DK2593452T3 - Heterocycliske forbindelser som IP-receptoragonister - Google Patents

Heterocycliske forbindelser som IP-receptoragonister Download PDF

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DK2593452T3
DK2593452T3 DK11732449.1T DK11732449T DK2593452T3 DK 2593452 T3 DK2593452 T3 DK 2593452T3 DK 11732449 T DK11732449 T DK 11732449T DK 2593452 T3 DK2593452 T3 DK 2593452T3
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alkyl
optionally substituted
mmol
alkoxy
pyrazin
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DK11732449.1T
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Steven John Charlton
Catherine Leblanc
Stephen Carl Mckeown
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Novartis Ag
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    • 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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (15)

1. Forbindelse repraesenteret ved formlen la
eller et farmaceutisk acceptabelt salt deraf, hvor AerN ellerCR'; R' er H, C-i-Cs alkyl eventuelt substitueret med ét eller flere halogenatomer; R1 er H, CrCe alkyl eventuelt substitueret med ét eller flere halogenatomer, Cr C4 alkyl, OH, OR', -NR19R21, CN eller C3-C7 cycloalkyl; eller R1 er-X-Y; eller R1 er -W-R7-X-Y; eller R1 er -S(0)2-W-X-Y; eller R1 er -S(0)2-W-R7-X-Y; R2 er H, C-i-Cs alkyl eventuelt substitueret med ét eller flere halogenatomer, Cr C4 alkyl, OH, OR', -NR19R21, CN eller C3-C7 cycloalkyl; eller R2 er -X-Y; eller R2 er -W-R7-X-Y; eller R2 er -S(0)2-W-X-Y; R2 er -S(0)2-W-R7-X-Y; hvor enten R1 eller R2 er -X-Y, -W-R7-X-Y, -S(0)2-W-X-Y; eller -S(0)2-W-R7-X-Y; R2a er hydrogen; R2 og R2a samlet er oxo; R3 er H, Ci-C4 alkoxy, OH, -NR19R21, CN, halogen, C3-C7 cycloalkyl eller CrCe alkyl eventuelt substitueret med ét eller flere halogenatomer; R4 er H, Ci-C4 alkoxy, OH, -NR19R21, CN, halogen, C3-C7 cycloalkyl eller Ci-Ce alkyl eventuelt substitueret med ét eller flere halogenatomer; R5 er Ci-Ce alkyl eventuelt substitueret med ét eller flere halogenatomer, Ci-C4 alkyl, OH, OR', -NR19R21, CN eller C3-C7 cycloalkyl; Ci-C8 alkoxy eventuelt substitueret med ét ellerflere halogenatomer; C6-C14 aryl; -(C0-C4 alkyl)-4 til 14 leddet heteroaryl, eller-(Co-C4 alkyl)-3 til 14 leddet heterocyclyl, hvor hetero-arylen og heterocyclylen indeholder i det mindste ét heteroatom valgt blandt N, O og S, hvor arylet, heteroarylen og heterocyclylen hver isaer eventuelt er substitueret med én ellerflere Z-substituenter; R6 er Cs-Ci4 aryl; -(C0-C4 alkyl)-4 til 14 leddet heteroaryl, -(C0-C4 alkyl)-3 til 14 leddet heterocyclyl, hvor heteroarylen og heterocyclylen Indeholder i det mindste ét heteroatom valgt blandt N, O og S, hvor arylet, heteroarylen og heterocyclylen hver isaer eventuelt er substitueret med én eller flere Z-substituenter; W er C1-C8 alkylen eventuelt substitueret med hydroxy, halogener eller C1-C4 alkyl; X er C1-C8 alkylen eventuelt substitueret med hydroxy, halogener eller C1-C4 alkyl; Y er carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, eller -C0NH-S(0)q-Rx, hvor Rx er -C1-C4 alkyl eller-NR19R21; q er 0, 1 eller 2; R7 er en divalent gruppe repraesenteret ved -O-, -NHC(O)-, -CH2=CH2-, -C6-C14 aryl-D-; -3 til 14 leddet heterocyclyl-D-, hvor heterocyclylen indeholder i det mindste ét heteroatom valgt blandt N, O og S, hvor D er O, S, NH eller ikke foreliggende; Z er uafhaengigt OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl eventuelt substitueret med én ellerflere OH-grupper eller NH2-grupper, C1-C6 alkyl eventuelt substitueret med ét eller flere halogenatomer, C1-C6 alkoxy eventuelt substitueret med én ellerflere OH-grupper, Ο-ι-Οβ alkoxy eventuelt substitueret med ét ellerflere halogenatomer, Ο-ι-Οβ alkoxy eventuelt substitueret med C1-C4 alkoxy, NR18(S02)R21, (S02)NR19R21, (S02)R21, NR18C(0)R21, C(0)NR19R21, NR18C(0)NR19R21, NR18C(0)0R19, NR19R21, C(0)0R19, C(0)R19, SR19, OR19, oxo, CN, NO2, halogen eller en 3 til 14 leddet heterocyclyl, hvor heterocyclylen indeholder i det mindste ét heteroatom valgt blandt N, O og S; R18 er uafhaengigt H eller C1-C6 alkyl; R19 og R21 er hver isaer uafhaengigt H; C-i-Ce alkyl; C3-C8 cycloalkyl; C1-C4 alkoxy-Ci-C4 alkyl; (C0-C4 alkyl)-aryl eventuelt substitueret med én ellerflere grupper valgt blandt Ci-Οθ alkyl, Ci-Οθ alkoxy og halogen; (C0-C4 alkyl)- 3- til 14-leddet heterocyclyl, idet heterocyclylen omfatter ét ellerflere heteroatomer valgt blandt N, O og S, eventuelt substitueret med én ellerflere grupper valgt blandt halogen, oxo, Ο-ι-Οβ alkyl og C(0)Ci-C6 alkyl; (C0-C4 alkyl)-0-aryl eventuelt substitueret med én ellerflere grupper valgt blandt C1-C6 alkyl, C1-C6 alkoxy og halogen; og (C0-C4 alkyl)- 0-3- til 14-leddet heterocyclyl, idet heterocyclylen omfatter ét ellerflere heteroatomervalgt blandt N, O og S, eventuelt substitueret med én ellerflere grupper valgt blandt halogen, C1-C6 alkyl eller C(0)Ci-C6 alkyl; hvor alkylgrupperne eventuelt er substitueret med ét ellerflere halogenatomer, C1-C4 alkoxy, C(0)NH2, C(0)NHCi-C6 alkyl eller C(0)N(Ci-C6 alkyl)2; eller R19 og R21 danner sammen med det nitrogenatom, hvortil de erforbundet, en 5-til 10-leddet heterocyclyl, idet heterocyclylen omfatter ét ellerflere yderligere heteroatomer valgt blandt N, O og S, idet heterocyclylen eventuelt er substitueret med én ellerflere substituenter valgt blandt OH; halogen; aryl; 5- til 10-leddet heterocyclyl omfattende ét ellerflere heteroatomer valgt blandt N, O og S; S(0)2-aryl; S(0)2-Ci-C6alkyl; C1-C6 alkyl eventuelt substitueret med ét ellerflere halogenatomer; C1-C6 alkoxy eventuelt substitueret med én ellerflere OH-grupper eller C1-C4 alkoxy; og C(0)0Ci-C6 alkyl, hvor aryl og heterocyclyl substituent-grupperne i sig selv eventuelt er substituerede med C1-C6 alkyl, C1-C6 halogen-alkyl eller C1-C6 alkoxy.
2. Forbindelse ifolge krav 1, hvor R1 er X-Y; eller -W-R7-X-Y, R2 er H, C-i-Cs alkyl eventuelt substitueret med ét ellerflere halogenatomer; Cr C4 alkyl, OH, eller OR'; R3 er H, C1-C4 alkoxy, OH, -NR19R21, CN, halogen, C3-C7 cycloalkyl eller C1-C4 alkyl, eventuelt substitueret med ét ellerflere halogenatomer; R4 er H, C1-C4 alkoxy, OH, -NR19R21, CN, halogen, C3-C7 cycloalkyl eller C1-C4 alkyl, eventuelt substitueret med ét ellerflere halogenatomer; W er C1-C6 alkylen eventuelt substitueret med hydroxy, halogener eller C1-C4 alkyl; X er C1-C6 alkylen eventuelt substitueret med hydroxy, halogener eller C1-C4 alkyl; Y er-C(0)0H, -C(0)ORxtetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkyl-carbamoyl, eller -C0NH-S(0)q-Rx, hvor Rx er -C1-C4 alkyl eller -NR19R21; q er 2; R' er H, C1-C4 alkyl eventuelt substitueret med ét ellerflere halogenatomer; R7 er en divalent gruppe repraesenteret ved -C6-C14 aryl-D-; -3 til 14-leddet heterocyclyl-D-, hvor heterocyclylen indeholder i det mindste ét heteroatom valgt blandt N, O og S, hvor D er O; og R19 og R21 er hver isaer uafhaengigt H; C-i-Cs alkyl.
3. Forbindelse if0lge krav 1 eller 2, hvor R1 er-(CH2)m-C(0)0R", eller -(CH2)m-R7-(CH2)n-C(0)0R"; R2 er H, C1-C4 alkyl eventuelt substitueret med ét eller flere halogenatomer; R3 er H, C1-C4 alkoxy, OH, -NR19R21, CN, halogen, C3-C7 cycloalkyl eller C1-C4 alkyl eventuelt substitueret med ét eller flere halogenatomer; R4 er H, C1-C4 alkoxy, OH, -NR19R21, CN, halogen, C3-C7 cycloalkyl eller C1-C4 alkyl eventuelt substitueret med ét eller flere halogenatomer; m er 1,2, 3, 4, 5, 6, 7 eller 8; n er 0, 1,2 eller 3; R" er H eller C1-C4 alkyl eventuelt substitueret med ét eller flere halogenatomer; og R7 er en divalent gruppe repraesenteret ved -C6-C14 aryl-D-; -3 til 14-leddet heterocyclyl-D-, hvor heterocyclylen indeholder i det mindste ét heteroatom valgt blandt N, O og S, hvor D er O.
4. Forbindelse ifolge ethvert af kravene 1 til 3, hvor R5 er phenyl eventuelt substitueret med OH, C1-C4 alkyl eventuelt substitueret med én eller flere OH-grupper eller NH2-grupper; C1-C4 alkyl eventuelt substitueret med ét eller flere halogenatomer; C1-C4 alkoxy eventuelt substitueret med én eller flere OH-grupper eller C1-C4 alkoxy; NR19R21; C(0)0R19; C(0)R19; SR19; OR19; CN; N02; eller halogen; og R6 er phenyl eventuelt substitueret med OH, C1-C4 alkyl eventuelt substitueret med én eller flere OH-grupper eller NH2-grupper; C1-C4 alkyl eventuelt substitueret med ét eller flere halogenatomer; C1-C4 alkoxy eventuelt substitueret med én eller flere OH-grupper eller C1-C4 alkoxy; NR19R21, C(0)0R19, C(0)R19, SR19, OR19, CN, N02 eller halogen.
5. Forbindelse ifolge ethvert af kravene 1 til 4, hvor A er N.
6. Forbindelse ifelge krav 1, valgt fra gruppen bestáende af 7-(2-phenyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptansyre; 7-(8-hydroxy-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptansyre; 7-(7-hydroxy-6-oxo-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptansyre; 7-(2,3-di-p-tolyl-7,8-dihydropyrido- [2,3-b]pyrazin-5(6H)-yl)heptansyre; 2-(3-((2,3-diphenyl-7,8-dihydropyrido[3,2-b]-pyrazin-5(6H)-yl)methyl)phenoxy)eddikesyre og 7-(3-phenyl-2-p-tolyl-7,8-dihydro-pyrido[2,3-b]pyrazin-5(6H)-yl)heptansyre; elleretfarmaceutisk acceptabelt salt deraf.
7. Forbindelse ifplge krav 1, som er 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptansyre af formlen
eller et farmaceutisk acceptabelt salt deraf.
8. Forbindelse ifolge krav 1, som er 7-(2-phenyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyra-zin-5(6FI)-yl)heptansyre af formlen
eller et farmaceutisk acceptabelt salt deraf.
9. Forbindelse ifolge krav 1, som er 7-(3-phenyl-2-p-tolyl-7,8-dihydropyrido[2,3-b]pyra-zin-5(6FI)-yl)heptansyre af formlen
eller et farmaceutisk acceptabelt salt deraf.
10. Forbindelse if0lge ethvert af kravene 6 til 9, hvorforbindelsen foreligger pá fri form.
11. Farmaceutisk sammensaetning omfattende: en terapeutisk effektiv maengde af forbindelsen ifplge ethvert af kravene 1 til 10, eller et farmaceutisk acceptabelt salt deraf, og ét eller flere farmaceutisk acceptable baerestoffer.
12. Farmaceutisk kombination omfattende: en terapeutisk effektiv maengde af forbindelsen ifolge ethvert af kravene 1 til 10, eller et farmaceutisk acceptabelt salt deraf, og et andet aktivt middel.
13. Forbindelse ifolge ethvert af kravene 1 til 10 eller et farmaceutisk acceptabelt salt deraf, til anvendelse som et medikament.
14. Forbindelse ifelge krav 13 eller et farmaceutisk acceptabelt salt deraf, til anvendelse ved behandling af PAH, sygdomme som har behov for en antithrombocytterapi, athero-sclerose, astma, COPD, hyperglykaemi, inflammatoriske sygdomme eller fibrotiske sygdomme.
15. Forbindelse ifplge krav 13 eller et farmaceutisk acceptabelt salt deraf, til anvendelse ved behandling af PAH, astma, COPD eller cystisk fibrose.
DK11732449.1T 2010-07-14 2011-07-14 Heterocycliske forbindelser som IP-receptoragonister DK2593452T3 (da)

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PCT/EP2011/062028 WO2012007539A1 (en) 2010-07-14 2011-07-14 Ip receptor agonist heterocyclic compounds

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EP (1) EP2593452B1 (da)
JP (1) JP5781159B2 (da)
KR (1) KR101491938B1 (da)
CN (1) CN103097385B (da)
AU (1) AU2011278279C1 (da)
BR (1) BR112013000946B1 (da)
CA (1) CA2804744C (da)
CL (1) CL2013000104A1 (da)
CO (1) CO6660445A2 (da)
CR (1) CR20130012A (da)
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EA (1) EA022046B1 (da)
EC (1) ECSP13012385A (da)
ES (1) ES2622519T3 (da)
GT (1) GT201300018A (da)
HR (1) HRP20170617T1 (da)
HU (1) HUE031710T2 (da)
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NZ (1) NZ605528A (da)
PE (1) PE20130404A1 (da)
PH (1) PH12013500084A1 (da)
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PT (1) PT2593452T (da)
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