U.S. patent application number 11/926697 was filed with the patent office on 2008-05-08 for novel aromatic fluoroglycoside derivatives, medicaments containing these compounds, and the use thereof.
This patent application is currently assigned to Sanofi-Aventis Deutschland GmbH. Invention is credited to Harm Brummerhop, Wendelin FRICK, Heiner Glombik, Hubert Heuer, Werner Kramer, Oliver Plettenburg.
Application Number | 20080108580 11/926697 |
Document ID | / |
Family ID | 32477574 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108580 |
Kind Code |
A1 |
FRICK; Wendelin ; et
al. |
May 8, 2008 |
NOVEL AROMATIC FLUOROGLYCOSIDE DERIVATIVES, MEDICAMENTS CONTAINING
THESE COMPOUNDS, AND THE USE THEREOF
Abstract
Novel aromatic fluoroglycoside derivatives, medicaments
containing these compounds, and the use thereof. The invention
relates to substituted aromatic fluoroglycoside derivatives of the
formula I ##STR1## in which the radicals have the stated meanings,
and their physiologically tolerated salts and process for their
preparation. The compounds are suitable for example as
antidiabetics.
Inventors: |
FRICK; Wendelin;
(Hunsteten-Beuerbach, DE) ; Glombik; Heiner;
(Hofheim, DE) ; Kramer; Werner; (Mainz-Laubenheim,
DE) ; Heuer; Hubert; (Schwabonheim, DE) ;
Brummerhop; Harm; (Frankfurt, DE) ; Plettenburg;
Oliver; (Frankfurt, DE) |
Correspondence
Address: |
ANDREA Q. RYAN;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
Sanofi-Aventis Deutschland
GmbH
Frankfurt
DE
|
Family ID: |
32477574 |
Appl. No.: |
11/926697 |
Filed: |
October 29, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10735179 |
Dec 12, 2003 |
7288528 |
|
|
11926697 |
Oct 29, 2007 |
|
|
|
60466329 |
Apr 29, 2003 |
|
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Current U.S.
Class: |
514/35 ;
536/18.4 |
Current CPC
Class: |
A61P 3/10 20180101; C07H
15/203 20130101; A61P 3/00 20180101 |
Class at
Publication: |
514/035 ;
536/018.4 |
International
Class: |
A61K 31/7004 20060101
A61K031/7004; C07H 15/207 20060101 C07H015/207; A61P 3/10 20060101
A61P003/10 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 12, 2002 |
DE |
10258007.3-43 |
Claims
1. A compound of formula I ##STR78## wherein: R1, R2 are each
independently OH, F or H with the proviso that when R1 is F, R2
cannot be OH; when R1 is OH, R2 cannot be F; and when R1 is OH, R2
cannot be OH; R3 is OH or F, with the proviso that at least one of
said R1, R2, R3 radicals must be F; A is O, NH, CH.sub.2, S or a
bond; R4, R5, R6 are each independently hydrogen, F, Cl, Br, I, OH,
NO.sub.2, CN, COOH, CO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.6)-alkoxy,
HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, phenyl or
benzyl, wherein said CO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.1-C.sub.6)-alkyl, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkoxy, HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl radicals are
optionally substituted with one or more fluorine atoms,
SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.o-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.o-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.o-phenyl, wherein the phenyl ring of said
S--(CH.sub.2).sub.o-phenyl, SO--(CH.sub.2).sub.o-phenyl and
SO.sub.2--(CH.sub.2).sub.o-phenyl radicals may be mono- or
disubstituted with F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl or
NH.sub.2 and wherein o is 0, 1, 2, 3, 4, 5 or 6, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, O--(CH.sub.2).sub.o-phenyl,
wherein the phenyl ring of said phenyl and
O--(CH.sub.2).sub.o-phenyl radicals may be mono-, di-, or
trisubstituted with F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, SO.sub.2--CH.sub.3, COOH,
COO--(C.sub.1-C.sub.6)-alkyl or CONH.sub.2 and wherein o is as
hereinabove defined; B is (C.sub.0-C.sub.15)-alkanediyl, wherein
one or more carbon atoms in said (C.sub.0-C.sub.15)-alkanediyl
radical are, independently of one another, optionally replaced by
--O--, --(C.dbd.O)--, --CH.dbd.CH--, --C.ident.C--, --S--,
--CH(OH)--, --CHF--, --CF.sub.2--, --(S.dbd.O)--, --(SO.sub.2)--,
--N((C.sub.1-C.sub.6)-alkyl)-, --N((C.sub.1-C.sub.6)-alkyl-phenyl)-
or --NH--; n is 0, 1, 2, 3 or 4; Cyc1 is a 3-, 4-, 5-, 6-, or
7-membered saturated, partially saturated or unsaturated ring,
wherein one carbon atom of said ring may be replaced by O, N or S;
R7, R8, R9 R7, R8, and R9 are each independently hydrogen, F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CO(C.sub.1-C.sub.4)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, wherein said
COO(C.sub.1-C.sub.6)-alkyl, CO(C.sub.1-C.sub.4)-alkyl,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl and
(C.sub.1-C.sub.6)-alkyl-(C.sub.1-C.sub.6)-alkyl radicals are
optionally substituted with one or more fluorine atoms,
SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.o-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.o-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.o-phenyl, wherein said
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2--(C.sub.1-C.sub.6)-alkyl radicals are optionally
substituted with one or more fluorine atoms, and wherein the phenyl
ring of said S--(CH.sub.2).sub.o-phenyl,
SO--(CH.sub.2).sub.o-phenyl and SO.sub.2--(CH.sub.2).sub.o-phenyl
radicals is optionally mono- or disubstituted with F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2, and wherein o is as
hereinabove defined, NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl
or O--(CH.sub.2).sub.o-phenyl, wherein the phenyl ring of said
phenyl and O--(CH.sub.2).sub.o-phenyl radicals is optionally mono-,
di-, or trisubstituted with F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, (C.sub.1-C.sub.8)-alkoxy, (C.sub.1-C.sub.6)-alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, SO.sub.2--CH.sub.3, COOH,
COO--(C.sub.1-C.sub.6)-alkyl or CONH.sub.2, and wherein o is as
hereinabove defined; or R8 and R9 taken together with the carbon
atoms to which they are attached form a 5-, 6- or 7-membered,
saturated, partially saturated or unsaturated ring herein referred
to as Cyc2, wherein one or two carbon atom(s) in said Cyc2 ring are
optionally replaced by N, O or S, and wherein said Cyc2 ring is
optionally substituted with (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.5alkenyl or (C.sub.2-C.sub.5)-alkynyl, wherein said
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl and
(C.sub.2-C.sub.5)-alkynyl radicals are optionally substituted with
F, Cl, OH, CF.sub.3, NO.sub.2, CN, COO(C.sub.1-C.sub.4)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.4)-alkyl or OCF.sub.3, and wherein a
--CH.sub.2-- group contained in said (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.5)-alkenyl and (C.sub.2-C.sub.5)-alkynyl radicals is
optionally replaced by --O--; and pharmaceutically acceptable salts
thereof.
2. The compound of claim 1 wherein: R1 and R2 are each
independently OH, F or H, with the proviso that at least one of
said radicals R1 and R2 must be F and With the further proviso that
when R1 is F, R2 is not OH, when R1 is OH, R2 is not F, and when R1
is OH, R2 is not OH; R3 is OH; A is O or NH; R4, R5, R6 are each
independently hydrogen, F, Cl, Br, I, OH, NO.sub.2, CN, COOH,
CO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.6)-alkoxy,
HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, phenyl, benzyl
or SO--(C1-C6)-alkyl, wherein said CO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.1-C.sub.6)-alkyl, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkoxy, HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl and
SO--(C1-C6)-alkyl radicals are optionally substituted with one or
more fluorine atoms, B is (C.sub.0-C.sub.15alkanediyl, wherein one
or more of the carbon atoms in said alkanediyl radical may be
replaced, independently of one another, with --O--, --(C.dbd.O)--,
--CH.dbd.CH--, --C.ident.C--, --S--, --CH(OH)--, --CHF--,
--CF.sub.2--, --(S.dbd.O)--, --(SO.sub.2)--,
--N((C.sub.1-C.sub.6)-alkyl), --N((C.sub.1-C.sub.6)-alkyl-phenyl)-
or --NH--; n is 0, 1, 2, 3 or 4; Cyc1 is a 3-, 4-, 5-, 6- or
7-membered saturated, partially saturated or unsaturated ring,
wherein one carbon atom of said ring may be replaced by O, N or S;
R7, R8, and R9 are each independently hydrogen, F, Cl, Br, I, OH,
CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl,
CO(C.sub.1-C.sub.4)-alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6 alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.8)-alkoxy, HO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl or
SO--(C.sub.1-C.sub.6)-alkyl, wherein said
COO(C.sub.1-C.sub.6)-alkyl, CO(C.sub.1-C.sub.4)-alkyl,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl and
SO--(C.sub.1-C.sub.6)-alkyl radicals are optionally substituted
with one or more fluorine atoms, or R8 and R9 taken together with
the carbon atoms to which they are attached form a 5-, 6- or
7-membered, saturated, partially saturated or unsaturated ring
herein referred to as Cyc2, wherein one or two carbon atom(s) in
said Cyc2 ring are optionally replaced by N, O or S, and wherein
said Cyc2 ring is optionally substituted with
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl or
(C.sub.2-C.sub.5)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.5)-alkenyl and (C.sub.2-C.sub.5)-alkynyl radicals
are optionally substituted with F, Cl, OH, CF.sub.3, NO.sub.2, CN,
COO(C.sub.1-C.sub.4)-alkyl, CONH.sub.2, CONH(C.sub.1-C.sub.4)-alkyl
or OCF.sub.3, and wherein a --CH.sub.2-- group contained in said
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl and
(C.sub.2-C.sub.5)-alkynyl radicals is optionally replaced by
--O--.
3. The compound of claim 1 wherein the sugar residues are
beta(.beta.) -linked and the stereochemistry in the 2, 3 and 5
position of the sugar residue has the D-gluco configuration.
4. The compound of claim 1 wherein: R1 and R2 are each
independently OH, F or H, with the proviso that at least one of
said radicals R1 and R2 must be F and with the further proviso that
when R1 is F, R2 is not OH, when R1 is OH, R2 is not F, and when R1
is OH, R2 is not OH, R3 is OH; A is O; R4, R5, R6 are each
independently hydrogen, F, Cl, Br, I, OH, NO.sub.2, CN, COOH,
CF.sub.3, OCF.sub.3, OCH2CF3, (C1-C4)-alkyl-CF2-,
COO(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.5)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkoxy, HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, phenyl or
benzyl, B is (C.sub.1-C.sub.4)-alkanediyl, wherein one or more of
the carbon atoms in said alkanediyl radical may be replaced,
independently of one another, with --O--, --(C.dbd.O)--,
--CH(OH)--, --CHF--, --CF.sub.2--,
--CO--N(C.sub.1-C.sub.6)-alkyl)-, --CO--NH-- or --NH--, n is 2 or
3; Cyc1 is an unsaturated 5- or 6-membered ring, wherein one carbon
atom of said ring may be replaced by O, N or S; R7, R8, and R9 are
each independently hydrogen, F, Cl, Br, OH,
(C.sub.1-C.sub.6)-alkyl, --(C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, or R8 and R9
taken together form the radicals --CH.dbd.CH--O--, --CH2-CH2-O--,
--CH.dbd.CH--S--, --CH.dbd.CH--CH.dbd.CH--,
--O--(CH.sub.2).sub.p--O-- wherein p is 1 or 2 and with the carbon
atoms to which said radicals are attached form a 5- or 6-membered,
saturated, partially saturated or completely unsaturated ring and,
in such instance, R7 is preferably methyl, ethyl, OMe, F, Cl, Br or
H.
5. The compound of claim 1 wherein: R1 is F and R2 is H; R1 is H
and R2 is F; or R1 is F and R2 is F R3 is OH; A is O; R4, R5, R6
are each independently hydrogen, OH, (C.sub.1-C.sub.4)-alkoxy,
CF.sub.3, (C.sub.1-C.sub.4)-alkyl, F, Cl, Br or I B is
--CH.sub.2--, --C.sub.2H.sub.4--, --C.sub.3H.sub.6--, --CH(OH)--,
--(C.dbd.O)--, --CO--NH--CH.sub.2--, --CO--CH.sub.2--CH.sub.2--,
--O-- or --NH--; n is 2 or 3; Cyc1 is an unsaturated 6-membered
ring, wherein one carbon atom of said 6-membered ring may be
replaced by N, or an unsaturated 5-membered ring, wherein one
carbon atom of said 5-membered ring may be replaced by S; R7, R8,
R9 are each independently hydrogen, OH, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.7)-alkoxy, OCF.sub.3 or halogen or R8 and R9 taken
together form the radicals --CH.dbd.CH--O--,
--CH.sub.2--CH.sub.2--O--, --CH.dbd.CH--CH.dbd.CH-- or
--O--(CH.sub.2).sub.p--O-- wherein p is 1 or 2, and, with the
carbon atoms to which they are attached, form a 5- or 6-membered
ring, and, in such instance, R7 is preferably methyl, ethyl,
methoxy, F, Cl, Br or hydrogen.
6. A compound of the formula Ia ##STR79## wherein R1 is F and R2 is
H; R1 is H and R2 is F; or R1 is F and R2 is F; R3 is OH; A is O;
R4 is hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy
or OH; R5 is hydrogen, F, methoxy or ethoxy; R6 is hydrogen or OH;
B is --CH.sub.2--, --CO--NH--CH.sub.2--; --O-- or
--CO--CH.sub.2--CH.sub.2--; Cyc1 is phenyl or thiophene; R7, R8, R9
are hydrogen, OH, Cl, OCF.sub.3, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy; or R8 and R9 taken together form
--CH.dbd.CH--O--, --CH.dbd.CH--CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--O-- and, with the carbon atoms to which they
are attached, form a 5- or 6-membered ring, and, in such instance,
R7 is preferably hydrogen.
7. A compound of the formula Ib ##STR80## wherein R1 is F and R2 is
H; R1 is H and R2 is F; or R1 is F and R2 is F; R3 is OH; A is O;
R4 is hydrogen, methyl, methoxy or OH; R5 is hydrogen, F or
methoxy; R6 is hydrogen or OH; B is --CH.sub.2--,
--CO--NH--CH.sub.2--, --O-- or CO--CH.sub.2--CH.sub.2--; Cyc1 is
phenyl; R7 is hydrogen; R8 is hydrogen, OH, ethyl, Cl, OCF.sub.3 or
methoxy; R9 is hydrogen; or R8 and R9 taken together form
--CH.dbd.CH--O-- or --CH.sub.2--CH.sub.2--O--, and, with the carbon
atoms to which they are attached form a 5-membered ring.
8. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising a compound of claim 1
and one or more blood glucose-lowering active ingredients.
10. A method of treating type 1 or type 2 diabetes which comprises
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
11. A method of lowering blood glucose which comprises
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
12. A method of treating type 1 or type 2 diabetes which comprises
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1 with at least one other
blood glucose-lowering active ingredient.
13. A method of lowering blood glucose which comprises
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1 with at least one other
blood glucose-lowering active ingredient.
Description
[0001] Novel aromatic fluoroglycoside derivatives, medicaments
containing these compounds, and the use thereof.
[0002] The invention relates to substituted aromatic
fluoroglycoside derivatives, their physiologically tolerated salts
and physiologically functional derivatives.
[0003] Several classes of substances having an SGLT effect have
already been disclosed in the literature. The model for all these
structures was the natural product phlorizin. From this were
derived the following classes which are described in the property
rights below: [0004] propiophenone glycosides of Tanabe (WO
0280936, WO 0280935, JP 2000080041 and EP 850948) [0005]
2-(glucopyranoslyoxy)benzylbenzenes of Kissei (WO 0244192, WO
0228872 and WO 0168660) [0006] glucopyranosyloxypyrazoles of Kissei
and Ajinomoto (WO 0268440, WO 0268439, WO 0236602 and WO 0116147)
[0007] O-glycoside benzamides of Bristol-Myers Squibb (WO 0174835
and WO 0174834) [0008] and C-aryl glycosides of Bristol-Myers
Squibb (WO 0127128 and US 2002137903).
[0009] All the known structures contain glucose as a very important
structural element.
[0010] Furthermore, diaryl sulfide compounds for the treatment of
inflammatory and immune diseases are known from US 2002/132807. EP
0 953 357 A1 describes in general glycoside compounds as renal drug
carriers and WO 95/23780 describes
4-hydroxyphenoxy-heterocycloalkyl compounds as skin lighteners.
[0011] The invention was based on the object of providing novel
compounds with which it is possible to prevent and treat type 1 and
type 2 diabetes. We have now surprisingly found that aromatic
fluoroglycoside derivatives increase the effect on SGLT. These
compounds are therefore particularly suitable for preventing and
treating type 1 and type 2 diabetes.
[0012] The invention therefore relates to compounds of the formula
I ##STR2## wherein: [0013] R1, R2 are each independently OH, F or H
with the proviso that [0014] when R1 F, R2 cannot be OH; [0015]
when R1 is OH, R2 cannot be F; and [0016] when R1 is OH, R2 cannot
be OH; [0017] R3 is OH or F with the proviso that at least one of
said R1, R2, R3 radicals must be F; [0018] A is O, NH, CH.sub.2, S
or a bond; [0019] R4, R5, R6 are each independently hydrogen, F,
Cl, Br, I, OH, NO.sub.2, CN, COOH, CO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alky].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.6)-alkoxy,
HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, phenyl or
benzyl, [0020] wherein said CO(C.sub.1-C.sub.6)-alkyl,
COO(C.sub.1-C.sub.6)-alkyl, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkoxy, HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.8)-alkyl radicals are
optionally substituted with one or more fluorine atoms, [0021]
SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.o-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.o-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.o-phenyl,
[0022] wherein the phenyl ring of said S--(CH.sub.2).sub.o-phenyl,
SO--(CH.sub.2).sub.o-phenyl and SO.sub.2--(CH.sub.2).sub.o-phenyl
radicals may be mono- or disubstituted with F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2 and wherein o is 0, 1, 2, 3, 4,
5 or 6, [0023] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
O--(CH.sub.2).sub.o-phenyl, [0024] wherein the phenyl ring of said
phenyl and O--(CH.sub.2).sub.o-phenyl radicals may be mono-, di-,
or trisubstituted with F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
NH.sub.2, NH(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, SO.sub.2--CH.sub.3, COOH,
COO--(C.sub.1-C.sub.6)-alkyl or CONH.sub.2 and wherein o is as
hereinabove defined; [0025] B is (C.sub.0-C.sub.15)-alkanediyl,
[0026] wherein one or more carbon atoms in said
(C.sub.0-C.sub.15)-alkanediyl radical are, independently of one
another, optionally replaced by --O--, --(C.dbd.O)--,
--CH.dbd.CH--, --C.ident.C--, --S--, --CH(OH)--, --CHF--,
--CF.sub.2--, --(S.dbd.O)--, --(SO.sub.2)--,
--N((C.sub.1-C.sub.6)-alkyl), --N((C.sub.1-C.sub.6)-alkyl-phenyl)-
or --NH--; [0027] n is 0, 1, 2, 3 or 4; [0028] Cyc1 is a 3-, 4-,
5-, 6-, or 7-membered saturated, partially saturated or unsaturated
ring, wherein one carbon atom of said ring may be replaced by O, N
or S; [0029] R7, R8, R9 R7, R8, and R9 are each independently
hydrogen, F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CO(C.sub.1-C.sub.4)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, [0030] wherein
said COO(C.sub.1-C.sub.6-alkyl, CO(C.sub.1-C.sub.4)-alkyl,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl and
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl radicals are
optionally substituted with one or more fluorine atoms, [0031]
SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.o-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.o-phenyl
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.o-phenyl, [0032] wherein said
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2--(C.sub.1-C.sub.6)-alkyl radicals are optionally
substituted with one or more fluorine atoms, and wherein the phenyl
ring of said S--(CH.sub.2).sub.o-phenyl,
SO--(CH.sub.2).sub.o-phenyl and SO.sub.2--(CH.sub.2).sub.o-phenyl
radicals is optionally mono- or disubstituted with F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2, and wherein o is as
hereinabove defined, [0033] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl
or O--(CH.sub.2).sub.o-phenyl, [0034] wherein the phenyl ring of
said phenyl and O--(CH.sub.2).sub.o-phenyl radicals is optionally
mono-, di-, or trisubstituted with F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, (C.sub.1-C.sub.8)-alkoxy,
(C.sub.1-C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, SO.sub.2--CH.sub.3, COOH,
COO--(C.sub.1-C.sub.6)-alkyl or CONH.sub.2, and wherein o is as
hereinabove defined; [0035] or R8 and R9 taken together with the
carbon atoms to which they are attached form a 5-, 6- or
7-membered, saturated, partially saturated or unsaturated ring
herein referred to as Cyc2, [0036] wherein one or two carbon
atom(s) in said Cyc2 ring is optionally replaced by N, O or S, and
wherein said Cyc2 ring is optionally substituted with
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl or
(C.sub.2-C.sub.5)-alkynyl, [0037] wherein said
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl and
(C.sub.2-C.sub.5)-alkynyl radicals are optionally substituted with
F, Cl, OH, CF.sub.3, NO.sub.2, CN, COO(C.sub.1-C.sub.4)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.4)-alkyl or OCF.sub.3, [0038] and
wherein a --CH.sub.2-- group contained in said
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl and
(C.sub.2-C.sub.5)-alkynyl radicals is optionally replaced by --O--;
and pharmaceutically acceptable salts thereof.
[0039] The linkage points of R4, R5, R6 and B to the phenyl ring
can be freely selected. All resulting compounds of the formula I
belong to the present invention. Compounds of the formula I in
which the B substituent on the phenyl ring is disposed in the
position ortho (neighboring position) to the A substituent are
preferred.
[0040] Preferred compounds of the formula I are those wherein:
[0041] R1 and R2 are each independently OH, F or H with the proviso
that at least one of said radicals R1 and R2 must be F and with the
further proviso that [0042] when R1 is F, R2 is not OH, [0043] when
R1 is OH, R2 is not F, and [0044] when R1 is OH, R2 is not OH;
[0045] R3 is OH; [0046] A is O or NH; [0047] R4, R5, R6 are each
independently hydrogen, F, Cl, Br, I, OH, NO.sub.2, CN, COOH,
CO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.6)-alkoxy,
HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, phenyl, benzyl
or SO--(C1-C6)-alkyl, [0048] wherein said
CO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.1-C.sub.6)-alkyl,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.6)-alkoxy,
HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl and
SO--(C1-C6)-alkyl radicals are optionally substituted with one or
more fluorine atoms, [0049] B is (C.sub.0-C.sub.15)-alkanediyl,
wherein one or more of the carbon atoms in said alkanediyl radical
may be replaced, independently of one another, with --O--,
--(C.dbd.O)--, --CH.dbd.CH--, --C.ident.C--, --S--, --CH(OH)--,
--CHF--, --CF.sub.2--, --(S.dbd.O)--, --(SO.sub.2),
--N((C.sub.1-C.sub.6)-alkyl)-, --N((C.sub.1-C.sub.6)-alkyl-phenyl)-
or --NH--; [0050] n is 0, 1, 2, 3 or 4; [0051] Cyc1 is a 3-, 4-,
5-, 6- or 7-membered saturated, partially saturated or unsaturated
ring, wherein one carbon atom of said ring may be replaced by O, N
or S; [0052] R7, R8, and R9 are each independently hydrogen, F, Cl,
Br, I, OH, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CO(C.sub.1-C.sub.4)-alkyl, CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl and
SO--(C.sub.1-C.sub.6)-alkyl, [0053] wherein said
COO(C.sub.1-C.sub.6)-alkyl, CO(C.sub.1-C.sub.4)-alkyl,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl and
SO--(C.sub.1-C.sub.6)-alkyl radicals are optionally substituted
with one or more fluorine atoms, [0054] or R8 and R9 taken together
with the carbon atoms to which they are attached form a 5-, 6- or
7-membered, saturated, partially saturated or unsaturated ring
herein referred to as Cyc2, [0055] wherein one or two carbon
atom(s) in said Cyc2 ring are optionally replaced by N, O or S, and
wherein said Cyc2 ring is optionally substituted with
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl or
(C.sub.2-C.sub.5)-alkynyl, [0056] wherein said
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.5)-alkenyl and
(C.sub.2-C.sub.5)-alkynyl radicals are optionally substituted with
F, Cl, OH, CF.sub.3, NO.sub.2, CN, COO(C.sub.1-C.sub.4)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.4)-alkyl or OCF.sub.3, [0057] and
wherein a --CH2- group contained in said (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.5)-alkenyl and (C.sub.2-C.sub.5)-alkynyl radicals is
optionally replaced by --O--.
[0058] Further preferred compounds of the formula I are those in
which the sugar residues are beta(s)-linked and the stereochemistry
in the 2, 3 and 5 position of the sugar residue has the D-gluco
configuration.
[0059] Particularly preferred compounds of formula I are those
wherein: [0060] R1 and R2 are each independently OH, F or H with
the proviso that at least one of said radicals R1 and R2 must be F
and with the further proviso that [0061] when R1 is F, R2 is not
OH, [0062] when R1 is OH, R2 is not F, and [0063] when R1 is OH, R2
is not OH, [0064] R3 is OH; [0065] A is O; [0066] R4, R5, R6 are
each independently hydrogen, F, Cl, Br, I, OH, NO.sub.2, CN, COOH,
CF3, OCF3, OCH2CF.sub.3, (C1-C4)-alkyl-CF2-,
COO(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkoxy, HO(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, phenyl or
benzyl, [0067] B is (C.sub.1-C.sub.4)-alkanediyl, wherein one or
more of the carbon atoms in said alkanediyl radical may be
replaced, independently of one another, with --O--, --(C.dbd.O)--,
--CH(OH)--, --CHF--, --CF.sub.2--,
--CO--N(C.sub.1-C.sub.6)-alkyl)-, --CO--NH-- or --NH--; [0068] n is
2 or 3; Cyc1 is an unsaturated 5- or 6-membered ring, wherein one
carbon atom of said ring may be replaced by O, N or S; [0069] R7,
R8, and R9 are each independently hydrogen, F, Cl, Br, OH,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.8)-alkoxy,
HO--(C.sub.1-C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl-O--(C.sub.1-C.sub.6)-alkyl, [0070] or R8
and R9 taken together form the radicals --CH.dbd.CH--O--,
--CH2-CH2-O--, --CH.dbd.CH--S--, --CH.dbd.CH--CH.dbd.CH--,
--O--(CH.sub.2).sub.p--O-- wherein p is 1 or 2 and with the carbon
atoms to which said radicals are attached form a 5- or 6-membered,
saturated, partially saturated or completely unsaturated ring and,
in such instance, R7 is preferably methyl, ethyl, OMe, F, Cl, Br or
H.
[0071] Very particularly preferred compounds of the formula I are
those wherein: [0072] R1 is F and R2 is H; [0073] R1 is H and R2 is
F; or [0074] R1 is F and R2 is F [0075] R3 is OH; [0076] A is O;
[0077] R4, R5, R6 are each independently hydrogen, OH,
(C.sub.1-C.sub.4)-alkoxy, CF.sub.3, (C.sub.1-C.sub.4)-alkyl, F, Cl,
Br or I [0078] B is --CH.sub.2--, --C.sub.2H.sub.4--,
--C.sub.3H.sub.6--, --CH(OH)--, --(C.dbd.O)--,
--CO--NH--CH.sub.2--, --CO--CH.sub.2--CH.sub.2--, --O-- or --NH--;
[0079] n is 2 or 3; [0080] Cyc1 is an unsaturated 6-membered ring,
wherein one carbon atom of said 6-membered ring may be replaced by
N, or an unsaturated 5-membered ring, wherein one carbon atom of
said 5-membered ring may be replaced by S; [0081] R7, R8, R9 are
each independently hydrogen, OH, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.7)-alkoxy, OCF.sub.3 or halogen or [0082] R8 and R9
taken together form the radicals --CH.dbd.CH--O--,
--CH.sub.2--CH.sub.2--O--, --CH.dbd.CH--CH.dbd.CH-- or
--O--(CH.sub.2).sub.p--O-- wherein p is 1 or 2, and, with the
carbon atoms to which they are attached, form a 5- or 6-membered
ring, and, in such instance, R7 is preferably methyl, ethyl,
methoxy, F, Cl, Br or hydrogen.
[0083] Further very particularly preferred are compounds of the
formula Ia ##STR3## wherein [0084] R1 is F and R2 is H; [0085] R1
is H and R2 is F; or [0086] R1 is F and R2 is F; [0087] R3 is OH;
[0088] A is O; [0089] R4 is hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy or OH; [0090] R5 is hydrogen, F, methoxy
or ethoxy; [0091] R6 is hydrogen or OH; [0092] B is --CH.sub.2--,
--CO--NH--CH.sub.2--; --O-- or --CO--CH.sub.2--CH.sub.2--; [0093]
Cyc1 is phenyl or thiophene; [0094] R7, R8, R9 are hydrogen, OH,
Cl, OCF.sub.3, (C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-alkoxy;
or R8 and R9 taken together form --CH.dbd.CH--O--,
--CH.dbd.CH--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--O-- and, with the
carbon atoms to which they are attached, form a 5- or 6-membered
ring, and, in such instance, R7 is preferably hydrogen.
[0095] Compounds of particularly preferred importance are also
those of the formula Ib ##STR4## wherein R1 is F and R2 is H; R1 is
H and R2 is F; or R1 is F and R2 is F; R3 is OH; A is O; R4 is
hydrogen, methyl, methoxy or OH; R5 is hydrogen, F or methoxy; R6
is hydrogen or OH; B is --CH.sub.2--, --CO--NH--CH.sub.2--, --O--
or --CO--CH.sub.2--CH.sub.2--; Cyc1 is phenyl; R7 is hydrogen; R8
is hydrogen, OH, ethyl, Cl, OCF.sub.3 or methoxy; R9 is hydrogen;
or [0096] R8 and R9 taken together form --CH.dbd.CH--O-- or
--CH.sub.2--CH.sub.2--O--, and, with the carbon atoms to which they
are attached form a 5-membered ring.
[0097] Additional very particularly preferred compounds of the
formula I are those in which R1 is H and R2 is F.
[0098] The invention relates to compounds of the formula I in the
form of their racemates, racemic mixtures and pure enantiomers and
to their diastereomers and mixtures thereof.
[0099] The alkyl radicals in the substituents R4, R5, R6, R7, R8
and R9 may be either straight-chain or branched. Halogen means F,
Cl, Br or I, preferably F or Cl.
[0100] "Patient" means a warm blooded animal, such as for example
rat, mice, dogs, cats, guinea pigs, and primates such as
humans.
[0101] "Treat" or "treating" means to alleviate symptoms, eliminate
the causation of the symptoms either on a temporary or permanent
basis, or to prevent or slow the appearance of symptoms of the
named disorder or condition.
[0102] "Therapeutically effective amount" means a quantity of the
compound which is effective in treating the named disorder or
condition.
[0103] "Pharmaceutically acceptable carrier" is a non-toxic
solvent, dispersant, excipient, adjuvant or other material which is
mixed with the active ingredient in order to permit the formation
of a pharmaceutical composition, i.e., a dosage form capable of
administration to the patient. One example of such a carrier is a
pharmaceutically acceptable oil typically used for parenteral
administration.
[0104] Pharmaceutically acceptable salts are, because their
solubility in water is greater than that of the initial or basic
compounds, particularly suitable for medical applications. These
salts must have a pharmaceutically acceptable anion or cation.
Suitable pharmaceutically acceptable acid addition salts of the
compounds of the invention are salts of inorganic acids such as
hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric
and sulfuric acid, and of organic acids such as, for example,
acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic,
fumaric, gluconic, glycolic, isethionic, lactic, lactobionic,
maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and
tartaric acid. Suitable pharmaceutically acceptable basic salts are
ammonium salts, alkali metal salts (such as sodium and potassium
salts), alkaline earth metal salts (such as magnesium and calcium
salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),
diethanolamine, lysine or ethylenediamine.
[0105] Salts with a pharmaceutically unacceptable anion such as,
for example, trifluoroacetate likewise belong within the framework
of the invention as useful intermediates for the preparation or
purification of pharmaceutically acceptable salts and/or for use in
nontherapeutic, for example in vitro, applications.
[0106] The term "physiologically functional derivative" used herein
refers to any physiologically tolerated derivative of a compound of
the formula I of the invention, for example an ester, which on
administration to a mammal such as, for example, a human is able to
form (directly or indirectly) a compound of the formula I or an
active metabolite thereof.
[0107] Physiologically functional derivatives include prodrugs of
the compounds of the invention, as described, for example, in H.
Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can
be metabolized in vivo to a compound of the invention. These
prodrugs may themselves be active or not. Carbonates at the 6
position of the sugar (see WO 0280936 and WO 0244192) are
preferred, particularly preferably methyl carbonate and ethyl
carbonate.
[0108] The compounds of the invention may also exist in various
polymorphous forms, for example as amorphous and crystalline
polymorphous forms. All polymorphous forms of the compounds of the
invention belong within the framework of the invention and are a
further aspect of the invention.
[0109] All references to "compound(s) of formula I" hereinafter
refer to compound(s) of the formula I as described above, and their
salts, solvates and physiologically functional derivatives as
described herein.
[0110] The compound(s) of formula (I) may also be administered in
combination with other active ingredients.
[0111] The amount of a compound of formula I necessary to achieve
the desired biological effect depends on a number of factors, for
example the specific compound chosen, the intended use, the mode of
administration and the clinical condition of the patient. The daily
dose is generally in the range from 0.3 mg to 100 mg (typically
from 3 mg and 50 mg) per day and per kilogram of bodyweight, for
example 3-10 mg/kg/day. An intravenous dose may be, for example, in
the range from 0.3 mg to 1.0 mg/kg, which can suitably be
administered as infusion of 10 ng to 100 ng per kilogram and per
minute. Suitable infusion solutions for these purposes may contain,
for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg,
per milliliter. Single doses may contain, for example, from 1 mg to
10 g of the active ingredient. Thus, ampoules for injections may
contain, for example, from 1 mg to 100 mg, and single-dose
formulations which can be administered orally, such as, for
example, tablets or capsules, may contain, for example, from 1.0 to
1000 mg, typically from 10 to 600 mg. For the therapy of the
abovementioned conditions, the compounds of formula I may be used
as the compound itself, but they are preferably in the form of a
pharmaceutical composition with an acceptable carrier. The carrier
must, of course, be acceptable in the sense that it is compatible
with the other ingredients of the composition and is not harmful
for the patient's health. The carrier may be a solid or a liquid or
both and is preferably formulated with the compound as a single
dose, for example as a tablet, which may contain from 0.05% to 95%
by weight of the active ingredient. Other pharmaceutically active
substances may likewise be present, including other compounds of
formula I. The pharmaceutical compositions of the invention can be
produced by one of the known pharmaceutical methods, which
essentially consist of mixing the ingredients with
pharmacologically acceptable carriers and/or excipients.
[0112] Pharmaceutical compositions of the invention are those
suitable for oral, rectal, topical, peroral (for example
sublingual) and parenteral (for example subcutaneous,
intramuscular, intradermal or intravenous) administration, although
the most suitable mode of administration depends in each individual
case on the nature and severity of the condition to be treated and
on the nature of the compound of formula I used in each case.
Coated formulations and coated slow-release formulations also
belong within the framework of the invention. Preference is given
to acid- and gastric juice-resistant formulations. Suitable
coatings resistant to gastric juice comprise cellulose acetate
phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of
methacrylic acid and methyl methacrylate.
[0113] Suitable pharmaceutical compounds for oral administration
may be in the form of separate units such as, for example,
capsules, cachets, suckable tablets or tablets, each of which
contain a defined amount of the compound of formula I; as powders
or granules; as solution or suspension in an aqueous or nonaqueous
liquid; or as an oil-in-water or water-in-oil emulsion. These
compositions may, as already mentioned, be prepared by any suitable
pharmaceutical method which includes a step in which the active
ingredient and the carrier (which may consist of one or more
additional ingredients) are brought into contact. The compositions
are generally produced by uniform and homogeneous mixing of the
active ingredient with a liquid and/or finely divided solid
carrier, after which the product is shaped if necessary. Thus, for
example, a tablet can be produced by compressing or molding a
powder or granules of the compound, where appropriate with one or
more additional ingredients. Compressed tablets can be produced by
tableting the compound in free-flowing form such as, for example, a
powder or granules, where appropriate mixed with a binder, glidant,
inert diluent and/or one (or more) surface-active/dispersing
agent(s) in a suitable machine. Molded tablets can be produced by
molding the compound, which is in powder form and is moistened with
an inert liquid diluent, in a suitable machine. Pharmaceutical
compositions which are suitable for peroral (sublingual)
administration comprise suckable tablets which contain a compound
of formula I with a flavoring, normally sucrose and gum arabic or
tragacanth, and pastilles which comprise the compound in an inert
base such as gelatin and glycerol or sucrose and gum arabic.
[0114] Pharmaceutical compositions suitable for parenteral
administration comprise preferably sterile aqueous preparations of
a compound of formula I, which are preferably isotonic with the
blood of the intended recipient. These preparations are preferably
administered intravenously, although administration may also take
place by subcutaneous, intramuscular or intradermal injection.
These preparations can preferably be produced by mixing the
compound with water and making the resulting solution sterile and
isotonic with blood. Injectable compositions of the invention
generally contain from 0.1 to 5% by weight of the active
compound.
[0115] Pharmaceutical compositions suitable for rectal
administration are preferably in the form of single-dose
suppositories. These can be produced by mixing a compound of the
formula I with one or more conventional solid carriers, for example
cocoa butter, and shaping the resulting mixture.
[0116] Pharmaceutical compositions suitable for topical use on the
skin are preferably in the form of ointment, cream, lotion, paste,
spray; aerosol or oil. Carriers which can be used are petrolatum,
lanolin, polyethylene glycols, alcohols and combinations of two or
more of these substances. The active ingredient is generally
present in a concentration of from 0.1 to 15% by weight of the
composition, for example from 0.5 to 2%.
[0117] Transdermal administration is also possible. Pharmaceutical
compositions suitable for transdermal uses can be in the form of
single plasters which are suitable for long-term close contact with
the patient's epidermis. Such plasters suitably contain the active
ingredient in an aqueous solution which is buffered where
appropriate, dissolved and/or dispersed in an adhesive or dispersed
in a polymer. A suitable active ingredient concentration is about
1% to 35%, preferably about 3% to 15%. A particular possibility is
for the active ingredient to be released by electrotransport or
iontophoresis as described, for example, in Pharmaceutical
Research, 2(6): 318 (1986).
[0118] The invention additionally relates to processes for
preparing the compounds of the formula I, which can be obtained in
accordance with the following reaction schemes of processes A to F.
Process A: ##STR5## Process B: ##STR6## Process C: ##STR7## Process
D: ##STR8## Process E: ##STR9## Process F: ##STR10##
[0119] The schemes depicted for processes A-F are self-explanatory
and can be carried out thus by the skilled worker. More details
are, nevertheless, indicated in the experimental part. The
compounds of examples 1 to 24 were obtained by processes A-F. Other
compounds of the formula I can be obtained correspondingly or by
known processes.
[0120] The compound(s) of the formula I can also be administered in
combination with other active ingredients.
[0121] Further active ingredients suitable for combination products
are:
[0122] all antidiabetics mentioned in the Rote Liste 2001, chapter
12. They may be combined with the compounds of the formula I of the
invention in particular for synergistic improvement of the effect.
Administration of the active ingredient combination may take place
either by separate administration of the active ingredients to the
patient or in the form of combination products in which a plurality
of active ingredients are present in one pharmaceutical
preparation. Most of the active ingredients listed below are
disclosed in the USP Dictionary of USAN and International Drug
Names, US Pharmacopeia, Rockville 2001.
[0123] Antidiabetics include insulin and insulin derivatives such
as, for example, Lantus.RTM. (see www.lantus.com) or HMR 1964,
fast-acting insulins (see U.S. Pat. No. 6,221,633), GLP-1
derivatives such as, for example, those disclosed in WO 98/08871 of
Novo Nordisk A/S, and orally effective hypoglycemic active
ingredients.
[0124] The orally effective hypoglycemic active ingredients
include, preferably, sulfonylureas, biguanides, meglitinides,
oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,
glucagon antagonists, GLP-1 agonists, potassium channel openers
such as, for example, those disclosed in WO 97/26265 and WO
99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of
liver enzymes involved in the stimulation of gluconeogenesis and/or
glycogenolysis, modulators of glucose uptake, compounds which alter
lipid metabolism, such as antihyperlipidemic active ingredients and
antilipidemic active ingredients, compounds which reduce food
intake, PPAR and PXR agonists and active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
[0125] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an HMGCoA reductase
inhibitor such as simvastatin, fluvastatin, pravastatin,
lovastatin, atorvastatin, cerivastatin, rosuvastatin.
[0126] In one embodiment of the invention, the compounds of the
formula I are administered combination with a cholesterol
absorption inhibitor such as, for example, ezetimibe, tiqueside,
pamaqueside.
[0127] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a PPAR gamma
agonist, such as, for example, rosiglitazone, pioglitazone,
JTT-501, GI 262570.
[0128] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a PPAR alpha
agonist, such as, for example, GW 9578, GW 7647.
[0129] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a mixed PPAR
alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE
8134, AVE 0847, AVE 0897 or as described in WO 00/64888, WO
00/64876, WO 03/20269.
[0130] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a fibrate such as,
for example, fenofibrate, clofibrate, bezafibrate.
[0131] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an MTP inhibitor
such as, for example, implitapide, BMS-201038, R-103757.
[0132] In one embodiment of the invention, the compounds of the
formula I are administered in combination with bile acid absorption
inhibitor (see, for example, U.S. Pat. No. 6,245,744 or U.S. Pat.
No. 6,221,897), such as, for example, HMR 1741.
[0133] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a CETP inhibitor,
such as, for example, JTT-705.
[0134] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a polymeric bile
acid adsorbent such as, for example, cholestyramine,
colesevelam.
[0135] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an LDL receptor
inducer (see U.S. Pat. No. 6,342,512), such as, for example,
HMR1171, HMR1586.
[0136] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an ACAT inhibitor,
such as, for example, avasimibe.
[0137] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an antioxidant, such
as, for example, OPC-14117.
[0138] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a lipoprotein lipase
inhibitor, such as, for example, NO-1886.
[0139] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an ATP-citrate lyase
inhibitor, such as, for example, SB-204990.
[0140] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a squalene
synthetase inhibitor, such as, for example, BMS-188494.
[0141] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a lipoprotein(a)
antagonist, such as, for example, Cl-1027 or nicotinic acid.
[0142] In one embodiment of the invention, the compounds of the
formula I are administered in combination with a lipase inhibitor,
such as, for example, orlistat.
[0143] In one embodiment of the invention, the compounds of the
formula I are administered in combination with insulin.
[0144] In one embodiment, the compounds of the formula I are
administered in combination with a sulfonylurea such as, for
example, tolbutamide, glibenclamide, glipizide or glimepiride.
[0145] In one embodiment, the compounds of the formula I are
administered in combination with a biguanide, such as, for example,
metformin.
[0146] In one further embodiment, the compounds of the formula I
are administered in combination with a meglitinide, such as, for
example, repaglinide.
[0147] In one embodiment, the compounds of the formula I are
administered in combination with a thiazolidinedione, such as, for
example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or
the compounds disclosed in WO 97/41097 of Dr. Reddy's Research
Foundation, in particular
5-[[(4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]--
2,4-thiazolidinedione.
[0148] In one embodiment, the compounds of the formula I are
administered in combination with an .alpha.-glucosidase inhibitor,
such as, for example, miglitol or acarbose.
[0149] In one embodiment, the compounds of the formula I are
administered in combination with an active ingredient which acts on
the ATP-dependent potassium channel of the beta cells, such as, for
example, tolbutamide, glibenclamide, glipizide, glimepiride or
repaglinide.
[0150] In one embodiment, the compounds of the formula I are
administered in combination with more than one of the
aforementioned compounds, e.g. in combination with a sulfonylurea
and metformin, with a sulfonylurea and acarbose, repaglinide and
metformin, insulin and a sulfonylurea, insulin and metformin,
insulin and troglitazone, insulin and lovastatin, etc.
[0151] In a further embodiment, the compounds of the formula I are
administered in combination with CART modulators (see
"Cocaine-amphetamine-regulated transcript influences energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A, et
al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558),
NPY antagonists, e.g. naphthalene-1-sulfonic acid
{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}amide;
hydrochloride (CGP 71683A)), MC4 agonists (e.g.
1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-
-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin
antagonists (e.g.
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea:
hydrochloride (SB-334867-A)), H3 agonists
(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-y-
l)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF
antagonists (e.g.
[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropyla-
mine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin
agonists, .beta.3 agonists (e.g.
1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6--
yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH
(melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g.
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexyl-ethyl)thiazol-2-ylca-
rbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid
salt (WO 99/15525)), serotonin reuptake inhibitors (e.g.
dexfenfluramine), mixed serotoninergic and noradrenergic compounds
(e.g. WO 00/71549), 5HT agonists e.g.
1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO
01/09111), bombesin agonists, galanin antagonists, growth hormone
(e.g. human growth hormone), growth hormone-releasing compounds
(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquino-
line-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH
agonists (see, for example, EP 0 462 884) uncoupling protein 2 or 3
modulators, leptin agonists (see, for example, Lee, Daniel W.;
Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia.
Leptin agonists as a potential is approach to the treatment of
obesity. Drugs of the Future (2001), 26(9), 873-81), DA agonists
(bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO
00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or
TR-.beta. agonists.
[0152] In one embodiment of the invention, the other active
ingredient is leptin; see, for example, "Perspectives in the
therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
Javier, Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001),
2(10), 1615-1622.
[0153] In one embodiment, the other active ingredient is
dexamphetamine or amphetamine.
[0154] In one embodiment, the other active ingredient is
fenfluramine or dexfenfluramine.
[0155] In another embodiment, the other active ingredient is
sibutramine.
[0156] In one embodiment, the other active ingredient is
orlistat.
[0157] In one embodiment, the other active ingredient is mazindol
or phentermine.
[0158] In one embodiment, the compounds of the formula I are
administered in combination with bulking agents, preferably
insoluble bulking agents (see, for example, carob/Caromax.RTM.
(Zunft H J; et al., Carob pulp preparation for treatment of
hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October),
18(5), 230-6.) Caromax is a carob-containing product from
Nutrinova, Nutrition Specialties & Food Ingredients GmbH,
Industriepark Hochst, 65926 Frankfurt/Main)). Combination with
Caromax.RTM. is possible in one preparation or by separate
administration of compounds of the formula I and Caromax.RTM..
Caromax.RTM. can in this connection also be administered in the
form of food products such as, for example, in bakery products or
muesli bars.
[0159] It will be appreciated that every suitable combination of
the compounds of the invention with one or more of the
aforementioned compounds and optionally one or more other
pharmacologically active substances is regarded as falling within
the protection conferred by the present invention.
[0160] The citation of any reference herein should not be construed
as an admission that such reference is available as "Prior Art" to
the instant application.
[0161] Various publications are cited herein, the disclosures of
which are incorporated by reference in their entireties. ##STR11##
##STR12##
[0162] The examples detailed below serve to illustrate the
invention without, however, restricting it. TABLE-US-00001 TABLE 1
Compounds of the formula Ib Ib ##STR13## Ex. R1 R2 R3 R4, R5, R6 R7
R8, R9 A B Cyc1 Cyc2 MS* 1 H F OH H, H, H H O--CH.sub.3, H O
CH.sub.2 Phenyl Ok 2 H F OH H, H, H H H, H O CH.sub.2 Phenyl Ok 3 F
H OH H, H, H H O--CH.sub.3, H O CH.sub.2 Phenyl Ok 4 H F OH
CH.sub.3, H, OH H --CH.dbd.CH--O-- O CO--CH.sub.2--CH.sub.2 Phenyl
Furenyl Ok 5 F H OH CH.sub.3, H, OH H --CH.dbd.CH--O-- O
CO--CH.sub.2--CH.sub.2 Phenyl Furenyl Ok 6 F H OH CH.sub.3, H, OH H
--CH.sub.2--CH.sub.2--O-- O CO--CH.sub.2--CH.sub.2 Phenyl Furanyl
Ok 7 H F OH CH.sub.3, H, OH H O--CH.sub.3, H O
CO--CH.sub.2--CH.sub.2 Phenyl Ok 8 H F OH CH.sub.3, H, OH H OH, H O
CO--CH.sub.2--CH.sub.2 Phenyl Ok 9 H F OH OH, H, OH H OH, H O
CO--CH.sub.2--CH.sub.2 Phenyl Ok 10 F H OH OH, H, OH H OH, H O
CO--CH.sub.2--CH.sub.2 Phenyl Ok 11 H F OH H, H, OH H H, H O
CO--NH--CH.sub.2 Phenyl Ok 12 F H OH H, H, OH H O--CH.sub.3, H O
CO--NH--CH.sub.2 Phenyl Ok 13 H F OH CH.sub.3, H, OH H O--CH.sub.3,
H O CO--NH--CH.sub.2 Phenyl Ok 14 F H OH CH.sub.3, H, OH H
O--CH.sub.3, H O CO--NH--CH.sub.2 Phenyl Ok 15 H F OH CH.sub.3, H,
OH H CH.sub.2CH.sub.3, H O CO--CH.sub.2--CH.sub.2 Phenyl Ok 16 H F
OH CH.sub.3, H, OH H CH.sub.3, H O CO--CH.sub.2--CH.sub.2 Phenyl Ok
17 H F OH CH.sub.3, H, OH H OCF.sub.3, H O CO--CH.sub.2--CH.sub.2
Phenyl Ok 18 H F OH CH.sub.3, H, OH H Cl, H O
CO--CH.sub.2--CH.sub.2 Phenyl Ok 19 F F OH H, H, H H H, H O
CH.sub.2 Phenyl Ok 20 H F OH H, H, H H CH.sub.2CH.sub.3, H O
CH.sub.2 Phenyl Ok 21 H F OH OCH.sub.3, H, H H O--CH.sub.3, H O
CH.sub.2 Phenyl Ok 22 H F OH H, F, H H O--CH.sub.3, H O CH.sub.2
Phenyl Ok 23 H F OH H, OCH.sub.3, H H CH.sub.2CH.sub.3, H O
CH.sub.2 Phenyl Ok 24 H F OH H, H, H H CH.sub.2CH.sub.3, H O O
Phenyl Ok *The indication "MS is ok" means that a mass spectrum or
HPLC/MS was recorded and the molecular peak (MH.sup.+) and/or M +
18 (MNH.sub.4.sup.+) and/or M + 23 (MNa.sup.+) was detected
therein
[0163] The compounds of the formula I are distinguished by
beneficial effects on glucose metabolism; in particular, they lower
the blood glucose level and are suitable for the treatment of type
1 and type 2 diabetes. The compounds can therefore be employed
alone or in combination with other blood glucose-lowering active
ingredients (antidiabetics).
[0164] The compounds of the formula I are further suitable for the
prevention and treatment of late damage from diabetes, such as, for
example, nephropathy, retinopathy, neuropathy and syndrome X,
obesity, myocardial infarct, myocardial infarction, peripheral
arterial occlusive diseases, thromboses, arteriosclerosis,
inflammations, immune diseases, autoimmune diseases such as, for
example, AIDS, asthma, osteoporosis, cancer, psoriasis,
Alzheimer's, schizophrenia and infectious diseases, with preference
for the treatment of type 1 and type 2 diabetes and the prevention
and treatment of late damage from diabetes, syndrome X and
obesity.
[0165] The activity of the compounds was tested as follows:
[0166] Preparation of brush border membrane vesicles from the small
intestine of rabbits, rats and pigs
[0167] Preparation of Brush Border Membrane Vesicles from the
Intestinal Cells of the Small intestine was carried out by the
so-called Mg.sup.2+ precipitation method. The mucosa of the small
intestine was scraped off and suspended in 60 ml of ice-cold
Tris/HCl buffer (ph 7.1)/300 mM mannitol, 5 mM EGTA. Dilution to
300 ml with ice-cold distilled water was followed by homogenization
with an Ultraturrax (18 shaft, IKA Werk Staufen, FRG) at 75% of the
max. power for 2.times.1 minute, while cooling in ice. After
addition of 3 ml of 1M MgCl.sub.2 solution (final concentration 10
mM), the mixture is left to stand at 0.degree. C. for exactly 15
minutes. Addition of Mg.sup.2+ causes the cell membranes to
aggregate and precipitate with the exception of the brush border
membranes. After centrifugation at 3000.times.g (5 000 rpm, SS-34
rotor) for 15 minutes, the precipitate is discarded and the
supernatant, which contains the brush border membranes, is
centrifuged at 26 700.times.g (15 000 rpm, SS-34 rotor) for 30
minutes. The supernatant is discarded, and the precipitate is
rehomogenized in 60 ml of 12 mM Tris/HCl buffer (ph 7.1)/60 mM
mannitol, 5 mM EGTA using a Potter Elvejhem homogenizer (Braun,
Melsungen, 900 rpm, 10 strokes). Addition of 0.1 ml of 1M
MgCl.sub.2 solution and incubation at 0.degree. C. for 15 minutes
is followed by centrifugation again at 3 000.times.g for 15
minutes. The supernatant is then centrifuged again at 46
000.times.g (20 000 rpm, SS-34 rotor) for 30 minutes. The
precipitate is taken up in 30 ml of 20 mM Tris/Hepes buffer (pH
7.4)/280 mM mannitol and homogeneously resuspended by 20 strokes in
a Potter Elveihem homogenizer at 1 000 rpm. After centrifugation at
48 000.times.g (20 000 rpm, SS-34 rotor) for 30 minutes, the
precipitate was taken up in 0.5 to 2 ml of Tris/Hepes buffer (pH
7.4)/280 mM mannitol (final concentration 20 mg/ml) and resuspended
using a tuberculin syringe with a 27 gauge needle. The vesicles
were either used directly after preparation for labeling or
transport studies or were stored at -196.degree. C. in 4 mg
portions in liquid nitrogen. To prepare brush border membrane
vesicles from rat small intestine, 6 to 10 male is Wistar rats
(bred at Kastengrund, Aventis Pharma) were sacrificed by cervical
dislocation, and the small intestines were removed and rinsed with
cold isotonic saline. The intestines were cut up and the mucosa was
scraped off. The processing to isolate brush border membranes took
place as described above. To remove cytoskeletal fractions, the
brush border membrane vesicles from rat small intestine were
treated with KSCN as chaotropic ion.
[0168] To prepare brush border membranes from rabbit small
intestine, rabbits were sacrificed by intravenous injection of 0.5
ml of an aqueous solution of 2.5 mg of tetracaine HCl, 100 mg of
m-butramide and 25 mg of mebezonium iodide. The small intestines
were removed, rinsed with ice-cold physiological saline and stored
frozen in plastic bags under nitrogen at -80.degree. C. and 4 to 12
weeks. For preparation of the membrane vesicles, the frozen
intestines were thawed at 30.degree. C. in a water bath and then
the mucosa was scraped off. Processing to give membrane vesicles
took place as described above.
[0169] To prepare brush border membrane vesicles from pig
intestine, jejunum segments from a freshly slaughtered pig were
rinsed with ice-cold isotonic saline and frozen in plastic bags
under nitrogen at -80.degree. C. Preparation of the membrane
vesicles took place as described above.
[0170] Preparation of Brush Border Membrane Vesicles from the Renal
Cortex of the Rat kidney
[0171] Brush border membrane vesicles were prepared from the cortex
of the rat kidney by the method of Biber et al. The kidneys from 6
to 8 rats (200 to 250 g) were removed and the cortex was cut off
each kidney as a layer about 1 mm thick. The kidneys were taken up
in 30 ml of ice-cold 12 mM Tris/HCl buffer (pH 7.4)/300 mM mannitol
and homogenized with an Ultraturrax shaft (level 180 V) for
4.times.30 seconds while cooling in ice. Addition of 42 ml of
ice-cold distilled water was followed by addition of 850 .mu.l of a
1M MgCl.sub.2 solution. Incubation at 0.degree. C. for 15 minutes
was followed by centrifugation at 4 500 rpm (Sorvall SS-34 rotor)
for 15 minutes. The precipitate was discarded, and the supernatant
was centrifuged at 16 000 rpm for 30 minutes. Resuspension of the
precipitate in 60 ml of 6 mM Tris/HCl buffer (pH 7.4)/150 mM
mannitol/2.5 mM EGTA by 10 strokes in a Potter-Elvejhem homogenizer
(900 rpm) and addition of 720 .mu.l of 1 mM MgCl.sub.2 solution was
followed by incubation at 0.degree. C. for 15 minutes. The
supernatant resulting after centrifugation at 4 500 rpm (SS-34
rotor) for 15 minutes was centrifuged at 16 000 rpm for 30 minutes.
The supernatant was homogenized by 10 strokes in 60 ml of 20 mM
Tris/Hepes buffer (pH 7.4)/280 mM mannitol, and the resulting
suspension was then centrifuged at 20 000 rpm for 30 minutes. The
precipitate was resuspended in 20 mM Tris/HCl buffer (pH 7.4)/280
mM mannitol using a tuberculin syringe with a 27 gauge needle and
was adjusted to a protein concentration of 20 mg/ml.
[0172] Measurement of the glucose uptake by brush border membrane
vesicles
[0173] The uptake of [.sup.14C]-labeled glucose into brush border
membrane vesicles was measured by the membrane filtration method.
10 .mu.l of the brush border membrane vesicle suspension in 10 mM
Tris/Hepes buffer (pH 7.4)/300 mM mannitol were added at 30.degree.
C. to 90 .mu.l of a solution of 10 mM [.sup.14C]D-glucose and the
appropriate concentrations of the relevant inhibitors (5-200 .mu.M)
in 10 mM Tris/Hepes buffer (pH 7.4)/100 mM NaCl/100 mM
mannitol.
[0174] After incubation for 15 seconds, the transport process was
stopped by adding 1 ml of ice-cold stop solution (10 mM Tris/Hepes
buffer (pH 7.4)/150 mM KCl) and the vesicle suspension was
immediately filtered with suction through a cellulose nitrate
membrane filter (0.45 .mu.m, 25 mm diameter, Schleicher &
Schull) under a vacuum of from 25 to 35 mbar. The filter was washed
with 5 ml of ice-cold stop solution. Each measurement was carried
out as duplicate or triplicate determination. To measure the uptake
of radiolabeled substrates, the membrane filter was dissolved in 4
ml of an appropriate scintillator (Quickszint 361, Zinsser Analytik
GmbH, Frankfurt am Main), and the radioactivity was determined by
liquid scintillation measurement. The measured values were obtained
as dpm (decompositions per minute) after calibration of the
instrument using standard samples and after correction for any
chemiluminescence present.
[0175] The active ingredients are compared for activity on the
basis of IC.sub.25 data obtained in the transport assay on rabbit
small intestine brush border membrane vesicles for selected
substances. (The absolute values may be species- and
experiment-dependent)
[0176] Example No. IC.sub.50 [.mu.M] TABLE-US-00002 Example No.
IC50 [.mu.M] Phlorizin 16 1 0.5 2 0.7 4 1.5 5 0.4 7 0.9
[0177] The preparation of various examples is described in detail
below, and the other compounds of the formula I were obtained
analogously:
Experimental Part:
[0178] Reaction Scheme: Synthesis of .alpha.-bromoglycosides
##STR14##
1-Bromo-4 deoxy-4-fluoro-2,3,6-tri-O-acetyl-alpha-D-glucose 2
[0179] ##STR15##
[0180] 5 g (27.5 mmol) of 4-deoxy-4-fluoro-D-glucopyranose I
(Apollo) are suspended in 50 ml of pyridine and 50 ml of acetic
anhydride. The reaction solution is stirred at 45.degree. C. for 4
hours. This results in a clear reaction solution which is then
concentrated. 12 g of crude product are obtained. This crude
product is dissolved in 160 ml of 33% strength HBr in glacial
acetic acid and left to stand at room temperature for 2 hours. The
reaction solution is then poured into a mixture of 300 g of ice and
300 ml of ethyl acetate. The organic phase is washed twice more
with aqueous NaCl solution, filtered through a little silica gel
and concentrated. The residue is separated by chromatography on
silica gel (ethyl acetate/heptane=1/1); 8.19 g (80% over 2 stages)
of 2 are obtained as a pale yellow solid.
1-Bromo-4-deoxy-4-fluoro-2,3,6-tri-O-acetyl-alpha-D-galactose 4
[0181] ##STR16##
[0182] 100 mg (0.55 mmol) of 3 are reacted with 3.5 ml of pyridine
and 3.5 ml of acetic anhydride in analogy to the preparation of
compound 2.89 mg (44%) of 4 are obtained as an amorphous solid.
1-Bromo-3-deoxy-3-fluoro-2,4,6-tri-O-acetyl-alpha-D-glucose 6
[0183] ##STR17##
[0184] 335 mg (1.84 mmol) of 5 are reacted with 10 ml of pyridine
and 10 ml of acetic anhydride in analogy to the preparation of
compound 2. 628 mg (92%) of 6 are obtained as an amorphous solid.
##STR18##
[0185] The following were prepared in an analogous manner.
##STR19##
EXAMPLE 1
Compound 9
[0186] ##STR20##
[0187] 100 mg (0.47 mmol) of 2-(4-methoxybenzyl)phenol 7 and 370 mg
(1.17 mmol) of bromide 2 are dissolved in 6 ml of methylene
chloride. 160 mg of Bu.sub.3BnNCl (PTC=phase transfer catalyst),
320 mg of K.sub.2CO.sub.3 and 0.4 ml of water are successively
added to this solution, which is then stirred at room temperature
for 20 hours. The reaction solution is diluted with 20 ml of ethyl
acetate and filtered through silica gel. The filtrate is
concentrated and the residue is separated by chromatography on
silica gel (ethyl acetate/heptane=1/1). 72 mg of 8 are obtained as
a colorless solid. The resulting 72 mg of 8 are taken up in 4 ml of
methanol, and 1 ml of 1N NaOMe/MeOH is added. After one hour, the
mixture is neutralized with methanolic HCl and concentrated, and
the residue is separated by chromatography on silica gel (methylene
chloride/methanol/conc. ammonia, 30/5/1). 29 mg of 9 are obtained
as a colorless solid. C.sub.20H.sub.23FO.sub.6 (378.40) MS
(ESI.sup.-) 423.22 (M+CHO.sub.2.sup.-).
EXAMPLE 2
Compound 10
[0188] ##STR21##
[0189] 100 mg (0.47 mmol) of 2-benzylphenol and 370 mg (1.17 mmol)
of bromide 2 are reacted in analogy to the synthesis of compound 9,
and 31 mg of 10 are obtained as a colorless solid.
C.sub.19H.sub.21FO.sub.5 (348.37) MS (ESI.sup.-) 393.15
(M+CHO.sub.2.sup.-).
EXAMPLE 3
Compound 11
[0190] ##STR22##
[0191] 200 mg (0.94 mmol) of 2-(4-methoxybenzyl)phenol 7 and 200 mg
(0.63 mmol) of bromide 4 are reacted in analogy to the synthesis of
compound 9, and 110 mg of 11 are obtained as a colorless solid.
C.sub.20H.sub.23FO.sub.6 (378.40) MS (ESI.sup.-) 423.22
(M+CHO.sub.2.sup.-). ##STR23##
[0192] The following were prepared in an analogous manner
##STR24##
EXAMPLE 4
Compound 14
[0193] ##STR25##
[0194] 90 mg (0.30 mmol) of
3-benzofuran-5-yl-1-(2,6-dihydroxy-4-methylphenyl)propan-1-one 12
and 280 mg (0.76 mmol) of bromide 2 are reacted in analogy to the
synthesis of compound 8, and 400 mg of 13 are obtained as crude
product which is directly deprotected with NaOMe/MeOH in analogy to
the synthesis of glucoside 9. 75 mg of 14 (54% over 2 stages) are
obtained as a colorless solid. C.sub.24H.sub.25FO.sub.8 (460.46) MS
(ESI.sup.-) 459.03 (M-H.sup.+).
EXAMPLE 5
Compound 15
[0195] ##STR26##
[0196] 100 mg (0.33 mmol) of
3-benzofuran-5-yl-1-(2,6-dihydroxy-4-methylphenyl)propan-1-one 12
and 150 mg (0.40 mmol) of bromide 4 are reacted in analogy to the
synthesis of compound 14, and 75 mg of 15 are obtained as a
colorless solid. C.sub.24H.sub.25FO.sub.8 (460.46) MS (ESI.sup.-)
459.03 (M-H.sup.+).
EXAMPLE 6
Compound 16
[0197] ##STR27##
[0198] 150 mg (0.5 mmol) of
3-(2,3-dihydroxybenzofuran-5-yl-1-(2,6-dihydroxy-4-methylphenyl)propan-1--
one and 150 mg (0.40 mmol) of bromide 4 are reacted in analogy to
the synthesis of compound 14, and 75 mg of 16 are obtained as a
colorless solid. C.sub.24H.sub.27FO.sub.8 (462.46) MS (ESI.sup.-)
461.03 (M-H.sup.+). ##STR28##
[0199] The following was prepared in an analogous manner:
##STR29##
EXAMPLE 7
Compound 20
[0200] ##STR30##
[0201] 1.0 g (6.0 mmol) of 1-(2,6-dihydroxy-4-methylphenyl)ethanone
17 and 1.0 g (2.7 mmol) of bromide 2 are dissolved in 30 ml of
methylene chloride. 800 mg of benzyltributylammonium chloride
(PTC), 1.6 g of potassium carbonate and 1.5 ml of water are
successively added to this solution while stirring vigorously. This
suspension is stirred with protection from light (aluminum foil)
for 18 hours and then diluted with 150 ml of ethyl acetate and 150
ml of n-heptane. The solid constituents are filtered through a
little silica gel and concentrated. The residue is separated by
chromatography on silica gel (ethyl acetate/heptane=1/2). 430 mg of
18 are obtained as a pale yellow solid (can be separated with
difficulty from an identically migrating byproduct, and thus the
purity is only about 50%. The byproduct can easily be removed at
the next stage). C.sub.21H.sub.25O.sub.10F (456.43) MS (ESI.sup.-):
455.25 (M-H.sup.+). ##STR31##
[0202] 200 mg of compound 18 (about 50% pure) and 225 mg of
anisaldehyde (Fluka) are dissolved in 10 ml of methanol. After
addition of 5 ml of 1N NaOMe/MeOH solution, the reaction solution
is boiled under reflux for 12 hours. The reaction solution is
neutralized with methanolic HCl and concentrated, and the residue
is separated by chromatography on silica gel (methylene
chloride/methanol/conc. ammonia, 30/5/1). 60 mg of 19 are obtained
as a yellow solid. ##STR32##
[0203] 60 mg (0.13 mmol) of chalcone 19 and 50 mg of Pd/C (10% Pd)
are suspended in 15 ml of methanol and hydrogenated under a 5 bar
hydrogen atmosphere at room temperature for 5 h. The reaction
solution is concentrated and the residue is purified by flash
chromatography (methylene chloride/methanol/conc. ammonia, 30/5/1).
Yield 25 mg (42%) of 20 as a white amorphous solid.
C.sub.23H.sub.27FO.sub.8 (424.47) MS (ESI.sup.-): 449.17
(M-H.sup.+).
EXAMPLE 8
Compound 21
[0204] ##STR33##
[0205] 200 mg of compound 18 (about 50% pure) and 350 mg of
p-benzyloxybenzaldehyde (Fluka) are reacted in analogy to the
synthesis of compound 20. 36 mg of 21 are obtained as a colorless
solid. C.sub.22H.sub.25FO.sub.8 (436.44) MS (ESI.sup.-) 481.08
(M+CHO.sub.2.sup.-). ##STR34##
EXAMPLE 9
Compound 27
[0206] ##STR35##
[0207] 350 mg of bromide 2, 100 mg of phenol 22 and 350 mg of
p-benzyloxybenzaldehyde (Fluka) are reacted in analogy to the
synthesis of compound 21. 40 mg of 27 are obtained as a colorless
solid. C.sub.21H.sub.23FO.sub.9 (438.41) MS (ESI.sup.-) 483.15
(M+CHO.sub.2.sup.-).
EXAMPLE 10
Compound 28
[0208] ##STR36##
[0209] 110 mg of bromide 4 80 mg of phenol 22 and 350 mg of
p-benzyloxybenzaldehyde (Fluka) are reacted in analogy to the
synthesis of compound 21. 50 mg of 28 are obtained as a colorless
solid. C.sub.21H.sub.23FO.sub.9 (438.41) MS (ESI.sup.-) 483.15
(M+CHO.sub.2.sup.-). ##STR37##
EXAMPLE 11
Compound 30
[0210] ##STR38##
[0211] 200 mg of bromide 2 and 300 mg of phenol 29 are reacted in
analogy to the synthesis of compound 14. 40 mg of 30 are obtained
as a colorless solid. C.sub.21H.sub.24FNO.sub.8 (437.43) MS
(ESI.sup.-) 482.15 (M+CHO.sub.2.sup.-).
EXAMPLE 12
Compound 31
[0212] ##STR39##
[0213] 200 mg of bromide 4 and 300 mg of phenol 29 are reacted in
analogy to the synthesis of compound 14. 115 mg of 31 are obtained
as a colorless solid. C.sub.21H.sub.24FNO.sub.8 (437.43) MS
(ESI.sup.-) 482.15 (M+CHO.sub.2.sup.-). ##STR40##
EXAMPLE 13
Compound 33
[0214] ##STR41##
[0215] 200 mg of bromide 2 and 300 mg of phenol 32 are reacted in
analogy to the synthesis of compound 14.80 mg of 33 are obtained as
a colorless solid. C.sub.22H.sub.26FNO.sub.8 (451.45) MS
(ESI.sup.-) 496.17 (M+CHO.sub.2.sup.-).
EXAMPLE 14
Compound 34
[0216] ##STR42##
[0217] 200 mg of bromide 4 and 300 mg of phenol 32 are reacted in
analogy to the synthesis of compound 14.130 mg of 34 are obtained
as a colorless solid. C.sub.21H.sub.24FNO.sub.8 (451.45) MS
(ESI.sup.-) 496.15 (M+CHO.sub.2.sup.-). ##STR43##
1-(2,6-Bisbenzyloxy-4-methylphenyl)ethanone 36
[0218] ##STR44##
[0219] 1.62 g (9.75 mmol) of
1-(2,6-dihydroxy-4-methylphenyl)ethanone (35) are dissolved in 30
ml of dimethylformamide, and 4.0 ml (33.7 mmol) of benzyl bromide
and 13.8 g (100 mmol) of potassium carbonate are added. The
reaction mixture is stirred at room temperature for 3 hours. This
is followed by addition of water and extraction twice with ethyl
acetate. The combined organic phases are washed with saturated
sodium chloride solution, dried over sodium sulfate and
concentrated in a rotary evaporator. 1.35 g (40%) of compound 36
are obtained as a colorless crystalline product.
C.sub.23H.sub.22O.sub.3 (346.2) MS (ESI.sup.+): 347.15
(M+H.sup.+).
1-(2,6-Bisbenzyloxy-4-methylphenyl)-3-(4-methoxyphenyl)propenone
37
[0220] ##STR45##
[0221] 3.46 g (10 mmol) of
1-(2,6-bisbenzyloxy-4-methylphenyl)ethanone (36) are dissolved in
150 ml of ethanol, and 1.34 ml of p-anisaldehyde are added. 7 ml of
aqueous potassium hydroxide solution are then added dropwise. The
reaction stirs at room temperature for 12 hours.
[0222] Half of the solvent is stripped off in a rotary evaporator.
The mixture is neutralized with 2 M hydrochloric acid while cooling
in ice and is then extracted three times with water and ethyl
acetate. The organic phases are combined, washed with saturated
sodium chloride solution, dried over sodium sulfate and
concentrated. The isolated oil crystallizes out. The crystals are
stirred in diethyl ether, filtered off with suction and dried. 4.3
g (92%) of the compound 37 are obtained as a colorless solid. g/mol
C.sub.31H.sub.28O.sub.4 (464.2) MS (ESI.sup.+): 465.10
(M+H.sup.+).
1-(2,6-Dihydroxy-4-methylphenyl)-3-(4-methoxyphenyl)propan-1-one
38
[0223] ##STR46##
[0224] 1.50 g (3.23 mmol) of
1-(2,6-bisbenzyloxy-4-methylphenyl)ethanone (37) are dissolved in
40 ml of ethyl acetate and, under an argon atmosphere, 400 mg of
palladium on activated carbon, 10%, are added. Hydrogenation is
carried out in a hydrogenation autoclave under 3 bar at room
temperature for 2 hours. The catalyst is then filtered off and
washed with ethyl acetate, and the resulting solution is
concentrated in a rotary evaporator. The crude product is purified
by column chromatography (SiO.sub.2, ethyl acetate/n-heptane
1:3).
[0225] 600 mg of the product 38 (65%) are isolated as a colorless
solid. C.sub.17H.sub.18O.sub.4 286.3 MS (ESI.sup.+): 287.10
(M+H.sup.+).
REFERENCE EXAMPLE 7
Compound 20
[0226] ##STR47##
[0227] 174.4 mg (0.61 mmol) of compound 38 are dissolved in 50 ml
of toluene, and 340 mg (0.61 mmol) of the bromide 60 and 421 mg of
cadmium carbonate (2.44 mmol) are added. The reaction mixture is
refluxed with a water trap for 1 h. Cadmium carbonate is filtered
off, and the resulting clear solution is concentrated in a rotary
evaporator. The crude product is suspended in 25 ml of methanol and
mixed with 5.0 ml of a 0.5 M methanolic NaOMe solution and stirred
at room temperature for 12 h. The reaction solution is neutralized
by adding methanolic HCl and is purified by flash chromatography
(SiO.sub.2, EtOAc/heptane 1:4.fwdarw.1:1). 78.8 mg (29%) of
compound 20 are obtained as a colorless solid.
C.sub.23H.sub.27FO.sub.8 450.5 MS (ESI.sup.+): 473.15
(M+Na.sup.+).
[0228] Compounds 40 (example 15), 41 (example 16), 42 (example 17)
and 43 (example 18) were prepared in an analogous manner.
##STR48##
1-Methoxy-4-deoxy-4,4-difluoro-2,3,6-tri-O-benzyl-alpha-D-glucose
45
[0229] ##STR49##
[0230] 3.69 g (7.9 mmol) of
1-methoxy-2,3,6-tri-O-benzyl-.alpha.-D-glucose 44 (Tetrahedron
Asymmetry 11 (2000) 385-387) are dissolved in 110 ml of methylene
chloride and, under an argon atmosphere, 3.6 g (8.5 mmol) of
Dess-Martin agent (Aldrich) are added dropwise. After 3 hours at
room temperature, the mixture is diluted with 300 ml of ethyl
acetate/n-heptane (1:1) and washed 1.times. with NaHCO.sub.3
solution and 1.times. with Na.sub.2S.sub.2O.sub.3 solution. The
organic phase is filtered through silica gel and concentrated. The
residue is separated by chromatography on silica gel (ethyl
acetate/n-heptane 1:1). 2.9 g (79%) of ketone are obtained. The
latter is dissolved in 30 ml of methylene chloride and, under an
argon atmosphere, 4 ml of BAST (Aldrich) are added dropwise. After
20 hours at room temperature, the mixture is diluted with 200 ml of
ethyl acetate and washed cautiously (strong effervescence) with
cooled NaHCO.sub.3 solution. The organic phase is filtered through
silica gel and concentrated. The residue is separated by
chromatography on silica gel (ethyl acetate/n-heptane 1:1). 2.6 g
(85%) of 45 are obtained as a colorless oil.
4-Deoxy-4,4-difluoro-1,2,3,6-tetra-acetyl-alpha-D-glucose 46
[0231] ##STR50##
[0232] 2.3 g (4.7 mmol) of 45 and 2 g of Pd/C (10% Pd) are
dissolved in 150 ml of methanol and 10 ml of acetic acid and
hydrogenated under an atmosphere of 5 bar of hydrogen at room
temperature for 16 h. The reaction solution is concentrated and the
residue is purified by flash chromatography (methylene
chloride/methanol/conc. ammonia, 30/5/1). Yield 850 mg (83%) of
1-methoxy-4-deoxy-4,4-difluoro-alpha-D-glucose as white amorphous
solid. C.sub.7H.sub.12F.sub.2O.sub.5 (214.17) MS (DCl): 215.4
(M+H.sup.+).
[0233] 700 mg (3.3 mmol) of this are dissolved in 3.5 ml of acetic
acid and 6.3 ml of acetic anhydride. Addition of 0.2 ml of conc.
H.sub.2SO.sub.4 is followed by stirring at 60.degree. C. for 5 h.
The reaction solution is then poured into a mixture of 30 g of ice
and 30 ml of ethyl acetate. The organic phase is washed twice more
with aqueous NaCl solution, filtered through a little silica gel
and concentrated. The residue is separated by chromatography on
silica gel (ethyl acetate/n-heptane 1:1). 300 mg (25%) of 46 are
obtained as a mixture of anomers. C.sub.14H.sub.18F.sub.2O.sub.9
(368.29) MS (DCl): 369.3 (M+H.sup.+).
1-Bromo-4-deoxy-4,4-difluoro-2,3,6-tri-O-acetyl-alpha-D-glucose
47
[0234] ##STR51##
[0235] 300 mg (0.8 mmol) of tetraacetate 46 are dissolved in 13 ml
of 33% strength HBr in glacial acetic acid and left to stand at
room temperature for 6 hours. The reaction solution is then poured
into a mixture of 10 g of ice and 10 ml of ethyl acetate. The
organic phase is washed twice more with aqueous NaCl solution,
filtered through a little silica gel and concentrated. The residue
is separated by chromatography on silica gel (ethyl acetate/heptane
1:1). 112 mg (35%) of 47 are obtained as a colorless solid.
C.sub.12H.sub.15BrF.sub.2O.sub.7 (389.15) MS (DCl): 389.2
(M+H.sup.+). ##STR52##
EXAMPLE 19
Compound 50
[0236] ##STR53##
[0237] 100 mg (0.47 mmol) of 2-benzylphenol (Aldrich) and 40 mg
(0.10 mmol) of difluoro bromide 47 are reacted in analogy to the
synthesis of compound 9, and 21 mg of 50 are obtained as a
colorless solid. C.sub.19H.sub.20F.sub.2O.sub.5 (366.37) MS
(ESI.sup.-) 411.15 (M+CHO.sub.2.sup.-). ##STR54##
(4-Methoxyphenyl).sub.42-methoxyphenyl)methanol 51
[0238] ##STR55##
[0239] 1.5 g of o-anisaldehyde are dissolved in THF and cooled to
0.degree. C. 24.2 ml of 4-methoxyphenylmagnesium bromide (0.5 M in
THF) are added to the mixture. The reaction solution is stirred at
room temperature overnight and then poured into a 20% NH.sub.4Cl
solution and extracted with ethyl acetate. 2.63 g of the product
are obtained, and this can be employed without further
purification. C.sub.15H.sub.16O.sub.3 (244.29) MS (ESI.sup.+)
227.05 (M-OH).sup.+
(4-Methoxyphenyl)-(2-methoxyphenyl)methanone 52
[0240] ##STR56##
[0241] 2.63 g of (4-methoxyphenyl)(2-methoxyphenyl)methanol 51 are
dissolved in dichloromethane, and 5.03 g of Dess-Martin reagent are
added. The mixture is stirred at room temperature for 2 h. Then 20%
Na.sub.2SO.sub.3 and NaHCO.sub.3 solution are added, and the
mixture is extracted with diethyl ether. The organic phase is
extracted with saturated NaCl solution and dried over sodium
sulfate. The solution is concentrated in vacuo and purified by
column filtration. 2.61 g of 52 are obtained.
C.sub.15H.sub.14O.sub.3 (242.28) MS (ESI.sup.+) 243.04
(M+H.sup.+)
[0242] Oxidation with Jones reagent can take place as an
alternative thereto:
[0243] 155 mg of (4-methoxyphenyl)(2-methoxyphenyl)methanol 51 are
dissolved in 10 ml of acetone, and 2 ml of Jones reagent are added
dropwise. After 2 h at room temperature, 50 l of MTB ether and 30
ml of water are added to the mixture. The organic phase is washed
several times with water, and the organic phase is extracted with
saturated NaCl solution, dried over sodium sulfate and evaporated
to dryness. The product (126 mg) obtained in this way has
sufficient purity for further reaction.
2-Hydroxyphenyl)(4-methoxyphenyl)methanone 53
[0244] ##STR57##
[0245] 2.61 g of (4-methoxyphenyl)(2-methoxyphenyl)methanone 52 are
dissolved in dichloromethane. The mixture is cooled in an ice bath,
and 3.71 g of boron tribromide-dimethyl sulfide complex are added.
The mixture is warmed to room temperature and left to stir for 3 h.
The reaction is then stopped by pouring into ice-water, the
dichloromethane phase is separated off, and the aqueous phase is
extracted several times with ethyl acetate. The combined organic
phase is washed with water and sodium chloride solution, dried over
sodium sulfate and concentrated. The crude product is
chromatographed on silica gel with ethyl acetate/heptane. 1.26 g of
the product are obtained. C.sub.14H.sub.12O.sub.3 (228.25) MS (DCl)
229.2 (M+H.sup.+)
2-(4-Methoxybenzyl)phenol 7
[0246] ##STR58##
[0247] 0.78 g of (2-hydroxyphenyl)(4-methoxyphenyl)methanone is
dissolved in acetonitrile and cooled to 0.degree. C. 2 ml of TMSCl
are added dropwise to the mixture, and then 1 g of sodium
cyanoborohydride is added. The mixture is stirred at room
temperature for 3 h. The reaction solution is diluted with
dichloromethane and filtered through Celite. The organic phase is
washed with water and saturated sodium chloride solution, dried
over sodium sulfate and concentrated in vacuo. The crude product is
chromatographed on silica gel with ethyl acetate/heptane (1/2).
0.72 g of the desired product is obtained. C.sub.14H.sub.14O.sub.2
(214.27) MS (ESI.sup.+): 232.20 (M+NH.sub.4.sup.+).sup.+
##STR59##
(4-Ethylphenyl)(2-methoxyphenyl)methanol 54
[0248] ##STR60##
[0249] 1.01 g of o-anisaldehyde are dissolved in THF and cooled to
0.degree. C. 16.29 ml of 4-ethylphenylmagnesium bromide (0.5 M in
THF) are added to the mixture. The reaction solution is stirred at
room temperature overnight and then poured into 20% NH.sub.4Cl
solution and extracted with ethyl acetate. 1.92 g of the product
are obtained, and this can be employed without further
purification. C.sub.16H.sub.16O.sub.2 (242.32) MS (ESI.sup.+)
225.15 (M-OH).sup.+
(4-Ethylphenyl)(2-methoxyphenyl)methane 55
[0250] ##STR61##
[0251] 1.34 g of (4-ethylphenyl)(2-methoxyphenyl)methanol are
dissolved in acetonitrile and cooled to 0.degree. C. 1.50 g of
sodium cyanoborohydride are added to the mixture and then 3.00 ml
of trimethylsilyl chloride are added. The mixture is stirred at
room temperature overnight. The reaction solution is filtered
through Celite and extracted with saturated NaCl solution. The
organic phase is dried over sodium sulfate and concentrated. The
crude product is chromatographed on silica gel with ethyl
acetate/heptane (1/12). 0.83 g of the product is obtained.
C.sub.16H.sub.18O (226.32) MS (DCl) 227.4 (M+H.sup.+)
2-(4-Ethylbenzyl)phenol 56
[0252] ##STR62##
[0253] 0.83 g of (4-ethylphenyl)(2-methoxyphenyl)methane 55 is
dissolved in dichloromethane. 11.0 ml of boron tribromide (1 M in
CH.sub.2Cl.sub.2) are added dropwise to the mixture. The mixture is
stirred at room temperature for 5 hours and, after addition of
water, the dichloromethane phase is separated off. The aqueous
phase is extracted with ethyl acetate. The combined organic phases
are washed with water and NaCl solution, dried over sodium sulfate
and concentrated. 0.77 g is obtained as crude product which can be
purified by chromatography. C.sub.15H.sub.16O (212.29) MS (ESI):
235.20 (M+Na.sup.+) ##STR63##
Methyl
2,3,6-tri-O-benzoyl-4-fluoro-4-deoxy-.alpha.-D-glucopyranoside
58
[0254] ##STR64##
[0255] 3 g of methyl
2,3,6-tri-O-benzoyl-.alpha.-D-galactopyranoside 57 (Reist et al.,
J. Org. Chem. 1965, 30, 2312) are introduced into dichloromethane
and cooled to -30.degree. C. Then 3.06 ml of
[bis(2-methoxyethyl)amino]sulfur trifluoride (BAST) are added
dropwise. The reaction solution is warmed to room temperature and
stirred overnight. The mixture is diluted with dichloromethane, and
the organic phase is extracted with H.sub.2O, NaHCO.sub.3 solution
and saturated NaCl solution. The organic phase is dried over
Na.sub.2SO.sub.4 and concentrated. The crude product is
crystallized from ethyl acetate and heptane. 1.95 g of 58 are
obtained as a colorless solid. C.sub.28H.sub.25FO.sub.8 (508.51) MS
(ESI.sup.+) 526.18 (M+NH.sub.4.sup.+). Alternatively, the reaction
can also be carried out using 2.8 eq. of diethylaminosulfur
trifluoride (DAST); in this case, the reaction solution is refluxed
for 18 h after the addition. The working up takes place in analogy
to the above description.
1-O-Acetyl-2,3,6-tri-O-benzoyl-4-fluoro-4-deoxyglucose 59
[0256] ##STR65##
[0257] 12 g of methyl
2,3,6-tri-O-benzoyl-4-fluoro-4-deoxy-.alpha.-D-glucopyranoside 58
are suspended in 150 ml of acetic anhydride. 8.4 ml of conc.
sulfuric acid are mixed with 150 ml of glacial acetic acid and
added to the mixture while cooling in ice. The mixture stirs at
room temperature for 60 h. The mixture is poured into NaHCO.sub.3
solution, and this solution is extracted with dichloromethane. The
organic phase is extracted with NaCl solution, dried with
Na.sub.2SO.sub.4 and concentrated. The residue is recrystallized
from ethyl acetate/heptane. 5.97 g of the product are obtained as a
colorless solid. C.sub.29H.sub.25FO.sub.9 (536.52) MS (ESI.sup.+)
554.15 (M+NH.sub.4.sup.+)
2,3,6-Tri-O-benzoyl-4-fluoro-4-deoxyglucosyl bromide 60
[0258] ##STR66##
[0259] 1.44 g of
1-O-acetyl-2,3,6-tri-O-benzoyl-4-fluoro-4-deoxyglucose are
dissolved in 20 ml of hydrobromic acid in glacial acetic acid (33%)
and stirred at room temperature. After 5 hours, the mixture is
poured into ice-water, and the aqueous phase is extracted three
times with dichloromethane. The collected organic phase is
extracted with saturated sodium chloride solution, dried over
sodium sulfate and evaporated to dryness. The crude product is
filtered through a silica gel column with ethyl acetate/heptane
70:30. 1.40 g of the product are obtained as a solid.
[0260] C.sub.27H.sub.22BrFO.sub.7 (557.37) MS (ESI.sup.+)
574.05/576.05 (M+NH.sub.4.sup.+) ##STR67##
2,3,6-Tri-O-benzoyl-4-fluoro-4-deoxyglucose 61
[0261] ##STR68##
[0262] 1.60 g of
1-O-acetyl-2,3,6-tri-O-benzoyl-4-fluoro-4-deoxyglucose are
dissolved in dichloromethane. 173 .mu.l of hydrazine hydrate are
added to this solution. After 16, h, the reaction solution is
partitioned between dichloromethane and H.sub.2O. The organic phase
is extracted with NaCl solution, dried over sodium sulfate and
evaporated to dryness. The crude product is purified by column
filtration. 1.22 g of the desired product are obtained.
C.sub.27H.sub.23FO.sub.8 (494.48) MS (ESI.sup.+): 512.15
(M+NH.sub.4.sup.+). Compound 62 ##STR69##
[0263] 248 mg of 2-(4-ethylbenzyl)phenol (56), 550 mg of
2,3,6-tri-O-benzoyl-4-fluoro-4-deoxyglucose (61) and 335 mg of
triphenylphosphine in 2 ml of dry dichloromethane are cooled to
0.degree. C. under argon. 0.193 ml of diethyl azodicarboxylate is
slowly added dropwise. This solution is brought to room temperature
and stirs overnight. The solution is then diluted with
dichloromethane and extracted with water, 0.5 M NaOH and saturated
NaCl solution. The organic phase is dried over sodium sulfate and
concentrated in vacuo. The residue is purified by chromatography
(heptane:ethyl acetate 3:1). 200 mg of the desired product are
obtained. C.sub.42H.sub.37FO.sub.8 (688.76) MS (ESI): 706.30
(M+NH.sub.4).sup.+. ##STR70##
[0264] 200 mg of 62 are taken up in 10 ml of absolute methanol, and
1 ml of sodium methanolate solution (10 mg of sodium methanolate
per ml of methanol) is added. The solution stirs for 8 h. Sodium is
removed by adding Amberlyst 15 (H.sup.+ form), the ion exchanger is
filtered off, and the residue is thoroughly washed. The resulting
product is purified by silica gel filtration
(dichloromethane:methanol 96:4). 56 mg of the desired product are
obtained. C.sub.21H.sub.25FO.sub.5 (376.43) MS (ESI): 394.25
(M+NH.sub.4.sup.+)
[0265] The following examples are prepared in an analogous manner
to example 20 using the appropriate aglycones: ##STR71##
[0266] The appropriate aglycones can be obtained for example by the
processes described for compounds 7 or 56. ##STR72##
1-[4-(2-Methoxyphenoxy)phenyl]ethanone 69
[0267] ##STR73##
[0268] 0.15 ml of guaiacol 67, 167 mg of 4-fluoroacetophenone 68
and 335 mg of potassium carbonate are heated in 5 ml of dimethyl
sulfoxide at 170.degree. C. in a microwave for 10 min. The reaction
solution is poured into water, and the emulsion is extracted three
times with an ethyl tert-butyl ether. The combined organic phase is
extracted twice with 1 N NaOH and once with saturated NaCl
solution, dried and concentrated in vacuo. 240 mg of the desired
product are obtained. C.sub.15H.sub.14O.sub.3 (242.28) MS (ESI):
215.10 (M+H.sup.+).
2-(4-Ethylphenoxy)methoxybenzene 70
[0269] ##STR74##
[0270] 960 mg of 1-[4-(2-methoxyphenoxy)phenyl]ethanone 69 are
dissolved in 20 ml of acetonitrile and cooled in an ice bath, and
1.05 g of sodium cyanoborohydride and 2.01 ml of trimethylsilyl
chloride are added. After 1 h, the mixture is diluted with
dichloromethane and filtered through Celite, and the organic phase
is extracted with sodium chloride solution, dried over sodium
sulfate and concentrated. The residue is purified by chromatography
(heptane:ethyl acetate 7:1). 710 mg of the desired product are
obtained. C.sub.15H.sub.16O.sub.2 (228.29) MS (ESI): 246.20
(M+NH.sub.4.sup.+).
2-(4-Ethylphenoxy)phenol 71
[0271] ##STR75##
[0272] 710 mg of 2-(4-ethylphenoxy)methoxybenzene 70 are dissolved
in 5 ml absolute dichloromethane. 0.6 ml of boron tribromide (1 M
dichloromethane) is added dropwise, and the solution stirs for 6 h.
Further BBr.sub.3 is added and the mixture is stirred until the
reaction is almost complete according to LCMS. The solution is
brought into ice-water, the organic phase is separated off, and the
aqueous phase is extracted three times with dichloromethane. The
combined organic phase is dried, evaporated to dryness and purified
by chromatography. 450 mg of the desired product are obtained.
C.sub.14H.sub.14O.sub.2 (214.27) MS (ESI): 215.10 (M+H.sup.+).
Compound 72 ##STR76##
[0273] Compound 61 (466 mg) and phenol 71 (242 mg) are reacted in
analogy to the synthesis of compound 62. The resulting product can
be purified by column chromatography (heptane:ethyl acetate 4:1).
240 mg of the desired product are obtained.
C.sub.41H.sub.35FO.sub.9 (690.73) MS (ESI): 708.25
(M+NH.sub.4.sup.+).
EXAMPLE 24
Compound 39
[0274] ##STR77##
[0275] 230 mg of compound 72 are reacted with sodium methanolate in
analogy to the liberation of example 20. The compound can be
purified by silica gel chromatography (dichloromethane:methanol
96:4). 119 mg of the desired product are obtained.
C.sub.20H.sub.23FO.sub.6 (378.40) MS (ESI): 396.15
(M+NH.sub.4.sup.+).
* * * * *
References