HU229833B1 - Epothilone d production process, and its use as cytostatic as well as phytosanitary agents - Google Patents

Epothilone d production process, and its use as cytostatic as well as phytosanitary agents Download PDF

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HU229833B1
HU229833B1 HU0000497A HUP0000497A HU229833B1 HU 229833 B1 HU229833 B1 HU 229833B1 HU 0000497 A HU0000497 A HU 0000497A HU P0000497 A HUP0000497 A HU P0000497A HU 229833 B1 HU229833 B1 HU 229833B1
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epothilone
spotilon
brain
experiment
polymerization
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Klaus Gerth
Gerhard Hoefle
Hans Reichenbach
Heinrich Steinmetz
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Biotechnolog Forschung Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/20—Bacteria; Substances produced thereby or obtained therefrom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/167—Heterorings having sulfur atoms as ring heteroatoms, e.g. vitamin B1, thiamine nucleus and open chain analogs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
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  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Silicon Polymers (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description

(57) Kivonat
A bejelentés D epotilon előállítását írja le Sorangium cellulosum DSM 6773 törzsből kiindulva, melyet adszorbens gyanta jelenlétében tenyésztenek, az adszorbens gyantát a tenyészetből eltávolítják, víz/metanol eleggyel mossák, metanollal eluálják, az eluátumot betöményítve nyers extraktumot kapnak, melyet etil-acetáttal extrahálnak, az extraktumot betöményítik, metanol és hexán között megosztják, a metanolos fázist betöményítve raffinátumot kapnak, a koncentrátumot Sephadex oszlopon frakcionálják, a mikroorganizmus által termelt metabolitokat tartalmazó frakciót C18 típusú reverz fázisú oszlopon metanol/víz eleggyel kromatografálják, a D epotilont tartalmazó frakciót elkülönítik.
1, ábra
A találtóny - egyik Mogvalósltási módja eljárás D apotilon előállítására oly módon, hagy (a) Sorangium oellulosam bők 8773 jelű törzset önmagában ismert módon adsrorbans gyanta jelenlétében tenyésztünk, (fe) az adszorbens gyantát a tenyészetből eltávolítjuk «Is viz/betanol alaggyal mossuk, fc) a mosott adszorbens gyantát metanollal alnáljok, és őz aluétum.oé botóményitve nyers eatrakéumot kapunk/ (d) a kapott koncentrátumot etii-acatátéal extraháljuk/ az eatraktumot feetöményXtják és metanol és bénán között magosatjuk# (e) a metanolon fázist betóményitze raf£Inátumot kapunk, és a kenoantrátumot Saphsdex ossiopon frakolonáljuk, (i) az alkalmazott mikroorganizmus által termált metabolitokat tartalmasé frakóiőt kapunk,
Cg) a kapott frakciót CXá ttpasű rovarz fázisú oszlopon metanol/víz elággyal krometografáljuk, és szekvenciálison egy A epotilont tartalmasé első frakciót és “ egy fe egeim k\u tartakomse oaaodix Hakeitt ™ agy első további epotilont (C apótiIon) tartalmasó ha rmadlk f rako1ót és ~ egy második további epotilont(b apóéiIon) tártaiba tó negyedik frakciót kapunk, és (h) a második további frakció epotiIonját <Ö epotilon) elkülönít jók.
& találmány tárgya továbbá ar alábbi képletü b epetilom
D epotilóó a ™ CHS
B vegyöiet tapasztalati képlete Ο«Κ^0§5 és te 1, Táblázatban megadott ''H-ée *SONMR spektrumai j ell emez hat <b
A D epei. Ilon felhasználható as alábbi 1 képleté vegyületek eléáilltásához# melyek a bk>A~9?/X9 Oáá sz. asabedaltd létráéban ismertetett származék képzési módéterekkel állíthatók elb.
A fenti X» képletben:
R «* R,, ;
R\ R:sf RC R% Rs - H, C©.-elk.ilf Cx~«~&ci 1-ben zoil #
Ca-^-tríaikíl-szilii# benzil# fenil#
Cx-s-alkeni·”#
Cp-aXkil-# hidroxi- és hal o génnel, helyettesített benzil vagy fenilí ahol az R* ~ R^ gyökök közül tette -jCH·?)» csoportot is alkothat# amelyben n jelentése 1 és 6 közötti szám# és a gyökökben lévő alkil- vagy acil-csoportöK egyenes vagy elágazó láncnak?
Y és 1 jelentése azonos vagy különböző lehet és egymástól függetlenül hidrogénatomot# halogénatomot (pl- F# Cl#- Ba vagy 1) # nszaadohalogént (pl. -HCO# -NCS vagy -Xcsoportot.}, 0B~# O~ { Cs.*} ~acil~# 0~ { C?-s) ~ai ki 1 ~ vagy 0benzöil-esoportpt képviselhet, Y és 2 jelentheti egy epoxid oxigénatomját is# mivel oltalmi igényünk az A és B epotilonra nem terjed ki# vagy egy C«C kettős kötés egyik € ~ C köt é s é t a 1 ko t j á k, & 12#·13·~kettős kötés szelektíven - hidrogénezhető.# például katalitikusén vagy diiminnel# ily módon olyan 1 képletü vegyületet kapunk# amelynek képletében Y ~ 2 *« H; vagy ~ epoxiddá alakítható# például dimetil-dioxiránnal vagy egy persawal# ily módon olyan 1 képletü vegyületet kapunk# amelynek képletében Y =» 2 - -0-, vagy dihalidokká# dipszeudohalidokká vagy diazidokká alakítható# ily módon olyan. 1 képletü vegyületet kapunk# amelynek képletében Y és i - Hal# p.szeudo~hal vagy B;;.
A találmány továbbá gyógyászati készítményekre külőnösen citosztatikumokra vonatkozik# amelyek D epotilont vagy epotiionnak egy vagy több szokásos hordozóanyággal és/vagy higitószerrel képetett kombinációiét tartalmazsák,
A találmányt az alábbi kiviteli példákkal rás zlet esebben is bemutatjuk.
D epotlXon
A, Az előállításhoz használt baktérlmi-törzs és &
SB~B~4£ 3S ö<2 », azahadalonfeen ieirtaknak belelnek meg.
a. 1 ap s 2 abada 1 ómba n és egy gyártó 700 I tér£ogatű
B. Blőállítás DSM 6773 tőrmel
1 tenyészetet az ismertetett módon tenyésztünk, fezmentálóberendezésben elhelyezet t, előállító közeget oltunk be vele, A közeg összetétele a: alábbi: 0,8 % keményítő, 0,2 % ssőlőcukor, 0,2 1 szójaliszt, 0,2 % élesztőkivonat, 0,1 % CaCls x 2X0, ö,“ % MgSÖ« x 7 H:í0, 8 mg/l Fe-EOTA, pH ~ 7,4 és kívánt esetbei 15 1 Ambrelíte XAD-16 adszorber gyanta- A fermentálás 30 1 hőmérsékleten 7-1Ö napig tart, a levegőztetést 0,1. NL/isr1 ~ rel végezzük. A rotáció sebességének kontrollálásával a pÖ2~t 30 %“on tartjuk.
C, Izolálás
Az adszorbens gyantát a tenyészettől 0,7 m2, 100 mesh. iyukméretö szörŐ alkalmazásával elválasztjuk, és az égy térfogatára számítva háromszoros mennyiségű, 2:1 arányú viz/metanol eleggyel mosassuk, hogy megszabadítsuk a poláros szennyeződésektől. Az ágy térfogatára számítva négyszeres mennyiségű metanollal történő eluálást követően nyers extraktumot kapunk# amelyet vákuumban a vizes fázis meg jozenésélg bogárólunk«
Ezt háromszor ugyanolyan mennyiségű etil™ acetátfal extraháljuk. A szerves fázist bepárolva 240 g nyers extraktumot kapunk# amelyet a lipofil szennyeződések leválasztása céljából metanol és heptán között megesztank. Az elegyek vákuumban bepároljak- Ily módon 180 g raffinátumot kapunk a metanolos fázisból# amit Sephadex LH~20 jelű oszlopon (20 x 100 cm# 20 mi/perc metanol) három részre frakcionálunk, Az epotilonokat a 240 - 300 perc retehciós idővel kioldódd frakció tartalmazza,# melynek ő'sszmennyisége 7.2 g. Az epotIlonok szétválasztása céljából a frakciót három részletben krőmatögrafáljak Idohroeorb RE-18 oszlopon <15 pm# 10 x 40 om-es oszlop# eluálószer: ISO ml/pere sebességgel átfolyatott# SS:3§ arányé metanol/víz elegy). Először az A és B# majd a € epotilon oldódik ki ss §0-95 perc), majd pedig a D epotilon 100-110 perc retenciós idővel„ Vákuumban történő bepárlés után valamennyi terméket szintélen olaj formájában kapjuk# ö#3 g hozammal.
1» Táblázati 0 epotilon *H~ és C-HMH adatai [b%] OMSO-ban, 300 MHt-en
D epotilon
8 (ppp) C atom 8 (pp.e)
1 170,1
2-Ha 2,35 2 33, 0
2-Hb 2, 30 3 70,0
3-H 4,1 0 4 53,2
3-OH 5,08 5 217,4
6-H 3,11 0 44,4
7-H 3,40 7 75, 5
7-OH 4,46 3 .36, 3
S-H 1,25 9 29,9
3~ Ha Λ í i 10 25, 9
9-Hb 1,30 11 31, 8*
10 -Ha 1,14* 12 130, 2
10-Hb 1,35* 13 120,3
11 -Ha 1, 7 5 14 31,6*
11-Hb 2,10 15 76, 0
12-H 16 137,2
13-H 5,08 1.7 119,2
14 -Ha 2, 30 10 152,1
14-Hb .2, 65 19 117, 7
1S~H 5,29 20 164,3
17-H 6,51 21 IS, 9
I9-H 7,35 22 19,7
21-Hs 2, 65 23 22,5
22~K3 0, 90 24 16, 4
23~H3 1,19 25 Λ $5 í 4
2 4-Hí 1,07 26 22, 3
2S~B3 0,91 27 14, X
.26-¾ 1 ? 03
27-¾ 2,11
* felcserélhető asssi^náeió ··*
Λ találmány eserinti D epotilont és at l^S, dseaehaeonllt.6 példa szerinti A, B, C, E és F epet Hont sejt tenyéeseteken /2.táblásat/ és a pollMerisáció elősegítésére /3, táblázat/ testteltük.
2. Táblázat;
Rpctilsm w 192 & SO? xto-so »'X \x 67? (ng/ssll 1·.' Sál SOS s: S 2 3
tgér kőfcőssöv&tl .sejt t 92$ 1 1. 100 20 20 1,5
Rüssáft daqsmsfcrts snjtvvr3l.sk:
EtoOG (XeukéxdLs) 0,2 0,2 20 3 2 0,3
to S 02 ;1wkésis) 0,2 0,2 20 10 2 o,s
0-033 (lp?qawss«) 0,2 0,2 10 3 1 0,2
SS-3, 1 {mátoyAtoákj 1 0,6 20 12 S 0,5
KB-V1 (cetrix: msXtlrés rák) 0,3 0,3 IS 3 S 0,6
,é~ 4 §§ (vsso rák) ... X,S ISO 20 20 3
toSiO Otáőőrák) 0,7 0,1 20 10 3 0,1
ái Η
ΛΑΑ.·
Paraméter: A kontroj eltelt idő fél“maximális polimerizációja le
20Ö
Reagens Reagens feji
Aj
100
Kontrol18 0
1S(
Spotilon
A ί bS
Epot iIon
v
EpotiIon

Claims (1)

125 ? 6
Spotilon
0 5 —Jt -x
120
106
Spotilon
Mi
5
Spotilon
F
4 9 56
Standard teszt G,9 mg tnbulin/ml és 1 μΜ minta koncentrációval
A polimerizációs kísérlet in vitro kísérlet, melynek során sértés agyából származó tisztított tubulint használunk. A kiértékelést fotörnetriásan végezzük. A polimer!rációt elősegítő anyagok, mint pl. az epotiIonok, csökkentik azt az időt, amely alatt a fél-maximális polimerizaciő végbemegy, vagyis minél rövidébe az idő, annál aktívabb a vegyüiet. W, x, y és z négy önálló kísérlet, a relatív aktivitást az utolsó oszlopban a kontroll %-ában fejezzük ki; a legjobb hatékonyságot itt is a legalacsonyabb értékek jelzik, A hatás-erősség sorrendje meglehetősen pontos egyezést mutat a seittenyés'setekkel végzett kísérlet során tapasztaltakkal.
(b) « AsX^tobmw <e) esXw
«x-íxakfetws'fc b^febs&ényX'tjW a»tM»l é» íwsc&a bfebtfc ttodtolfc ? éss ssskvsaciálix^&n feáfelót kapa
Λ· ·&·
‘ikmtkésit tWfcéáte £eXW#»»á£&«*a «8JY a 8, &a«lafci .ΑSSíSswWí siws
A
SZOLGÁLÓ VÁIJOZ * > v * * > > ♦ ♦» φ * * « φ .»♦ « » x *
Χ . ábra
BgV XAD gyanta eiuábumanak HPLC atalyaise agy Carmen tán© én folyamat végén λ , ábra 1 es e apóexion fai dán óláén. farm ont.lében. A én S epet bion oi agyénak fcatapiaiáao után, Ar nnai i ri gy 48 órás lakúbafás után végeakuk.
ÁWOtATÓM
SZAGA;:A; ;A vOXGYOORODA ? Z.Ö V AAO Q YöZ G y ί ΟΥΥό
Aíf ASOYO 08. Ο.
,vA-?hV\
U] XteKte'noáR
All V O (ÍA'RRN T
Ö8ÁBÁDÁÍ.MX& VföteBöY (RteOA 5 KOVK^RGteteRte'Y te íR sí ’í ábra .8 epotxlon biotranszforeácnősa S: epotxlomjá
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HU0000497A 1996-11-18 1997-11-18 Epothilone d production process, and its use as cytostatic as well as phytosanitary agents HU229833B1 (en)

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Application Number Priority Date Filing Date Title
DE19647580 1996-11-18
DE19707506 1997-02-25
PCT/EP1997/006442 WO1998022461A1 (de) 1996-11-18 1997-11-18 Epothilone c, d, e und f, deren herstellung und deren verwendung als cytostatische mittel bzw. als pflanzenschutzmittel

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HUP0000497A2 HUP0000497A2 (hu) 2000-06-28
HUP0000497A3 HUP0000497A3 (en) 2001-10-29
HU229833B1 true HU229833B1 (en) 2014-09-29

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