HRP20210446T1 - Selektivni modulatori receptora sfingozin 1 fosfata i postupci za kiralnu sintezu - Google Patents
Selektivni modulatori receptora sfingozin 1 fosfata i postupci za kiralnu sintezu Download PDFInfo
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- HRP20210446T1 HRP20210446T1 HRP20210446TT HRP20210446T HRP20210446T1 HR P20210446 T1 HRP20210446 T1 HR P20210446T1 HR P20210446T T HRP20210446T T HR P20210446TT HR P20210446 T HRP20210446 T HR P20210446T HR P20210446 T1 HRP20210446 T1 HR P20210446T1
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- 238000000034 method Methods 0.000 title claims 30
- 230000015572 biosynthetic process Effects 0.000 title claims 3
- 238000003786 synthesis reaction Methods 0.000 title claims 2
- 229940127530 Sphingosine 1-Phosphate Receptor Modulators Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 56
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims 6
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 5
- 229910052799 carbon Inorganic materials 0.000 claims 5
- 239000003153 chemical reaction reagent Substances 0.000 claims 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims 4
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical group CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 claims 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 3
- 239000005711 Benzoic acid Substances 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 235000010233 benzoic acid Nutrition 0.000 claims 3
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 238000010511 deprotection reaction Methods 0.000 claims 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- 239000012069 chiral reagent Substances 0.000 claims 2
- 230000008878 coupling Effects 0.000 claims 2
- 238000010168 coupling process Methods 0.000 claims 2
- 238000005859 coupling reaction Methods 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 239000012279 sodium borohydride Substances 0.000 claims 1
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
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- 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
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A61K31/425—Thiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
- C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
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- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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Claims (24)
1. Postupak za sintezu spoja koji sadrži indanov ostatak koji posjeduje kiralni ugljik u peteročlanom prstenu indanovog ostatka, naznačen time, da je spoj enantiomerno obogaćen u odnosu na kiralni ugljik, pri čemu postupak obuhvaća sljedeće korake:
(i) pripravljanje indanovog dijela ostatka, tako, da na mjestu gdje je poželjna kiralna supstitucija, ugljik iz prstena peteročlanog prstena indanovog ostatka je oksosupstituiran na tom ugljiku, pri čemu spoj ima sljedeću strukturu:
[image]
(ii) reakcija spoja iz koraka (i) s kiralnim reagensom, pri čemu kiralni reagens jest t-Bu-S(=O)NH2, čime se tvori spoj jedne od sljedećih struktura:
[image]
(iii) tvorba kiralnog centra na ugljiku indanovog ostatka, koji je prethodno vezan na okso skupinu, putem reakcije spoja iz koraka (ii) sa sredstvom za reduciranje, čime se tvori spoj jedne od sljedećih struktura:
[image]
(iv) pretvaranje spoja iz koraka (iii) u kiralni amin, čime se tvori spoj jedne od sljedećih struktura:
[image]
(v) pretvaranje spoja iz koraka (iv) u zaštićeni kiralni amin, čime se tvori spoj jedne od sljedećih struktura:
[image]
(vi) reakcija spoja iz koraka (v) s R''-halidom, gdje R'' jest -CH2CH2OTBS, čime se tvori spoj jedne od sljedećih struktura:
[image]
i
(vii) obrada spoja iz koraka (vi) s hidroksilaminom ili hidroksilamin hidrokloridom u svrhu pretvaranja cijano supstituenta u hidroksiamidin na poziciji 4 indanovog ostatka, čime se tvori spoj jedne od sljedećih struktura:
[image]
2. Postupak prema patentnom zahtjevu 1, naznačen time, da
spoj stvoren u koraku (ii) jest:
[image]
spoj stvoren u koraku (iii) jest:
[image]
spoj stvoren u koraku (iv) jest:
[image]
spoj stvoren u koraku (v) jest:
[image]
spoj stvoren u koraku (vi) jest:
[image]
i
spoj stvoren u koraku (vii) jest:
[image]
3. Postupak prema patentnom zahtjevu 1, naznačen time, da
spoj stvoren u koraku (ii) jest:
[image]
spoj stvoren u koraku (iii) jest:
[image]
spoj stvoren u koraku (iv) jest:
[image]
spoj stvoren u koraku (v) jest:
[image]
spoj stvoren u koraku (vi) jest:
[image]
i
spoj stvoren u koraku (vii) jest:
[image]
4. Postupak prema patentnom zahtjevu 1, naznačen time, da se korak (vii) izvodi u prisutnosti baze.
5. Postupak prema patentnom zahtjevu 1, naznačen time, da postupak nadalje obuhvaća korak:
(viii) stavljanja u doticaj spoja iz koraka (vii) sa supstituiranom benzojevom kiselinom i reagensom za vezanje u svrhu tvorbe spoja jedne od sljedećih struktura:
[image]
6. Postupak prema patentnom zahtjevu 5, naznačen time, da je reagens za vezanje mješavina koja sadrži hidroksibenzotriazol (HOBt) i 1-etil-3-(3-dimetilaminopropil)-karbodiimid (EDC).
7. Postupak prema patentnom zahtjevu 1, naznačen time, da je spoj iz koraka (vii) enantiomerno obogaćen najmanje 90%, najmanje 95%, najmanje 98%, ili najmanje 99%.
8. Postupak prema patentnom zahtjevu 5, naznačen time, da postupak nadalje obuhvaća korak:
(ix) uklanjanja zaštite spoja iz koraka (viii) u svrhu tvorbe spoja jedne od sljedećih struktura:
[image]
9. Postupak prema patentnom zahtjevu 8, naznačen time, da spoj iz koraka (ix) jest:
[image]
10. Postupak prema patentnom zahtjevu 8, naznačen time, da spoj iz koraka (ix) jest:
[image]
11. Postupak prema patentnom zahtjevu 1, naznačen time, da:
spoj koji je stvoren u koraku (ii) jest:
[image]
spoj koji je stvoren u koraku (iii) jest:
[image]
spoj koji je stvoren u koraku (iv) jest:
[image]
spoj koji je stvoren u koraku (v) jest:
[image]
spoj koji je stvoren u koraku (vi) jest:
[image]
pri čemu R''-halid jest (2-bromoetoksi)(terc-butil)dimetilsilan;
spoj koji je stvoren u koraku (vii) jest:
[image]
gdje postupak nadalje obuhvaća sljedeće korake:
(viii) stavljanje u doticaj spoja iz koraka (vii) sa supstituiranom benzojevom kiselinom i reagensom za vezanje u svrhu tvorbe spoja sljedeće strukture:
[image]
i
(ix) uklanjanje zaštite spoja iz koraka (viii) u svrhu tvorbe spoja sljedeće strukture:
[image]
12. Postupak prema patentnom zahtjevu 1, naznačen time, da
spoj koji je stvoren u koraku (ii) jest:
[image]
spoj koji je stvoren u koraku (iii) jest:
[image]
spoj koji je stvoren u koraku (iv) jest:
[image]
spoj koji je stvoren u koraku (v) jest:
[image]
spoj koji je stvoren u koraku (vi) jest:
[image]
pri čemu R''-halid jest (2-bromoetoksi)(terc-butil)dimetilsilan;
spoj koji je stvoren u koraku (vii) jest:
[image]
gdje postupak nadalje obuhvaća sljedeće korake:
(viii) stavljanje u doticaj spoja iz koraka (vii) sa supstituiranom benzojevom kiselinom i reagensom za vezanje u svrhu tvorbe spoja sljedeće strukture:
[image]
i
(ix) uklanjanje zaštite spoja iz koraka (viii) u svrhu tvorbe spoja sljedeće strukture:
[image]
13. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se korak (ii) provodi u prisutnosti Ti(OEt)4.
14. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se kod sredstva za reduciranje u koraku (iii) radi o natrijevom borohidridu.
15. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se korak (iv) ostvaruje u prisutnosti klorovodične kiseline.
16. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se korak (v) izvršava pomoću dodavanja di-terc-butil dikarbonata (Boc2O).
17. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se korak (vi) izvršava u prisutnosti natrijevog hidrida.
18. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se korak (vii) izvršava u prisutnosti hidroksilamin hidroklorida i trietilamina.
19. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se kod reagensa za vezanje u koraku (viii) radi o mješavini koja sadrži hidroksibenzotriazol (HOBt) i 1-etil-3-(3-dimetilaminopropil)-karbodiimid (EDC).
20. Postupak prema patentnom zahtjevu 19, naznačen time, da se primjenjuje zagrijavanje slijedom nakon dodavanja agensa za vezanje.
21. Postupak prema bilo kojem od patentnih zahtjeva 11 i 12, naznačen time, da se korak (ix) ostvaruje u prisutnosti klorovodične kiseline.
22. Postupak prema bilo kojem od patentnih zahtjeva 11 do 21, naznačen time, da je spoj u koraku (viii) enantiomerno obogaćen najmanje 90%, najmanje 95%, najmanje 98%, ili najmanje 99%.
23. Postupak prema patentnom zahtjevu 1, naznačen time, da R''-halid jest (2-bromoetoksi)-terc-butildimetilsilan.
24. Postupak prema bilo kojem od patentnih zahtjeva 1, 11 ili 12, naznačen time, da se u koraku (vii) spoj iz koraka (vi) obrađuje hidroksilamin hidrokloridom.
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EP18160667.4A EP3406142B8 (en) | 2009-11-13 | 2010-11-15 | Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
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HRP20210446T1 true HRP20210446T1 (hr) | 2021-05-14 |
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HRP20210446TT HRP20210446T1 (hr) | 2009-11-13 | 2021-03-17 | Selektivni modulatori receptora sfingozin 1 fosfata i postupci za kiralnu sintezu |
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- 2019-07-09 IL IL267956A patent/IL267956B/en active IP Right Grant
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2020
- 2020-11-18 HU HUS2000045C patent/HUS2000045I1/hu unknown
- 2020-11-18 LT LTPA2020533C patent/LTC2498610I2/lt unknown
- 2020-11-18 FR FR20C1059C patent/FR20C1059I2/fr active Active
- 2020-11-18 NO NO2020039C patent/NO2020039I1/no unknown
- 2020-11-19 CY CY2020035C patent/CY2020035I2/el unknown
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2021
- 2021-03-17 HR HRP20210446TT patent/HRP20210446T1/hr unknown
- 2021-03-22 CY CY20211100241T patent/CY1124121T1/el unknown
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