HRP20170185T1 - Nove 5-aminotetrahidrokinolin-2-karboksilne kiseline i njihova uporaba - Google Patents

Nove 5-aminotetrahidrokinolin-2-karboksilne kiseline i njihova uporaba Download PDF

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HRP20170185T1
HRP20170185T1 HRP20170185TT HRP20170185T HRP20170185T1 HR P20170185 T1 HRP20170185 T1 HR P20170185T1 HR P20170185T T HRP20170185T T HR P20170185TT HR P20170185 T HRP20170185 T HR P20170185T HR P20170185 T1 HRP20170185 T1 HR P20170185T1
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formula
compound
solvates
salts
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Michael Hahn
Markus Follmann
Walter Hübsch
Eva-Maria Becker-Pelster
Johannes-Peter Stasch
Jörg Keldenich
Martina Delbeck
Hanna Tinel
Frank Wunder
Joachim Mittendorf
Ildiko Terebesi
Dieter Lang
René Martin
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links

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  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (13)

1. Spoj s formulom (I) [image] naznačen time da R1 predstavlja vodik ili fluor, L1 predstavlja etan-1,2-diil ili 1,4-fenilen, i A predstavlja skupinu s formulom [image] u kojoj * označava odgovarajuću točku vezanja na ostatak molekule, L3 predstavlja vezu, -O-, -CH2-, -CH2-CH2- ili -CH=CH-, i R3C predstavlja supstituent odabran iz skupine koja sadrži fluor, klor, brom, cijano, (C1-C4)-alkil, difluormetil, trifluormetil, (C1-C4)-alkoksi, difluormetoksi i trifluormetoksi, i R3D predstavlja supstituent odabran iz skupine koja sadrži vodik, fluor, klor, brom, cijano, (C1-C4)-alkil, difluormetil, trifluormetil, (C1-C4)-alkoksi, difluormetoksi i trifluormetoksi, i soli, solvati i solvati njihovih soli.
2. Spoj s formulom (I) prema zahtjevu 1, naznačen time da R1 predstavlja vodik ili fluor, L1 predstavlja etan-1,2-diil ili 1,4-fenilen, i A predstavlja skupinu s formulom [image] u kojoj * označava odgovarajuću točku vezanja na ostatak molekule, L3 predstavlja vezu, -CH2-CH2- ili -CH=CH-, R3C predstavlja fluor, klor, metil ili trifluormetil, i R3D predstavlja vodik, fluor, klor, cijano, metil, trifluormetil, metoksi ili trifluormetoksi, i soli, solvati i solvati njihovih soli.
3. Spoj s formulom (I) prema zahtjevu 1 ili 2, naznačen time da R1 predstavlja vodik ili fluor, L1 predstavlja etan-1,2-diil ili 1,4-fenilen, i A predstavlja skupinu s formulom [image] u kojoj * označava odgovarajuću točku vezanja na ostatak molekule, L3 predstavlja vezu, -CH2-CH2- ili -CH=CH-, R3C predstavlja fluor, klor, metil ili trifluormetil, i R3D predstavlja vodik, fluor, klor, cijano, metil, trifluormetil ili trifluormetoksi, i soli, solvati i solvati njihovih soli.
4. Spoj s formulom (I) prema zahtjevu 1, 2 ili 3, naznačen time da R1 predstavlja vodik ili fluor, L1 predstavlja etan-1,2-diil ili 1,4-fenilen, i A predstavlja skupinu s formulom [image] u kojoj * označava odgovarajuću točku vezanja na ostatak molekule, L3 predstavlja vezu ili -CH2-CH2-, R3C predstavlja klor, i R3D predstavlja vodik, fluor ili trifluormetil, i soli, solvati i solvati njihovih soli.
5. 5-{[2-(4-karboksifenil)etil][2-(2-{[3-klor-4'-(trifluormetil)bifenil-4-il]metoksi}fenil)etil]amino}-5,6,7,8-tetrahidrokinolin-2-karboksilna kiselina prema formuli u nastavku [image] i soli, solvati i solvati njihovih soli.
6. 5-{(4-karboksibutil)[2-(2-{[3-klor-4'-(trifluormetil)bifenil-4-il]metoksi}fenil)etil]amino}-5,6,7,8-tetrahidrokinolin-2-karboksilna kiselina prema formuli u nastavku [image] i soli, solvati i solvati njihovih soli.
7. Postupak za pripremanje spoja s formulom (I) kako je definirano u bilo kojem od zahtjeva 1 do 6, naznačen time da ili [A] spoj s formulom (II) [image] u kojoj R1 i L1 imaju značenja dodijeljena u bilo kojem od zahtjeva 1 do 6 i T1 i T2 su identični ili različiti i predstavljaju (C1-C4)-alkil, reagira u prisutnosti baze sa spojem s formulom (III) [image] u kojoj A ima značenja dodijeljena u bilo kojem od zahtjeva 1 do 6 i X1 predstavlja odlazeću skupinu kao što je, na primjer, klor, brom, jod, mesilat, triflat ili tosilat, ili [B] spoj s formulom (IV) [image] u kojoj R1 i A imaju značenja dodijeljena u bilo kojem od zahtjeva 1 do 6 i T2 predstavlja (C1-C4)-alkil, reagira u prisutnosti baze sa spojem s formulom (V) [image] u kojoj L1 ima značenja dodijeljena u bilo kojem od zahtjeva 1 do 6, T1 predstavlja (C1-C4)-alkil, i X2 predstavlja odlazeću skupinu kao što je, na primjer, klor, brom, jod, mesilat, triflat ili tosilat, i odgovarajući nastali spoj s formulom (VI) [image] u kojoj R1, A, L1, T1 i T2 imaju gore navedena značenja, se zatim prevodi hidrolizom skupina estera -C(O)OT1 i -C(O)OT2 u odgovarajuću dikarboksilnu kiselinu s formulom (I) i na ovaj način dobiveni spojevi s formulom (I) se proizvoljno rastavljaju na njihove enantiomere i/ili dijastereomere i/ili proizvoljno prevode s odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama u njihove solvate, soli i/ili solvate soli.
8. Spoj kako je definirano u bilo kojem od zahtjeva 1 do 6, naznačen time da je za liječenje i/ili prevenciju bolesti.
9. Spoj kako je definirano u bilo kojem od zahtjeva 1 do 6, naznačen time da je za uporabu u postupku za liječenje i/ili prevenciju primarnih i sekundarnih oblika plućne hipertenzije, zatajenja srca, angine pektoris, hipertenzije, tromboembolijskih poremećaja, ishemija, vaskularnih poremećaja, oštećenja mikrocirkulacije, insuficijencije bubrega, fibroznih poremećaja i arterioskleroze.
10. Uporaba spoja kako je definirano u bilo kojem od zahtjeva 1 do 6, naznačena time da je za dobivanje lijeka za liječenje i/ili prevenciju primarnih i sekundarnih oblika plućne hipertenzije, zatajenja srca, angine pektoris, hipertenzije, tromboembolijskih poremećaja, ishemija, vaskularnih poremećaja, oštećenja mikrocirkulacije, insuficijencije bubrega, fibroznih poremećaja i arterioskleroze.
11. Lijek, naznačen time da sadrži spoj kako je definirano u bilo kojem od zahtjeva 1 do 6 u kombinaciji s jednom ili više inertnih netoksičnih farmaceutski prihvatljivih pomoćnih tvari.
12. Lijek, naznačen time da sadrži spoj kako je definirano u bilo kojem od zahtjeva 1 do 6 u kombinaciji s jednim ili više daljnjih aktivnih spojeva koji su odabrani iz skupine koju čine organski nitrati, donori NO, inhibitori PDE 5, analozi prostaciklina, agonisti IP receptora, antagonisti receptora endotelina, stimulatori gvanilat ciklaze, inhibitori tirozin kinaze, anti-opstruktivna sredstva, protuupalna i/ili imunosupresivna sredstva, antitrombotici, sredstva za snižavanje krvnog tlaka i sredstva koja mijenjaju metabolizam masti.
13. Lijek prema zahtjevu 11 ili 12, naznačen time da je za liječenje i/ili prevenciju primarnih i sekundarnih oblika plućne hipertenzije, zatajenja srca, angine pektoris, hipertenzije, tromboembolijskih poremećaja, ishemija, vaskularnih poremećaja, oštećenja mikrocirkulacije, insuficijencije bubrega, fibroznih poremećaja i arterioskleroze.
HRP20170185TT 2012-07-20 2013-07-16 Nove 5-aminotetrahidrokinolin-2-karboksilne kiseline i njihova uporaba HRP20170185T1 (hr)

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EP12177284 2012-07-20
EP13167967 2013-05-16
PCT/EP2013/065017 WO2014012934A1 (de) 2012-07-20 2013-07-16 Neue 5-aminotetrahydrochinolin-2-carbonsäuren und ihre verwendung
EP13744464.2A EP2875003B1 (de) 2012-07-20 2013-07-16 Neue 5-aminotetrahydrochinolin-2-carbonsäuren und ihre verwendung

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