HRP20211290T1 - Sinteza omekamtiv mekarbila - Google Patents

Sinteza omekamtiv mekarbila Download PDF

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Publication number
HRP20211290T1
HRP20211290T1 HRP20211290TT HRP20211290T HRP20211290T1 HR P20211290 T1 HRP20211290 T1 HR P20211290T1 HR P20211290T T HRP20211290T T HR P20211290TT HR P20211290 T HRP20211290 T HR P20211290T HR P20211290 T1 HRP20211290 T1 HR P20211290T1
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HR
Croatia
Prior art keywords
pmec
fnb
image
mixing
phosphate hydrate
Prior art date
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HRP20211290TT
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English (en)
Inventor
Sebastien Caille
Kyle QUASDORF
Philipp ROOSEN
Xianqing Shi
Andrew COSBIE
Fang Wang
Zufan WU
Archana NEERGUNDA
Bin Peter Quan
Lianxiu GUAN
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Amgen Inc.
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Publication date
Application filed by Amgen Inc. filed Critical Amgen Inc.
Publication of HRP20211290T1 publication Critical patent/HRP20211290T1/hr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205Radicals derived from carbonic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72Nitrogen atoms
    • C07D213/75Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hospice & Palliative Care (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pyridine Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Claims (14)

1. Piperazin metil karboksilat fosfat hidrat [image] („PMEC“).
2. Postupak za sintetiziranje piperazin metil karboksilat [image] („PMEC“) fosfat hidrata, naznačen time, da obuhvaća: (a) miješanje piperazina i metil kloroformata u svrhu tvorbe PMEC; (b) miješanje PMEC i 0,5 molarnih ekvivalenata fosforne kiseline u vodenoj otopini u svrhu tvorbe PMEC fosfat hidrata; i (c) opcionalno filtriranje PMEC fosfat hidrata iz smjese u koraku (b).
3. Postupak prema patentnom zahtjevu 2, naznačen time, da nadalje obuhvaća izoliranje PMEC stvorenog u koraku (a) kao otopine u metilen kloridu, dikloretanu, 2-metiltetrahidrofuranu, ili njihovoj mješavini.
4. Postupak prema patentnom zahtjevu 3, naznačen time, da se izoliranje provodi putem (i) ispiranja dobivenog PMEC iz koraka (a) s organskim otapalom; (ii) modificiranja pH vrijednosti na 8 do 14 dodavanjem baze u svrhu tvorbe bazične vodene otopine; i (iii) ekstrahiranja PMEC iz bazične vodene otopine iz koraka (ii) s metilen kloridom, dikloretanom, 2-metil tetrahidrofuranom, ili njihovom mješavinom.
5. Postupak prema patentnom zahtjevu 2, naznačen time, da se korak (a) provodi u vodenoj otopini.
6. Postupak prema bilo kojem od patentnih zahtjeva 2 do 5, naznačen time, da se korak (a) provodi na temperaturi od 20 do 55 °C u vremenu od 1 do 12 sati.
7. Postupak za sintetiziranje metil 4-(2-fluoro-3-nitrobenzil)piperazin-1-karboksilata [image] (PIPN), naznačen time, da obuhvaća (a) miješanje 2-fluoro-3-nitrotoluena, natrijevog bromata i natrijevog bisulfita u izopropilacetatu i vodi u svrhu tvorbe 1-(bromometil)-2-fluoro-3-nitrobenzena [image] (FNB); (b) opcionalno ispiranje FNB s vodenim natrijevim tiosulfatom, s vodenim natrijevim kloridom, ili s oba; i (c) miješanje FNB, trialkilaminske baze i piperazin metil karboksilat [image] („PMEC“) fosfat hidrata u svrhu tvorbe PIPN.
8. Postupak prema patentnom zahtjevu 7, naznačen time, da se FNB ispire s vodenim natrijevim tiosulfatom i vodenim natrijevim kloridom.
9. Postupak za sintetiziranje metil 4-(2-fluoro-3-nitrobenzil)piperazin-1-karboksilata [image] (PIPN), naznačen time, da obuhvaća: (a) miješanje 2-fluoro-3-nitrotoluena, benzoil peroksida, N-bromosukcinimida i octene kiseline na temperaturi od 70 do 95 °C u svrhu tvorbe 1-(bromometil)-2-fluoro-3-nitrobenzena [image] (FNB); (b) opcionalno ekstrahiranje FNB s toluenom, ispiranje FNB s vodenom bazičnom otopinom, ili oboje; (c) miješanje FNB, trialkilaminske baze i piperazin metil karboksilat [image] („PMEC“) fosfatnog hidrata u svrhu tvorbe PIPN.
10. Postupak prema patentnom zahtjevu 9, naznačen time, da se FNB ekstrahira s toluenom i ispire s vodenim natrijevim hidroksidom.
11. Postupak prema bilo kojem od patentnih zahtjeva 7 do 10, naznačen time, da se PIPN tvori kao hidrokloridna sol.
12. Postupak prema bilo kojem od patentnih zahtjeva 7 do 11, naznačen time, da se PMEC fosfat hidrat pripravlja putem postupka prema bilo kojem od patentnih zahtjeva 2 do 6.
13. Postupak prema bilo kojem od patentnih zahtjeva 7 do 12, naznačen time, da trialkilaminska baza sadrži diizopropiletilamin ili trietilamin.
14. Postupak prema bilo kojem od patentnih zahtjeva 7 do 13, naznačen time, da prije miješanja FNB, trialkilaminske baze i PMEC fosfat hidrata, postupak nadalje obuhvaća dodavanje dietilfosfita i trialkilamina, i miješanje rezultirajuće smjese na temperaturi od 30 do 65 °C.
HRP20211290TT 2017-06-30 2021-08-11 Sinteza omekamtiv mekarbila HRP20211290T1 (hr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201762527174P 2017-06-30 2017-06-30
US201862664363P 2018-04-30 2018-04-30
EP18743314.9A EP3645518B1 (en) 2017-06-30 2018-06-29 Synthesis of omecamtiv mecarbil
PCT/US2018/040176 WO2019006231A1 (en) 2017-06-30 2018-06-29 SYNTHESIS OF OMECAMTIV MECARBIL

Publications (1)

Publication Number Publication Date
HRP20211290T1 true HRP20211290T1 (hr) 2021-11-12

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ID=62976317

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Application Number Title Priority Date Filing Date
HRP20211290TT HRP20211290T1 (hr) 2017-06-30 2021-08-11 Sinteza omekamtiv mekarbila

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US (3) US11040956B2 (hr)
EP (3) EP3925950B1 (hr)
JP (2) JP7181896B2 (hr)
KR (1) KR102625774B1 (hr)
CN (1) CN110799503B (hr)
AU (1) AU2018294254C1 (hr)
BR (1) BR112019028205A2 (hr)
CA (1) CA3063102A1 (hr)
CL (2) CL2019003898A1 (hr)
CY (1) CY1124427T1 (hr)
DK (1) DK3645518T3 (hr)
ES (1) ES2882905T3 (hr)
GE (1) GEP20227340B (hr)
HR (1) HRP20211290T1 (hr)
HU (1) HUE055242T2 (hr)
IL (2) IL270663B (hr)
LT (1) LT3645518T (hr)
MD (1) MD3645518T2 (hr)
MX (2) MX2021013326A (hr)
PL (1) PL3645518T3 (hr)
PT (1) PT3645518T (hr)
RS (1) RS62328B1 (hr)
SG (1) SG10202111790YA (hr)
SI (1) SI3645518T1 (hr)
TW (2) TW202235415A (hr)
UA (1) UA127517C2 (hr)
WO (1) WO2019006231A1 (hr)

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PL2970123T3 (pl) 2013-03-14 2020-03-31 Amgen Inc. Sól omekamtywu mekarbilu i sposób otrzymywania soli
WO2019006235A1 (en) 2017-06-30 2019-01-03 Amgen Inc. METHODS OF TREATING CARDIAC INSUFFICIENCY WITH CARDIAC SARCOMER ACTIVATORS
IL270663B (en) 2017-06-30 2022-08-01 Amgen Inc Synthesis of omecamtib from carbyl
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WO2021070123A1 (en) * 2019-10-09 2021-04-15 Dr. Reddy’S Laboratories Limited Solid forms of omecamtiv mecarbil dihydrochloride and processes thereof
US20220411374A1 (en) * 2019-10-09 2022-12-29 Dr. Reddy's Laboratories Limited Alternate processes for the preparation of omecamtiv mecarbil
BR112023018095A2 (pt) 2021-03-10 2023-12-12 Amgen Inc Processos para sintetizar 2-fluoro-3-nitrotolueno, 1-(bromometil)-2-fluoro-3-nitrobenzeno e para preparar omecamtiv mecarbil ou um sal do mesmo, um hidrato do mesmo ou um hidrato de sal do mesmo
WO2023205291A2 (en) * 2022-04-21 2023-10-26 The Board Of Regents Of The University Of Oklahoma Targeting myocardial tissue for delivery of therapeutic and imaging agents
US11986474B1 (en) 2023-06-27 2024-05-21 Cytokinetics, Incorporated Methods for treating heart failure by administering cardiac sarcomere activators

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BR112023018095A2 (pt) 2021-03-10 2023-12-12 Amgen Inc Processos para sintetizar 2-fluoro-3-nitrotolueno, 1-(bromometil)-2-fluoro-3-nitrobenzeno e para preparar omecamtiv mecarbil ou um sal do mesmo, um hidrato do mesmo ou um hidrato de sal do mesmo

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HUE055242T2 (hu) 2021-11-29
BR112019028205A2 (pt) 2020-10-06
CA3063102A1 (en) 2019-01-03
KR102625774B1 (ko) 2024-01-16
US11753394B2 (en) 2023-09-12
US20210371397A1 (en) 2021-12-02
IL270663B (en) 2022-08-01
TWI769272B (zh) 2022-07-01
EP3925950C0 (en) 2023-09-06
RS62328B1 (sr) 2021-10-29
TW201906826A (zh) 2019-02-16
ES2882905T3 (es) 2021-12-03
EP4265597A2 (en) 2023-10-25
CL2019003898A1 (es) 2020-07-31
MD3645518T2 (ro) 2021-11-30
GEP20227340B (en) 2022-01-25
EP3925950B1 (en) 2023-09-06
CY1124427T1 (el) 2022-07-22
SI3645518T1 (sl) 2021-11-30
PL3645518T3 (pl) 2021-12-06
AU2018294254B2 (en) 2022-04-07
MX2021013326A (es) 2022-08-11
IL270663A (hr) 2020-01-30
JP2022166243A (ja) 2022-11-01
WO2019006231A1 (en) 2019-01-03
CL2021002167A1 (es) 2022-03-18
JP7181896B2 (ja) 2022-12-01
PT3645518T (pt) 2021-08-23
AU2018294254C1 (en) 2022-10-13
CN110799503B (zh) 2023-06-27
MX2021009594A (es) 2022-10-24
US11040956B2 (en) 2021-06-22
EP3925950A1 (en) 2021-12-22
AU2018294254A1 (en) 2019-11-21
EP4265597A3 (en) 2023-11-22
EP3645518B1 (en) 2021-05-19
IL294834A (en) 2022-09-01
KR20200018664A (ko) 2020-02-19
US20230373955A1 (en) 2023-11-23
SG10202111790YA (en) 2021-12-30
TW202235415A (zh) 2022-09-16
LT3645518T (lt) 2021-10-11
UA127517C2 (uk) 2023-09-20
DK3645518T3 (en) 2021-08-02
EP3645518A1 (en) 2020-05-06
CN110799503A (zh) 2020-02-14
JP2020526476A (ja) 2020-08-31
US20200308143A1 (en) 2020-10-01
AU2022204648A1 (en) 2022-07-28

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