DK2819982T3 - Pro-drugs af vitamin k - Google Patents

Pro-drugs af vitamin k Download PDF

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DK2819982T3
DK2819982T3 DK13709348.0T DK13709348T DK2819982T3 DK 2819982 T3 DK2819982 T3 DK 2819982T3 DK 13709348 T DK13709348 T DK 13709348T DK 2819982 T3 DK2819982 T3 DK 2819982T3
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alkyl
group
compound according
compound
formula
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DK13709348.0T
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Mona Moller
Marcel Sandberg
Inger Reidun Aukrust
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Kappa Bioscience As
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/28—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/098—Esters of polyphosphoric acids or anhydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
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  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (17)

1. Forbindelse med formel (I)
hvor hver R uafhængigt er hydrogen, en -PCR^y-gruppe, hvor y er 2 eller 3, -SO2R4, -COOH, -COOCi-ealkyl, -CON(R2)2, COAr, -COCi-e alkylgruppe; - CO(CH2)pCOOR3, CO(CH2)PCON(R2)2 eller -CO(CHR6)PN(R5)2 hvor mindst en R-gruppe ikke er hydrogen og begge R-grupper ikke er COCH3; hver R1 er uafhængigt OH, halo, Ci-e-alkyl, OPh, Obenzyl, OCi-6-alkyl eller oxo således at valensen af P-atomet er 3 eller 5; hver R2-gruppe er uafhængigt hydrogen eller Ci-6-alkyl; R3 er H, Ci-6-alkyl, Ar, (CH2)PAr; R4 er OH, Ci-6 alkyl, Ph, CF3, eller tolyl; hver R5 er H, en aminobeskyttelsesgruppe såsom Boc, eller Cl-6 alkyl; hver R6 er H eller Cl-6 alkyl; en hvilken som helst Ci-e-alkylgruppe er er eventuelt substitueret med én eller flere grupper valgt fra -OR2, N(R2)2 eller COOR2; hver Ar er en eventuelt substitueret phenyl- eller naphthylgruppe, substituenten er Cl-6 alkyl CHalH2, CHal2H, CHab, OH, OCi-6Alkyl, COOR6; hver p er 1 til 4; og n er 3 til 8; eller et salt eller solvat deraf.
2. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor n er 4 til 7, fortrinsvis 5.
3. Forbindelse ifølge et hvilket som helst af de foregående krav med formel (la)
hvor hver R uafhængigt er hydrogen, en -PfR^y-gruppe, hvor y er 2 eller 3, COAr, -COC2-6 alkylgruppe; -CO(CH2)PCOOH; eller-CO(CHR6)PN(R5)2 hvor mindst en R-gruppe ikke er hydrogen og fortrinsvis er R-grupperne forskellige; hver R1 er uafhængigt OH, halo, Ci-e-alkyl, OPh, Obenzyl, OCi-6-alkyl eller oxo således at valensen af P-atomet er 3 eller 5; hver R5 er H, en aminobeskyttelsesgruppe såsom Boc, eller Cl-6 alkyl; R6 er H eller Cl-6 alkyl; en hvilken som helst Ci-6-alkylgruppe er er eventuelt substitueret med én eller flere grupper valgt fra -OR2, N(R2)2 eller COOR2; hver Ar er en eventuelt substitueret phenyl- eller naphthylgruppe, substituenten er Cl-6 alkyl CHalH2, CHal2H, CHab, OH, OCl-6-Alkyl, COOR6; hver p er 1 til 4; og n er 4 til 7; eller et salt eller solvat deraf.
4. Forbindelse ifølge et hvilket som helst af de foregående krav med formel (V)
hvor én R er uafhængigt hydrogen, en -PCR^y-gruppe, hvor y er 2 eller 3; -CO(CH2)pCOOH; eller -CO(CHR6)PN(R5)2 og én R er COAr eller -COCi-6 alkylgruppe; hver R1 er uafhængigt OH, halo, Ci-6-alkyl, OPh, Obenzyl, OCi-e-alkyl eller oxo således at valensen af P-atomet er 3 eller 5; hver R5 er H, en aminobeskyttelsesgruppe såsom Boc, eller Cl-6 alkyl; R6 er H eller Cl-6 alkyl; hver Ar er en eventuelt substitueret phenyl- eller naphthylgruppe, substituenten er Cl-6 alkyl CHalH2, CHal2H, CHab, OH, OCl-6-Alkyl, COOR6; hver p er 1 til 4; og n er 4 til 7; eller et salt eller solvat deraf.
5. Forbindelse ifølge et hvilket som helst af de foregående krav med formel (Ib)
hvor hver R uafhængigt er hydrogen, a -PCR^y-gruppe, hvor y er 2 eller 3, -SO2R4, -COOH, -COOCi-ealkyl, -CON(R2)2, COAr, eller -COCi-e alkyl-gruppe, hvor mindst én R-gruppe ikke er hydrogen; hver R1 er uafhængigt OH, halo, Ci-e-alkyl, OPh, Obenzyl, OCi-6-alkyl eller oxo således at valensen af P-atomet er 3 eller 5; hver R2 gruppe er uafhængigt hydrogen eller Ci-e-alkyl; en hvilken som helst Ci-6-alkylgruppe er er eventuelt substitueret med én eller flere grupper valgt fra -OR2, N(R2)2 eller COOR2; hver R4 er OH, C1-6 alkyl, Ph, CF3, eller tolyl; hver Ar er en eventuelt substitueret phenyl- eller naphthylgruppe, substituenten er Cl-6 alkyl; og n er 4-7; eller et salt eller solvat deraf.
6. Forbindelse ifølge krav 1, hvor ingen R er hydrogen.
7. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor begge R-grupper er identiske.
8. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor R-grupperne er forskellige.
9. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor begge R-grupper ikke er COCH3.
10. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor ét R er en -C0C2-6-alkylgruppe eller COAr-gruppe, hvor Ar er en eventuelt substitueret phenyl- eller naphthylgruppe, substituenten er Cl-6 alkyl CHalH2, CHal2H, CHaH, OH, OCl-6-alkyl, COOR6; og R6 er H eller Cl-6 alkyl.
11. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor ét R er en -PfR^y-gruppe, hvor y er 2 eller 3; -CO(CH2)PCOOH; eller -CO(CHR6)pN(R5)2 hver R1 er uafhængigt OH, halo, Ci-6-alkyl, OPh, Obenzyl, OCi-e-alkyl eller oxo således at valensen af P-atomet er 3 eller 5; hver R5 er H, en aminobeskyttelsesgruppe såsom Boc, eller Cl-6 alkyl; R6 er H eller Cl-6 alkyl; og hver p er 1 til 4;
12. Forbindelse ifølge et hvilket som helst af de foregående krav med formel (II) til (IV):
(IV) hvor n er 5.
13. Kosttilskuds- eller farmaceutisk sammensætning omfattende en forbindelse ifølge krav 1 til 12.
14. Sammensætning omfattende en monosubstitueret forbindelse med formel (I) ifølge krav 1 (dvs. hvor én R-gruppe er H) og en MK-n-forbindelse, fortrinsvis en MK-n-forbindelse svarende til den monosubstituerede forbindelse med formel (I), fx MK-7.
15. Forbindelse ifølge krav 1 til 12 til anvendelse i medicin.
16. Forbindelse ifølge krav 1 til 12 til anvendelse i behandlingen afen tilstand forbundet med vitamin K2 såsom til behandlingen af osteoporose og tilstande af det kardiovaskulære system såsom arteriosclerose.
17. Forbindelser
eller:
hvor Hal er et halid, især bromid og R er er som defineret i krav 1.
DK13709348.0T 2012-03-02 2013-03-04 Pro-drugs af vitamin k DK2819982T3 (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1203705.7A GB201203705D0 (en) 2012-03-02 2012-03-02 Prodrugs
PCT/EP2013/054298 WO2013128037A1 (en) 2012-03-02 2013-03-04 Prodrugs of vitamine k

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US (2) US9512153B2 (da)
EP (1) EP2819982B1 (da)
CN (1) CN104395273A (da)
AU (1) AU2013224857B2 (da)
DK (1) DK2819982T3 (da)
GB (1) GB201203705D0 (da)
HU (1) HUE029261T2 (da)
IN (1) IN2014MN01778A (da)
PL (1) PL2819982T3 (da)
WO (1) WO2013128037A1 (da)

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GB201203705D0 (en) 2012-03-02 2012-04-18 Kappa Bioscience As Prodrugs
GB201314245D0 (en) * 2013-08-08 2013-09-25 Kappa Bioscience As Provitamins
KR102500913B1 (ko) 2014-05-05 2023-02-16 바스프 에스이 지용성 비타민 제형
JP6630364B2 (ja) 2015-03-27 2020-01-15 ボストン バイオメディカル， インコーポレイテッド 水溶性プロドラッグ
WO2019059344A1 (ja) 2017-09-22 2019-03-28 大日本住友製薬株式会社 化学活性化型水溶性プロドラッグ
AU2019282420A1 (en) 2018-06-08 2021-01-07 Epizon Pharma, Inc. Methods and compositions for preventing or treating tissue calcification
SG11202012055PA (en) 2018-06-08 2021-01-28 Epizon Pharma Inc Methods and compositions for preventing or treating calciphylaxis
WO2020055678A1 (en) * 2018-09-12 2020-03-19 Epizon Pharma, Inc. Menaquinol compositions and methods of treatment
JP7394433B2 (ja) * 2019-03-19 2023-12-08 学校法人福岡大学 光曝露下に適用されるビタミンｋ剤及びそれを用いた皮膚外用剤、点眼剤、眼軟膏剤
WO2022147047A1 (en) * 2020-12-30 2022-07-07 Epizon Pharma, Inc. Compositions of biologically active menaquinol derivatives and methods of treatment
US11912654B2 (en) 2021-09-03 2024-02-27 Synergia Life Sciences Pvt. Ltd. Process for stereospecific synthesis of vitamin K2 and its novel intermediates
WO2023119230A1 (en) 2021-12-22 2023-06-29 L'oreal Coagulation pathway and nicotinamide-adenine dinucleotide pathway modulating compositions and methods of their use
WO2023129141A1 (en) * 2021-12-28 2023-07-06 Epizon, Inc. Compositions of biologically active menaquinol derivatives and methods of treatment
WO2023235259A1 (en) * 2022-05-30 2023-12-07 Epizon Pharma, Inc. Pegylated menaquinol compositions and methods of treatment
WO2023232643A1 (en) 2022-05-31 2023-12-07 Region Syddanmark Vitamin k2 for use in treatment of coronary artery calcification

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US10159687B2 (en) 2018-12-25
AU2013224857B2 (en) 2016-03-17
AU2013224857A1 (en) 2014-09-25
WO2013128037A1 (en) 2013-09-06
HUE029261T2 (en) 2017-02-28
US9512153B2 (en) 2016-12-06
EP2819982A1 (en) 2015-01-07
IN2014MN01778A (da) 2015-07-03
US20150031651A1 (en) 2015-01-29
US20170079994A1 (en) 2017-03-23
EP2819982B1 (en) 2016-09-14
GB201203705D0 (en) 2012-04-18
CN104395273A (zh) 2015-03-04
PL2819982T3 (pl) 2017-01-31

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