公开(公告)号：DK0417725T3

公开(公告)日：1997-11-03

申请号：DK90117470

申请日：1990-09-11

Applicant: HOECHST AG

Inventor： KRAMER WERNER DR ,  WESS G

IPC: A61K38/00 ,  A61K31/575 ,  A61K31/58 ,  A61P1/16 ,  A61P3/06 ,  A61P43/00 ,  C07D213/26 ,  C07D213/56 ,  C07D213/81 ,  C07J9/00 ,  C07J17/00 ,  C07J31/00 ,  C07J41/00 ,  C07J43/00 ,  C07J51/00 ,  C07K5/06 ,  C07K5/062

Abstract: Bile acid derivatives of the formula I W-X-G in which G is a bile acid residue, W is an active substance portion of a medicament and X is a linker between bile acid residue and active substance portion, are outstandingly suitable for introducing active substances into the enterohepatic circulation. The compounds I are absorbed and enter the bloodstream. This makes it possible by utilising the natural reabsorption of the bile acids to improve the absorption of drugs which are absorbed with difficulty, if at all. W can be, for example, a peptide, an antibiotic, an antiviral substance, an anticancer agent, a liver protective, an antihyperlipidaemic, a diuretic, an agent to lower blood pressure, a renin inhibitor, a substance to treat cirrhosis of the liver or a substance for treating diabetes. G is a bile acid residue in the form of the free, natural or chemically modified acids, the esters and amides, the salt forms and forms derivatised on alcohol groups. X is a large number of intermediate members or else a bond.

公开(公告)号：YU189991A

公开(公告)日：1995-10-03

申请号：YU189991

申请日：1991-12-06

Applicant: HOECHST AG

Inventor： KRAMER W ,  WESS G ,  MULLNER S ,  NEUBAUER H

IPC: A61K31/575 ,  A61K31/58 ,  A61P3/06 ,  C07J9/00 ,  C07J31/00 ,  C07J41/00 ,  C07J43/00

Abstract: Pronalazak se odnosi na derivate žučnih kiselina kao i na postupak za njihovo dobijanje. Derivati žučnih kiselina, prema pronalasku imaju formulu I G1 - X - G2 I u kojoj je značenje za G1 jedinjenje formule II u kojoj je Y -NHCH2-COOH; -NH-CH2-CH2-CH2-SO3H; -N-CH2 CH2 SO3H; N-CH2 COOH; -NH-CH COOH CH3 - CH3 R6 R6 C1-C4-alkil; 4-OH benzil: H3CSCH2CH2 R1 prosta veza ili H; zasićeni ili nezasićeni C1-C10-alkilostatak; fenil, benzil, bifenilmetil, trifenilmetil, naftil ili piridil, R2 i R3 ili R4 i R5 zajedno označavaju 0 karbonilne grupe ili svaki pojedinačno vodonik; C1-C6-alkoksi; alkil (C1-C10) merkapto; SC(C1-C10) alkil ili NH-CO (C1-C10) alkil, X -(CH2)n; -(CH2)2-O'-(CH2)2-; -N-(CH2)m-N-H H -N-(CH2)3-NH CO-(CH2)2 CONH (CH2)3-N-; ili H H -N-(CH2)2-O-(CH2)2-O-(CH2)2-N-H H n ceo broj od 3 - 12 m ceo broj od 3 - 6 Značenje za G2 je jedinjenje formule III u kojoj Y i R1 imaju ranije navedena značenja, R7 i R8 i R9 i R10 zajedno označavaju kiseonik karbonilne grupe i svaki pojedinačno H; C1-C10-alkoksi, -S (C1-C10)-alkil; -NH (C1-C10) alkil; COO (C1-C10)-alkil; -S-C-(C1-C10)-alkil, -NHC (C1-C10) alkil; Postupak za dobijanje jedinjenja formule I, okarakterisan je: a) reagovanjem reakcijski sposobnih oblika G1 i G2. b) reagovanjem reakcijski sposobnih oblika G1 -X i G2 ili G2- X i G1 c) reagovanjem G1 - X1 i G2 ili G2 - X2 i G1, pri čemu se reakcijom kondenzacije ili supstancije X1 i X2 prevode u X. Jedinjenja prema pronalasku imaju veliki afinitet prema specifičnom sistemu tankog creva za transport žučnih kiselina i kanališu resorpciju žučnih kiselina na kompatitivan i od koncentracije zavisan način.

公开(公告)号：NZ217366A

公开(公告)日：1989-08-29

申请号：NZ21736686

申请日：1986-08-27

Applicant: HOECHST AG

Inventor： WESS G ,  GRANZER E ,  BECK G ,  LAU H-H

IPC: A61K31/365 ,  C07D309/10 ,  C07D309/30 ,  C07F7/18 ,  C07C59/68 ,  A61K31/19

Abstract: 1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the general formula I see diagramm : EP0216127,P57,F1 in which R**1 and R**5 are identical or different and denote a) halogen, b) cycloalkyl having 4-8 carbon atoms, or a phenyl radical which can be substituted in the nucleus once to 3 times by halogen, trifluoromethyl, and/or alkyl or alkoxy each having 1-4 carbon atoms, or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms, or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, it being possible for the alkyl and alkenyl radicals in turn to be substituted 1-3 times by alpha) straight-chain or branched alkoxy radicals having up to 10 carbon atoms, or cycloalkyl radicals having 3 to 7 carbon atoms, or straight-chain or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms, beta) halogen, hydroxyl, cycloalkyl having 3-7 carbon atoms, unsubstituted phenyl or alpha- or beta-thienyl radicals, or phenyl or alpha- or beta-thienyl radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, gamma) unsubstituted phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals, or phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, delta) the group see diagramm : EP0216127,P57,F2 R**6 denoting : a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical each having 3-8 carbon atoms, or an unsubstituted phenyl radical, or a phenyl radical which in turn is substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, or a 3-pyridyl radical, R**2 and R**4 denote hydrogen, and R**3 is alkyl or alkenyl having up to 4 carbon atoms, halogen or alkoxy having 1-4 carbon atoms, and the corresponding open-chain dihydroxy carboxylic acid, their pharmacologically tolerated salts with bases, and their pharmacologically tolerated esters. 1. Claims for the Contracting State : AT A process for the preparation of a 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the general formula I see diagramm : EP0216127,P62,F1 in which R**1 and R**5 are identical or different and denote a) halogen, b) cycloalkyl having 4-8 carbon atoms, or a phenyl radical which can be substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy each having 1-4 carbon atoms, or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms, or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, it being possible for the alkyl and alkenyl radicals in turn to be substituted 2-3 times by alpha) straight-chain or branched alkoxy radicals having up to 10 carbon atoms, or cycloalkoxy radicals having 3 to 7 carbon atoms, or straight-chain or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms, beta) halogen, hydroxyl, cycloalkyl having 3-7 carbon atoms, unsubstituted phenyl or alpha- or beta-thienyl radicals, or phenyl or alpha- or beta-thienyl radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, gamma) unsubstituted phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals, or phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, delta) the group see diagramm : EP0216127,P62,F2 R**6 denoting : a straight-chain or branched alkyl or alkenyl having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical each having 3-8 carbon atoms, or an unsubstituted phenyl radical, or a phenyl radical which in turn is substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, or a 3-pyridyl radical, R**2 and R**4 denote hydrogen, and R**3 is alkyl or alkenyl having up to 4 carbon atoms, halogen or alkoxy having 1-4 carbon atoms, and the corresponding open-chain dihydroxy carboxylic acid, their pharmacologically tolerated salts with bases, and their pharmacologically tolerated esters, which comprises a) conversion of an appropriately substituted phenol of the formula II see diagramm : EP0216127,P62,F3 in which R**1 , R**2 , R**3 , R**4 and R**5 have the indicated meanings, with the chiral iodide of the formula III see diagramm : EP0216127,P63,F1 in which R**10 denotes a protective group which is stable to bases and weak acids, into an ether of the formula IV see diagramm : EP0216127,P63,F2 in which R**1 to R**5 have the meanings indicated for formula I and R**10 has the meanings indicated for formula III, b) hydrolysis of the ether of the formula IV to give the corresponding hemiacetal of the formula V see diagramm : EP0216127,P63,F3 in which R**1 to R**5 and R**10 have the meanings indicated for formula I or III, c) oxidation of the hemiacetal of the formula V to give the corresponding lactone of the formula VI see diagramm : EP0216127,P64,F1 in which R**1 to R**5 have the meanings indicated for formula I and R**10 has the meanings indicated for formula III, and d) conversion of the protected hydroxylactone of the formula VI into the 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the formula I see diagramm : EP0216127,P64,F2 where appropriate the compound of the formula I which has been obtained being converted into the corresponding open-chain dihydroxy carboxylic acid of the formula VII see diagramm : EP0216127,P64,F3 its salt or its ester, where appropriate a salt or ester which has been obtained being converted into the free dihydroxy carboxylic acid or, where appropriate, the free carboxylic acid being converted into the salt or ester.