DK1689757T3 - Heterocykliske borsyreforbindelser - Google Patents

Heterocykliske borsyreforbindelser Download PDF

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DK1689757T3
DK1689757T3 DK04810839.3T DK04810839T DK1689757T3 DK 1689757 T3 DK1689757 T3 DK 1689757T3 DK 04810839 T DK04810839 T DK 04810839T DK 1689757 T3 DK1689757 T3 DK 1689757T3
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compound
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inhibitors
alkyl
insulin
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David Alan Campbell
David Winn
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Sino Med Internat Alliance Inc
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Claims (21)

1. Forbindelse med formel (I):
omfattende cykliske isomerer deraf med formlen
stereoisomerer deraf, solvater deraf, hydrater deraf og farmaceutisk acceptable salte deraf, hvor: n er 1; X er CH2; Z er H; R1 og R2 uafhængigt eller sammen er -OH, en hydroxylbærende- eller borsyrebeskyttelsesgruppe, eller en gruppe der er egnet til at blive hydrolyseret til en hydroxylgruppe i en vandig opløsning ved fysiologisk pH eller i biologiske fluider; R3 og R4 er hydrogen og R5 er:
R20 er hydrogen, (Ci-s)alkyl, (Ci-6)alkylcarbonyl, di-(Ci-6)alkylaminocarbonyl, (C3-8)cycloalkylcarbonyl, benzyl, benzoyl, (Ci-6)alkyloxycarbonyl, aralkyloxycarbonyl, pyridinyl, pyrimidinyl, phenyl, phenyl-substitueret thiazolyl, phenylaminocarbonyl, alkylsulfonyl, eller phenylsulfonyl; hvor benzyl-, benzoyl-, pyridinyl-, pyrimidinyl-, phenyl-, phenylaminocarbonyl-, alkylsulfonyl- og phenylsulfonylgrupperne eventuelt er mono- eller uafhængigt di-substitueret med R12; R12 er halogen, trifluormethyl, cyano, nitro, (Ci-6)alkyl, (Ci-6)alkoxy, cycloalkyl, carboxy, acetamido, hydroxy, hydroxy(Ci-6)alkyl, hydroxymethyl, trifluormethoxy, sulfamoyl, carbamoyl, sulfonamido, alkylsufonyl, phenylsulfonyl, aryl, eller heteroaryl; hvor aryl- og heteroarylgrupperne eventuelt er mono- eller uafhængigt pluri-substitueret med R7; R7 er halogen, (Ci-io)alkyl, (Ci-io)alkoxy, (Ci-io)alkylamino, (Ci-io)dialkylamino, benzyl, benzyloxy, hydroxy(Ci-6)alkyl, hydroxymethyl, nitro, trifluormethyl, trifluormethoxy, trifluormethylthio, N-hydroxyamino, cyano, carboxy, acetamido, hydroxy, sulfamoyl, sulfonamido, carbamoyl; Rx er hydrogen, (Ci-s)alkyl, (C3-12) cycloalkyl, benzyl, eller phenyl; hvor benzyl- og phenylgrupperne eventuelt er mono- eller uafhængigt di-substitueret på ringen med R12; Ry er fraværende eller er halogen, (Ci-s)alkyl, (Ci-s)alkoxy, O-alkylcarboxylat, 0-aralkylcarboxylat, N-alkylcarboxamido, N-aralkylcarboxamido, eller phenyl; s er 1 til 6; t er O til 6; og u er O til 3; og, hvor en binding gennemskåret ved en bølgelinje betegner et bindingspunkt.
2. Forbindelse ifølge krav 1, hvor R1 og R2 er hydroxyl.
3. Forbindelse ifølge krav 2, hvor R5 er
4. Forbindelse ifølge krav 2, hvor R5 er:
5. Forbindelse ifølge et hvilket som helst af kravene 1-4, hvor R1 og R2 uafhængigt eller sammen er hydroxyl bærende borsyrebeskyttelsesgruppen dannet fra (+)-pinandiol; pinacol; 1,2-dicyclohexyl-ethandiol; 1,2-ethandiol; 2,2-diethanolamine; 1,3-propandiol; 2.3- butandiol, diisopropyltartrat; 1,4-butandiol; diisopropylethandiol; (S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethandiol; (2R, 3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl- 2.3- butandiol; methanol; ethanol; isopropanol; catechol; eller 1-butanol.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R1 og R2 uafhængigt eller sammen er en gruppe der er egnet til at blive hydrolyseret til en hydroxylgruppe i en vandig opløsning ved fysiologisk pH eller i biologiske fluider dannet fra 1,2-dicyclohexylethandiol; 1,2-ethandiol; 1,3-propandiol; 2,3-butandiol; 1,4-butandiol; diisopropylethandiol; methanol; ethanol; isopropanol; eller 1-butanol.
7. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1-6 og mindst én farmaceutisk acceptabel bærer.
8. Forbindelse ifølge et hvilket som helst af kravene 1-6 eller en sammensætning ifølge krav 7 til inhibering af dipeptidylpeptidase-IV, hvorved dipeptidylpeptidase-IV bringes i kontakt med en effektiv mængde af en forbindelse ifølge et hvilket som helst af kravene 1-6 eller en sammensætning ifølge krav 7.
9. Forbindelse ifølge et hvilket som helst af kravene 1-6 eller en sammensætning ifølge krav 7 til behandlingen af en sygdom hos et pattedyr der kan blive reguleret eller normaliseret via inhibering af dipeptidylpeptidase-IV.
10. Forbindelse eller sammensætning ifølge krav 9, hvor sygdommen er en metabolisk lidelse.
11. Forbindelse eller sammensætning ifølge krav 9, hvor sygdommen er diabetes.
12. Forbindelse eller sammensætning ifølge krav 9 og en terapeutisk effektiv mængde af et antidiabetisk middel valgt fra gruppen bestående af et andet medikament der forøger insulinudskillelse, forøger insulinfølsomhed, nedsætter optagelsen af sukker fra fordøjelseskanalen, eller forbedrer virkningen af peptider eller proteiner der påvirker glykæmisk kontrol, eller en hvilken som helst kombination deraf.
13. Terapeutisk effektiv mængde af en første forbindelse ifølge et hvilket som helst af kravene 1-6 eller en første sammensætning ifølge krav 7 og ét eller flere anden medikamenter valgt fra gruppen bestående af a) andre dipeptidylpeptidase-IV-inhibitorer; b) insulin-sensibilisatorer valgt fra gruppen bestående af (i) PPAR-agonister, (ii) biguanider, og (iii) proteinphosphatase-lB-inhibitorer; c) insulin eller insulinmimetika; d) sulfonylurinstoffer eller andre insulinsekretagoger; e) a-glucosidase-inhibitorer; f) glucagonreceptor-agonister; g) GLP-1, GLP-l-mimetika, og GLP-1 receptor-agonister; h) GLP-2, GLP-2-mimetika, og GLP-2 receptor-agonister; i) GIP, GIP-mimetika, og GIP receptor-agonister; j) PACAP, PACAP mimetika, og PACAP receptor 3-agonister; k) Cholesterolsænkende midler valgt fra gruppen bestående af (i) HMG-CoA reductase-inhibitorer, (ii) sekvestrationsmidler, (iii) nikotinylalkohol, nikotinsyre eller et salt deraf, (iv) PPARa-agonister, (v) PPARa/y-dual-agonister, (vi)-inhibitorer of cholesterol absorption, (vii) acyl-CoA:cholesterolacyltransferase-inhibitorer, og(viii) anti-oxidanter; l) PPAR-agonister; m) anti-fedme-forbindelser; n) en ileal galdesyre-transporterinhibitor; o) antiinflammatoriske midler; p) G-CSF, G-CSF mimetika, og G-CSF receptor-agonister; og q) EPO, EPO mimetika, og EPO receptor-agonister til behandling, kontrol eller forebyggelse hos en pattedyr-patient med behov for en sådan behandling af én eller flere tilstande valgt fra gruppen bestående af (1) hyperglykæmi, (2) lav glucosetolerance, (3) insulinresistens, (4) fedme, (5) lipid-forstyrrelser, (6) dyslipidæmi, (7) hyperlipidæmi, (8) hypertriglyceridæmi, (9) hypercholesterolæmi, (10) lave FIDL-niveauer, (11) høje LDL-niveauer, (12) atherosklerose og dens følgevirkninger, (13) vaskulær restenose, (14) irritabel tarmsyndrom, (15) inflammatorisk tarmsygdom, herunder Crohn's sygdom og ulcerativ colitis, (16) rheumatoid arthritis, (17) andre inflammatoriske tilstande, (18) pancreatitis, (19) abdominal fedme, (20) neurodegenerativ sygdom, (21) multipel sklerose , (22) retinopati, (23) nephropati, (24) neuropati, (25) syndrom X, (26) ovarie-hyperandrogenisme, (27) transplatafstødning i transplantation, (28) type II-diabetes, (29) væksthormonunderskud, (30) neutropeni, (31) anæmi, (32) neuronale forstyrrelser, (33) tumorvækst og metastaser, (34) benign prostatahypertrofi, (35) gingivitis, (36) hypertension, (37) osteoporose, og andre tilstande der kan behandles ved inhibering af dipeptidyl peptidase-IV.
14. Farmaceutisk kombination omfattende en forbindelse ifølge et hvilket som helst af kravene 1-6 eller en sammensætning ifølge krav 7; og et antidiabetisk middel der forøger insulinudskillelse, forøger insulinfølsomhed, nedsætter optagelsen af sukker fra fordøjelseskanalen, eller forbedrer virkningen af peptider eller proteiner der påvirker glykæmisk kontrol, eller en hvilken som helst kombination deraf.
15. Farmaceutisk kombination ifølge krav 14, hvor vægtforholdet af forbindelsen og det antidiabetiske middel er fra ca. 0,01:1 til ca. 100:1.
16. Farmaceutisk kombination ifølge krav 14, hvor det antidiabetiske middel er 1, 2, 3 eller derover af metformin, glyburid, glipizid, chlorpropamid, gliclazid, acarbose, miglitol, nateglinid, pioglitazon, troglitazon, rosiglitazon, insulin, GI-262570, isaglitazon, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinid, nateglinid, KAD1129, APR-H039242, GW-409544, KRP297, AC2993, LY307161, NN2211, og/eller LY315902.
17. Farmaceutisk kombination ifølge krav 14, hvor det andet medikamenter er egnet til behandling af en diabetestilstand.
18. Fremgangsmåde til fremstilling af en forbindelse ifølge krav 1 omfattende: at bringe en forbindelse med formel (XXX)
i kontakt med en forbindelse med formel (XXXI)
hvor L omfatter en leaving-gruppe under tilstande der er egnede til at tilvejebringe forbindelsen ifølge krav 1, og hvor R1, R2, R3, R4, R5, X, Z, og n er som defineret i krav 1.
19. Fremgangsmåden ifølge krav 18, hvor L er halo.
20. Fremgangsmåden ifølge krav 18, hvor L er chlor.
21. Fremgangsmåden ifølge krav 18 yderligere omfattende fremstilling af en forbindelse med formlen XXX, hvor R1 og R2 hver er OFI ved at bringe syre i kontakt med en forbindelse med formlen XXX, hvor R1 og R2 hver er hydroxyl bærende en borsyre-beskyttelsesgruppe.
DK04810839.3T 2003-11-12 2004-11-12 Heterocykliske borsyreforbindelser DK1689757T3 (da)

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PCT/US2004/037820 WO2005047297A1 (en) 2003-11-12 2004-11-12 Heterocyclic boronic acid compounds

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