Bile acid derivatives, process for their preparation and use of these compounds as pharmaceuticals
First Claim
1. A dimeric bile acid derivative of formula (I)
wherein G1 is a compound of formula (II) ##STR732## in which V is O, NH or CH2Y is a free valency for bonding the group X of --OL, --NHL, --NL2, an amino acid or aminosulfonic acid bonded via the amino group and their (C1 -C4) alkyl esters and alkali metal and alkaline earth metal salts, --O--M, where M is a cation selected from an alkali metal ion, an alkaline earth metal ion or a quarternary ammonium ion, and in which L is H, a saturated or unsaturated alkyl radical having 1-10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3-8 carbon atoms, a phenyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1-4)-alkoxy, a benzyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, is methyl, isopropyl, isobutyl, 2-butyl, benzyl, 4-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl, H3 CSCH2 CH2 --, HO2 CCH2 -- or HO2 CCH2 CH2 --,R1 is a free valency for bonding the group X or H, a saturated or unsaturated alkyl radical having 1-10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3-8 carbon atoms, a phenyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3-, a benzyl radical which is unsubstituted in the ring or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl, (C1 -C4)-alkoxy, --N+ H3, --OPO3- or phenyl, which can in turn be monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3-, a biphenylmethyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3-, a triphenylmethylradical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3- , a 1- or 2-naphthylmethyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3 --, a 9-fluorenyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, -N+ H3, --OPO3-a 2-, 3- or 4-pyridyl radical, a radical ##STR733## where L has the above-mentioned meaning, R2 to R5, where R2 and R3 or R4 and R5 in each case together are the oxygen of a carbonyl group, or individually and in each case independently of one another are ##STR734## where L has the above mentioned meaning and T has the meaning of L or a free valency for bonding the group X,with the restriction that altogether only one free valency for bonding the group X starts from G1,X is a single bond or a group of formula III ##STR735## where A is an alkylene chain which is branched or unbranched, saturated or unsaturated and can be optionally interrupted in the chain by --O--, --S-- or arylene, where the linkage ##STR736## takes place and the chain contains altogether 2 to 12 chain members p;
B is an alkylene chain which is branched or unbranched, saturated or unsaturated and can be optionally interrupted in the chain by --O--, --S-- or arylene, where the linkage ##STR737## takes place and the chain contains altogether 2 to 18 chain members n, L1, L2 and L3 are identical or different and have the meaning of L, andq is 0-5,r is 0 or 1 ands is 0 or 1,t is 0 or 1,G2 is a compound of formula (IV) ##STR738## in which V, Y and R1 have the meaning indicated under G1 and R7 to R10, where R7 and R8 or R9 and R10 in each case are the oxygen of a carbonyl group or individually and in each case independently of one another are H, OT, --ST, --NHT PG,236 ##STR739## where L and T have the meaning indicated under G1, likewise with the restriction that altogether only one free valency for bonding the group X starts from G2 derivative is not and wherein the linkage of the radicals G1 and G2 is unsymmetrical.
1 Assignment
0 Petitions
Accused Products
Abstract
The invention relates to bile acid derivatives of the formula I
G1--X--G2 (I)
in which
G1 and G2 are bile acid radicals or modified bile acid radicals in the form of the free acids, the esters or amides, the salt forms and also the forms derivatized on the alcohol groups and
X is a bridge group or a single covalent bond, it being possible for G1 and G2 to be optionally bonded via X.
The compounds according to the invention have a high affinity for the specific bile acid transport system of the small intestine and inhibit bile acid absorption in a concentration-dependent and competitive manner.
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Citations
9 Claims
- 1. A dimeric bile acid derivative of formula (I)
- space="preserve" listing-type="equation">G1--X--G2 (I)
wherein G1 is a compound of formula (II) ##STR732## in which V is O, NH or CH2 Y is a free valency for bonding the group X of --OL, --NHL, --NL2, an amino acid or aminosulfonic acid bonded via the amino group and their (C1 -C4) alkyl esters and alkali metal and alkaline earth metal salts, --O--M, where M is a cation selected from an alkali metal ion, an alkaline earth metal ion or a quarternary ammonium ion, and in which L is H, a saturated or unsaturated alkyl radical having 1-10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3-8 carbon atoms, a phenyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1-4)-alkoxy, a benzyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, is methyl, isopropyl, isobutyl, 2-butyl, benzyl, 4-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl, H3 CSCH2 CH2 --, HO2 CCH2 -- or HO2 CCH2 CH2 --, R1 is a free valency for bonding the group X or H, a saturated or unsaturated alkyl radical having 1-10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3-8 carbon atoms, a phenyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3-, a benzyl radical which is unsubstituted in the ring or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl, (C1 -C4)-alkoxy, --N+ H3, --OPO3- or phenyl, which can in turn be monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3-, a biphenylmethyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3-, a triphenylmethylradical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3- , a 1- or 2-naphthylmethyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, --N+ H3, --OPO3 --, a 9-fluorenyl radical which is unsubstituted or monosubstituted to trisubstituted by F, Cl, Br, (C1 -C4)-alkyl or (C1 -C4)-alkoxy, -N+ H3, --OPO3- a 2-, 3- or 4-pyridyl radical, a radical ##STR733## where L has the above-mentioned meaning, R2 to R5, where R2 and R3 or R4 and R5 in each case together are the oxygen of a carbonyl group, or individually and in each case independently of one another are ##STR734## where L has the above mentioned meaning and T has the meaning of L or a free valency for bonding the group X, with the restriction that altogether only one free valency for bonding the group X starts from G1, X is a single bond or a group of formula III ##STR735## where A is an alkylene chain which is branched or unbranched, saturated or unsaturated and can be optionally interrupted in the chain by --O--, --S-- or arylene, where the linkage ##STR736## takes place and the chain contains altogether 2 to 12 chain members p;
B is an alkylene chain which is branched or unbranched, saturated or unsaturated and can be optionally interrupted in the chain by --O--, --S-- or arylene, where the linkage ##STR737## takes place and the chain contains altogether 2 to 18 chain members n, L1, L2 and L3 are identical or different and have the meaning of L, andq is 0-5, r is 0 or 1 and s is 0 or 1, t is 0 or 1, G2 is a compound of formula (IV) ##STR738## in which V, Y and R1 have the meaning indicated under G1 and R7 to R10, where R7 and R8 or R9 and R10 in each case are the oxygen of a carbonyl group or individually and in each case independently of one another are H, OT, --ST, --NHT PG,236 ##STR739## where L and T have the meaning indicated under G1, likewise with the restriction that altogether only one free valency for bonding the group X starts from G2 derivative is not and wherein the linkage of the radicals G1 and G2 is unsymmetrical. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
Specification
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- Resources
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Current AssigneeHoechst Aktiengesellschaft (Sanofi )
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Original AssigneeHoechst Aktiengesellschaft (Sanofi )
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InventorsNeubauer, Horst, Kramer, Werner, Mullner, Stefan, Wess, Gunther
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Primary Examiner(s)Cintins, Marianne M.
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Assistant Examiner(s)PRIOR, KIMBERLY
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Application NumberUS07/802,413Time in Patent Office671 DaysField of Search552/509, 514/182, 514/179, 514/177US Class Current514/177CPC Class CodesA61P 3/06 AntihyperlipidemicsC07J 31/006 not covered by C07J31/003C07J 41/0016 OximesC07J 41/0055 the 17-beta position being ...C07J 41/0061 one of the carbon atoms bei...C07J 41/0094 containing nitrile radicals...C07J 43/003 not condensedC07J 9/005 containing a carboxylic fun...
