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DK2651896T3 - Neprilysininhibitorer - Google Patents

Neprilysininhibitorer Download PDF

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Publication number
DK2651896T3
DK2651896T3 DK11808444.1T DK11808444T DK2651896T3 DK 2651896 T3 DK2651896 T3 DK 2651896T3 DK 11808444 T DK11808444 T DK 11808444T DK 2651896 T3 DK2651896 T3 DK 2651896T3
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DK
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Prior art keywords
alkyl
alkylene
hydroxy
phenyl
compound
Prior art date
Application number
DK11808444.1T
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English (en)
Inventor
Roland Gendron
Melissa Fleury
Adam D Hughes
Original Assignee
Theravance Biopharma R & D Ip Llc
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Publication of DK2651896T3 publication Critical patent/DK2651896T3/da

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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    • 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
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    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K31/4196—1,2,4-Triazoles
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    • 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
    • A61K31/42—Oxazoles
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    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/425—Thiazoles
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    • 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
    • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Claims (30)

1. Forbindelse med formlen I:
hvor: R1 er valgt blandt -OR7 og -NR8R9; R2 er H eller -P(0)(0H)2, eller R2 sammen med R7 danner -CR18R19- eller sammen med R8 danner -C(O)-; X er -Ci-gheteroaryl; R3 er fraværende eller er valgt blandt H; halogen; -Co-salkylen-OH; -NH2; -Ci-ealkyl; -CF3; -C3-7cycloalkyl; -Co-2alkylen-0-Ci-6alkyl; -C(0)R2°; -Co-ialkylen- COOR21; -C(0)NR22R23; -NHC(0)R24; =0; -N02; -C(CH3)=N(OH); phenyl eventuelt substitueret med en eller to grupper indbyrdes uafhængigt valgt blandt halogen, -OH, -CF3, -OCH3, -NHC(0)CH3 og phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl eventuelt substitueret med methyl; thiophenyl eventuelt substitueret med methyl eller halogen; furanyl; og -CH2-morpholinyl; og R3, når den findes, er bundet til et carbonatom; R4 er fraværende eller er valgt blandt H; -OH; -Ci-6alkyl; -Ci-2alkylen-COOR35; -CH20C(0)CH(R36)NH2; -0CH20C(0)CH(R36)NH2; -0CH20C(0)CH3; -CH20P(0)(0H)2 -CH2CH(OH)CH2OH; -CH[CH(CH3)2]-NHC(0)0-Ci^alkyl; pyridinyl; og phenyl eller benzyl eventuelt substitueret med en eller flere grupper valgt blandt halogen, -COOR35, -OCH3, -OCF3 og -SCF3; og R4, når den findes, er bundet til et carbon- eller nitrogenatom; eller R3 og R4 sammen danner -phenylen-0-(CH2)i-3- eller -phenylen-0-CH2-CH0H-CH2-; a er O eller 1; R5 er valgt blandt halogen, -CH3, -CF3 og -CN; b er O eller et helt tal fra 1 til 3; hver R6 er indbyrdes uafhængigt valgt blandt halogen, -OH, -CH3, -OCH3 og -CF3; R7 er valgt blandt H, -Ci-salkyl, -Ci-3alkylen-C6-ioaryl, -Ci-3alkylen-Ci-9heteroaryl, -C3-rcycloalkyl, -[(CH2)20]i-3CH3, -Ci-6alkylen-0C(0)R1°, -Ci-6alkylen-NR12R13, -Ci-ealkylen-C(0)R31, -Co-6alkylenmorpholinyl, -Ci-6alkylen-S02-Ci-6alkyl,
R10 er valgt blandt -Ci-ealkyl, -O-Ci^alkyl, -C3-7cycloalkyl, -0-C3-7cycloalkyl, phenyl, -O-phenyl, -NR12R13, -CH[CH(CH3)2]-NH2, -CH[CH(CH3)2]-NHC(0)0-Ci^alkyl og -CH(NH2)CH2COOCH3; og R12 og R13 indbyrdes uafhængigt er valgt blandt H, -Ci-6alkyl og benzyl; eller R12 og R13 sammen er -(CH2)3-6-, -C(0)-(CH2)3-eller -(CH2)20(CH2)2-; R31 er valgt blandt -0-Ci-6alkyl, -O-benzyl og -NR12R13; og R32 er -Ci-ealkyl eller -Co-6alkylen-C6-ioaryl; R8 er valgt blandt H, -OH, -0C(0)R14, -CH2COOH, -O-benzyl, -pyridyl og -OC(S)NR15R16; R14 er valgt blandt H, -Ci-6alkyl, -C6-ioaryl, -OCH2-C6-ioaryl, -CH2O-C6-ioaryl og -NR15R16; og R15 og R16 indbyrdes uafhængigt er valgt blandt H og -Ci-»alkyl; R9 er valgt blandt H, -Ci-6alkyl og -C(0)-R17; og R17 er valgt blandt H, -Ci-6alkyl, -C3-7cycloalkyl, -C6-ioaryl og -Ci-gheteroaryl; R18 og R19 indbyrdes uafhængigt er valgt blandt H, -Ci-ealkyl og -0-C3-7cycloalkyl, eller R18 og R19 sammen danner =0; R20 er valgt blandt H og -Ci-6alkyl; R21 og R35 indbyrdes uafhængigt er valgt blandt H, -Ci-6alkyl, -Ci-3alkylen-Ce-ioaryl, -Ci-3alkylen-Ci-9heteroaryl, -C3-7cycloalkyl, -[(CH2)20]i-3CH3, -Ci-6alkylen-0C(0)R25, -Ci-ealkylen-NR27R28, -Ci-6alkylen-C(0)R33, -C0-6alkylen-morpholinyl, -Ci-6alkylen-S02-Ci-ealkyl,
R25 er valgt blandt -Ci-6alkyl, -O-Ci-ealkyl, -C3-7cycloalkyl, -0-C3-7cycloalkyl, phenyl, -0-phenyl, -NR27R28, -CH[CH(CH3)2]-NH2, -CH[CH(CH3)2]-NHC(0)0-Ci^alkyl og -CH(NH2)CH2COOCH3; R27 og R28 indbyrdes uafhængigt er valgt blandt H, -Ci-6alkyl og benzyl; eller R27 og R28 sammen danner -(CH2)3-6-, -C(0)-(CH2)3- eller -(CH2)20(CH2)2-; R33 er valgt blandt -O-Ci-ealkyl, -O-benzyl og -NR27R28; og R34 er -Ci-6alkyl eller -Co-6alkylen-Ce-ioaryl; R22 og R23 indbyrdes uafhængigt er valgt blandt H, -C1-6- alkyl, -CH2COOH, -(CH2)2OH, -(CH2)20CH3! -(CH2)2S02NH2! -(CH2)2N(CH3)2, -C0-1-alkylen-Ci.7cycloalkyl og -(CH2)2-imidazolyl; eller R22 og R23 sammen danner en mættet eller delvis umættet -C3-5heteroring, som eventuelt er substitueret med halogen, -OH, -COOH, eller -CONH2; og eventuelt indeholder et oxygenatom i ringen; R24 er valgt blandt -Ci^alkyl; -Co-ialkylen-O-Ci-ealkyl; phenyl eventuelt substitueret med halogen eller -OCH3; og -Ci-gheteroaryl; og R36 er valgt blandt H, -CH(CH3)2, phenyl og benzyl; hvor hver alkylgruppe i R1 R3 og R4 eventuelt er substitueret med 1 til 8 fluoratomer; og; hvor methylen-forbindelsesgruppen på biphenylgruppen eventuelt er substitueret med en eller to -Ci-6alkylgrupper eller cyclopropyl; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifølge krav 1, hvor X er valgt blandt pyrazol, imidazol, triazol, benzotriazol, furan, pyrrol, tetrazol, pyrazin, thiophen, oxazol, isoxazol, thiazol, isothiazol, oxadiazol, thiadiazol, pyridazin, pyridin, pyrimidin, pyran, benzimidazol, benzoxazol, benzothiazol, pyridylimidazol og pyridyltriazol.
3. Forbindelse ifølge krav 2, hvor X er valgt blandt pyrazol, triazol, benzotriazol, furan, tetrazol, pyrazin, thiophen, oxazol, isoxazol, thiazol, oxadiazol, pyridazin, pyridin, pyrimidin, benzoxazol, pyridylimidazol og pyridyltriazol.
4. Forbindelse ifølge krav 3 med formlen III:
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R1 er valgt blandt -OR7 og -NR8R9, R7 er H, R8 er H eller -OH, og R9 er H.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor: R1 er -OR7; og R7 er valgt blandt -Ci-ealkyl, -Ci-3alkylen-C6-ioaryl, -Ci-3alkylen-Ci-gheteroaryl, -C3-7cycloalkyl, -[(CH2)20]i-3CH3, -Ci-6alkylen-0C(0)R1°, -Ci-ealkylen-NR12R13, -Ci-6alkylen-C(0)R31, -Co-6alkylenmorpholinyl, -Ci-6alkylen-S02-Ci-6alkyl,
eller R1 er -NR8R9; R8 er valgt blandt -0C(0)R14, -CH2COOH, -O-benzyl, pyridyl og -OC(S)NR15R16; og R9 er H; eller R1 er -NR8R9; R8 er valgt blandt -0C(0)R14, -CH2COOH, -O-benzyl, pyridyl og -OC(S)NR15R16; og R9 er-Ci^alkyl eller -C(0)R17; R1 er -NR8R9; R8 er valgt blandt H og -OH; og R9 er valgt blandt -Ci-6alkyl og -C(0)R17; R1 er -OR7, og R2 sammen med R7 danner -CR18R19-; eller R1 er -NR8R9, og R2 sammen med R8 danner -C(O)-.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R1 er -OR7, og R7 er valgt blandt H, -Ci-ealkyl, -Ci-6alkylen-0C(0)R1°, -Co-6alkylenmorpholinyl, -Ci-6alkylen-S02-Ci-6alkyl og
R10 er -0-C3-7cycloalkyl; og R32 er -CH3.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R1 er -NR8R9, hvor R8 er H, og R9 er H.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8, hvor R2 er H.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R3 er fraværende eller er valgt blandt H; halogen; -Co-salkylen-OH; -NH2; -Ci-ealkyl; -CF3; -C3-7cycloalkyl; -Co-2alkylen-0-Ci-6alkyl; -C(0)R2°; -C0-ialkylen-COOR21; -C(0)NR22R23; -NHC(0)R24; =0; -NO2; -C(CH3)=N(0H); phenyl eventuelt substitueret med en eller to grupper indbyrdes uafhængigt valgt blandt halogen, -OH, -CF3, -OCH3, -NHC(0)CH3 og phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl eventuelt substitueret med methyl; thiophenyl eventuelt substitueret med methyl eller halogen; furanyl; og -CH2-morpholinyl; og R21 er H.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R3 er -Co-ialkylen-COOR21; og R21 er valgt blandt -Ci^alkyl, -C2-3alkylen-C6-ioaryl, -Ci-3alkylen-Ci-gheteroaryl, -C3-7cycloalkyl, -[(CH2)20]i^CH3, -Ci-6alkylen-0C(0)R25, -Ci-ealkylen-NR27R28, -Ci^alkylen-C(0)R33, -Co-6alkylenmorpholinyl, -Ci-6alkylen-S02-Ci^alkyl,
12. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R3 er fraværende eller er valgt blandt H; halogen; -Co-salkylen-OH; -NH2; -Ci-ealkyl; -CF3; -C3-7cycloalkyl; -Co-2alkylen-0-Ci-6alkyl; -C(0)R20; -C0-ialkylen-COOR21; -C(0)NR22R23; -NHC(0)R21; =0; -C(CH3)=N(OH); phenyl eventuelt substitueret med en eller to grupper indbyrdes uafhængigt valgt blandt halogen, -OH, -CF3, -OCH3, -NHC(0)CH3 og phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl substitueret med methyl; thiophenyl substitueret med methyl eller halogen; furanyl; og -CH2-morpholinyl; R20 er -Ci-6alkyl; R21 er valgt blandt H og -Ci-ealkyl; R22 er valgt blandt H og -Ci-6alkyl; og R23 er valgt blandt H, -Ci-6alkyl, -CH2COOH, -(CH2)2OH, -(CH2)20CH3, -(CH2)2N(CH3)2, -C3-7cycloalkyl og -(CH2)2-imidazolyl; eller R22 og R23 sammen danner azetidin, pyrrolidin, piperidin eller morpholin, alle eventuelt substitueret med -OH eller -CONH2; og R24 er valgt blandt -Ci-ealkyl; -Co-ialkylen-0-Ci-6alkyl; phenyl substitueret med halogen eller-OCH3; og pyridin.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 12, hvor R4 er fraværende eller er valgt blandt H; -OH; -Ci-6alkyl; -Ci-2alkylen-COOR35; -CH20C(0)CH(R36)NH2; -CH2CH(OH)CH2OH; pyridinyl; og phenyl eller benzyl eventuelt substitueret med en eller flere grupper valgt blandt halogen, -COOR35, -OCH3, -OCF3 og -SCF3; og R35 er H.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 12, hvor R4 er valgt blandt -0CH20C(0)CH3; -CH20P(0)(0H)2; -Ci-2alkylen-COOR35; og phenyl eller benzyl substitueret med mindst en -COOR35-gruppe; hvor R35 er valgt blandt -Ci^alkyl, -C1.3-alkylen-Ce-ioaryl, -Ci-3alkylen-Ci-9heteroaryl, -C3-7cycloalkyl, -[(CH2)20]i-3CH3, -C1-6-alkyien-0C(0)R25, -Ci-6alkylen-NR27R28, -Ci-6alkylen-C(0)R33, -C0-6alkylen-morpholinyl, -Ci-6alkylen-S02-Ci-6alkyl,
15. Forbindelse ifølge et hvilket som helst af kravene 1 til 12, hvor R4 er fraværende eller er valgt blandt H; -OH; -Ci-6alkyl; -Ci-2alkylen-COOR35; -CH20C(0)CH(R36)NH2; -CH2CH(0H)CH20H; pyridinyl; phenyl eventuelt substitueret med en halogengruppe; og benzyl eventuelt substitueret med en eller flere grupper valgt blandt halogen, -COOH, -OCH3, -OCF3 og -SCF3; R35 er H; og R36 er -CH(CH3)2; eller R3 og R4 sammen danner -phenylen-0-(CH2)i-3- eller -phenylen-0-CH2-CH0H-CH2-.
16. Forbindelse ifølge et hvilket som helst af kravene 1 til 15, hvor a er 0; eller a er 1, og R5 er 3-chlor.
17. Forbindelse ifølge et hvilket som helst af kravene 1 til 16, hvor b er 0; eller b er 1, og R6 er 3'-chlor, 3'-methyl eller 2'-methoxy; eller b er 2, og R6 er 2'-fluor-5'-chlor, 2',5'-dichlor, 2'-methyl-5'-chlor eller 3'-chlor-5'-hydroxy.
18. Forbindelse ifølge et hvilket som helst af kravene 1 til 17, hvor methylen-forbindelsesgruppen på biphenylgruppen er substitueret med 2 methylgrupper.
19. Forbindelse ifølge krav 1, hvor R1 er -OR7; R7 er valgt blandt H, -Ci-ealkyl, -Ci-6alkylen-0C(0)R1°, -Co-6alkylen-morpholinyl, -Ci-6alkylen-S02-Ci^alkyl og
R10 er -0-C3-7cycloalkyl; R32 er -CH3; R8 er H; R9 er H; R2 er H; X er valgt blandt pyrazol, triazol, benzotriazol, furan, tetrazol, pyrazin, thiophen, oxazol, isoxazol, thiazol, oxadiazol, pyridazin, pyridin, pyrimidin, benzoxazol, pyridylimidazol og pyridyltriazol; R3 er fraværende eller er valgt blandt H; halogen; -Co-salkylen-OH; -NH2; -C1-6-alkyl; -CF3; -C3-7cycloalkyl; -Co-2alkylen-0-Ci-6alkyl; -C(0)R2°; -Co-ialkylen-COOR21; -C(0)NR22R23; -NHC(0)R24; =0; -C(CH3)=N(OH); phenyl eventuelt substitueret med en eller to grupper indbyrdes uafhængigt valgt blandt halogen, -OH, -CF3, -OCH3, -NHC(0)CH3 og phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl substitueret med methyl; thiophenyl substitueret med methyl eller halogen; furanyl; og -CH2-morpholinyl; R4 er fraværende eller er valgt blandt H; -OH; -Ci^alkyl; -Ci-2alkylen- COOR35; -CH20C(0)CH(R36)NH2; -CH2CH(OH)CH2OH; pyridinyl; phenyl eventuelt substitueret med en halogengruppe; og benzyl eventuelt substitueret med en eller flere grupper valgt blandt halogen, -COOH, -OCH3, -OCF3 og -SCF3; eller R3 og R4 sammen danner -phenylen-0-(CH2)i-3- eller -phenylen-0-CH2-CH0H- CH2-; a er 0; eller a er 1, og R5 er 3-chlor; b er 0; eller b er 1, og R6 er 3'-chlor, 3'-methyl eller 2-methoxy; eller b er 2, og R6 er 2'-fluor-5'-chlor, 2',5'-dichlor, 2'-methyl-5'-chlor eller 3'-chlor-5'-hydroxy; R20 er -Ci-ealkyl; R21 er valgt blandt H og -Ci-ealkyl; R22 er valgt blandt H og -Ci-ealkyl; og R23 er valgt blandt H, -Ci-ealkyl, -CH2COOH, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2N(CH3)2, -C3-7cycloalkyl og -(CH2)2-imidazolyl; eller R22 og R23 sammen danner azetidin, pyrrolidin, piperidin eller morpholin, alle eventuelt substitueret med -OH eller -CONH2; R24 er valgt blandt -Ci-6alkyl; -0-Ci-6alkyl; -CH2-0-Ci-6alkyl; phenyl substitueret med halogen eller -OCH3; og pyridinyl; R35 er H; R36 er -CH(CHi)2; og methylen-forbindelsesgruppen på biphenylgruppen eventuelt er substitueret med 2 methylgrupper.
20. Forbindelse ifølge krav 1, hvor R1 er -OR7; R2 er H; X er valgt blandt pyrazol, triazol, benzotriazol, isoxazol, pyridazin, pyrimidin og pyridyltriazol; R3 er valgt blandt H; halogen; -Co-salkylen-OH; -Ci-6alkyl; -CF3; -C3-7cycloalkyl; -Co-2alkylen-0-Ci-6alkyl; -CCOJR20; -C0-ialkylen-COOR21; -C(0)NR22R23; -NHC(0)R24; =0; -C(CH3)=N(0H); phenyl eventuelt substitueret med en eller to grupper indbyrdes uafhængigt valgt blandt halogen, -OH og -OCH3; pyridinyl; pyrazinyl; og thiophenyl substitueret med methyl eller halogen; R4 er valgt blandt H; -OH; -Ci-ealkyl; -Ci-2alkylen-COOR35; -CH2CH(OH)CH2OH; pyridinyl; og phenyl eventuelt substitueret med et halogenatom; eller R3 og R4 sammen danner -phenylen-0-(CH2)i-3-; a er 0; eller a er 1, og R5 er 3-chlor; b er 0; eller b er 1, og R6 er 3-chlor, 3-methyl eller 2-methoxy; eller b er 2, og R6 er 2'-fluor-5'-chlor, 2',5'-dichlor, 2'-methyl-5'-chlor eller 3'-chlor-5'-hydroxy; R20 er -Ci-6alkyl; R21 er H; R22 er valgt blandt H og -Ci-6alkyl; og R23 er valgt blandt -Ci-6alkyl, -(CH2)2OCH3 og -C3-7cycloalkyl; eller R22 og R23 sammen danner azetidin, pyrrolidin eller piperidin, alle eventuelt substitueret med -OH eller-CONH2; R24 er phenyl substitueret med halogen eller-OCH3; R35 er H; og methylen-forbindelsesgruppen på biphenylgruppen eventuelt er substitueret med 2 methylgrupper.
21. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1 til 20 omfattende det trin at koble en forbindelse med formlen 1 med en forbindelse med formlen 2:
til fremstilling af en forbindelse med formlen I; hvor P1 er H eller en amino-beskyttelsesgruppe valgt blandt tert.butoxycarbonyl, trityl, benzyloxycarbonyl, 9- fluorenylmethoxycarbonyl, formyl, trimethylsilyl og tert.butyldimethylsilyl; og hvor fremgangsmåden endvidere omfatter afbeskyttelse af forbindelsen med formlen 1, når P1 er en aminobeskyttelsesgruppe.
22. Mellemprodukt, der er anvendeligt ved syntesen af en forbindelse ifølge et hvilket som helst af kravene 1 til 20, og som har formlen 1:
hvor P1 er H eller en aminobeskyttelsesgruppe valgt blandt tert.butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl og tert.butyldimethylsilyl; eller et salt deraf.
23. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1 til 20 omfattende det trin at afbeskytte en forbindelse valgt blandt:
eller a salt deraf; hvor R1P er valgt blandt -O-P3, -NHP2 og -NH(0-P4); R3P er valgt blandt -Co-salkylen-O-P4, -Co-ialkylen-COO-P3 og phenyl substitueret med -O-P4; R4P er valgt blandt -O-P4; -Ci-2alkylen-COO-P3; og phenyl eller benzyl substitueret med -COO-P3; P2 er en aminobeskyttelsesgruppe valgt blandt tert.butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl og tert.butyl-dimethylsilyl; P3 er en carboxybeskyttelsesgruppe valgt blandt methyl, ethyl, tert.bufyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, tert.butyldimethylsilyl og diphenylmethyl; og P4 er a hydroxylbeskyttelsesgruppe valgt blandt -Ci-ealkyl, tri-Ci-6-alkylsilyl, -Ci-6alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl og diphenylmethyl.
24. Mellemprodukt, der er anvendeligt ved syntesen af en forbindelse ifølge et hvilket som helst af kravene 1 til 20, valgt blandt:
eller et salt deraf; hvor R1P er valgt blandt -O-P3, -NHP2 og -NH(0-P4); R3P er valgt blandt -Co-salkylen-O-P4, -Co-ialkylen-COO-P3 og phenyl substitueret med -O-P4; R4P er valgt blandt -O-P4; -Ci-2alkylen-COO-P3; og phenyl eller benzyl substitueret med -COO-P3; P2 er en aminobeskyttelsesgruppe valgt blandt tert.butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl og tert.butyldimethylsilyl; P3 er en carboxybeskyttelsesgruppe valgt blandt methyl, ethyl, tert.butyl, benzyl, p- methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, tert.butyldimethylsilyl og diphenyl-methyl; og P4 er en hydroxylbeskyttelsesgruppe valgt blandt -Ci-ealkyl, tri-Ci-6-alkylsilyl, -Ci-ealkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl og diphenylmethyl.
25. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1 til 20 og et farmaceutisk acceptabelt bærestof.
26. Farmaceutisk sammensætning ifølge krav 25, som endvidere omfatter et terapeutisk middel valgt blandt adenosinreceptorantagonister, α-adrenoceptorantagonister, βι-adrenoceptorantagonister, 32-adrenoceptoragonister, dobbeltvirkende β-adrenoceptor-antagonist/cd-receptorantagonister, avancerede glykeringsslutproduktspaltere, aldosteronantagonister, aldosteronsyntaseinhibitorer, aminopeptidase-N-inhibitorer, androgener, inhibitorer af angiotensinomdannende enzym og dobbeltvirkende inhibitorer af angiotensinomdannende enzym og neprilysin, aktivatorer og stimulatorer af angiotensinomdannende enzym 2, angiotensin-ll-vacciner, antikoagulanter, antidiabetesmidler, antidiarremidler, antiglaucommidler, antilipidmidler, antinociceptive midler, antithrombotiske midler, ATVreceptorantagonister og dobbeltvirkende inhibitorer af ATi-receptorantagonister og neprilysin og multifunktionelle angiotensinreceptor-blokkere, bradykininreceptorantagonister, calciumkanalblokere, chymaseinhibitorer, digoxin, diuretika, dopaminagonister, inhibitorer af endothelinomdannende enzym, endothelinreceptorantagonister, HMG-CoA-reduktaseinhibitorer, østrogener, østrogen-receptoragonister og/eller -antagonister, monoamingenoptagelsesinhibitorer, muskel-relaxanter, natriuretiske peptider og deres analoge, antagonister mod receptoren med clearance for natriuretiske peptider, neprilysininhibitorer, nitrogenoxiddonorer, ikke-steroide antiinflammatoriske midler, N-methyl-d-aspartat-receptorantagonister, opioidreceptoragonister, phosphodiesteraseinhibitorer, prostaglandinanaloge, prostaglandinreceptoragonister, renininhibitorer, selektive serotoningenoptagelses-inhibitorer, natriumkanalblokkere, opløselige guanylatcyclasestimulatorer og -aktivatorer, tricycliske antidepressiva, vasopressinreceptorantagonister og kombinationer deraf.
27. Farmaceutisk sammensætning ifølge krav 26, hvori det terapeutiske middel er en AT i-receptorantagonist.
28. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse i terapi.
29. Forbindelse ifølge krav 28 til anvendelse ved behandling af hypertension, hjertesvigt eller nyresygdom.
30. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1 til 20 til fremstilling af et medikament til behandling af hypertension, hjertesvigt eller nyresygdom.
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ES2609810T3 (es) 2012-05-31 2017-04-24 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina donadores de óxido nítrico
HRP20171037T1 (hr) 2012-06-08 2017-10-06 Theravance Biopharma R&D Ip, Llc Inhibitori neprilizina
JP6162229B2 (ja) 2012-06-08 2017-07-12 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー ネプリライシン阻害剤
PL2882716T3 (pl) 2012-08-08 2017-06-30 Theravance Biopharma R&D Ip, Llc Inhibitory neprylizyny

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