U.S. patent application number 12/731225 was filed with the patent office on 2010-07-29 for triazolopyridine derivatives as inhibitors of lipases and phospholipases.
This patent application is currently assigned to SANOFI-AVENTIS. Invention is credited to Karl-Heinz BARINGHAUS, Hubert HEUER, Gunter MULLER, Stefan PETRY, Gerhard ZOLLER.
Application Number | 20100190801 12/731225 |
Document ID | / |
Family ID | 37487398 |
Filed Date | 2010-07-29 |
United States Patent
Application |
20100190801 |
Kind Code |
A1 |
PETRY; Stefan ; et
al. |
July 29, 2010 |
TRIAZOLOPYRIDINE DERIVATIVES AS INHIBITORS OF LIPASES AND
PHOSPHOLIPASES
Abstract
The invention relates to triazolopyridine derivatives of general
formula (I), which are defined as cited in the description, to
their pharmaceutically applicable salts and to their use as
medicaments. ##STR00001##
Inventors: |
PETRY; Stefan; (Kelkheim,
DE) ; ZOLLER; Gerhard; (Schoenck, DE) ;
MULLER; Gunter; (Sulzbach, DE) ; BARINGHAUS;
Karl-Heinz; (Wolfersheim, DE) ; HEUER; Hubert;
(Schwabenheim, 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
Paris
FR
|
Family ID: |
37487398 |
Appl. No.: |
12/731225 |
Filed: |
March 25, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12099922 |
Apr 9, 2008 |
7718669 |
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12731225 |
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PCT/EP2006/009856 |
Oct 12, 2006 |
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12099922 |
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Current U.S.
Class: |
514/253.04 ;
514/278; 514/300; 514/307; 544/362; 546/117; 546/146; 546/16 |
Current CPC
Class: |
A61P 17/12 20180101;
A61P 1/04 20180101; A61P 3/08 20180101; A61P 11/06 20180101; A61P
25/28 20180101; A61P 3/00 20180101; A61P 15/00 20180101; A61P 3/04
20180101; A61P 9/10 20180101; A61P 35/02 20180101; A61P 11/00
20180101; A61P 9/00 20180101; A61P 9/04 20180101; A61P 17/00
20180101; A61P 25/00 20180101; A61P 25/16 20180101; A61P 29/00
20180101; A61P 1/18 20180101; A61P 3/10 20180101; A61P 43/00
20180101; C07D 487/04 20130101; A61P 9/12 20180101; A61P 7/02
20180101; A61P 31/20 20180101; C07D 471/04 20130101; A61P 3/06
20180101; A61P 17/06 20180101; A61P 17/08 20180101; A61P 19/06
20180101; A61P 27/02 20180101; A61P 7/00 20180101; A61P 35/00
20180101; A61P 19/02 20180101 |
Class at
Publication: |
514/253.04 ;
514/278; 514/300; 514/307; 544/362; 546/16; 546/117; 546/146 |
International
Class: |
A61K 31/4995 20060101
A61K031/4995; A61K 31/438 20060101 A61K031/438; A61K 31/4545
20060101 A61K031/4545; A61K 31/4725 20060101 A61K031/4725; C07D
401/14 20060101 C07D401/14; C07D 221/20 20060101 C07D221/20; C07D
471/04 20060101 C07D471/04; C07D 217/26 20060101 C07D217/26; A61P
3/00 20060101 A61P003/00; A61P 3/04 20060101 A61P003/04; A61P 3/10
20060101 A61P003/10; A61P 3/06 20060101 A61P003/06; A61P 9/00
20060101 A61P009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 19, 2005 |
DE |
102005049954.6 |
Claims
1. A compound of the formula I: ##STR00079## wherein: X is
identically or differently .dbd.C(--R)-- or .dbd.N--, where at
least one and at most two X is .dbd.N--; W is --(C.dbd.O)--,
--(S.dbd.O)-- or --(SO.sub.2)--; R is identically or differently
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-alkyloxy-(C.sub.1-C.sub.3)-alkylene, hydroxy,
phenoxy, amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino, cyano, nitro, COOR3,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkylmercapto, (C.sub.1-C.sub.6)-alkylsulfinyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, aryl, heteroaryl,
(C.sub.3-C.sub.12)-cycloalkyl, (C.sub.1-C.sub.6)-alkylcarbonyl,
O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--OH,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--NR3R3a or unsubstituted or
mono- or poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy; R1 is
(C.sub.5-C.sub.16)-alkyl, (C.sub.5-C.sub.12)-cycloalkyl, Y-aryl,
Y-heteroaryl, Y--(C.sub.5-C.sub.12)-cycloalkyl, or bicycle, where
aryl, heteroaryl, cycloalkyl or bicycle are optionally substituted
one or more times by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, hydroxy,
(C.sub.1-C.sub.6)-alkylmercapto, amino,
(C.sub.1-C.sub.6)-alkylamino, di-(C.sub.2-C.sub.12)-alkylamino,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl, d
i-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, nitro, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
Y is (C.sub.1-C.sub.3)-alkylene which is optionally substituted one
or more times by halogen, (C.sub.1-C.sub.2)-alkyl or hydroxy; R2 is
hydrogen or (C.sub.4-C.sub.12)-alkyl; or R1 and R2 together with
the nitrogen atom carrying them form a monocyclic, saturated or
partly unsaturated 4- to 7-membered ring system or a bicyclic
saturated or partly unsaturated 8- to 14 membered ring system whose
individual members of the ring systems may be replaced by one to
three atoms or atomic groups from the series --CHR4-, --CR4R5-,
.dbd.(C--R4)-, --NR5-, --C(.dbd.O)--, --O--, --S--, --SO-- or
--SO.sub.2--, with the proviso that two units from the series
--O--, --S--, --SO-- or --SO.sub.2-- are not adjacent to each
other; R3, R3a are identically or differently hydrogen,
(C.sub.1-C.sub.6)-alkyl or benzyl; and R4, R5 are identically or
differently (C.sub.1-C.sub.12)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
halogen, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-haloalkyloxy, COOR3, nitro, cyano, aryl,
heterocycle, (C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.1-C.sub.3)-alkylene-aryl,
(C.sub.1-C.sub.3)-alkylene-heterocycle or
(C.sub.1-C.sub.3)-alkylene-cycloalkyl, where aryl, heterocycle or
cycloalkyl are optionally substituted one or more times by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
O--(C.sub.1-C.sub.3)-alkylene-aryl, trifluoromethyl,
trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl or
NR3R3a; or a tautomer thereof or a physiologically tolerated salt
thereof, with the proviso that the compound with the meanings of X
in position 4, 5 and 6=C(--R)-- and in position 7=N--, W is
--(C.dbd.O--)--, R is H and R1 and R2 form a morpholine, is
excluded; and with the proviso that the compounds with the meanings
of X in position 4 and 6=C(--R)--, and in position 5 and 7=N--, W
is --(C.dbd.O)--, and R is aryl, heteroaryl or phenoxy, are
excluded.
2. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently .dbd.C(--R)-- or .dbd.N--, where one
X is .dbd.N--; and W is --(C.dbd.O)--.
3. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently .dbd.C(--R)-- or .dbd.N--, where one
X is .dbd.N--; W is --(C.dbd.O)--; R is identically or differently
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl, trifluoromethyl,
(C.sub.1-C.sub.3)-alkyloxy-(C.sub.1-C.sub.3)-alkylene, hydroxy,
phenoxy, amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino, cyano, nitro, COOR3,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkyl-aminocarbonyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, phenyl, (C.sub.1-C.sub.6)-alkylcarbonyl,
O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--OH,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--NR3R3a or unsubstituted or
mono- or poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy; R1 is
(C.sub.6-C.sub.12)-alkyl, (C.sub.5-C.sub.12)-cycloalkyl, Y-phenyl,
Y-heteroaryl or bicycle, where phenyl, heteroaryl, cycloalkyl or
bicycle are optionally substituted one or more times by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy, hydroxy,
(C.sub.1-C.sub.6)-alkylmercapto, amino,
(C.sub.1-C.sub.6)-alkylamino, di-(C.sub.2-C.sub.12)-alkylamino,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, nitro, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl or
aminosulfonyl; Y is --CH.sub.2--, which is optionally substituted
once by fluorine, methyl or hydroxy; R2 is hydrogen or
(C.sub.5-C.sub.10)-alkyl; or R1 and R2 together with the nitrogen
atom carrying them form a monocyclic, saturated or partly
unsaturated 5- to 6-membered ring system or a bicyclic saturated or
partly unsaturated 9- to 10-membered ring system whose individual
members of the ring systems may be replaced by one to three atoms
or atomic groups from the series --CHR4-, --CR4R5-, .dbd.(C--R4)-,
--NR5-, --C(.dbd.O)--, --O--, --S-- or --SO.sub.2--, with the
proviso that two units from the series --O--, --S-- or --SO.sub.2--
are not adjacent to each other; R3, R3a are identically or
differently hydrogen, (C.sub.1-C.sub.6)-alkyl or benzyl; and R4, R5
are identically or differently (C.sub.1-C.sub.10)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, halogen, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-haloalkyloxy, COOR3, nitro, cyano, aryl,
heterocycle, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.3)-alkylene-aryl, or
(C.sub.1-C.sub.3)-alkylene-heteroaryl, where aryl, heterocycle or
cycloalkyl are optionally substituted one or more times by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
O--(C.sub.1-C.sub.3)-alkylene-aryl, trifluoromethyl,
trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl or
NR3R3a; or a tautomer thereof or a physiologically tolerated salt
thereof.
4. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently =C(--R)-- or .dbd.N--, where one X is
.dbd.N--; W is --(C.dbd.O)--; R is identically or differently
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl, trifluoro-methyl,
hydroxy, amino, cyano, COOR3,
mono-(C.sub.1-C.sub.6)-alkylamino-carbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, (C.sub.1-C.sub.6)-alkylcarbonyl,
O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl or
unsubstituted or mono- or poly-F-substituted
(C.sub.1-C.sub.6)-alkyloxy; R1 is (C.sub.6-C.sub.12)-alkyl,
Y-phenyl, Y-heteroaryl or bicycle, where aryl, heteroaryl or
bicycle are optionally substituted one or more times by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy, hydroxy,
amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl or
aminosulfonyl; Y is --CH.sub.2--; R2 is hydrogen or
(C.sub.5-C.sub.10)-alkyl; or R1 and R2 together with the nitrogen
atom carrying them form a monocyclic, saturated or partly
unsaturated 5- to 6-membered ring system or a bicyclic saturated or
partly unsaturated 9- to 10-membered ring system whose individual
members of the ring systems may be replaced by one to three atoms
or atomic groups from the series --CHR4-, --CR4R5-, .dbd.(C--R4)-,
--NR5-, --C(.dbd.O)--, --O-- or --S--, with the proviso that two
units from the series --O-- or --S--, are not adjacent to each
other; R3, R3a are identically or differently hydrogen,
(C.sub.1-C.sub.6)-alkyl or benzyl; and R4, R5 are identically or
differently (C.sub.1-C.sub.10-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
halogen, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-haloalkyloxy, COOR3, nitro, cyano, aryl,
heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.3)-alkylene-aryl or
(C.sub.1-C.sub.3)-alkylene-heteroaryl, where aryl, heteroaryl or
cycloalkyl are optionally substituted one or more times by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
O--(C.sub.1-C.sub.3)-alkylene-aryl, trifluoromethyl,
trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl or
amino; or a tautomer thereof or a physiologically tolerated salt
thereof.
5. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently .dbd.C(--R)-- or .dbd.N--, where one
X is .dbd.N--; W is --(C.dbd.O)--; R is identically or differently
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl, trifluoro-methyl,
hydroxy, amino, cyano, COOR3, (C.sub.1-C.sub.6)-alkylsulfonyl,
aminosulfonyl, (C.sub.1-C.sub.6)-alkylcarbonyl or unsubstituted or
mono- or poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy; R1 is
(C.sub.6-C.sub.12)-alkyl or Y-phenyl, where phenyl may be
substituted one to three times by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, hydroxy, amino,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
Y is --CH.sub.2--; R2 is hydrogen or (C.sub.5-C.sub.10)-alkyl; or
R1 and R2 together with the nitrogen atom carrying them may form a
monocyclic, saturated 5- to 6-membered ring system or a bicyclic
saturated or partly unsaturated 9- to 10-membered ring system whose
individual members of the ring systems may be replaced by one to
three atoms or atomic groups from the series --CHR4-, --CR4R5-,
.dbd.(C--R4)-, --NR5-, --C(.dbd.O)--, --O-- or --S--, with the
proviso that two units from the series --O-- or --S-- may not be
adjacent; R3, R3a are identically or differently hydrogen or
(C.sub.1-C.sub.6)-alkyl; and R4, R5 are identically or differently
(C.sub.1-C.sub.10-alkyl, (C.sub.1-C.sub.6)-alkyloxy, halogen,
trifluoromethyl, trifluoromethoxy, COOR3, cyano, aryl, cyclopropyl
or (C.sub.1-C.sub.3)-alkylene-phenyl, where aryl may be substituted
one or more times by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, O--(C.sub.1-C.sub.3)-alkylene-phenyl,
trifluoromethyl, trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl or CO--O--(C.sub.1-C.sub.6)-alkyl,
amino; or a tautomer thereof or a physiologically tolerated salt
thereof.
6. The compound of the formula I as claimed in claim 1, wherein:
NR1R2 is a monocyclic saturated 5- to 6-membered ring system which
comprises in position 4 an atom or atomic member from the series
--CHR4-, --CR4R5-, --NR5-, --(C.dbd.O) or is a bicyclic saturated
or partly unsaturated 9- to 10-membered ring system whose
individual members of the ring system may be replaced by one or two
atomic groups from the series --CHR4-, --(C=R4)-, .dbd.(C--R4)-,
--NR5- or --(C.dbd.O)--.
7. The compound of the formula I as claimed in claim 1, wherein: R1
and R2 together with the nitrogen atom carrying them form a
monocyclic, saturated 5- to 6-membered ring system or a bicyclic
saturated or partly unsaturated 9- to 10-membered ring system,
whose individual members of the ring systems may be replaced by an
atomic group from the series --CHR4- or --NR5.
8. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently .dbd.C(--R)-- or .dbd.N--, where one
X is .dbd.N--; R is identically or differently hydrogen or Cl; NR1
R2 is piperidine which comprises in position 4 the atomic member
--CHR4-; or is piperazine which comprises in position 4 the atomic
member --NR5; and R4, R5 are (C.sub.1-C.sub.8)-alkyl, phenyl,
--(C.sub.1-C.sub.2)-alkylene-phenyl, naphthyl, pyrrolidin-2-one or
benzofuranyl, where phenyl may be substituted once, twice or three
times by methyl, ethyl, t-butyl, methoxy, ethoxy, F, Cl, Br, OH,
CF.sub.3, NH.sub.2, CO--OCH.sub.3, CO--CH.sub.3, phenyl or
--O-benzyl.
9. The compound of the formula I as claimed in claim 1, wherein:
NR1 R2 is piperidine which comprises in position 4 the atomic
member --CHR4-, or is piperazine which comprises in position 4 the
atomic member --NR5; and R4, R5 are methyl or phenyl which may be
substituted once or twice by methyl, methoxy, ethoxy, F, Cl, Br,
OH, CF.sub.3, NH.sub.2, CO--OCH.sub.3, CO--CH.sub.3, phenyl or
--O-benzyl.
10. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently .dbd.C(--R--)-- or .dbd.N--, where
one X is .dbd.N--; R is identically or differently hydrogen or Cl;
NR1R2 is tetrahydroquinoline or tetrahydroisoquinoline which may be
substituted once or twice by methoxy.
11. The compound of the formula I as claimed in claim 1, wherein:
R2 is hydrogen.
12. The compound of the formula I as claimed in claim 1, wherein:
R1 is (C.sub.6-C.sub.12)-alkyl or Y-phenyl, where phenyl may be
substituted one to three times by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, hydroxy, amino,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl or
aminosulfonyl; Y is --CH.sub.2--; and R2 is hydrogen.
13. The compound of the formula I as claimed in claim 1, wherein: X
is identically or differently .dbd.C(--R)-- or .dbd.N--, where one
X is .dbd.N--; R is identically or differently hydrogen or Cl; R1
is hexyl or Y-phenyl, where phenyl is optionally substituted by
methyl; Y is --CH.sub.2--; and R2 is hydrogen.
14. The compound of the formula I as claimed in claim 1, wherein: X
in position 4, 5 and 6 is identically or differently .dbd.C(--R)--,
and in position 7 is .dbd.N--.
15. The compound of the formula I, as claimed in claim 1, wherein:
X optionally in position 4 or 7 is .dbd.C(--R)-- with R=hydrogen or
.dbd.N--, and in position 5 or 6 is .dbd.C(--R)-- wherein R is not
hydrogen.
16. A pharmaceutical composition comprising one or more compounds
of the formula I as claimed in claim 1 or a tautomer thereof or a
pharmaceutically acceptable salt thereof in combination with at
least one pharmaceutically acceptable excipient.
17. A method for the treatment of disorders of fatty acid
metabolism and glucose utilization disorders comprising
administering to a patient in need of said treatment a
therapeutically effective amount of a compound of the formula I as
claimed in claim 1 or a pharmaceutically acceptable salt
thereof.
18. A method for the treatment of disorders in which insulin
resistance is involved comprising administering to a patient in
need of said treatment a therapeutically effective amount of a
compound of the formula I as claimed in claim 1 or a
pharmaceutically acceptable salt thereof.
19. A method for the treatment of diabetes mellitus and the
sequelae associated therewith comprising administering to a patient
in need of said treatment a therapeutically effective amount of a
compound of the formula I as claimed in claim 1 or a
pharmaceutically acceptable salt thereof.
20. A method for the treatment of dyslipidemia and its sequelae
comprising administering to a patient in need of said treatment a
therapeutically effective amount of a compound of the formula I as
claimed in claim 1 or a pharmaceutically acceptable salt
thereof.
21. A method for the treatment of conditions associated with the
metabolic syndrome comprising administering to a patient in need of
said treatment a therapeutically effective amount of a compound of
the formula I as claimed in claim 1 or a pharmaceutically
acceptable salt thereof.
22. A method for the treatment of conditions associated with a
reduced HDL level comprising administering to a patient in need of
said treatment a therapeutically effective amount of a compound of
the formula I as claimed in claim 1 or a pharmaceutically
acceptable salt thereof.
23. A method for the treatment of atherosclerotic disorders
comprising administering to a patient in need of said treatment a
therapeutically effective amount of a compound of the formula I as
claimed in claim 1 or a pharmaceutically acceptable salt
thereof.
24. A method for the treatment of disorders in which insulin
resistance is involved comprising administering to a patient in
need of said treatment a therapeutically effective amount of a
compound of the formula I as claimed in claim 1 or a
pharmaceutically acceptable salt thereof in combination with at
least one other active ingredient.
25. A process for producing a medicament comprising one or more of
the compounds of the formula I as claimed in claim 1, which
comprises mixing said compounds with a pharmaceutically suitable
carrier to form a mixture and converting said mixture into a form
suitable for administration.
26. A process for preparing compounds of the formula I as claimed
in claim 1, which comprises: a) acylating triazolopyridine
derivative of the formula II with a carbamoyl chloride of the
formula III; or b) reacting in two stages firstly with phosgene or
its equivalents chosen from trichloromethyl chlorocarbonate,
ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and in a
second step with amines of the formula IV; ##STR00080## wherein X,
R1 and R2 are as defined in claim 1; and, where appropriate,
separating the regioisomers.
27. A process for preparing compounds of the formula I, wherein R2
is hydrogen as claimed in claim 1, which comprises: reacting
triazolopyridine derivatives of the formula II with isocyanates of
the formula V: O.dbd.C.dbd.N--R1, and, where appropriate,
separating the regioisomers; and ##STR00081## wherein X and R1 are
as defined in claim 1.
Description
[0001] This application is a continuation of International
application No. PCT/EP2006/009,856, filed Oct. 12, 2006, which is
incorporated herein by reference in its entirety; which claims the
benefit of priority of German Patent Application No.
102005049954.6, filed Oct. 19, 2005.
[0002] The present invention relates to triazolopyridine
derivatives of the formula I, the pharmaceutically usable salts
thereof and their use as medicinal substances.
[0003] Benzotriazoles are already known in a wide variety of fields
such as, for example, photochemistry (U.S. Pat. No. 4,255,510,
Kodak) or as orexin antagonists (WO 02/090355, SKB). In addition
the preparation of benzotriazoles is described by Katritzky et al.
in J. Org. Chem. 1997, 62, 4155-4158.
[0004] Triazolopyrimidine derivatives are described as purinergic
receptor antagonists in WO 02/055083.
[0005] Indazoles are described as hormone-sensitive lipase
inhibitors in WO 2005/073199.
[0006] Also known are carbamates as lipase inhibitors such as, for
example, Shamkant Patkar et al. in Paul Woolley, Steffen B.
Petterson (ed), Lipase (1994) 207-227, WO 03/051842 or WO
2004/035550.
[0007] It is an object of the present invention to provide
compounds which bring about an inhibition of hormone-sensitive
lipase or of endothelial lipase.
[0008] The invention relates to triazolopyridine derivatives of the
formula I
##STR00002##
in which the meanings are: [0009] X identically or differently
.dbd.C(--R)-- or .dbd.N--, where at least one and at most two X is
.dbd.N--; [0010] W--(C.dbd.O)--, --(S.dbd.O)--, --(SO.sub.2)--;
[0011] R identically or differently hydrogen, halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-alkyloxy-(C.sub.1-C.sub.3)-alkylene, hydroxy,
phenoxy, amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino, cyano, nitro, COOR3,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkylmercapto, (C.sub.1-C.sub.6)-alkylsulfinyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, aryl, heteroaryl,
(C.sub.3-C.sub.12)-cycloalkyl, (C.sub.1-C.sub.6)-alkylcarbonyl,
O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--OH,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--NR3R3a or unsubstituted or
mono- or poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy; [0012]
(C.sub.5-C.sub.16)-alkyl, (C.sub.5-C.sub.12)-cycloalkyl, Y-aryl,
Y-heteroaryl, Y-(C.sub.5-C.sub.12)-cycloalkyl, bicycle, where aryl,
heteroaryl, cycloalkyl or bicycle may be substituted one or more
times by preferably halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, hydroxy,
(C.sub.1-C.sub.6)-alkylmercapto, amino,
(C.sub.1-C.sub.6)-alkyl-amino, di-(C.sub.2-C.sub.12)-alkylamino,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkyl-carbonyl, cyano, nitro, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
[0013] Y (C.sub.1-C.sub.3)-alkylene which may be substituted one or
more times by halogen, (C.sub.1-C.sub.2)-alkyl or hydroxy; [0014]
R2 hydrogen, (C.sub.4-C.sub.12)-alkyl; or [0015] R1 and R2 together
with the nitrogen atom carrying them may form a monocyclic,
saturated or partly unsaturated 4- to 7-membered ring system or a
bicyclic saturated or partly unsaturated 8- to 14 membered ring
system whose individual members of the ring systems may be replaced
by one to three atoms or atomic groups from the series --CHR4-,
--CR4R5-, .dbd.(C--R4)-, --NR5-, --C(.dbd.O)--, --O--, --S--,
--SO--, --SO.sub.2--, with the proviso that two units from the
series --O--, --S--, --SO--, --SO.sub.2-- may not be adjacent;
[0016] R3, R3a identically or differently hydrogen,
(C.sub.1-C.sub.6)-alkyl, benzyl; [0017] R4, R5 identically or
differently (C.sub.1-C.sub.12)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
halogen, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-haloalkyloxy, COOR3, nitro, cyano, aryl,
heterocycle, (C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.1-C.sub.3)-alkylene-aryl,
(C.sub.1-C.sub.3)-alkylene-heterocycle,
(C.sub.1-C.sub.3)-alkylene-cycloalkyl, where aryl, heterocycle or
cycloalkyl may be substituted one or more times by preferably
halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
O--(C.sub.1-C.sub.3)-alkylene-aryl, trifluoromethyl,
trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl,
NR3R3a; [0018] the tautomeric forms of the compounds and their
physiologically tolerated salts, [0019] with the proviso that the
compound of the formula I with the meanings of X in position 4, 5
and 6=C(--R--)-- and in position 7=N--, W is --(C.dbd.O)--, R is H
and R1 and R2 form a morpholine, is excluded; and [0020] with the
proviso that the compounds of the formula I with the meanings of X
in position 4 and 6=C(--R--)--, and in position 5 and 7=N--, W is
--(C.dbd.O)--, R is aryl, heteroaryl or phenoxy, are excluded.
[0021] The object of the invention is also the compounds of the
formula I, in which [0022] R is identically or differently
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-alkyloxy-(C.sub.1-C.sub.3)-alkylene, hydroxy,
amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino, cyano, nitro, COOR3,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkylmercapto, (C.sub.1-C.sub.6)-alkylsulfynyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, (C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--OH,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO-NR3R3a or unsubstituted or
mono- or poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy.
[0023] Preference is given to compounds of the formula I in which
[0024] X is identically or differently .dbd.C(--R)-- or .dbd.N--,
where one X is .dbd.N--; [0025] W is --(C.dbd.O)--.
[0026] Particular preference is given to compounds of the formula I
in which the meanings are [0027] X identically or differently
.dbd.C(--R)-- or .dbd.N--, where one X is .dbd.N--; [0028] W
--(C.dbd.O)--; [0029] R identically or differently hydrogen,
halogen, (C.sub.1-C.sub.6)-alkyl, trifluoromethyl,
(C.sub.1-C.sub.3)-alkyloxy-(C.sub.1-C.sub.3)-alkylene, hydroxy,
phenoxy, amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino, cyano, nitro, COOR3,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, phenyl, (C.sub.1-C.sub.6)-alkylcarbonyl,
O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--OH,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--NR3R3a or unsubstituted or
mono- or poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy; [0030] R1
(C.sub.6-C.sub.12)-alkyl, (C.sub.5-C.sub.12)-cycloalkyl, Y-phenyl,
Y-heteroaryl, bicycle, where phenyl, heteroaryl, cycloalkyl or
bicycle may be substituted one or more times by preferably halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy, hydroxy,
(C.sub.1-C.sub.6)-alkylmercapto, amino,
(C.sub.1-C.sub.6)-alkylamino, di-(C.sub.2-C.sub.12)-alkylamino,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylamino-carbonyl,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, nitro, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
[0031] Y--CH.sub.2--, which may be substituted once by fluorine,
methyl or hydroxy; [0032] R2 hydrogen, (C.sub.5-C.sub.10)-alkyl; or
[0033] R1 and R2 together with the nitrogen atom carrying them may
form a monocyclic, saturated or partly unsaturated 5- to 6-membered
ring system or a bicyclic saturated or partly unsaturated 9- to 10
membered ring system whose individual members of the ring systems
may be replaced by one to three atoms or atomic groups from the
series --CHR4-, --CR4R5-, .dbd.(C--R4)-, --NR5-, --C(.dbd.O)--,
--O--, --S--, --SO.sub.2--, with the proviso that two units from
the series --O--, --S--, --SO.sub.2-- may not be adjacent; [0034]
R3, R3a identically or differently hydrogen,
(C.sub.1-C.sub.6)-alkyl, benzyl; [0035] R4, R5 identically or
differently (C.sub.1-C.sub.10)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
halogen, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-haloalkyloxy, COOR3, nitro, cyano, aryl,
heterocycle, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.3)-alkylene-aryl,
(C.sub.1-C.sub.3)-alkylene-heteroaryl, where aryl, heterocycle or
cycloalkyl may be substituted one or more times by preferably
halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
O--(C.sub.1-C.sub.3)-alkylene-aryl, trifluoromethyl,
trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylamino-carbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl,
NR3R3a; [0036] the tautomeric forms of the compounds and their
physiologically tolerated salts.
[0037] Particular preference is further given to compounds of the
formula I in which the meanings are [0038] X identically or
differently .dbd.C(--R)-- or .dbd.N--, where one X is .dbd.N--;
[0039] W --(C.dbd.O)--; [0040] R identically or differently
hydrogen, halogen, (C.sub.1-C.sub.6)-alkyl, trifluoro-methyl,
hydroxy, amino, cyano, COOR3,
mono-(C.sub.1-C.sub.6)-alkylamino-carbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
pentafluorosulfanyl, (C.sub.1-C.sub.6)-alkylcarbonyl,
O--CO--NR3R3a,
O--CO--(C.sub.1-C.sub.6)-alkylene-CO--O--(C.sub.1-C.sub.6)-alkyl or
unsubstituted or mono- or poly-F-substituted
(C.sub.1-C.sub.6)-alkyloxy; [0041] R1 (C.sub.6-C.sub.12)-alkyl,
Y-phenyl, Y-heteroaryl, bicycle, where aryl, heteroaryl or bicycle
may be substituted one or more times by preferably halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy, hydroxy,
amino, (C.sub.1-C.sub.6)-alkylamino,
di-(C.sub.2-C.sub.12)-alkylamino,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
[0042] Y--CH.sub.2--; [0043] R2 hydrogen, (C.sub.5-C.sub.10)-alkyl;
or [0044] R1 and R2 together with the nitrogen atom carrying them
may form a monocyclic, saturated or partly unsaturated 5- to
6-membered ring system or a bicyclic saturated or partly
unsaturated 9- to 10 membered ring system whose individual members
of the ring systems may be replaced by one to three atoms or atomic
groups from the series --CHR4-, --CR4R5-, .dbd.(C--R4)-, --NR5-,
--C(.dbd.O)--, --O--, --S--, with the proviso that two units from
the series --O--, --S--, may not be adjacent;
[0045] R3, R3a identically or differently hydrogen,
(C.sub.1-C.sub.6)-alkyl, benzyl;
[0046] R4, R5 identically or differently (C.sub.1-C.sub.10)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, halogen, (C.sub.1-C.sub.3)-haloalkyl,
(C.sub.1-C.sub.3)-haloalkyloxy, COOR3, nitro, cyano, aryl,
heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.1-C.sub.3)-alkylene-aryl,
(C.sub.1-C.sub.3)-alkylene-heteroaryl, where aryl, heteroaryl or
cycloalkyl may be substituted one or more times by preferably
halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
O--(C.sub.1-C.sub.3)-alkylene-aryl, trifluoromethyl,
trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl, amino;
[0047] the tautomeric forms of the compounds and their
physiologically tolerated salts.
[0048] Very particular preference is given to compounds of the
formula I in which the meanings are [0049] X identically or
differently =C(--R)-- or .dbd.N--, where one X is .dbd.N--; [0050]
W--(C.dbd.O)--; [0051] R identically or differently hydrogen,
halogen, (C.sub.1-C.sub.6)-alkyl, trifluoro-methyl, hydroxy, amino,
cyano, COOR3, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl or unsubstituted or mono- or
poly-F-substituted (C.sub.1-C.sub.6)-alkyloxy; [0052] R1
(C.sub.6-C.sub.12)-alkyl, Y-phenyl, where phenyl may be substituted
one to three times by preferably halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, hydroxy, amino,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
[0053] Y--CH.sub.2--; [0054] R2 hydrogen, (C.sub.5-C.sub.10-alkyl;
or [0055] R1 and R2 together with the nitrogen atom carrying them
may form a monocyclic, saturated 5- to 6-membered ring system or a
bicyclic saturated or partly unsaturated 9- to 10 membered ring
system whose individual members of the ring systems may be replaced
by one to three atoms or atomic groups from the series --CHR4-,
--CR4R5-, .dbd.(C--R4)-, --NR5-, --C(.dbd.O)--, --O--, --S--, with
the proviso that two units from the series --O--, --S-- may not be
adjacent; [0056] R3, R3a identically or differently hydrogen,
(C.sub.1-C.sub.6)-alkyl; [0057] R4, R5 identically or differently
(C.sub.1-C.sub.10-alkyl, (C.sub.1-C.sub.6)-alkyloxy, halogen,
trifluoromethyl, trifluoromethoxy, COOR3, cyano, aryl, cyclopropyl,
(C.sub.1-C.sub.3)-alkylene-phenyl, where aryl may be substituted
one or more times by preferably halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, O--(C.sub.1-C.sub.3)-alkylene-phenyl,
trifluoromethyl, trifluoromethoxy, hydroxy,
mono-(C.sub.1-C.sub.6)-alkylaminocarbonyl,
di-(C.sub.2-C.sub.8)-alkylaminocarbonyl,
CO--(C.sub.1-C.sub.6)-alkyl, CO--O--(C.sub.1-C.sub.6)-alkyl, amino;
[0058] the tautomeric forms of the compounds and their
physiologically tolerated salts.
[0059] Very particular preference is also given to compounds of the
formula I in which [0060] (6)NR1R2 is a monocyclic saturated 5- to
6-membered ring system which comprises in position 4 at atom or
atomic member from the series --CHR4-, --CR4R5-, --NR5-,
--(C.dbd.O) or is a bicyclic saturated or partly unsaturated 9- to
10-membered ring system whose individual members of the ring system
may be replaced by one or two atomic groups from the series
--CHR4-, --(C.dbd.R4)-, .dbd.C--R4)=.-MR5-.-(C.dbd.O)--.
[0061] Very particular preference is further given to compounds of
the formula I in which [0062] R1 and R2 together with the nitrogen
atom carrying them form a monocyclic, saturated 5- to 6-membered
ring system or a bicyclic saturated or partly unsaturated 9- to
10-membered ring system, whose individual members of the ring
systems may be replaced by an atomic group from the series --CHR4-,
--NR5.
[0063] An especially very particularly preferred embodiment are
compounds of the formula I in which [0064] X is identically or
differently .dbd.C(--R--)-- or .dbd.N--, where one X is .dbd.N--
[0065] R is identically or differently hydrogen, Cl; [0066] NR1 R2
is piperidine which comprises in position 4 the atomic member
--CHR4-; or is piperazine which comprises in position 4 the atomic
member --NR5; [0067] R4, R5 are (C.sub.1-C.sub.8)-alkyl, phenyl,
--(C.sub.1-C.sub.2)-alkylene-phenyl, naphthyl, pyrrolidin-2-one,
benzofuranyl, where phenyl may be substituted once, twice or three
times by methyl, ethyl, t-butyl, methoxy, ethoxy, F, Cl, Br, OH,
CF.sub.3, NH.sub.2, CO--OCH.sub.3, CO--CH.sub.3, phenyl,
--O-benzyl.
[0068] Particular preference is also given especially to the
compounds of the formula I in which [0069] NR1 R2 is piperidine
which comprises in position 4 the atomic member --CHR4-, or is
piperazine which comprises in position 4 the atomic member --NR5;
[0070] R4, R5 are methyl or phenyl which may be substituted once or
twice by methyl, methoxy, ethoxy, F, Cl, Br, OH, CF.sub.3,
NH.sub.2, CO--OCH.sub.3, CO--CH.sub.3, phenyl, --O-benzyl.
[0071] A further especially very particularly preferred embodiment
are compounds of the formula I in which the meanings are [0072] X
identically or differently .dbd.C(--R--)-- or .dbd.N--, where one X
is .dbd.N--; [0073] R identically or differently hydrogen, Cl;
[0074] NR1R2 is tetrahydroquinoline or tetrahydroisoquinoline which
may be substituted once or twice by methoxy.
[0075] Particular preference is further given to compounds of the
formula I in which [0076] R2 is hydrogen.
[0077] Very particular preference is also given to compounds of the
formula I in which [0078] R1 is (C.sub.6-C.sub.12)-alkyl, Y-phenyl,
where phenyl may be substituted one to three times by preferably
halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyloxy,
hydroxy, amino, (C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
[0079] Y is --CH.sub.2--; [0080] R2 is hydrogen.
[0081] Very particular preference is further given to compounds of
the formula I in which [0082] R1 is (C.sub.6-C.sub.8)-alkyl,
Y-phenyl, where phenyl may be substituted one to three times by
preferably halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyloxy, hydroxy, amino,
(C.sub.1-C.sub.6)-alkyloxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonyl, cyano, trifluoromethyl,
trifluoromethyloxy, (C.sub.1-C.sub.6)-alkylsulfonyl, aminosulfonyl;
[0083] Y is --CH.sub.2--; [0084] R2 is hydrogen.
[0085] A further especially very particularly preferred embodiment
is compounds of the formula I in which [0086] X is identically or
differently .dbd.C(--R--)-- or .dbd.N--, where one X is .dbd.N--;
[0087] R is identically or differently hydrogen, Cl; [0088] R1 is
hexyl, Y-phenyl, where phenyl may be substituted by methyl,
preferably in position 2; [0089] Y is --CH.sub.2--; [0090] R2 is
hydrogen.
[0091] Very particular preference is also given to compounds of the
formula I in which [0092] X in position 4, 5 and 6 is identically
or differently .dbd.C(--R)--, and in position 7 is .dbd.N--.
[0093] Further very particularly preferred compounds of the formula
I are those in which [0094] X optionally in position 4 or 7 is
.dbd.C(--R)-- with R=hydrogen or .dbd.N--, and in position 5 or 6
is .dbd.C(--R)-- with R not hydrogen.
[0095] The invention relates to compounds of the formula I in the
form of their salts, racemates, racemic mixtures and pure
enantiomers, and to their diastereomers and mixtures thereof.
[0096] The alkyl radicals in the substituents R, R1, R2, R3, R3a,
R4, R5 may be either straight-chain or branched. Methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,
octyl and dodecyl may be mentioned by way of example. Halogen is
fluorine, chlorine, bromine or iodine, in particular fluorine or
chlorine.
[0097] Haloalkyl means an alkyl radical which is substituted one or
more times by halogen.
[0098] An aryl radical means a phenyl, naphthyl or biphenyl
radical.
[0099] The aryl radicals may be substituted one or more times by
suitable groups such as, for example: F, Cl, Br, I, CF.sub.3, OH,
OCF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CONRC.sub.1-C.sub.6)alkyl].sub.2, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-aryl, [0100] PO.sub.3H.sub.2, SO.sub.3H,
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.n-aryl,
S--(CH.sub.2).sub.n-heterocycle, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2,
SO.sub.2--N((CH.sub.2).sub.n-(heterocycle).sub.2,
NH--(CH.sub.2).sub.n-aryl, NH--(CH.sub.2).sub.n-heterocycle,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
N((C.sub.1-C.sub.6)alkyl)(CH.sub.2).sub.n-heterocycle, [0101]
C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocycle,
NH--COO-aryl, NH--COO-heterocycle,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl, NH--CO--NH-aryl,
NH--CO--NH-heterocycle, aryl, O--(CH.sub.2).sub.n-aryl,
O--(CH.sub.2).sub.n-heterocycle, where n may be 0-6, where the aryl
radical or heterocyclic radical may be substituted one to 3 times
by 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,
CONH.sub.2.
[0102] Heterocycle is a mono- or bicyclic ring system having 5 to
12 ring members in which at least one atom in the ring system is a
heteroatom from the series N, O and S. This definition also
includes ring systems in which the heterocycle is fused to a
benzene nucleus. (C.sub.5-C.sub.7)-heterocycle is a monocyclic,
(C.sub.8-C.sub.12)-heterocycle is a bicyclic ring system.
[0103] Heteroaryl is a subgroup of heterocycle and is a mono- or
bicyclic aromatic ring system having 5 to 12 ring members, in which
at least one atom in the ring system is a heteroatom from the
series N, O and S.
[0104] Preferred heteroaryl radicals are thienyl and pyridyl, in
particular thienyl.
[0105] Suitable "heterocyclic rings" or "heterocyclic radicals" are
azocinyl, benzimidazolyl, benzofuryl, benzothienyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl,
carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl,
pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,
pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and
xanthenyl.
[0106] Pyridyl is both 2-, 3- and 4-pyridyl. Thienyl is both 2- and
3-thienyl. Furyl is both 2- and 3-furyl.
[0107] Also included are the corresponding N-oxides of these
compounds, i.e. for example 1-oxy-2-, 3- or 4-pyridyl.
[0108] The heterocyclic radicals or the heteroaromatic radicals may
be substituted one or more times by suitable groups such as, for
example, F, Cl, Br, I, CF.sub.3, OH, OCF.sub.3, NO.sub.2, CN, COOH,
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.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-aryl, [0109] PO.sub.3H.sub.2, SO.sub.3H,
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.n-Aryl,
S--(CH.sub.2).sub.n-heterocycle, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2,
SO.sub.2--N((CH.sub.2).sub.n-(heterocycle).sub.2,
NH--(CH.sub.2).sub.n-aryl, NH--(CH.sub.2).sub.n-heterocycle,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle, [0110]
C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alky1).sub.2, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocycle,
NH--COO-aryl, NH--COO-heterocycle,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl, NH--CO--NH-aryl,
NH--CO--NH-heterocycle, aryl, O--(CH.sub.2).sub.n-aryl,
O--(CH.sub.2).sub.n-heterocycle, where n may be 0-6, where the aryl
radical or heterocyclic radical may be substituted one to 3 times
by 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,
CONH.sub.2.
[0111] A cycloalkyl radical means a ring system which comprises one
or more rings, which is saturated or partly unsaturated (having one
or two double bonds) and which is composed exclusively of carbon
atoms, such as, for example, cyclopropyl, cyclopentyl,
cyclopentenyl, cyclohexyl or adamantyl.
[0112] The cycloalkyl radicals may be substituted one or more times
by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3,
OH, OCF.sub.3, NO.sub.2, CN, COOH, 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.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-aryl, [0113] PO.sub.3H.sub.2, SO.sub.3H,
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.n-aryl,
S--(CH.sub.2).sub.n-heterocycle, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2,
SO.sub.2--N((CH.sub.2).sub.n-(heterocycle).sub.2,
NH--(CH.sub.2).sub.n-aryl, NH--(CH.sub.2).sub.n-heterocycle,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle, [0114]
C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocycle,
NH--COO-aryl, NH--COO-heterocycle,
NH--CO--NH-(C.sub.1-C.sub.6)-alkyl, NH--CO--NH-aryl,
NH--CO--NH-heterocycle, aryl, O--(CH.sub.2).sub.n-aryl,
O--(CH.sub.2).sub.n-heterocycle, where n may be 0-6, where the aryl
radical or heterocyclic radical may be substituted one to 3 times
by 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,
CONH.sub.2.
[0115] Bicycle is a partly unsaturated bicyclic ring system having
8 to 14 ring members which has exclusively carbon atoms as ring
members. Examples which may be mentioned are the
tetrahydronaphthyl, alpha- or beta-tetralone, indanyl or
indan-1-onyl radical. Preferred bicyclic radicals are
tetrahydronaphthyl and indanyl.
[0116] The bicyclic radicals may be substituted one or more times
by suitable groups such as, for example: F, Cl, Br, I, CF.sub.3,
OH, OCF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)alkyl,
CONRC.sub.1-C.sub.6)alkyl].sub.2, (C.sub.3-C.sub.10)-cycloalkyl,
(C.sub.1-C.sub.10)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, O--CO--(C.sub.1-C.sub.6)-alkyl,
O--CO--(C.sub.1-C.sub.6)-aryl, [0117] PO.sub.3H.sub.2, SO.sub.3H,
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.n-aryl,
S--(CH.sub.2).sub.n-heterocycle, SO--(C.sub.1-C.sub.6)-alkyl,
SO--(CH.sub.2).sub.n-aryl, SO--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2).sub.n-aryl,
SO.sub.2--(CH.sub.2).sub.n-heterocycle,
SO.sub.2--NH(CH.sub.2).sub.n-aryl,
SO.sub.2--NH(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
SO.sub.2--N(C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle,
SO.sub.2--N((CH.sub.2).sub.n-aryl).sub.2,
SO.sub.2--N((CH.sub.2).sub.n-(heterocycle).sub.2,
NH--(CH.sub.2).sub.n-aryl, NH--(CH.sub.2).sub.n-heterocycle,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-aryl,
N((C.sub.1-C.sub.6)-alkyl)(CH.sub.2).sub.n-heterocycle,
C(NH)(NH.sub.2), NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N((C.sub.1-C.sub.6)-alkyl).sub.2, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--COO--(C.sub.1-C.sub.6)-alkyl, NH--CO-aryl, NH--CO-heterocycle,
NH--COO-aryl, NH--COO--heterocycle,
NH--CO--NH--(C.sub.1-C.sub.6)-alkyl, NH--CO--NH-aryl,
NH--CO--NH-heterocycle, aryl, O--(CH.sub.2).sub.n-aryl,
O--(CH.sub.2).sub.n-heterocycle, where n may be 0-6, where the aryl
radical or heterocyclic radical may be substituted one to 3 times
by 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,
CONH.sub.2.
[0118] 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.
[0119] 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) and alkaline earth metal salts (such as magnesium and
calcium salts) and salts of trometamol
(2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine
or ethylenediamine.
[0120] 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.
[0121] The term "physiologically functional derivative" used herein
refers to any physiologically tolerated derivative of a compound of
the invention of the formula I, 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.
[0122] Physiologically functional derivatives also include prodrugs
of the compounds of the invention as, for example, described 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.
[0123] 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.
[0124] 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.
Use
[0125] The compounds of the invention of the formula I have a
surprising inhibitory effect on hormone sensitive lipase, HSL, an
allosteric enzyme in adipocytes which is inhibited by insulin and
is responsible for the breakdown of fats in fat cells and thus for
transferring fat constituents into the blood stream. Inhibition of
this enzyme is therefore equivalent to an insulin-like effect of
the compounds of the invention, eventually leading to a reduction
of free fatty acids in the blood and of blood glucose. They can
therefore be employed for metabolic derangements such as, for
example, for non-insulin-dependent diabetes mellitus, for diabetic
syndrome and for direct pancreatic damage.
[0126] The compounds of the invention of the formula I, in
particular those in which R2 is hydrogen, may have an inhibitory
effect on endothelial lipase (EL). The preferred substrate for EL
is HDL, which has antiatherosclerotic activity. A reduction in the
HDL level leads to progression of atherosclerosis and its sequelae
such as metabolic syndrome and coronary heart disease. An
inhibition of EL should thus lead to prevention of atherosclerotic
disorders.
[0127] The compounds of the invention of the formula I may also
have an inhibitory effect on triglyceride lipase.
[0128] It has further been found that the inhibitory effect of the
compounds of the invention of the formula I is selective in
relation to other lipases.
[0129] Compounds of this type are particularly suitable for the
treatment and/or prevention of [0130] 1.--Disorders of fatty acid
metabolism and glucose utilization disorders [0131] 2. Disorders of
the insulin sensitivity of myo-, adipo- and hepatocytes (insulin
resistance)-metabolic syndrome [0132] 3. Diabetes mellitus,
especially type 2 diabetes, including the prevention of the
sequelae associated therewith.
[0133] Particular aspects in this connection are
[0134] hyperglycemia,
[0135] improvement in insulin resistance,
[0136] improvement in glucose tolerance,
[0137] protection of the pancreatic .beta. cells
[0138] prevention of macro- and microvascular disorders [0139] 4.
Dyslipidemias and their sequelae such as, for example,
atherosclerosis, coronary heart disease, cerebrovascular disorders
etc, especially those (but not restricted thereto) which are
characterized by one or more of the following factors:
[0140] high plasma triglyceride concentrations, high postprandial
plasma triglyceride concentrations
[0141] low HDL cholesterol concentration
[0142] low apoA lipoprotein concentrations
[0143] high LDL cholesterol concentrations
[0144] small dense LDL cholesterol particles
[0145] high apoB lipoprotein concentrations [0146] 5. Various other
conditions which may be associated with the metabolic syndrome,
such as:
[0147] obesity (excess weight), including central obesity
[0148] thromboses, hypercoagulable and prothrombotic stages
(arterial and venous)
[0149] high blood pressure
[0150] heart failure such as, for example (but not restricted
thereto), following myocardial infarction, hypertensive heart
disease or cardiomyopathy [0151] 6. Other disorders or conditions
in which inflammatory reactions or cell differentiation is for
example involved are:
[0152] atherosclerosis such as, for example (but not restricted
thereto), coronary sclerosis including angina pectoris or
myocardial infarction, stroke
[0153] vascular restenosis or reocclusion
[0154] chronic inflammatory bowel diseases such as, for example,
Crohn's disease and ulcerative colitis
[0155] pancreatitis
[0156] other inflammatory states
[0157] retinopathy
[0158] adipose cell tumors
[0159] adipose cell carcinomas such as, for example,
liposarcomas
[0160] solid tumors and neoplasms such as, for example (but not
restricted thereto), carcinomas of the gastrointestinal tract, of
the liver, of the biliary tract and of the pancreas, endocrine
tumors, carcinomas of the lungs, of the kidneys and the urinary
tract, of the genital tract, prostate carcinomas etc
[0161] acute and chronic myeloproliferative disorders and
lymphomas
[0162] angiogenesis
[0163] neurodegenerative disorders
[0164] Alzheimer's disease
[0165] multiple sclerosis
[0166] Parkinson's disease
[0167] erythemato-squamous dermatoses such as, for example,
psoriasis
[0168] acne vulgaris
[0169] other skin disorders and dermatological conditions which are
modulated by PPAR
[0170] eczemas and neurodermatitis
[0171] dermatitis such as, for example, seborrheic dermatitis or
photodermatitis
[0172] keratitis and keratoses such as, for example, seborrheic
keratoses, senile keratoses, actinic keratosis, photo-induced
keratoses or keratosis follicularis
[0173] keloids and keloid prophylaxis
[0174] warts, including condylomata or condylomata acuminata
[0175] human papilloma viral (HPV) infections such as, for example,
venereal papillomata, viral warts such as, for example, molluscum
contagiosum, leukoplakia
[0176] papular dermatoses such as, for example, lichen planus
[0177] skin cancer such as, for example, basal-cell carcinomas,
melanomas or cutaneous T-cell lymphomas
[0178] localized benign epidermal tumors such as, for example,
keratoderma, epidermal naevi
[0179] chilblains
[0180] high blood pressure
[0181] syndrome X
[0182] polycystic ovary syndrome (PCOS)
[0183] asthma
[0184] osteoarthritis
[0185] lupus erythematosus (LE) or inflammatory rheumatic disorders
such as, for example, rheumatoid arthritis
[0186] vasculitis
[0187] wasting (cachexia)
[0188] gout
[0189] ischemia/reperfusion syndrome
[0190] acute respiratory distress syndrome (ARDS)
Formulations
[0191] The amount of a compound of the invention 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 to 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
0.05 to 1000 mg, typically from 0.5 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 the invention. 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.
[0192] 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 formulae I or II 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,
hydroxypropylmethyl-cellulose phthalate and anionic polymers of
methacrylic acid and methyl methacrylate.
[0193] Suitable pharmaceutical preparations 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.
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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%.
[0198] Transdermal administration is also possible. Pharmaceutical
compositions suitable for transdermal uses can be in the form of
single patches which are suitable for long-term close contact with
the patient's epidermis. Such patches 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).
[0199] The compounds of the formulae I are distinguished by
favorable effects on metabolic disorders. They beneficially
influence lipid and sugar metabolism, in particular they lower the
triglyceride level and are suitable for the prevention and
treatment of type II diabetes and arteriosclerosis and the diverse
sequealae thereof.
Combinations with Other Medicaments
[0200] The compounds of the invention can be administered alone or
in combination with one or more further pharmacologically active
ingredients. In particular the compounds of the invention can be
administered with active ingredients, which have a similar
pharmacological effect to themselves. For example, they can be
administered in combination with active ingredients which have
favorable effects on metabolic disturbances or disorders frequently
associated therewith. Examples of such medicaments are [0201] 1.
medicaments which lower blood glucose, antidiabetics, [0202] 2.
active ingredients for the treatment of dyslipidemias, [0203] 3.
antiatherosclerotic medicaments, [0204] 4. antiobesity agents,
[0205] 5. antiinflammatory active ingredients [0206] 6. active
ingredients for the treatment of malignant tumors [0207] 7.
antithrombotic active ingredients [0208] 8. active ingredients for
the treatment of high blood pressure [0209] 9. active ingredients
for the treatment of heart failure and [0210] 10. active
ingredients for the treatment and/or prevention of complications
caused by diabetes or associated with diabetes. [0211] 11.active
ingredients for the treatment of neurodegenerative diseases [0212]
12. active ingredients for the treatment of diseases of the central
nervous system [0213] 13. active ingredients for the treatment of
dependence on drugs, nicotine and alcohol [0214] 14. analgesics
[0215] They can be combined with the compounds of the invention of
the formula I in particular for a synergistic improvement in the
effect. Administration of the active ingredient combination can
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.
[0216] Further active ingredients particularly suitable for the
combination products are: All antidiabetics which are mentioned in
the Rote Liste 2006, chapter 12; all weight-reducing
agents/appetite suppressants which are mentioned in the Rote Liste
2006, chapter 1; all lipid-lowering agents which are mentioned in
the Rote Liste 2006, chapter 58. They can be combined with the
compound of the invention of the formula I in particular for a
synergistic improvement in the effect. Administration of the active
ingredient combination can 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 mentioned hereinafter are disclosed in the
USP Dictionary of USAN and International Drug Names, US
Pharmacopeia, Rockville 2001.
[0217] Antidiabetics include insulin and insulin derivatives such
as, for example, Lantus.RTM. (see www.lantus.com) or HMR 1964 or
those described in WO 2005/005477 (Novo Nordisk), fast-acting
insulins (see U.S. Pat. No. 6,221,633), inhalable insulins such as,
for example, Exubera.RTM. or oral insulins such as, for example,
IN-105 (Nobex) or Oral-lyn.TM. (Generex Biotechnology),
GLP-1-derivatives such as, for example, exenatide, liraglutide or
those which have been disclosed in WO 98/08871 or WO 2005/027978 of
Novo Nordisk NS, in WO 01/04156 of Zealand or in WO 00/34331 of
Beaufour-Ipsen, Pramlintide Acetate (Symlin; Amylin
Pharmaceuticals), and orally effective hypoglycemic active
ingredients.
[0218] The active ingredients include preferably [0219]
sulfonylureas, [0220] biguanides, [0221] meglitinides, [0222]
oxadiazolidinediones, [0223] thiazolidinediones, [0224] glucosidase
inhibitors, [0225] inhibitors of glycogen phosphorylase, [0226]
glucagon antagonists, [0227] glucokinase activators, [0228]
inhibitors of fructose-1,6-bisphosphatase, [0229] modulators of
glucose transporter 4 (GLUT4), [0230] inhibitors of
glutamine-fructose-6-phosphate amidotransferase (GFAT), GLP-1
agonists, [0231] potassium channel openers such as, for example,
those which have been disclosed in WO 97/26265 and WO 99/03861 of
Novo Nordisk NS, [0232] inhibitors of dipeptidylpeptidase IV
(DPP-IV), [0233] insulin sensitizers, [0234] inhibitors of liver
enzymes involved in stimulating gluconeogenesis and/or
glycogenolysis, [0235] modulators of glucose uptake, of glucose
transport and of glucose reabsorption, inhibitors of 11.beta.-HSD1,
[0236] inhibitors of protein tyrosine phosphatase 1B (PTP1B),
[0237] modulators of the sodium-dependent glucose transporter 1 or
2 (SGLT1, SGLT2), [0238] compounds which alter lipid metabolism
such as antihyperlipidemic active [0239] ingredients and
antilipidemic active ingredients, [0240] compounds which reduce
food intake, [0241] compounds which increase thermogenesis, [0242]
PPAR and RXR modulators and [0243] active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
[0244] In one embodiment of the invention, the compound of the
formula I is administered in combination with an HMGCoA reductase
inhibitor such as simvastatin, fluvastatin, pravastatin,
lovastatin, atorvastatin, cerivastatin, rosuvastatin or
L-659699.
[0245] In one embodiment of the invention, the compound of the
formula I is administered in combination with a cholesterol
absorption inhibitor such as, for example, ezetimibe, tiqueside,
pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate;
Forbes Medi-Tech, WO 2005/042692), MD-0727 (Microbia Inc., WO
2005/021497) or with compounds as described in WO 2002/066464
(Kotobuki Pharmaceutical Co. Ltd.), WO 2005/062824 (Merck &
Co.) or WO 2005/061451 and WO 2005/061452 (AstraZeneca AB).
[0246] In one embodiment of the invention, the compound of the
formula I is administered in combination with a PPAR gamma agonist
such as, for example, rosiglitazone, pioglitazone, JTT-501, GI
262570, R-483 or CS-011 (rivoglitazone).
[0247] In one embodiment of the invention, the compound of the
formula I is administered in combination with a PPAR alpha agonist
such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or
DRF-10945.
[0248] In one embodiment of the invention, the compound of the
formula I is administered in combination with a mixed PPAR
alpha/gamma agonist such as, for example, muraglitazar,
tesaglitazar, naveglitazar, LY-510929, ONO-5129, E-3030 or as
described in WO 00/64888, WO 00/64876, WO 03/020269, WO
2004/075891, WO 2004/076402, WO 2004/075815, WO 2004/076447, WO
2004/076428, WO 2004/076401, WO 2004/076426, WO 2004/076427, WO
2006/018118, WO 2006/018115, and WO 2006/018116 or in J. P. Berger
et al., TRENDS in Pharmacological Sciences 28(5), 244-251,
2005.
[0249] In one embodiment of the invention, the compound of the
formula I is administered in combination with a PPAR delta agonist
such as, for example, GW-501516, or as described in WO 2005/097762,
WO 2005/097786, W02005/097763, WO 2006/029699.
[0250] In one embodiment of the invention, the compound of the
formula I is administered in combination with metaglidasen or with
MBX-2044 or other partial PPAR gamma agonists/antagonists.
[0251] In one embodiment of the invention, the compound of the
formula I is administered in combination with a fibrate such as,
for example, fenofibrate, clofibrate or bezafibrate.
[0252] In one embodiment of the invention, the compound of the
formula I is administered in combination with an MTP inhibitor such
as, for example, implitapide, BMS-201038, R-103757 or those
described in WO 2005/085226.
[0253] In one embodiment of the invention, the compound of the
formula I is administered in combination with a CETP inhibitor such
as, for example, torcetrapib or JTT-705.
[0254] In one embodiment of the invention, the compound of the
formula I is administered in combination with a bile acid
absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744,
U.S. Pat. No. 6,221,897 or WO 00/61568), such as, for example, HMR
1741 or those as described in DE 10 2005 033099.1 and DE 10 2005
033100.9.
[0255] In one embodiment of the invention, the compound of the
formula I is administered in combination with a polymeric bile acid
adsorbent such as, for example, cholestyramine or colesevelam.
[0256] In one embodiment of the invention, the compound of the
formula I is administered in combination with an LDL receptor
inducer (see U.S. Pat. No. 6,342,512), such as, for example,
HMR1171, HMR1586 or those as described in WO 2005/097738.
[0257] In one embodiment, the compound of the formula I is
administered in combination with Omacor.RTM. (Omega-3 fatty acids;
highly concentrated ethyl esters of eicosapentaenoic acid and of
docosahexaenoic acid).
[0258] In one embodiment of the invention, the compound of the
formula I is administered in combination with an ACAT inhibitor
such as, for example, avasimibe.
[0259] In one embodiment of the invention, the compound of the
formula I is administered in combination with an antioxidant such
as, for example, OPC-14117, probucol, tocopherol, ascorbic acid,
.beta.-carotene or selenium.
[0260] In one embodiment of the invention, the compound of the
formula I is administered in combination with a vitamin such as,
for example, vitamin B6 or vitamin B12.
[0261] In one embodiment of the invention, the compound of the
formula I is administered in combination with a lipoprotein lipase
modulator such as, for example, ibrolipim (NO-1886).
[0262] In one embodiment of the invention, the compound of the
formula I is administered in combination with an ATP citrate lyase
inhibitor such as, for example, SB-204990.
[0263] In one embodiment of the invention, the compound of the
formula I is administered in combination with a squalene synthetase
inhibitor such as, for example, BMS-188494 or as described in WO
2005/077907.
[0264] In one embodiment of the invention, the compound of the
formula I is administered in combination with a lipoprotein(a)
antagonist such as, for example, gemcabene (CI-1027).
[0265] In one embodiment of the invention, the compound of the
formula I is administered in combination with an HM74A receptor
agonist such as, for example, nicotinic acid.
[0266] In one embodiment of the invention, the compound of the
formula I is administered in combination with a lipase inhibitor
such as, for example, orlistat or cetilistat (ATL-962).
[0267] In one embodiment of the invention, the compound of the
formula I is administered in combination with insulin.
[0268] In one embodiment of the invention, the compound of the
formula I is administered in combination with a sulfonylurea such
as, for example, tolbutamide, glibenclamide, glipizide or
glimepiride.
[0269] In one embodiment of the invention, the compound of the
formula I is administered in combination with a biguanide such as,
for example, metformin.
[0270] In another embodiment of the invention, the compound of the
formula I is administered in combination with a meglitinide such
as, for example, repaglinide or nateglinide.
[0271] In one embodiment of the invention, the compound of the
formula I is 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.
[0272] In one embodiment of the invention, the compound of the
formula I is administered in combination with an a-glucosidase
inhibitor such as, for example, miglitol or acarbose.
[0273] In one embodiment of the invention, the compound of the
formula I is 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.
[0274] In one embodiment of the invention, the compound of the
formula I is administered in combination with more than one of the
aforementioned compounds, e.g. in combination with a sulfonylurea
and metformin, a sulfonylurea and acarbose, repaglinide and
metformin, insulin and a sulfonylurea, insulin and metformin,
insulin and troglitazone, insulin and lovastatin, etc.
[0275] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
glycogen phosphorylase, such as, for example, PSN-357 or FR-258900
or those as described in WO 2003/084922, WO 2004/007455, WO
2005/073229-31 or WO 2005/067932.
[0276] In one embodiment of the invention, the compound of the
formula I is administered in combination with glucagon receptor
antagonists such as, for example, A-770077, NNC-25-2504 or as
described in WO 2004/100875 or WO 2005/065680.
[0277] In one embodiment of the invention, the compound of the
formula I is administered in combination with activators of
glucokinase, such as, for example, RO-4389620, LY-2121260 (WO
2004/063179), PSN-105, PSN-110, GKA-50 or those as are described
for example by Prosidion in WO 2004/072031, WO 2004/072066, WO
05/103021 or WO 06/016178, by Roche in WO 00/058293, WO 00/183465,
WO 00/183478, WO 00/185706, WO 00/185707, WO 01/044216, GB
02385328, WO 02/008209, WO 02/014312, WO 02/46173, WO 02/48106, DE
10259786, WO 03/095438, U.S. Pat. No. 04,067,939 or WO 04/052869,
by Novo Nordisk in EP 1532980, WO 03/055482, WO 04/002481, WO
05/049019, WO 05/066145 or WO 05/123132, by Merck/Banyu in WO
03/080585, WO 03/097824, WO 04/081001, WO 05/063738 or WO
05/090332, by Eli Lilly in WO 04/063194, or by Astra Zeneca in WO
01/020327, WO 03/000262, WO 03/000267, WO 03/015774, WO 04/045614,
WO 04/046139, WO 05/044801, WO 05/054200, WO 05/054233, WO
05/056530, WO 05/080359, WO 05/080360 or WO 05/121110.
[0278] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
gluconeogenesis, such as, for example, FR-225654.
[0279] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
fructose-1,6-bisphosphatase (FBPase), such as, for example,
CS-917.
[0280] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of glucose
transporter 4 (GLUT4), such as, for example, KST-48 (D.-O. Lee et
al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
[0281] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
glutamine-fructose-6-phosphate amidotransferase (GFAT), as are
described for example in WO 2004/101528.
[0282] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
dipeptidylpeptidase IV (DPP-IV), such as, for example, vildagliptin
(LAF-237), sitagliptin (MK-0431), saxagliptin (BMS-477118),
GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200,
GW-825964X or as are described in WO 2003/074500, WO 2003/106456,
WO 2004/50658, WO 2005/058901, WO 2005/012312, WO 2005/012308,
PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002,
PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10
2005 012873.4.
[0283] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
11-beta-hydroxysteroid dehydrogenase 1 (11.beta.-HSD1), such as,
for example, BVT-2733 or those as are described for example in WO
2001/90090-94, WO 2003/43999, WO 2004/112782, WO 2003/44000, WO
2003/44009, WO 2004/112779, WO 2004/113310, WO 2004/103980, WO
2004/112784, WO 2003/065983, WO 2003/104207, WO 2003/104208, WO
2004/106294, WO 2004/011410, WO 2004/033427, WO 2004/041264, WO
2004/037251, WO 2004/056744, WO 2004/065351, WO 2004/089367, WO
2004/089380, WO 2004/089470-71, WO 2004/089896, WO 2005/016877 or
WO 2005/097759.
[0284] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of protein
tyrosine phosphatase 1B (PTP1B), as are described for example in WO
2001/19830-31, WO 2001/17516, WO 2004/506446, WO 2005/012295,
PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151,
PCT/EP2005/01294 or DE 10 2004 060542.4.
[0285] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of the
sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), such
as, for example, KGA-2727, T-1095 and SGL-0010 or as are described
for example in WO 2004/007517, WO 2004/52903, WO 2004/52902, WO
2005/121161, WO 2005/085237, JP2004359630 or by A. L. Handlon in
Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.
[0286] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
hormone-sensitive lipase (HSL) as described for example in WO
01/17981, WO 01/66531, WO 2004/035550, WO 2005/073199 or WO
03/051842.
[0287] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
acetyl-CoA carboxylase (ACC), such as, for example, those as
described in WO 1999/46262, WO 2003/72197, WO 2003/072197 or WO
2005/044814.
[0288] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
phosphoenolpyruvate carboxykinase (PEPCK), such as, for example,
those as described in WO 2004/074288.
[0289] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
glycogen synthase kinase 3 beta (GSK-3 beta), as described for
example in US2005222220, WO 2004/046117, WO 2005/085230, WO
2005/111018, WO 2003/078403, WO 2004/022544, WO 2003/106410, WO
2005/058908, US2005038023, WO 2005/009997, US2005026984, WO
2005/000836, WO 2004/106343, EP1460075, WO 2004/014910, WO
2003/076442, WO 2005/087727 or WO 2004/046117.
[0290] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
protein kinase C beta (PKC beta), such as, for example,
ruboxistaurin.
[0291] In one embodiment of the invention, the compound of the
formula I is administered in combination with an endothelin A
receptor antagonist such as, for example, avosentan (SPP-301).
[0292] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
"I-kappaB kinase" (IKK inhibitors), as are described for example in
WO 2001/000610, WO 2001/030774, WO 2004/022553 or WO
2005/097129.
[0293] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of the
glucocorticoid receptor, like those described for example in WO
2005/090336.
[0294] In a further embodiment of the invention, the compound of
the formula I is administered in combination with CART modulators
(see "Cocaine-amphetamine-regulated transcript influences energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A. et
al.: Hormone and Metabolic Research (2001), 33(9), 554-558); NPY
antagonists such as, for example, naphthalene-1-sulfonic acid
{4-[(4-amino-quinazolin-2-ylamino)methyl]cyclohexylmethyl}amide
hydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogous
compounds, such as, for example, CJC-1682 (PYY3-36 conjugated with
human serum albumin via Cys34), CJC-1643 (derivative of PYY3-36
which conjugates in vivo to serum albumin) or those as are
described in WO 2005/080424; [0295] cannabinoid receptor 1
antagonists such as, for example, rimonabant, SR147778 or those as
are described for example in EP 0656354, WO 00/15609, WO 02/076949,
WO 2005/080345, WO 2005/080328, WO 2005/080343, WO 2005/075450, WO
2005/080357, WO 2001/70700, WO 2003/026647-48, WO 2003/02776, WO
2003/040107, WO 2003/007887, WO 2003/027069, U.S. Pat. No.
6,509,367, WO 2001/32663, WO 2003/086288, WO 2003/087037, WO
2004/048317, WO 2004/058145, WO 2003/084930, WO 2003/084943, WO
2004/058744, WO 2004/013120, WO 2004/029204, WO 2004/035566, WO
2004/058249, WO 2004/058255, WO 2004/058727, WO 2004/069838,
US20040214837, US20040214855, US20040214856, WO 2004/096209, WO
2004/096763, WO 2004/096794, WO 2005/000809, WO 2004/099157,
US20040266845, WO 2004/110453, WO 2004/108728, WO 2004/000817, WO
2005/000820, US20050009870, WO 2005/00974, WO 2004/111033-34, WO
2004/11038-39, WO 2005/016286, WO 2005/007111, WO 2005/007628,
US20050054679, WO 2005/027837, WO 2005/028456, WO 2005/063761-62,
WO 2005/061509 or WO 2005/077897; [0296] 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-chlorophenyl)-2-oxoethyl]amide; (WO 01/91752)) or LB53280,
LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those
that are described in WO 2005/060985, WO 2005/009950, WO
2004/087159, WO 2004/078717, WO 2004/078716, WO 2004/024720,
US20050124652, WO 2005/051391, WO 2004/112793, WOUS20050222014,
US20050176728, US20050164914, US20050124636, US20050130988,
US20040167201, WO 2004/005324, WO 2004/037797, WO 2005/042516, WO
2005/040109, WO 2005/030797, US20040224901, WO 2005/01921, WO
2005/09184, WO 2005/000339, EP1460069, WO 2005/047253, WO
2005/047251, EP1538159, WO 2004/072076, WO 2004/072077 or WO
2006/024390; [0297] orexin receptor antagonists (e.g.
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea
hydrochloride (SB-334867-A) or those as are described for example
in WO 2001/96302, WO 2001/85693, WO 2004/085403 or WO 2005/075458);
histamine H3 receptor agonists (e.g.
3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-y-
l)propan-1-one oxalic acid salt (WO 00/63208) or those as are
described in WO 2000/64884, WO 2005/082893); [0298] CRF antagonists
(e.g.
[2-methyl-9-(2,4,6-trimethylpheny1)-9H-1,3,9-triazafluoroen-4-yl]dipropyl-
amine (WO 00/66585)); [0299] CRF BP antagonists (e.g. urocortin);
[0300] urocortin agonists; [0301] .beta.3 agonists (such as, for
example,
1-(4-chloro-3-methanesulfonylmethylpheny1)-2-[2-(2,3-dimethyl-1H-indol-6--
yloxy)ethylamino]ethanol hydrochloride (WO 01/83451)); [0302] MSH
(melanocyte-stimulating hormone) agonists; [0303] MCH
(melanin-concentrating hormone) receptor antagonists (such as, for
example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71,
GW-803430 or compounds such as are described in WO 2003/15769, WO
2005/085200, WO 2005/019240, WO 2004/011438, WO 2004/012648, WO
2003/015769, WO 2004/072025, WO 2005/070898, WO 2005/070925, WO
2006/018280, WO 2006/018279, WO 2004/039780, WO 2003/033476, WO
2002/006245, WO 2002/002744, WO 2003/004027 or FR2868780); [0304]
CCK-A agonists (such as, for example,
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcar-
bamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid
salt (WO 99/15525), SR-146131 (WO 0244150) or SSR-125180);
serotonin reuptake inhibitors (e.g. dexfenfluramine); [0305] mixed
serotoninergic and noradrenergic compounds (e.g. WO 00/71549); 5-HT
receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic
acid salt (WO 01/09111); [0306] 5-HT2C receptor agonists (such as,
for example, APD-356, BVT-933 or those as are described in WO
2000/77010, WO 2007/7001-02, WO 2005/019180, WO 2003/064423, WO
2002/42304 or WO 2005/082859); [0307] 5-HT6 receptor antagonists as
are described for example in WO 2005/058858; [0308] bombesin
receptor agonists (BRS-3 agonists); [0309] galanin receptor
antagonists; [0310] growth hormone (e.g. human growth hormone or
AOD-9604); [0311] growth hormone releasing compounds (tertiary
butyl
6-benzyloxy-1-(2-diisopropyl-aminoethylcarbamoyl)-3,4-dihydro-1H-is-
oquinoline-2-carboxylate (WO 01/85695)); [0312] growth hormone
secretagogue receptor antagonists (ghrelin antagonists) such as,
for example, A-778193 or those as are described in WO 2005/030734;
[0313] TRH agonists (see, for example, EP 0 462 884); [0314]
uncoupling protein 2 or 3 modulators; [0315] leptin agonists (see,
for example, Lee, Daniel W.; Leinung, Matthew C.; [0316]
Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a
potential approach to the treatment of obesity. Drugs of the Future
(2001), 26(9), 873-881); [0317] DA agonists (bromocriptine or
Doprexin); [0318] lipase/amylase inhibitors (like those described
for example in WO 00/40569); [0319] inhibitors of diacylglycerol
O-acyltransferases (DGATs) as described for example in
US2004/0224997, WO 2004/094618, WO 2000/58491, WO 2005/044250, WO
2005/072740, JP2005206492 or WO 2005/013907; [0320] inhibitors of
fatty acid synthase (FAS) such as, for example, C75 or those as
described in WO 2004/005277; [0321] oxyntomodulin; [0322]
oleoyl-estrone [0323] or thyroid hormone receptor agonists such as,
for example: KB-2115 or those as described in WO 2005/8279, WO
2001/72692, WO 2001/94293, WO 2003/084915, WO 2004/018421 or WO
2005/092316.
[0324] In one embodiment of the invention, the further 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.
[0325] In one embodiment of the invention, the further active
ingredient is dexamphetamine or amphetamine.
[0326] In one embodiment of the invention, the further active
ingredient is fenfluramine or dexfenfluramine.
[0327] In another embodiment of the invention, the further active
ingredient is sibutramine.
[0328] In one embodiment of the invention, the further active
ingredient is mazindole or phentermine.
[0329] In one embodiment of the invention, the compound of the
formula I is 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 Hoechst, 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.
[0330] In one embodiment of the invention, the compound of the
formula I is administered in combination with PDE inhibitors
(phosphodiesterase), like those described for example in WO
2003/077949 or WO 2005/012485.
[0331] In one embodiment of the invention, the compound of the
formula I is administered in combination with NAR-1 (nicotinic acid
receptor) agonists like those described for example in WO
2004/094429.
[0332] In one embodiment of the invention, the compound of the
formula I is administered in combination with CB2 (cannabinoid
receptor) agonists like those described for example in
US2005/143448.
[0333] In one embodiment of the invention, the compound of the
formula I is administered in combination with histamine 1 agonists
like those described for example in WO 2005/101979.
[0334] In one embodiment of the invention, the compound of the
formula I is administered in combination with bupropion as
described in WO 2006/017504.
[0335] In one embodiment of the invention, the compound of the
formula I is administered in combination with opioid antagonists
like those described for example in WO 2005/107806 or WO
2004/094429.
[0336] In one embodiment of the invention, the compound of the
formula I is administered in combination with neutral endopeptidase
inhibitors like those described for example in WO 2002/02513, WO
2002/06492, WO 2002/040008, WO 2002/040022 or WO 2002/047670.
[0337] In one embodiment of the invention, the compound of the
formula I is administered in combination with NPY inhibitors
(neuropeptide Y) like those described for example in WO
2002/047670.
[0338] In one embodiment of the invention, the compound of the
formula I is administered in combination with sodium/hydrogen
exchange inhibitors like those described for example in WO
2003/092694.
[0339] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of the
glucocorticoid receptor like those described for example in WO
2005/090336.
[0340] In one embodiment of the invention, the compound of the
formula I is administered in combination with nicotine receptor
agonists like those described for example in WO 2004/094429.
[0341] In one embodiment of the invention, the compound of the
formula I is administered in combination with NRIs (norepinephrine
reuptake inhibitors) like those described for example in WO
2002/053140.
[0342] In one embodiment of the invention, the compound of the
formula I is administered in combination with MOA
(E-beta-methoxyacrylate) such as, for example, segeline or like
those described for example in WO 2002/053140.
[0343] In one embodiment of the invention, the compound of the
formula I is administered in combination with antithrombotic active
ingredients such as, for example, clopidogrel.
[0344] 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.
[0345] Some of the formulae for the development codes mentioned
above are detailed hereinafter.
##STR00003## ##STR00004## ##STR00005## ##STR00006## ##STR00007##
##STR00008##
[0346] The activity of the compounds of the invention of the
formula I was tested in the following enzyme assay systems:
HSL Inhibition Sssay
[0347] Preparation of the partially purified HSL:
[0348] Isolated rat fat cells are obtained from epididymal adipose
tissue from untreated male rats (Wistar, 220-250 g) by collagenase
treatment in accordance with published methods (e.g. S. Nilsson et
al., Anal. Biochem. 158, 1986, 399-407; G. Fredrikson et al., J.
Biol. Chem. 256, 1981, 6311-6320; H. Tornquist et al., J. Biol.
Chem. 251, 1976, 813-819). The fat cells from 10 rats are washed
three times by flotation with 50 ml of homogenization buffer (25 ml
Tris/HCl, pH 7.4, 0.25 M sucrose, 1 mM ETDA, 1 mM DTT, 10 .mu.g/ml
leupeptin, 10 .mu.g/ml antipain, 20 .mu.g/ml pepstatin) each time
and finally taken up in 10 ml of homogenization buffer. The fat
cells are homogenized in a Teflon-in-glass homogenizer
(Braun-Melsungen) by 10 strokes at 1500 rpm and 15.degree. C. The
homogenate is centrifuged (Sorvall SM24 tubes, 5000 rpm, 10 min,
4.degree. C.). The subnatant between the layer of fat at the top
and the pellet is removed and the centrifugation is repeated. The
subnatant resulting therefrom is centrifuged again (Sorvall SM24
tubes, 20 000 rpm, 45 min, 4.degree. C.). The subnatant is removed,
and 1 g of heparin-Sepharose (Pharmacia-Biotech, CL-6B, washed
5.times. with 25 mM Tris/HCl, pH 7.4, 150 mM NaCl) is added. After
incubation at 4.degree. C. for 60 min (shaking at intervals of 15
min), the mixture is centrifuged (Sorvall SM24 tubes, 3000 rpm, 10
min, 4.degree. C.). The supernatant is adjusted to pH 5.2 by adding
glacial acetic acid and is incubated at 4.degree. C. for 30 min.
The precipitates are collected by centrifugation (Sorvall SS34, 12
000 rpm, 10 min, 4.degree. C.) and suspended in 2.5 ml of 20 mM
Tris/HCl, pH 7.0, 1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10
.mu.g/ml leupeptin/pepstatin/antipain. The suspension is dialyzed
against 25 mM Tris/HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10
.mu.g/mlleupeptin, pepstatin, antipain at 4.degree. C. overnight
and then loaded onto a hydroxiapatite column (0.1 g per 1 ml of
suspension, equilibrated with 10 mM potassium phosphate, pH 7.0,
30% glycerol, 1 mM DTT). The column is washed with four volumes of
equilibration buffer at a flow rate of 20 to 30 ml/h. The HSL is
eluted with one volume of equilibration buffer containing 0.5 M
potassium phosphate and then dialyzed (see above) and concentrated
5- to 10-fold by ultrafiltration (Amicon Diaflo PM 10 Filter) at
4.degree. C. The partially purified HSL can be stored at
-70.degree. C. for 4 to 6 weeks.
HSL Activity Assay:
[0349] To prepare the substrate, 25-50 .mu.Ci of
[3H]trioleoylglycerol (in toluene), 6.8 .mu.mol of unlabeled
trioleoylglycerol and 0.6 mg of phospholipids
(phosphatidylcholine/phosphatidylinositol 3:1 w/v) are mixed, dried
with N.sub.2 and then taken up in 2 ml of 0.1 M KPi (pH 7.0) by
ultrasound treatment (Branson 250, microtip, setting 1-2, 2.times.1
min with an interval of 1 min). After addition of 1 ml of KPi and
renewed ultrasound treatment (4.times.30 sec on ice with intervals
of 30 sec), 1 ml of 20% BSA (in KPi) is added (final concentration
of trioleoylglycerol 1.7 mM). For the reaction, 100 .mu.l of
substrate solution are pipetted into 100 .mu.l of HSL solution (HSL
prepared as above, diluted in 20 mM KPi, pH 7.0, 1 mM EDTA, 1 mM
DTT, 0.02% BSA, 20 .mu.g/ml pepstatin, 10 .mu.g/ml leupeptin) and
incubated at 37.degree. C. for 30 min. Addition of 3.25 ml of
methanol/chloroform/heptane (10:9:7) and of 1.05 ml of 0.1 M
K.sub.2CO.sub.3, 0.1 M boric acid (pH 10.5) is followed by thorough
mixing and finally centrifugation (800.times.g, 20 min). After
phase separation, one equivalent of the upper phase (1 ml) is
removed and the radioactivity is determined by liquid scintillation
measurement.
[0350] Substances are normally tested in four independent mixtures.
The inhibition of the
[0351] HSL enzymatic activity by a test substance is determined by
comparing with an uninhibited control reaction. The IC.sub.50 is
calculated from an inhibition plot with at least 10 concentrations
of the test substance. The GRAPHIT, Elsevier-BIOSOFT software
package is used to analyze the data.
EL Inhibition Assay:
[0352] EL is released as secretory protein in high concentration
into cell culture medium (conditioned medium) by recombinant cell
lines (CHO, HEK293). This is employed as enzyme solution after
concentration.
[0353] The phospholipase-specific substrate
1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecan-
oyl)-sn-glycero-3-phosphocholine, (manufacturer Molecular Probes)
is used to characterize the enzymatic activity of endothelial
lipase and the effect of inhibitors. Hydrolysis of the A1 ester
linkage of this phospholipid by the enzyme liberates the
fluorescent dye Bodipy which can be detected after separation by
thin-layer chromatography on an HPTLC plate (silica gel 60, Merck)
or directly in the reaction vessel by measuring the fluorescence.
The substrate solution is prepared by taking up 100 .mu.g of
1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecan-
oyl)-sn-glycero-3-phospho-choline (manufacturer Molecular Probes),
2.4 mg of tripalmitin (Sigma) and 7.9 mg of DOP--choline
(1,2-dioleoyl-sn-glycero-3-phosphocholine) in 393 .mu.l of
chloroform and then transferring 157 .mu.l into a fresh reaction
vessel. After evaporation of the solvent, the lipid mixture is
dissolved in 4 ml of 200 mM TRIS-HCl, 150 mM sodium chloride,
pH=7.4, by sonication twice. The subsequent enzymic reaction takes
place at 37.degree. C. for 60 minutes. For this purpose, 45 .mu.l
of the substrate solution are incubated with 1 .mu.l of inhibitor
of appropriate concentration (dissolved in DMSO, pure DMSO solution
is used as control) and 5 .mu.l of enzyme solution (conditioned
medium). Then 3 .mu.l of the assay mixture are loaded onto an HPTLC
plate (silica gel 60, Merck), and the liberated fluorescent dye is
separated for detection with an eluent (diethyl ether:petroleum
benzene:acetic acid [78:22:1]). After evaporation of the eluent,
the plate is read in a fluorescence scanner. An increased release
of the fluorescent dye in the uninhibited reaction is to be
observed as a measure of the enzymic activity.
[0354] The enzymatic activity is reduced as a function of the
inhibitor concentration used, and the inhibitor concentration at
which a half-maximum enzymic activity is observed is called
IC.sub.50.
[0355] In these assays, the compounds of the examples showed the
following IC.sub.50 values:
TABLE-US-00001 IC.sub.50 [.mu.M] IC.sub.50 [.mu.M] Example HSL EL 1
0.5 4 0.07 5 0.3 14 0.607 23 0.45 24 0.175 25 0.215 26 0.198 30
0.585 31 0.136 33 0.112 35 0.78 37 0.576 41 0.062 42 0.159 43 0.763
48 0.662 50 0.367 51 0.237 53 0.826 54 0.74 55 0.58 56 0.04 61 0.03
62 0.16 63 0.965 64 0.03 66 0.15 68 1.24
Preparation Processes
[0356] The compounds of the invention of the formula I are prepared
by methods known per se, e.g. by acylation of substituted or
unsubstituted triazolopyridine II with carbamoyl chlorides III
(method A), or in two stages by reacting triazolopyridine II with
phosgene or equivalents such as trichloromethyl chlorocarbonate,
ditrichloromethyl carbonate or 4-nitrophenyl chloroformate and
further reaction of the resulting triazolopyridinecarboxylic acid
derivative with amines IV (method B). For compounds in which R1 is
hydrogen, the triazolopyridine II can also be reacted with the
appropriate isocyanates V R1-N.dbd.C.dbd.O.
##STR00009##
[0357] Since acids are usually liberated in these reactions, it is
advisable to add bases such as pyridine, triethylamine, sodium
hydroxide solution or alkali metal carbonates for expedition. The
reactions can be carried out in wide temperature ranges. It has
usually proved to be advantageous to operate at from 0.degree. C.
to the boiling point of the solvent used. Examples of solvents
employed are methylene chloride, THF, DMF, toluene, ethyl acetate,
n-heptane, dioxane, diethyl ether or pyridine. If anhydrous
conditions are used, strong bases such as lithium hydride, sodium
hydride or potassium tert-butoxide in aprotic solvents such as THF
or DMF have also proved suitable.
[0358] The triazolopyridine derivatives employed as starting
compounds II are commercially available or can be prepared by
processes known from the literature (e.g. I. Torrini, G. P.
Zecchini, F. Agrosi and M. P. Paradisi, J. Het. Chem. (1986) 23,
1459-1463; W. v. Bebenburg, G. Steinmetz, K. Thiele, Chem. Zeit.
(1979) 103, 387-399).
[0359] The examples detailed below serve to illustrate the
invention without, however, restricting it.
EXAMPLES
Examples
General Procedure Method A
[0360] A solution of a secondary amine (0.5 mmol) in THF (3 ml) and
pyridine (0.5 ml) is added dropwise to a solution of phosgene (20%
in toluene, 550 .mu.l) at 25.degree. C. and stirred at 25.degree.
C. for 1 hour. The reaction mixture is then evaporated to dryness
in vacuo, and the residue is taken up in THF (5 ml) and added to a
solution of 1H-[1,2,3]triazolo[4,5-b]pyridine (60 mg, 0.5 mmol) in
pyridine (5 ml). The mixture is stirred at 25.degree. C. for 16 h
and then evaporated to dryness in vacuo.
[0361] The product is obtained as a mixture of the regioisomers
which can be separated by known methods, in particular
chromatographic methods.
4-Methylpiperidine-1-carbonyl chloride
[0362] 9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100
mmol) of triethylamine were added at -30.degree. C. to 54.9 ml (100
mmol) of phosgene in toluene (20 percent) and 100 ml of THF and,
after stirring for 2.5 h, the reaction mixture was allowed to warm
to room temperature. The reaction mixture was concentrated and the
residue was mixed with methylene chloride and filtered off, and the
filtrate was concentrated. The crude product (12.7 g) was reacted
without further purification.
Example 5
Method A
(6-Chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(4-methyl-piperidin-1-yl)-me-
thanone
[0363] 6-Chloro-1H-[1,2,3]triazolo[4,5-b]pyridine (200 mg, 1.29
mmol) and 4-methyl-piperidin-1-carbonyl chloride (418 mg, 2.56
mmol) were dissolved in 10 ml of pyridine. Then triethylamine (180
.mu.l, 3.88 mmol) was added and stirred at room temperature for 4 h
and left to stand overnight. The reaction mixture was concentrated
and the residue was mixed with water and ethyl acetate. The organic
phase was separated off, the aqueous phase was extracted once more,
and the combined organic phases were washed with water and
concentrated. The crude product was purified by preparative HPLC
(PR18, acetonitrile/water 0.1% TFA). Yield: 106 mg (29%) of
(6-chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(4-methyl-piperidin-1-yl)-m-
ethanone, M+H+: 280.2.
Example 3 and 66
(5-Chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(3,4-dihydro-1H-isoquinolin--
2-yl)-methanone and
(5-chloro-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-(3,4-dihydro-1H-isoquinolin--
2-yl)-methanone
[0364] 5-Chloro-3H-[1,2,3]triazolo[4,5-b]pyridine (500 mg, 3.23
mmol) and 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride (950 mg,
4.85 mmol) were dissolved in 25 ml of pyridine. Then triethylamine
(675 .mu.l, 4.85 mmol) was added and stirred at room temperature
for 9 h and left to stand overnight. The reaction mixture was
concentrated and the residue was mixed with water and ethyl
acetate. The organic phase was separated off, the aqueous phase was
extracted once more, and the combined organic phases were washed
with water and concentrated. The crude product was purified by
preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield:
[0365] 183 mg of
(5-chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(3,4-dihydro-1H-isoquinolin-
-2-yl)-methanone, M+H+: 314.03 and
[0366] 23 mg of
(5-chloro-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-(3,4-dihydro-1H-isoquinolin-
-2-yl)-methanone, M+H+: 314.03.
Example 1 and 61
(5-Chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(4-methylpiperidin-1-yl)-met-
hanone and
(5-chloro-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-(4-methylpiperidin-1-yl)-met-
hanone
[0367] 5-Chloro-3H-[1,2,3]triazolo[4,5-b]pyridine (100 mg, 0.65
mmol) were dissolved in 10 ml of THF. Then triethylamine (135
.mu.l, 0.97 mmol) and 4-methylpiperidin-1-carbonyl chloride (146
mg, 0.9 mmol) were added and stirred at room temperature for 4 h
and left to stand overnight. The reaction mixture was concentrated
and the residue was mixed with water and ethyl acetate. The organic
phase was separated off, the aqueous phase was extracted once more,
and the combined organic phases were washed with water and
concentrated. The crude product was purified by preparative HPLC
(PR18, acetonitrile/water 0.1% TFA). Yield:
[0368] 25 mg (14%) of
(5-chloro-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-(4-methylpiperidin-1-yl)-me-
thanone, M+H+: 280.04 and
[0369] 41 mg (23%) of
(5-chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(4-methylpiperidin-1-yl)-me-
thanone M+H+: 280.04.
Example 57 and 59
(4-Methylpiperidin-1-yl)-[1,2,3]triazolo[4,5-c]pyridin-1-yl-methanone
and
(4-methylpiperidin-1-yl)-[1,2,3]triazolo[4,5-c]pyridin-3-yl-methanone
[0370] 3H-[1,2,3]Triazolo[4,5-c]pyridine (50 mg, 0.41 mmol) were
dissolved in 10 ml of pyridine. Then triethylamine (135 .mu.l, 0.97
mmol) and 4-methylpiperidin-1-carbonyl chloride (101 mg, 0.62 mmol)
were added and stirred at 120.degree. C. for 5 h and left to stand
overnight. The reaction mixture was concentrated and the residue
was mixed with water and ethyl acetate. The organic phase was
separated off, the aqueous phase was extracted once more and the
combined organic phases were washed with water and concentrated.
The crude product was purified by preparative HPLC (PR18,
acetonitrile/water 0.1% TFA). Yield:
[0371] 13 mg (13%) of (4-methylpiperid
in-1-yl)-[1,2,3]triazolo[4,5-c]pyridin-1-yl-methanone, M+H+: 246.15
and
[0372] 34 mg (33%) of
(4-methylpiperidin-1-yl)-[1,2,3]triazolo[4,5-c]pyridin-3-yl-methanone
M+H+: 246.15.
[0373] The following examples were prepared analogously:
[0374] (The identity of the compounds was checked by mass
spectrometry)
TABLE-US-00002 Example Structure 1 ##STR00010## 2 ##STR00011## 3
##STR00012## 4 ##STR00013## 5 ##STR00014## 6 ##STR00015## 7
##STR00016## 8 ##STR00017## 9 ##STR00018## 10 ##STR00019## 11
##STR00020## 12 ##STR00021## 13 ##STR00022## 14 ##STR00023## 15
##STR00024## 16 ##STR00025## 17 ##STR00026## 18 ##STR00027## 19
##STR00028## 20 ##STR00029## 21 ##STR00030## 22 ##STR00031## 23
##STR00032## 24 ##STR00033## 25 ##STR00034## 26 ##STR00035## 27
##STR00036## 28 ##STR00037## 29 ##STR00038## 30 ##STR00039## 31
##STR00040## 32 ##STR00041## 33 ##STR00042## 34 ##STR00043## 35
##STR00044## 36 ##STR00045## 37 ##STR00046## 38 ##STR00047## 39
##STR00048## 40 ##STR00049## 41 ##STR00050## 42 ##STR00051## 43
##STR00052## 44 ##STR00053## 45 ##STR00054## 46 ##STR00055## 47
##STR00056## 48 ##STR00057## 49 ##STR00058## 50 ##STR00059## 51
##STR00060## 52 ##STR00061## 53 ##STR00062## 54 ##STR00063## 55
##STR00064## 56 ##STR00065## 57 ##STR00066## 58 ##STR00067## 59
##STR00068## 60 ##STR00069## 61 ##STR00070## 62 ##STR00071## 63
##STR00072## 64 ##STR00073## 65 ##STR00074## 66 ##STR00075## 67
##STR00076## 68 ##STR00077## 69 ##STR00078##
[0375] Although the invention has been illustrated by certain of
the preceding examples, it is not to be construed as being limited
thereby; but rather, the invention encompasses the generic area as
hereinbefore disclosed. Various modifications and embodiments can
be made without departing from the spirit and scope thereof.
* * * * *
References