HRP20180527T1 - Modulatori receptora sfingozin 1-fosfata i postupci kiralne sintheze - Google Patents
Modulatori receptora sfingozin 1-fosfata i postupci kiralne sintheze Download PDFInfo
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- HRP20180527T1 HRP20180527T1 HRP20180527TT HRP20180527T HRP20180527T1 HR P20180527 T1 HRP20180527 T1 HR P20180527T1 HR P20180527T T HRP20180527T T HR P20180527TT HR P20180527 T HRP20180527 T HR P20180527T HR P20180527 T1 HRP20180527 T1 HR P20180527T1
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- compound
- tetrahydronaphthalene
- alkyl
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- 238000000034 method Methods 0.000 title claims 12
- 230000015572 biosynthetic process Effects 0.000 title claims 3
- 238000003786 synthesis reaction Methods 0.000 title claims 3
- 229940127530 Sphingosine 1-Phosphate Receptor Modulators Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 23
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims 16
- 229910052799 carbon Inorganic materials 0.000 claims 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 7
- 229920006395 saturated elastomer Polymers 0.000 claims 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 6
- 125000004043 oxo group Chemical group O=* 0.000 claims 5
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 125000005842 heteroatom Chemical group 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 239000012069 chiral reagent Substances 0.000 claims 3
- 125000002883 imidazolyl group Chemical group 0.000 claims 3
- 125000002757 morpholinyl group Chemical group 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 125000003386 piperidinyl group Chemical group 0.000 claims 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 2
- -1 cyclobutynyl Chemical group 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 239000012453 solvate Substances 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- 125000000335 thiazolyl group Chemical group 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 claims 1
- JRCCMJGRDJTQNS-UHFFFAOYSA-N 1-azido-1,2,3,4-tetrahydronaphthalene Chemical compound C1=CC=C2C(N=[N+]=[N-])CCCC2=C1 JRCCMJGRDJTQNS-UHFFFAOYSA-N 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 208000011231 Crohn disease Diseases 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
- 125000002393 azetidinyl group Chemical group 0.000 claims 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 230000021615 conjugation Effects 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- 206010022000 influenza Diseases 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 239000003223 protective agent Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- 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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- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Claims (14)
1. Spoj sa strukturnom Formulom I-R ili I-S, ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat:
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naznačen time što
X je -NR′R′′ ili -OR′′′;
Y je -CN, -Cl, -CF3, I, -COOH, ili -COOR1;
R′ je H, C1-4 alkil, n-hidroksi C1-4 alkil, -SO2-R1 ili -CO-R1;
R′′ je H, -SO2-R3, C1-4 alkil, koji može biti supstituiran s 1 ili više R2, ili prstenasti ostatak, koji može biti supstituiran s R4, gdje je takav prstenasti ostatak piperidinil, cikloheksil, morfolinil, tiazolil, pirazolil, pirolidinil, imidazolil ili fenil;
ili R′ i R′′, uzeti zajedno s atom dušika na kojeg su vezani, tvore 4, 5 ili 6-eročlani zasićeni heterociklički prsten, koji sadrži 0 ili 1 dodatni heteroatom, gdje je takav dodatni heteroatom O ili N, gdje takav heterocikl može biti jednostruko ili višestruko supstituiran supstituentima koje se neovisno bira iz skupine koju čine -OH, okso, - NH2, n-hidroksi-C1-4 alkil, -COOH, -(CH2)m-COOH, -(CH2)m-COOR1, -N(R1R1), te -(CH2)m-CO-N(R5R5);
R′′′ je H, C1-4 alkil ili -CO-R1;
svaki R1 je neovisno C1-4 alkil ili H;
svaki R2 je neovisno H, halogen, OH, okso, =NH, NH2, -COOH, F, -NHR1, -N(R5R5), -SO2-R1, -SO2-N(R5R5), -N(R1)-SO2-R1, -COOR1, -OCO-R1, -CO-N(R5R5), -N(R1)-COR1, C1-3 alkil, C1-3 alkoksi, i prstenasti ostatak, koji može biti supstituiran s R4, gdje je takav prstenasti ostatak piperazinil, piperidinil, morfolinil, pirolidinil, pirazolil, imidazolil, benzimidazolil, azetidinil, ciklobutinil ili fenil;
svaki R3 je neovisno R2, C1-4 alkil, C3-6 cikloalkil ili C1-4 alkil, koji može biti supstituiran s 1 ili više R2;
svaki R4 je neovisno halogen, OH, -NH2, -NHR1, -N(R1R1), -COOH, -COOR1, -NHCO-R1;
svaki R5 je neovisno C1-4 alkil ili H, ili dva R5, uzeta zajedno s atom dušika na kojeg su vezani, tvore 4, 5 ili 6-eročlani zasićeni heterociklički prsten, koji sadrži 0 ili 1 dodatni heteroatom, gdje je takav dodatni heteroatom O ili N, gdje takav heterocikl može biti supstituiran s -OH, -NH2, -N(R1R1), n-hidroksi C1-4 alkilom, -(CH2)m-COOH, -(CH2)m-COOR1; i
svaki m je neovisno 0, 1, 2 ili 3.
2. Spoj u skladu s patentnim zahtjevima 1, naznačen time što je spoj uglavnom enantiomerno čist.
3. Spoj u skladu s patentnim zahtjevima 1-2, naznačen time što je X -NR′R′′.
4. Spoj u skladu s patentnim zahtjevima 1-2, naznačen time što se spoj bira između spojeva 1-55:
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ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat.
5. Farmaceutski pripravak, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1-4.
6. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-4, ili pripravak u skladu s patentnim zahtjevom 5, naznačeni time što su namijenjeni upotrebi u liječenju multiple skleroze, odbacivanja presatka, sindroma akutnog respiratornog distresa, ulceroznog kolitisa, influence, Crohnove bolesti ili sindroma respiratornog distresa kod odraslih.
7. Postupak sinteze spoja Formule I-R ili I-S u skladu s patentnim zahtjevima 1-4, koji sadrži tetrahidronaftalenski ostatak, koji ima kiralni ugljik u šesteročlanom zasićenom prstenu tetrahidronaftalenskog ostatka, gdje je spoj enantiomerno obogaćen u odnosu na kiralni ugljik, naznačen time što se postupak sastoji u koracima
(i) osiguravanja spoja koji sadrži tetrahidronaftalenski ostatak, gdje je ugljik u prstenu šesteročlanog zasićenog prstena tetrahidronaftalenskog ostatka na kojem se želi postići kiralnu supstituciju okso supstituiran na takvom ugljiku;
(ii) reakcije takvog spoja s kiralnim reagensom kako bi se dobilo kiralni centar na ugljiku u tetrahidronaftalenskom ostatku, prethodno vezan na skupinu okso.
8. Postupak u skladu s patentnim zahtjevom 7, naznačen time što se spoj koji sadrži tetrahidronaftalenski ostatak dobiven u koraku (i) stavlja u kontakt s kiralnim reagensom kako bi se u koraku (ii) dobilo Formulu VI-R ili VI-S:
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gdje je Z -CN, -Cl ili -CF3.
9. Postupak u skladu s patentnim zahtjevom 8, naznačen time što postupak dodatno uključuje korak reverzije kiralne konfiguracije na kiralnom ugljiku u šesteročlanom zasićenom prstenu tetrahidronaftalenskog ostatka prethodno vezanom na skupinu okso obradom Formule VI-R ili VI-S difenilfosforil-azidom (DPPA) kako bi se dobilo azidotetrahidronaftalen Formule VII-S ili VII-R:
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gdje supstituent azido u šesteročlanom zasićenom prstenu tetrahidronaftalenskog ostatka zamjenjuje supstituent hidroksi, a kiralni ugljik vezan na supstituent azido ima obratnu kiralnu konfiguraciju na kiralnom ugljiku u odnosu na kada je bio prethodno vezan na hidroksi supstituent.
10. Postupak u skladu s patentnim zahtjevom 9, naznačen time što je Z -CN, a postupak dodatno uključuje korak dobivanja supstituiranog 1,2,4-oksadiazola na tetrahidronaftalenskom ostatku
(a) reakcijom međuprodukta VII-R ili VII-S sa zaštitnim sredstvom, te reakcijom dobivenog zaštićenog oblika međuprodukta VII-R ili VII-S s hidroksilaminom ili hidroksilamin-hidrokloridom kako bi se dobilo hidroksiamidin na fenilnom ugljiku na kojeg je Z vezan, gdje spoj dobiven takvom reakcijom ima Formulu VIII-R ili VIII-S:
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(b) stavljanjem u kontakt međuprodukta Formule VIII-R ili VIII-S sa supstituiranom benzojevom kiselinom i konjugacijskim reagensom kako bi se dobilo spoj Formule IX-R ili IX-S:
[image]
[image]
,
gdje je X OH, N3, NH-PG, NH2 ili NR′R′′; PG je zaštitna skupina; R′ je H, C1-4 alkil, n-hidroksi C1-4 alkil, -SO2-R1 ili -CO-R1; R′′ je H, -SO2-R3, C1-4 alkil, koji može biti supstituiran s 1 ili više R2, ili prstenasti ostatak, koji može biti supstituiran s R4, gdje je takav prstenasti ostatak piperidinil, cikloheksil, morfolinil, tiazolil, pirazolil, pirolidinil, imidazolil ili fenil; Ra je niži alkil, a R1, R2, R3, te R4 su definirani kao u patentnom zahtjevu 1.
11. Postupak u skladu s patentnim zahtjevom 10, naznačen time što spoj Formule IX-R ili IX-S ima strukture prikazane niže:
[image]
[image]
.
12. Postupak u skladu s patentnim zahtjevima 7-11, naznačen time što je dobiveni spoj koji sadrži tetrahidronaftalenski ostatak, koji ima kiralni ugljik u šesteročlanom zasićenom prstenu tetrahidronaftalenskog ostatka, enantiomerno obogaćen najmjanje 90%.
13. Spoj, naznačen time što ga se bira iz skupine koju čine:
[image]
,
[image]
,
[image]
,
[image]
,
[image]
,
[image]
,
[image]
,
[image]
.
14. Postupak sinteze spoja Formule I-R ili I-S u skladu s patentnim zahtjevom 1, koji sadrži tetrahidronaftalenski ostatak, koji ima kiralni ugljik u šesteročlanom zasićenom prstenu tetrahidronaftalenskog ostatka, gdje je spoj enantiomerno obogaćen u odnosu na kiralni ugljik, naznačen time što se postupak sastoji u koracima
(i) osiguravanja spoja koji sadrži tetrahidronaftalenski ostatak, gdje je ugljik u prstenu šesteročlanog zasićenog prstena tetrahidronaftalenskog ostatka na kojem se želi postići kiralnu supstituciju okso supstituiran na takvom ugljiku;
(ii) reakcije takvog spoja s kiralnim reagensom kako bi se dobilo kiralni centar na ugljiku u tetrahidronaftalenskom ostatku, prethodno vezan na skupinu okso.
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| US26247409P | 2009-11-18 | 2009-11-18 | |
| EP10830877.6A EP2498611B1 (en) | 2009-11-13 | 2010-11-15 | Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
| PCT/US2010/056757 WO2011060389A1 (en) | 2009-11-13 | 2010-11-15 | Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
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| LT (1) | LT2498611T (hr) |
| MX (1) | MX2012005562A (hr) |
| MY (1) | MY160907A (hr) |
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| PL3406142T3 (pl) * | 2009-11-13 | 2021-08-30 | Receptos Llc | Selektywne modulatory receptora sfingozyno-1-fosforanu i sposoby syntezy chiralnej |
| CN102724880B (zh) | 2009-11-13 | 2016-09-14 | 瑞塞普托斯有限责任公司 | 1-磷酸鞘氨醇受体调节剂及手性合成方法 |
| EP2706999B1 (en) * | 2011-05-13 | 2019-08-28 | Celgene International II Sàrl | Selective heterocyclic sphingosine 1 phosphate receptor modulators |
| CN103251950B (zh) * | 2012-02-16 | 2018-10-02 | 中国人民解放军军事科学院军事医学研究院辐射医学研究所 | S1p受体调节剂防治肠型放射病及放射性肠炎的用途 |
| JP6267221B2 (ja) * | 2012-11-16 | 2018-01-24 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | ２−トリフルオロメチルイソニコチン酸及びエステルの調製方法 |
| KR101939657B1 (ko) | 2013-02-20 | 2019-01-17 | 주식회사 엘지화학 | 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물 |
| US20170165236A1 (en) * | 2013-11-01 | 2017-06-15 | Celgene International Ii Sàrl | Selective sphingosine 1 phosphate receptor modulators and combination therapy therewith |
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| EP3448519A4 (en) * | 2016-04-29 | 2020-01-22 | Board Of Regents, The University Of Texas System | SIGMA RECEIVER BINDERS |
| US11192886B2 (en) * | 2016-07-22 | 2021-12-07 | Medshine Discovery Inc. | S1P1 agonist and application thereof |
| CN106749213B (zh) * | 2016-11-25 | 2019-07-02 | 济南大学 | 一种具有1,2,4-恶二唑结构的吲哚衍生物及制备方法和在制备抗菌药物中的应用 |
| CN108727291A (zh) * | 2017-04-21 | 2018-11-02 | 宁波爱诺医药科技有限公司 | 奥扎莫德及其中间体的制备方法 |
| CN108727292A (zh) * | 2017-04-21 | 2018-11-02 | 宁波爱诺医药科技有限公司 | 一种奥扎莫德及其中间体的制备方法 |
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| CN110256288A (zh) * | 2019-05-13 | 2019-09-20 | 苏州山青竹生物医药有限公司 | 一种制备(s)-1-氨基-2,3-二氢-1h-茚-4-甲腈的方法 |
| CN112062785B (zh) * | 2019-06-11 | 2023-06-27 | 广东东阳光药业有限公司 | 奥扎莫德及其中间体的制备方法 |
| JPWO2021157682A1 (hr) | 2020-02-06 | 2021-08-12 | ||
| EP4116295A4 (en) | 2020-03-04 | 2023-08-02 | Helioeast Pharmaceutical Co., Ltd. | TRICYCLIC COMPOUNDS AND THEIR USE |
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