĂĄrĂtjuk, majd az oldĂłszert ledesztillĂĄljuk. A visszamaradĂł kristĂĄlyokat leszƱrjĂŒk, etil-acetĂĄt Ă©s hexĂĄn elegyĂ©bĆl ĂĄtkristĂĄlyosĂtjuk, majd metanol Ă©s hexĂĄn elegyĂ©bĆl kristĂĄlyosĂtjuk ĂĄt Ă©s Ăgy 0,62 g (41 %) (2S,4R)-(+)-N-[4-(dietoxi-foszforil-metil)-fenilj-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamidot kapunk szĂntelen prizmĂĄk formĂĄjĂĄban.
Olvadåspont: 183-184 °C.
Optikai forgatóképesség [a]D (23 °C) +190,5° (c = 0,50, kloroform).
A talĂĄlmĂĄny szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ vegyĂŒlet kivĂĄlĂł oszteogenezis elĆsegĂtĆ hatĂĄsĂș, Ă©s ezĂ©rt hasznos csontbetegsĂ©gek megelĆzĂ©sĂ©re vagy gyĂłgyszerezĂ©sĂ©re, csontbetegsĂ©gek között emlĂthetĆk az anyagcsere jellegƱ csontbetegsĂ©gek, beleĂ©rtve az oszteoporĂłzist, csonttörĂ©st, csonthiĂĄnyossĂĄgot Ă©s olyan csontbetegsĂ©geket, mint amilyen az ortopĂ©dia terĂŒletĂ©n az oszteoartritisz. HatĂĄsos tovĂĄbbĂĄ a fogĂĄszat terĂŒletĂ©n a periodontĂĄlis szövetkĂĄrosodĂĄsok gyĂłgyĂtĂĄsĂĄnĂĄl, mestersĂ©ges foggyökĂ©r stabilizĂĄlĂĄsĂĄnĂĄl Ă©s a farkastorok gyĂłgyĂtĂĄsĂĄnĂĄl Ă©s fog tarĂ©j kĂ©pzĆdĂ©s stabilizĂĄlĂĄsĂĄra.
Claims (12)
- Szabadalmi igĂ©nypontok1. (I) ĂĄltalĂĄnos kĂ©pletĂŒ optikailag aktĂv vegyĂŒlet - aholR jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport,R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl rövidszĂ©nlĂĄncĂș alkilcsoport vagy egyĂŒtt rövidszĂ©nlĂĄncĂș alkilĂ©ncsoportot kĂ©pez.
- 2. Az 1. igĂ©nypont szerinti vegyĂŒlet, ahol R, R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl 1 - 4 szĂ©natomos alkilcsoport.
- 3. Az 1. igĂ©nypont szerinti vegyĂŒlet: )2R,4S)-(-)-N-[4-(d i etoxi-foszf Ćri I-m e t i l)-fen i I]-1,2,4,5-tetrahidro-4-metil-7,8-metilĂ©n-dioxi-5-oxo-3-benzotiepin-2-karboxamid.
- 4. EljĂĄrĂĄs (I) ĂĄltalĂĄnos kĂ©pletĂŒ optikailag aktĂv vegyĂŒlet elĆĂĄllĂtĂĄsĂĄra, aholR jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport,R1 Ă©s R2 egymĂĄstĂłl fĂŒggetlenĂŒl rövidszĂ©nlĂĄncĂș alkilcsoport vagy egyĂŒtt rövidszĂ©nlĂĄncĂș alkilĂ©ncsoportot kĂ©pez, azzal jellemezve, hogy egy (II) ĂĄltalĂĄnos kĂ©pletĂŒ optikailag aktĂv vegyĂŒletet, ahol R jelentĂ©se a fenti vagy reakciĂłkĂ©pes szĂĄrmazĂ©kĂĄt vagy karboxilcsoporton kĂ©pezett sĂłjĂĄt (III) ĂĄltalĂĄnos kĂ©pletĂŒ vegyĂŒlettel - ahol R1 Ă©s R2 jelentĂ©se a fenti - vagy reakciĂłkĂ©pes szĂĄrmazĂ©kĂĄval vagy az aminocsoporton kĂ©pezett sĂłjĂĄval reagĂĄltatjuk.
- 5. (II) ĂĄltalĂĄnos kĂ©pletĂŒ optikailag aktĂv vegyĂŒlet, ahol R jelentĂ©se rövidszĂ©nlĂĄncĂș alkilcsoport vagy reakciĂłkĂ©pes szĂĄrmazĂ©ka vagy karboxilcsoporton kĂ©pezett sĂłja.
- 6. Az 1. igĂ©nypont szerinti (I) ĂĄltalĂĄnos kĂ©pletĂŒ optikailag aktĂv vegyĂŒletet tartalmazĂł oszteogenezis elĆsegĂtĆ szer.⹠· ···· ⊠·· ·· ⹠· ···· ··
- 7. A 6. igĂ©nypont szerinti oszteogenezis elĆsegĂtĆ szer, amely orĂĄlisan abszorbeĂĄlhatĂł.
- 8. Egy 1. igĂ©nypont szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletet tartalmazĂł szer csontbetegsĂ©gek megelĆzĂ©sĂ©re vagy kezelĂ©sĂ©re.
- 9. Az 1. igĂ©nypont szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒletet tartalmazĂł csonttörĂ©s gyĂłgyĂtĂĄsĂĄt elĆsegĂtĆ szer.
- 10. Az 1. igĂ©nypont szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet alkalmazĂĄsa oszteogenezis elĆsegĂtĆ szer gyĂĄrtĂĄsĂĄra.
- 11. Az 1. igĂ©nypont szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet alkalmazĂĄsa csontbetegsĂ©gek kezelĂ©sĂ©re vagy megelĆzĂ©sĂ©re szolgĂĄlĂł szer gyĂĄrtĂĄsĂĄra.
- 12. Az 1. igĂ©nypont szerinti (I) ĂĄltalĂĄnos kĂ©pletƱ optikailag aktĂv vegyĂŒlet alkalmazĂĄsa csonttörĂ©s gyĂłgyĂtĂĄsĂĄt elĆsegĂtĆ szer gyĂĄrtĂĄsĂĄra.
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|---|---|---|---|
| JP32727594 | 1994-12-28 |
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|---|---|
| US (2) | US6346521B1 (hu) |
| EP (1) | EP0719782B1 (hu) |
| KR (1) | KR960022542A (hu) |
| CN (1) | CN1058718C (hu) |
| AR (1) | AR002018A1 (hu) |
| AT (1) | ATE202782T1 (hu) |
| AU (1) | AU689004B2 (hu) |
| BR (1) | BR9506098A (hu) |
| CA (1) | CA2166152A1 (hu) |
| DE (1) | DE69521595T2 (hu) |
| DK (1) | DK0719782T3 (hu) |
| ES (1) | ES2158034T3 (hu) |
| FI (1) | FI956273A (hu) |
| GR (1) | GR3036757T3 (hu) |
| HU (1) | HUT74562A (hu) |
| NO (1) | NO303641B1 (hu) |
| NZ (1) | NZ280745A (hu) |
| PT (1) | PT719782E (hu) |
| RU (1) | RU2162083C2 (hu) |
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| US5910492A (en) * | 1995-06-05 | 1999-06-08 | Takeda Chemical Industries, Ltd. | Osteogenic promoting pharmaceutical composition |
| WO1996039134A1 (en) * | 1995-06-05 | 1996-12-12 | Takeda Chemical Industries, Ltd. | Osteogenetic promoting pharmaceutical composition |
| AU6471896A (en) * | 1995-07-24 | 1997-02-18 | Takeda Chemical Industries Ltd. | Production of optically active benzothiepin salts |
| AU3868997A (en) * | 1996-08-26 | 1998-03-19 | Takeda Chemical Industries Ltd. | Pharmaceutical composition containing osteogenesis-promoting substance and a polyethylene glycol |
| AU4571097A (en) * | 1996-10-09 | 1998-05-05 | Takeda Chemical Industries Ltd. | A method for producing a microparticle |
| EP1087774A2 (en) * | 1998-06-15 | 2001-04-04 | Takeda Chemical Industries, Ltd. | Compositions for treating cartilage disease comprising certain sulfur-containing heterocyclic compounds |
| EP1103552A4 (en) | 1998-08-07 | 2003-01-15 | Takeda Chemical Industries Ltd | BENZOTHIEPINE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| WO2000009100A2 (en) * | 1998-08-12 | 2000-02-24 | Takeda Chemical Industries, Ltd. | Benzothiepine compounds as enhancer of cell differentiation induction factor |
| AU5998799A (en) * | 1998-09-30 | 2000-04-17 | Takeda Chemical Industries Ltd. | Bone repair materials/artificial bone compositions |
| US6794544B2 (en) * | 2000-03-10 | 2004-09-21 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
| CA2454200A1 (en) * | 2001-07-17 | 2003-01-30 | Teva Pharmaceutical Industries Ltd. | Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate |
| US20050026871A1 (en) * | 2002-07-17 | 2005-02-03 | Moshe Flashner-Barak | Method of increasing bioavailability of alendronate or other bis-phosphonate by predose administration of vitamin D derivative |
| EP1640010A1 (en) * | 2003-07-01 | 2006-03-29 | Astellas Pharma Inc. | Agent inducing increase in bone mass |
| WO2009006226A1 (en) * | 2007-06-29 | 2009-01-08 | Kci Licensing Inc. | Activation of bone and cartilage formation |
| EP2380878B1 (en) | 2009-01-19 | 2013-08-14 | Daiichi Sankyo Company, Limited | Cyclic compound having hetero atom |
| KR20120006016A (ko) | 2009-04-06 | 2012-01-17 | ë€ìŽìŽì° ì°ìż ê°ë¶ìí€ê°ìŽì€ | ìčí íëêž°ë„Œ ê°ë êł ëŠŹí íí©ëŹŒ |
| AU2011246067A1 (en) | 2010-04-28 | 2012-09-27 | Daiichi Sankyo Company, Limited | [5,6] heterocyclic compound |
| WO2015030189A1 (ja) | 2013-08-29 | 2015-03-05 | äșŹéœèŹćć·„æ„æ ȘćŒäŒç€Ÿ | æ°èŠèłéŠæććç©ăăăłăăźçšé |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5158943A (en) * | 1988-11-21 | 1992-10-27 | Takeda Chemical Industries, Ltd. | Sulfur-containing heterocyclic compounds |
| DK656789A (da) * | 1988-12-28 | 1990-06-29 | Takeda Chemical Industries Ltd | Benzoheterocykliske forbindelser |
| DK0460488T3 (da) * | 1990-05-30 | 2001-09-17 | Takeda Chemical Industries Ltd | Svovlholdige heterocykliske forbindelser |
| JP3165866B2 (ja) * | 1990-06-06 | 2001-05-14 | æŠç°èŹćć·„æ„æ ȘćŒäŒç€Ÿ | ć«çĄ«é»è€çŽ ç°ććç© |
-
1995
- 1995-12-20 TW TW084113629A patent/TW403757B/zh not_active IP Right Cessation
- 1995-12-21 NZ NZ280745A patent/NZ280745A/en unknown
- 1995-12-22 DK DK95120444T patent/DK0719782T3/da active
- 1995-12-22 AT AT95120444T patent/ATE202782T1/de not_active IP Right Cessation
- 1995-12-22 AU AU40693/95A patent/AU689004B2/en not_active Ceased
- 1995-12-22 PT PT95120444T patent/PT719782E/pt unknown
- 1995-12-22 EP EP95120444A patent/EP0719782B1/en not_active Expired - Lifetime
- 1995-12-22 DE DE69521595T patent/DE69521595T2/de not_active Expired - Fee Related
- 1995-12-22 ES ES95120444T patent/ES2158034T3/es not_active Expired - Lifetime
- 1995-12-27 CA CA002166152A patent/CA2166152A1/en not_active Abandoned
- 1995-12-27 BR BR9506098A patent/BR9506098A/pt unknown
- 1995-12-27 NO NO955305A patent/NO303641B1/no not_active IP Right Cessation
- 1995-12-27 HU HU9503802A patent/HUT74562A/hu unknown
- 1995-12-27 RU RU95122478/04A patent/RU2162083C2/ru active
- 1995-12-27 FI FI956273A patent/FI956273A/fi unknown
- 1995-12-28 US US08/579,731 patent/US6346521B1/en not_active Expired - Fee Related
- 1995-12-28 CN CN95121715A patent/CN1058718C/zh not_active Expired - Fee Related
- 1995-12-28 AR ARP950100805A patent/AR002018A1/es unknown
- 1995-12-28 KR KR1019950061545A patent/KR960022542A/ko not_active Application Discontinuation
-
2000
- 2000-08-09 US US09/635,067 patent/US6632807B1/en not_active Expired - Fee Related
-
2001
- 2001-09-28 GR GR20010401614T patent/GR3036757T3/el not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE69521595T2 (de) | 2002-05-23 |
| PT719782E (pt) | 2001-10-31 |
| CA2166152A1 (en) | 1996-06-29 |
| CN1131669A (zh) | 1996-09-25 |
| NO955305D0 (no) | 1995-12-27 |
| RU2162083C2 (ru) | 2001-01-20 |
| EP0719782B1 (en) | 2001-07-04 |
| NZ280745A (en) | 1997-09-22 |
| FI956273A (fi) | 1996-06-29 |
| AU4069395A (en) | 1996-07-04 |
| ES2158034T3 (es) | 2001-09-01 |
| US6346521B1 (en) | 2002-02-12 |
| CN1058718C (zh) | 2000-11-22 |
| NO303641B1 (no) | 1998-08-10 |
| US6632807B1 (en) | 2003-10-14 |
| KR960022542A (ko) | 1996-07-18 |
| FI956273A0 (fi) | 1995-12-27 |
| GR3036757T3 (en) | 2001-12-31 |
| EP0719782A1 (en) | 1996-07-03 |
| BR9506098A (pt) | 1997-12-23 |
| AU689004B2 (en) | 1998-03-19 |
| HU9503802D0 (en) | 1996-02-28 |
| NO955305L (no) | 1996-07-01 |
| AR002018A1 (es) | 1998-01-07 |
| ATE202782T1 (de) | 2001-07-15 |
| DK0719782T3 (da) | 2001-09-24 |
| DE69521595D1 (de) | 2001-08-09 |
| TW403757B (en) | 2000-09-01 |
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