DK2882716T3 - Neprilysin hæmmere - Google Patents

Neprilysin hæmmere Download PDF

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DK2882716T3
DK2882716T3 DK13750454.4T DK13750454T DK2882716T3 DK 2882716 T3 DK2882716 T3 DK 2882716T3 DK 13750454 T DK13750454 T DK 13750454T DK 2882716 T3 DK2882716 T3 DK 2882716T3
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alkyl
chrd
chroc
compound
ch2oc
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Melissa Fleury
Adam D Hughes
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Theravance Biopharma R&D Ip Llc
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Claims (25)

1. Forbindelse af formlen I:
(i) hvor: (i) X er el.
’ og (a) Ra og Rb er H; R2 er H; og R7 er valgt blandt -CH2CF2CH3l -CH2CF2CF3! -(CH2)5CH3, -(CH2)6CH3, og
eller R2 er -Ci-6alkyl eller -C(0)-Ci-6alkyl, og R7 er H; eller (b) Ra er valgt blandt -CH3, -OCH3 og Cl, og Rb er H; eller Ra er valgt blandt H, -CH3, Cl og F, og Rb er Cl; eller Ra er H og Rb er valgt blandt -CH3 og -CN; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2-30Re og -(CH2)2-3NReRe; og R7 er valgt blandt H, -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHRc0C(0)-Ci-4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHROC(0)0-C2-4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2-4alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
eller (c) Ra er H og Rb er F; eller Ra er F og Rb er H; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2.3ORe og -(CH2)2.3NReRe; og R7 er valgt blandt -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHRc0C(0)-Ci-4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-Salkyl, -CHROC(0)0-C2.4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2.4-alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
9 eller (ii) X er
? og (a) Ra er Cl og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci.6alkyl, -(CH2)2-30Re og -(CH2)2.3-NReRe; R4 er valgt blandt-OH, -OCH3, -OCH2CH3 og -Ci^alkyl; og R7 er valgt blandt H, -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci.4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci.6alkyl, -CHROC(0)0-C2^alkyl,-CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
eller (b) Ra er F og Rb er H; R2 er H; R4 er -OH; og R7 er valgt blandt -Ci^alkyl, -[(CH2)20]i.3CH3, -CHRc0C(0)-Ci^alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHROC(0)0-C2^alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)OCH3, -C2-4alkylen-N(CH3)2, -Co-ealkylenmorpholinyl, og
? eller (iii) X er
el. 9 og (a) Ra er Cl og Rb is H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2.3ORe, og -(CH2)2.3-NReRe; og R7 er valgt blandt H, -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci-»alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci^alkyl, -CHRc0C(0)0-C2^alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2^alkylen-N(CH3)2, -Cwr alkylenmorpholinyl, og
eller (b) R3 er F og Rb er H; R2 er H; og R7 er valgt blandt -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci^alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci^alkyl, -CHROC(0)0-C2-4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -Cm-alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
·> eller (iv) X er
5 (a) Ra og Rb er H; R2 er valgt blandt -Ci-6alkyl, -(CH2)2-3ORe og -(CH2)2-3NReRe; R3 er valgt blandt -OH, -OCH3, -OCH2CH3 og -Ci-4alkyl; og R7 er H; eller
(b) Ra er valgt blandt Cl og F og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2.3ORe og -(CH2)2.3NReRe; R3 er valgt blandt -OH, -OCH3, -OCH2CH3 og -Ci-4alkyl; og R7 er valgt blandt H, -Ci^alkyl, -[(CH2)20]i-3CH3, -CHRc0C(0)-Ci.4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHROC(0)0-C2^alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og ’ eller (v) X er el ’
Ra er valgt blandt Cl og F og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2-30Re og -(CH2)2-3NReRe; R3 er valgt blandt -OH, -OCH3, -OCH2CH3 og -CMalkyl; R4 er valgt blandt H, -Ci-ealkyl og phenyl; og R7 er valgt blandt H, -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci^alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci.6alkyl, -CHROC(0)0-C2.4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2-4alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
eller (vi) X er el.
Ra er valgt blandt Cl og F og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2-3ORe og -(CH2)2.3NReRe; R4 er valgt blandt H, -Ci-6alkyl og phenyl; og R7 er valgt blandt H, -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHRcOC(0)-Ci-4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHRc0C(0)0-C2^alkyl,-CHRc0C(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-ealkylenmorpholinyl, og
eller (vii) X er
s Ra er valgt blandt Cl og F og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2-3ORe og -(CH2)2.3NReRe; og R7 er valgt blandt H, -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHROC(O)-Ci-4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci.salkyl, -CHROC(0)0-C2.4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2.4alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
? eller (viii) X er
9 Ra er valgt blandt Cl og F og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-ealkyl, -(CH2)2-30Re og -(CH2)2-3NReRe; og R7 er valgt blandt H, -Ci-ealkyl, -[(CH2)20]i.3CH3, -CHROC(O)-Ci-4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci^alkyl, -CHROC(0)0-C2-4alkyl, - CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)OCH3, -C2^alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
5 hvor hver Rc er uafhængigt H eller -Ci-3alkyl; hver Rd er uafhængigt H, -CH3, -CH(CH3)2, phenyl eller benzyl; og hver Re er uafhængigt H eller -CH3; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifølge krav 1 af formlen Ila eller llb:
(Ha) (llb).
3. Forbindelse ifølge krav 2, hvor Ra og Rb er H; og R2 er H; og R7 er valgt blandt -CH2CF2CH3, -CH2CF2CF3! -(CH2)5CH3, -(CH2)6CH3, og
eller R2 er -Ci-6alkyl eller -C(0)-Ci-6alkyl, fortrinsvis -CH3, -CH2CH3,-C(0)CH3, -C(0)CH(CH3)2 og -C(0)CH2CH(CH3)2, og R7 er H.
4. Forbindelse ifølge krav 2, hvor Ra er valgt blandt -CH3, -OCH3 og Cl, og Rb er H; eller Ra er valgt blandt H, -CH3, Cl og F, og Rb er Cl; eller Ra er H og Rb er valgt blandt -CH3 og -CN; og enten R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2-3ORe og -(CH2)2-3NReRe, og R7 er valgt blandt H, -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHRc0C(0)0-C2.4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -C0-6alkylen-morpholinyl, og
eller R2 er valgt blandt H, -Ci-ealkyl og -(CH^OR®, hvor Re er H eller -CH3, og R7 er H.
5. Forbindelse ifølge krav 2, hvor Ra er H og Rb er F; eller Ra er F og Rb er H; R2 er valgt blandt H, -Ci-6alkyl, -(CH2)2.3ORe og -(CH2)2.3NReRe; og R7 er valgt blandt -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHROC(0)0-C24alkyl,-CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-ealkylenmorpholinyl, og
6. Forbindelse ifølge krav 1 af formlen III:
(III).
7. Forbindelse ifølge krav 6, hvor Ra er Cl og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-ealkyl, -(CH2)2.30Re og -(CH2)2.3NReRe; R4 er valgt blandt -OH, -OCH3, -OCH2CH3 og -Ci-4-alkyl; og R7 er valgt blandt H, -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci-4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHROC(0)0-C2-4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-6alkylen-morpholinyl, og
9 eller hvor Ra er F, Rb er Cl, R2 er H, R4 is -OCH3 eller -OCH2CH3, og R7 er H.
8. Forbindelse ifølge krav 6, hvor Ra er F og Rb er H; R2 er H; R4 er -OH; og R7 er valgt blandt -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHRc0C(0)-Ci4alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHRc0C(0)0-C24alkyl,-CHRc0C(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-ealkylenmorpholinyl, og
9. Forbindelse ifølge krav 1 af formlen IVa eller IVb:
(IVa) (IVb).
10. Forbindelse ifølge krav 9, hvor Ra er Cl og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-ealkyl, -(CH2)2.3ORe og -(CH2)2-3NReRe; og R7 er valgt blandt H, -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHRcOC(0)-CMalkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci.6alkyl, -CHROC(0)0-C2.4alkyl, -CHRcOC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2.4-alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
? eller hvor Ra er F, Rb er Cl, R2 er H, og R7 er H.
11. Forbindelse ifølge krav 9, hvor Ra er F og Rb er H; R2 er H; og R7 er valgt blandt -Ci-ealkyl, -[(CH2)20]i-3CH3, -CHROCCOJ-C^alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci^alkyl, -CHROC(0)0-C2^alkyl,-CHRc0C(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C24alkylen-N(CH3)2, -Co-ealkylenmorpholinyl, og
12. Forbindelse ifølge krav 1, af formlen V:
(V).
13. Forbindelse ifølge krav 12, hvor Ra og Rb er H; R2 er valgt blandt -Ci-ealkyl, -(CH2)2.3ORe og -(CH2)2-3NReRe; R3 er valgt blandt -OH, -OCH3, -OCH2CH3, og -CM-alkyl; og R7 er H; eller hvor Ra og Rb er H, R2 er -CH3, R3 er -OH eller -OCH3, og R7 er H.
14. Forbindelse ifølge krav 12, hvor Ra er valgt blandt Cl og F og Rb er H; eller Ra er H og Rb er valgt blandt Cl, F, -CH3 og -CN; eller Ra er F og Rb er Cl; R2 er valgt blandt H, -Ci-ealkyl, -(CH2)2.3ORe og -(CH2)2-3NReRe; R3 er valgt blandt -OH, -OCH3, -OCH2CH3 og -Ci-4alkyl; og R7 er valgt blandt H, -Ci-6alkyl, -[(CH2)20]i-3CH3, -CHROC(0)-Ci-4-alkyl, -CH20C(0)CHRd-NH2, -CH20C(0)CHRd-NHC(0)0-Ci-6alkyl, -CHROC(0)0-C2.4alkyl, -CHROC(0)0-cyclohexyl, -CH2CH(NH2)C(0)0CH3, -C2-4alkylen-N(CH3)2, -Co-6alkylenmorpholinyl, og
15. Forbindelse ifølge krav 14, hvor Ra er H, Rb er Cl, R2 er H, -CH3, -CH2CH3 eller -(CH2)2OH, R3 er -OH eller -OCH3; og R7 er H; eller Ra er F, Rb er Cl, R2 er H eller -Ci-ealkyl, R3 er-OH, -OCH3 eller -Ci-4alkyl, og R7 er H.
16. Forbindelse ifølge krav 1, af formlen Via eller Vlb:
(Via) (Vlb) hvor Ra er H eller F; Rb er Cl; R2 er H eller -Ci-6alkyl; R3 er -OCH3, -OCH2CH3 eller -Ci-4alkyl; R4, hvis den foreligger, er H; og R7 er H.
17. Forbindelse ifølge krav 1 af formlen Vila eller VIIb:
(Vila) (Vllb) hvor Ra er F, Rb er Cl, R2 er H eller-Ci^alkyl, R4, hvis den foreligger, er H, og R7 er H.
18. Forbindelse ifølge krav 1, af formlen VIII:
(VIII).
19. Forbindelse ifølge krav 1, af formlen IX:
(IX).
20. Forbindelse ifølge krav 1, som er (2S,4F?)-5-(5'-chlor-2'-fluorbiphenyl-4-yl)-2-ethoxymethyl-4-[(3-hydroxyisoxazol-5-carbonyl)amino]-2-methylpentansyre.
21. Farmaceutisk sammensætning omfattende et farmaceutisk acceptabelt bærestof og en forbindelse ifølge ethvert af kravene 1 til 20, eventuelt yderligere omfattende et yderligere terapeutisk middel.
22. Farmaceutisk sammensætning ifølge krav 21, i hvilken det yderligere terapeutiske middel er valgt blandt adenosinreceptorantagonister, α-adrenergisk receptorantagonister, βι-adrenergisk receptorantagonister, 32-adrenergisk receptorantagonister, dobbeltvirkende β-adrenergiske receptorantagonister/a-i-receptorantagonister, avancerede glycationslutprodukt-brydere, aldosteronantagonister, aldosteronsynthase-hæmmere, aminopeptidase N hæmmere, androgener, angiotensin-konverterende enzymhæmmere og dobbeltvirkende angiotensin-konverterende enzym/neprilysin-hæmmere, angiotensin-konverterende enzym 2 aktivatorer og stimulatorer, angio-tensin-ll-vacciner, antikoagulanter, anti-diabetiske midler, anti-diarrheale midler, anti-glaucomamidler, anti-lipidmidler, anti-nociceptive midler, anti-thrombotiske midler, ATi receptorantagonister og dobbeltvirkende ATi receptorantagonist/neprilysinhæmmere og multifunktionelle angiotensinreceptorblokkere, bradykininreceptorantagonister, calciumkanalblokkere, chymasehæmmere, digoxin, diuretika, dopaminagonister, endothelinkonverterende enzymhæmmere, endothelinreceptorantagonister, HMG-CoA reduktasehæmmere, østrogener, østrogenreceptoragonister og/eller antagonister, monoamingenoptagelseshæmmere, muskelafslappere, natriuretiske peptider og disses analoger, natriuretiske peptidfrigørelsesreceptorantagonister, neprilysin-hæmmere, kvælstofoxiddonorer, ikke-steroide antiinflammatoriske midler, N-methyl d-aspartatreceptorantagonister, opioidreceptoragonister, phosphodiesterasehæmmere, prostaglandinanaloger, prostaglandinreceptoragonister, reninhæmmere, selektive serotoningenoptagelseshæmmere, natriumkanalblokkere, opløselig guanylatcyclase-stimulatorer og aktivatorer, tricycliske antidepressiver, vasopressinreceptor-antagonister, og kombinationer deraf.
23. Farmaceutisk sammensætning ifølge krav 22, hvor det terapeutiske middel er en ATi receptorantagonist.
24. Forbindelse ifølge ethvert af kravene 1 til 20 til terapeutisk anvendelse.
25. Forbindelse ifølge krav 24, til anvendelse ved behandling af hypertension, hjertefejl eller nyresygdom.
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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR084290A1 (es) 2010-12-15 2013-05-08 Theravance Inc Inhibidores de neprilisina, metodos para su preparacion e intermediarios utilizados en los mismos, composiciones farmaceuticas que los comprenden y su uso en la fabricacion de medicamentos para tratar enfermedades mediadas por la inhibicion de nep
CA2817368C (en) 2010-12-15 2019-12-31 Theravance, Inc. Neprilysin inhibitors
US8449890B2 (en) 2011-02-17 2013-05-28 Theravance, Inc. Neprilysin inhibitors
ES2582640T3 (es) 2011-02-17 2016-09-14 Theravance Biopharma R&D Ip, Llc Derivados aminobutíricos sustituidos como inhibidores de neprilisina
CA2835216A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
TWI560172B (en) 2011-11-02 2016-12-01 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
TWI562986B (en) * 2012-02-15 2016-12-21 Theravance Biopharma R&D Ip Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
US8871792B2 (en) 2012-06-08 2014-10-28 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
US9126956B2 (en) 2012-08-08 2015-09-08 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
CA2902456A1 (en) 2013-03-05 2014-09-12 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
RU2016135057A (ru) * 2014-01-30 2018-03-12 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи Производные 5-бифенил-4-гетероарилкарбониламинопентановой кислоты в качестве ингибиторов неприлизина
MX2016009760A (es) 2014-01-30 2016-11-08 Theravance Biopharma R&D Ip Llc Inhibidores de neprilisina.
CN107074744B (zh) * 2014-12-03 2019-06-18 上海翰森生物医药科技有限公司 Nep抑制剂结晶型游离酸、钙盐多晶型及其制备方法和应用
MY187899A (en) 2015-02-11 2021-10-27 Theravance Biopharma R&D Ip Llc (2s,4r)-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid as neprilysin inhibitor
HUE052732T2 (hu) 2015-02-19 2021-05-28 Theravance Biopharma R&D Ip Llc (2R,4R)-5-(5'-klór-2'-fluorbifenil-4-il)-2-hidroxi-4-[(5-metiloxazol-2-karbonil)amino]pentánsav
CA3015505C (en) 2016-03-08 2024-03-05 Theravance Biopharma R&D Ip, Llc Crystalline (2s,4r)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof
CN105753741A (zh) * 2016-04-26 2016-07-13 常州制药厂有限公司 一种抗心衰药物Sacubitril中间体的制备方法
CN107903191A (zh) * 2017-12-04 2018-04-13 武汉药明康德新药开发有限公司 2‑NH‑Boc‑3‑(3`,4`‑二甲基‑[1,1`‑联苯]‑4)丙酸的制法
UY38072A (es) 2018-02-07 2019-10-01 Novartis Ag Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos
CN113166204A (zh) 2018-11-27 2021-07-23 诺华股份有限公司 作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型（PCSK9）抑制剂的环状肽
EP3887363A1 (en) 2018-11-27 2021-10-06 Novartis AG Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder
UY38485A (es) 2018-11-27 2020-06-30 Novartis Ag Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación
RU2736511C1 (ru) * 2020-01-24 2020-11-17 Автономная некоммерческая образовательная организация высшего образования "Сколковский институт науки и технологий" Производные бифенила, обладающие биологической активностью, фармацевтические композиции и способы лечения на основе этих соединений и их применение
WO2023084449A1 (en) 2021-11-12 2023-05-19 Novartis Ag Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder
KR102485499B1 (ko) * 2022-07-15 2023-01-09 오가노이드사이언스 주식회사 신장 질환의 치료 또는 예방용 조성물

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4189604A (en) 1975-07-22 1980-02-19 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Bestatin
US4206232A (en) 1976-05-10 1980-06-03 E. R. Squibb & Sons, Inc. Relieving hypertension with carboxyalkylacylamino acids
IL58849A (en) 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
FR2480747A1 (fr) 1980-04-17 1981-10-23 Roques Bernard Derives d'acides amines et leur application therapeutique
US4906615A (en) 1980-12-18 1990-03-06 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
US4722810A (en) 1984-08-16 1988-02-02 E. R. Squibb & Sons, Inc. Enkephalinase inhibitors
US4939261A (en) 1984-06-08 1990-07-03 Ciba-Geigy Corporation N-substituted butyramide derivatives useful for treatment of conditions responsive to inhibition of enkephalinase
EP0225292A3 (en) 1985-12-06 1988-11-30 Ciba-Geigy Ag Certain n-substituted butyramide derivatives
US4929641B1 (en) 1988-05-11 1994-08-30 Schering Corp Mercapto-acylamino acid antihypertensives
KR880007441A (ko) 1986-12-11 1988-08-27 알렌 제이.스피겔 스피로-치환된 글루타르아미드 이뇨제
FR2623498B1 (fr) 1987-11-24 1990-04-06 Bioprojet Soc Civ Nouveaux composes enantiomeres derives d'amino-acides, leur procede de preparation et leurs applications therapeutiques
GB8820844D0 (en) 1988-09-05 1988-10-05 Pfizer Ltd Therapeutic agents
US5599951A (en) 1989-09-15 1997-02-04 Societe Civile Bioprojet Amino acid derivatives, the process for their preparation and their applications to therapy
US5155100A (en) 1991-05-01 1992-10-13 Ciba-Geigy Corporation Phosphono/biaryl substituted dipeptide derivatives
US5294632A (en) 1991-05-01 1994-03-15 Ciba-Geigy Corporation Phosphono/biaryl substituted dipetide derivatives
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
US5508272A (en) 1993-06-15 1996-04-16 Bristol-Myers Squibb Company Compounds containing a fused bicycle ring and processes therefor
DE19510566A1 (de) 1995-03-23 1996-09-26 Kali Chemie Pharma Gmbh Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
US5977075A (en) 1995-04-21 1999-11-02 Novartis Ag N-aroylamino acid amides as endothelin inhibitors
US6660756B2 (en) 2001-03-28 2003-12-09 Pfizer Inc. N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
GB0119305D0 (en) 2001-04-12 2001-10-03 Aventis Pharma Gmbh Mercaptoacetylamide derivatives,a process for their preparation and their use
WO2006027680A1 (en) 2004-09-10 2006-03-16 Pfizer Limited 3-(1-carbamoylcyclohexyl) propionic acid derivatives as inhibitors of neutral endopeptidase enzyme
AR057882A1 (es) 2005-11-09 2007-12-26 Novartis Ag Compuestos de accion doble de bloqueadores del receptor de angiotensina e inhibidores de endopeptidasa neutra
WO2007106708A2 (en) 2006-03-10 2007-09-20 Novartis Ag Combinations of the angiotensin ii antagonist valsartan and the nep inhibitor daglutril
MY153432A (en) 2007-01-12 2015-02-13 Novartis Ag Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
TWI448284B (zh) 2007-04-24 2014-08-11 Theravance Inc 雙效抗高血壓劑
PE20091364A1 (es) 2008-01-17 2009-10-13 Novartis Ag Proceso para la preparacion de inhibidores de nep
AU2010251967B9 (en) * 2009-05-28 2014-04-03 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
EA201101672A1 (ru) * 2009-05-28 2012-06-29 Новартис Аг Замещенные производные аминомасляной кислоты в качестве ингибиторов неприлизина
KR101372456B1 (ko) * 2009-06-15 2014-03-11 토요잉크Sc홀딩스주식회사 우레탄 수지, 활성 에너지선 경화성 접착제, 및 태양전지용 이면 보호 시트
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors
RU2564024C2 (ru) 2010-01-22 2015-09-27 Новартис Аг Промежуточные продукты для получения ингибиторов нейтральной эндопептидазы и способ их получения
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
CA2817368C (en) * 2010-12-15 2019-12-31 Theravance, Inc. Neprilysin inhibitors
AR084290A1 (es) 2010-12-15 2013-05-08 Theravance Inc Inhibidores de neprilisina, metodos para su preparacion e intermediarios utilizados en los mismos, composiciones farmaceuticas que los comprenden y su uso en la fabricacion de medicamentos para tratar enfermedades mediadas por la inhibicion de nep
US8449890B2 (en) 2011-02-17 2013-05-28 Theravance, Inc. Neprilysin inhibitors
ES2582640T3 (es) * 2011-02-17 2016-09-14 Theravance Biopharma R&D Ip, Llc Derivados aminobutíricos sustituidos como inhibidores de neprilisina
CN103748070B (zh) 2011-05-31 2015-06-24 施万生物制药研发Ip有限责任公司 脑啡肽酶抑制剂
CA2835216A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
ES2699773T3 (es) 2011-05-31 2019-02-12 Theravance Biopharma R&D Ip Llc Inhibidores de neprilisina
TWI560172B (en) 2011-11-02 2016-12-01 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
TWI562986B (en) * 2012-02-15 2016-12-21 Theravance Biopharma R&D Ip Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
CN104350052B (zh) 2012-05-31 2017-05-31 施万生物制药研发Ip有限责任公司 一氧化氮供体脑啡肽酶抑制剂
US8871792B2 (en) 2012-06-08 2014-10-28 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
PT2864292T (pt) 2012-06-08 2017-07-10 Theravance Biopharma R&D Ip Llc Inibidores de neprisilina
US9126956B2 (en) 2012-08-08 2015-09-08 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
MX2016009760A (es) 2014-01-30 2016-11-08 Theravance Biopharma R&D Ip Llc Inhibidores de neprilisina.

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