FI77847B - Foerfarande foer framstaellning av terapeutiskt anvaendbara alkensyraderivat. - Google Patents

Foerfarande foer framstaellning av terapeutiskt anvaendbara alkensyraderivat. Download PDF

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FI77847B
FI77847B FI822205A FI822205A FI77847B FI 77847 B FI77847 B FI 77847B FI 822205 A FI822205 A FI 822205A FI 822205 A FI822205 A FI 822205A FI 77847 B FI77847 B FI 77847B
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ester
alkensyraderivat
formula
compounds
compound
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Alec Todd
Stephen Richard Baker
William Boffey Jamieson
William James Ross
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Lilly Industries Ltd
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
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    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
    • C07D303/42—Acyclic compounds having a chain of seven or more carbon atoms, e.g. epoxidised fats
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07F9/02—Phosphorus compounds
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Description

χ 77847
Menetelmä terapeuttisesti käyttökelpoisten alkeenihappo-johdannaisten valmistamiseksi
Keksinnön kohteena on menetelmä farmaseuttisesti 5 aktiivisen yhdisteen valmistamiseksi, jolla on kaava
OH
I COOZ1 C11H23CH=CHNAV^^^ T CH3 ^^NHCOCH3
10 S-C-CH
^H^^COOZ2 1 2 jossa Z ja Z kumpikin on vety, alkalimetalli tai alempi alkyyli.
15 Yhdisteet ovat farmaseuttisesti aktiivisia SRS-A:n antagonisteina.
Läheisiä yhdisteitä tunnetaan mm. EP-hakemusjulkaisusta 36 663 sekä julkaisuista J. of American Chem. Soc. 102 (1980) s. 1436-39 (erityisesti s. 1438 kaava 17) ja 20 Chem. Abstr. 94 (1981), 154001 d sekä Chem. Abstr. 95 (1981), 59785 z.
Keksinnön mukaiset yhdisteet valmistetaan siten, että yhdiste, jolla on kaava . C11H23CH=CH—-—CH^^-^^COOH (IV) tai sen suola tai esteri saatetaan reagoimaan tiolin kanssa, jolla on kaava 30 CH3 ___^nhcoch3 - (V)
“ I "''•-COOH
C2H5 35 Δ 5 tai sen suolan tai esterin kanssa, 2 77847 minkä jälkeen esteriryhmä/esteriryhmät haluttaessa hydrolysoidaan .
Menetelmä suoritetaan vahvan emäksen (pKa<12), kuten trialkyyliamiinin, esim. trietyyliamiinin läsnäollessa 5 ja inertissä polaarisessa liuottimessa, kuten alkanolissa, esim. metanolissa. Sopiva reaktiolämpötila on 10° - 50°C, edullisesti huoneenlämmössä. Reaktiota voidaan katalysoida adsorboimalla kaavan (V) mukainen tioli aktiiviseen alumiinioksidiin .
10 Menetelmässä on edullista käyttää yhdistettä (IV) esterimuodossa, edullisesti C^_4-alkyyliesterimuodossa ja erikoisesti metyyliesterimuodossa. Keksinnön mukainen yhdiste valmistetaan siten aluksi vastaavassa esterimuodossa.
Tässä reaktiossa isomeerinen 5-tio-6-hydroksiyhdis-15 te voi muodostua samalla kun haluttu 5-hydroksi-6-tio- yhdiste. Isomeerinen sivutuote voidaan poistaa seoksesta happomuodon muodostuksella, jota seuraa laktonisaatio, esim. kuumentamalla inertissä luottimessa kuten tolueenis-sa ja vain 5-hydroksi-yhdiste läpikäy laktonisaation.
20 Saadut keksinnön mukaiset yhdisteet voidaan erot taa ja puhdistaa tavanomaisesti.
Keskinäinen muuttaminen useiden keksinnön mukaisten yhdisteiden muotojen välillä, esim. suola-, vapaa happo- ja esterimuotojen välillä voidaan suorittaa tavanomai-25 sesti. Esimerkiksi esterimuodot voidaan muuttaa suolamuo-doiksi käsittelemällä sopivalla vesipitoisella laimealla emäksellä pH-arvossa 9-10. Suolamuodot voidaan muuttaa vapaiksi happomuodoiksi hapon muodostuksella vesipitoisessa väliaineessa. Suola- tai vapaat happomuodot voidaan 30 muuttaa esterimuodoiksi emäksen tai hapon katalysoimalla esteröinnillä käyttäen sopivaa alkoholia. Välituoteyhdis-teet ovat joko tunnettuja tai ne voidaan valmistaa saatavissa olevista lähtöaineista tavanomaisesti.
Kaavan (IV) mukaiset epoksidit voidaan valmistaa 35 hapettamalla kaavan (II) mukaisia yhdisteitä
C11H23CH=CH>^^\^^>S\ COOK
3 77847 edullisesti esterimuodossa käyttäen hapettimena m-kloori-perbentsoehappoa tai vetyperoksidia. Kun hapettimena käytetään m-klooriperbentsoehappoa, hapetus suoritetaan kloroformissa ja kun käytetään vetyperoksidia# hapetus suori-5 tetaan metanolissa.
Keksinnön mukaiset yhdisteet ovat farmaseuttisesti aktiivisia SRS-A:n antagonisteina, kuten on osoitettu seuraavilla kokeilla: in vitro kokeella marsun sykkyräsuo-lisegmentillä väkevyyksissä 10-50 yug julkaisussa Schild, 10 1947 Brit. J. Pharm. 2 197-206 kuvatun menetelmän mukaan (keksinnön mukaisilla yhdisteillä ICj-q SRS-A:ta vastaan on alle 10 4 moolia); in vivo marsun keuhkotoimintakokeel-la (Austen ja Drazen 1974 J. Clin. Invest. 53:1679-1685) laskimonsisäisillä annospitoisuuksilla 0,05 yug - 5,0 mg/kg 15 ja modifioidussa "Herxheimer"-kokeessa annospitoisuuksilla 25-200 mg/kg. "Herxheimer"-koe perustuu marsuihin aikaansaatuun allergiseen keuhkoputken kouristukseen, joka läheisesti muistuttaa astmaattista kohtausta ihmisellä. Keuhkoputken kouristuksen aiheuttavat mediaattorit ovat 20 hyvin samanlaisia kuin ne, jotka vapautuvat kun ihmisen herkistettyyn keuhkokudokseen vaikuttaa antigeeni. Modifioidussa kokeessa, jota käytettiin keksinnön mukaisilla yhdisteillä, eläimet esikäsiteltiin histamiinin antagonistilla, mepyramiinilla aluksi annospitoisuudella 0,5 mg/kg 25 30 min ennen varsinaista annostusta. Tämä modifikaatio peittää histamiinin vaikutuksen niin että SRS-A:n vaikutus tulee paremmin esille.
Esimerkin 1 mukaisen yhdisteen IC^-arvo SRS-A:ta vastaan marsun sykkyräsuolikokeessa (Schild, Brit. J.
30 Pharm. 2 (1947) 197-206) oli 10 ^ ja esimerkin 2 mukaisen -5 yhdisteen 10
Yhdisteet ovat niin ollen sopivia terapeuttista käyttöä varten hoidettaessa keuhkojärjestelmän allergisia reaktioita, joissa SRS-A:ta pidetään keuhkoputken kouris-• · 35 tusta aiheuttavana mediaattorina, so. allergisissa keuhko sairauksissa kuten ulkosyntyisessä astmassa ja teollisuus- A 77847 4 astmoissa kuten maanviljelijän ja kyyhkyskasvattajän keuhkoastmassa, samoin kuin muissa allergisissa sairauksissa, tulehdussairauksissa tai keuhkosairauksissa, joissa SRS-A:ta pidetään mediaattorina.
5 Aktiiviset yhdisteet ovat tehokkaita laajalla an- nostusalueella ja esimerkiksi päivittäiset annostukset ovat 0,5-300 mg/kg, useimmiten 5-100 mg/kg.
Seuraavat esimerkit valaisevat keksintöä.
Esimerkki 1 10 (a) (DL-N-asetyyli-3-merkaptoisoleusyyli)glysiinimetyy- liesteri
Etyyliklooriformaatti (0,12 ml) lisätään sekoitettuun liuokseen, jossa on DL-N-asetyyli-3-merkapto-isoleu-siiniä (0,20 g) dikloorimetaanissa (10 ml) ja trietyyli-15 amiinia (0,28 ml) -10°C:ssa. Liuoksen annetaan lämmetä huoneenlämpöön, pestään laimealla suolahapolla ja sen jälkeen natriumbikarbonaattiliuoksella, kuivataan ja haihdutetaan, jolloin saadaan 3-asetamido-4-etyyli-4-metyyli-2-tioetanoni vaaleana öljynä.
20 Tämän tiolaktonin liuokseen dikloorimetaanissa (5 ml) lisätään kiinteää glysiinimetyyliesterihydrokloridia (0,15 g) ja trietyyliamiinia (0,20 ml) ja seosta sekoitetaan 16 tuntia. Kirkas liuos pestään laimealla suolahapolla ja sen jälkeen natriumbikarbonaattiliuoksella, kuiva-25 taan ja haihdutetaan ja jäännös kiteytetään metanoli-ve-*: destä, jolloin saadaan otsikoitu yhdiste, sp. 136°C.
(b) 5- (S) -hydroksi-6 (R) -Z.T2- (N-asetyyliamino) -2-metok- sikarbonyyli-l-etyyli-l-metyylietyyli)-tiQ/-7-(Z)-nonadekeenihappo ja sen 5-(R)-6-(S)-isomeeri 30 Metyyli-5,6-(E)-oksido-7-(Z)-nonadekenoaatin (162 mg) annetaan reagoida 50°C:ssa 3-4 päivää liuoksen \ kanssa, jossa oli DL-N-asetyyli--merkaptoisoleusiinime- tyyliesteriä (216 mg) ja trietyyliamiinia (200 ^ul) kuivas-; sa metanolissa (500 pl). Kun metanoli on poistettu typpi- 35 virran avulla, jäännös liuotetaan seokseen, jossa on di-etyylieetteri-heksaania 50/50 v/v ja kromatografoidaan 5 77847 käyttäen silikageeliä. Kehittäminen samalla liuotinseok-sella antoi aluksi reagoimattoman epoksidin. Edelleen eluoiminen dikloorimetaani/metanolin 95/5 v/v seoksen kanssa antaa halutun dimetyyliesterin, joka sisältää epäpuh-5 tautena vähän vapaata tiolia, vaaleankeltaisena öljynä.
Sen jälkeen dimetyyliesteri liuotetaan metanoliin (3 ml) ja lisätään 2 M natriumkarbonaattiliuosta (1,5 ml) ja muutama pisara vettä, jolloin saadaan samea liuos. Hydrolyy-sin annetaan jatkua huoneenlämmössä 3 päivää, jonka jäl-10 keen melkein kirkas liuos tehdään varovasti happameksi pH-arvoon 3,5 (käyttäen laimeaa suolahappoa) ja uutetaan dikloorimetaanilla. Yhdistetyt uutteet pestään vedellä, kuivataan magnesiumsulfaatilla ja haihdutetaan tyhjössä, jolloin saadaan otsikoitu yhdiste vaaleankeltaisena vis-15 koosina öljynä.
Esimerkki 2 5- (S) -hydroksi-6- (R) -Z_l2- (N-asetyyliamino) -2-karb-oksi-l-etyyli-l-metyylietyyli)tig7-7-(Z)-nonadekee-nihappo ja sen 5-(R)-6-(S)-isomeeri 20 Esimerkin 1 monometyyliesteri (89 mg) liuotetaan tetrahydrofuraaniin (4 ml) ja lisätään 4 M litiumhydroksi-diliuosta (1 ml) ja sen jälkeen edelleen vettä (3 ml), jolloin saadaan homogeeninen liuos, jota kuumennetaan 48°C:ssa 4 päivän ajan. Tetrahydrofuraani poistetaan haih-25 duttamalla tyhjössä ja jäännös jaetaan dikloorimetaanin ja veden kesken pH-arvossa 3 (säädetty laimealla suolahapolla) . Dikloorimetaaniuute kuivataan magnesiumsulfaatilla ja haihdutetaan typpivirrassa, jolloin saadaan haluttu dikarboksyylihappo värittömänä viskoosina öljynä.

Claims (3)

  1. 6 77847 Patenttivaatimus Menetelmä farmaseuttisesti aktiivisen yhdisteen valmistamiseksi, jolla on kaava
  2. 5 OH I COOZ1 C H?1CH=CH 1. ch3 ^^nhcoch3 S-C-CH^ J^—COOZ^
  3. 10 C2H5 1 . 2 jossa Z ja Z kumpikin on vety, alkalimetalli tai alempi alkyyli, tunnettu siitä, että yhdiste, jolla on kaava 15 ^ C11H 2<3Η-(ίΗ--CH * COOH (IV) tai sen suola tai esteri saatetaan reagoimaan tiolin kanssa, jolla on kaava 20 ^Η3 ^^^NHCOCH3 HS-C -ClC" (V) I ^^-COOH C2H5 25 tai sen suolan tai esterin kanssa, minkä jälkeen esteriryhmä/esteriryhmät haluttaessa hydrolysoidaan .
FI822205A 1981-06-18 1982-06-18 Foerfarande foer framstaellning av terapeutiskt anvaendbara alkensyraderivat. FI77847C (fi)

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GB8118720 1981-06-18
GB8118720 1981-06-18
GB8213211 1982-05-07
GB8213211 1982-05-07

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FI822205L FI822205L (fi) 1982-12-19
FI77847B true FI77847B (fi) 1989-01-31
FI77847C FI77847C (fi) 1989-05-10

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FI822205L (fi) 1982-12-19
FI822205A0 (fi) 1982-06-18
PT75058A (en) 1982-07-01
NZ200984A (en) 1985-01-31
CS456582A2 (en) 1985-07-16
ES513221A0 (es) 1983-07-01
CS241109B2 (en) 1986-03-13
FI77847C (fi) 1989-05-10
DE3261237D1 (en) 1984-12-20
IE53522B1 (en) 1988-12-07
PL236992A1 (en) 1983-08-15
KR890000622B1 (ko) 1989-03-22
IE821443L (en) 1982-12-18
BG37226A3 (en) 1985-04-15
GR76838B (fi) 1984-09-04
EP0068739B1 (en) 1984-11-14
PL240482A1 (en) 1983-09-12
ZA824294B (en) 1983-06-29
GB2101594A (en) 1983-01-19
ES8404307A1 (es) 1984-05-01
ES8307212A1 (es) 1983-07-01
PT75058B (en) 1985-07-26
RO83706B (ro) 1984-03-30
PL137766B1 (en) 1986-07-31
ES520670A0 (es) 1984-05-01
IL66056A0 (en) 1982-09-30
PL240484A1 (en) 1983-09-12
EP0068739A1 (en) 1983-01-05
PL240483A1 (en) 1983-09-12
US4513005A (en) 1985-04-23
HU192105B (en) 1987-05-28
KR840000483A (ko) 1984-02-22
PH23051A (en) 1989-03-10
ES520671A0 (es) 1984-05-01
DK271682A (da) 1982-12-19
GB2101594B (en) 1985-12-24
CA1224795A (en) 1987-07-28
RO83706A (ro) 1984-03-15
DD202697A5 (de) 1983-09-28
AU8500882A (en) 1982-12-23
ES8404322A1 (es) 1984-05-01
AU549814B2 (en) 1986-02-13

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