U.S. patent application number 09/995137 was filed with the patent office on 2002-05-30 for new compounds, their preparation and use.
Invention is credited to Bury, Paul Stanley, Jeppesen, Lone, Sauerberg, Per.
Application Number | 20020065268 09/995137 |
Document ID | / |
Family ID | 27221244 |
Filed Date | 2002-05-30 |
United States Patent
Application |
20020065268 |
Kind Code |
A1 |
Jeppesen, Lone ; et
al. |
May 30, 2002 |
New compounds, their preparation and use
Abstract
The present invention relates to compounds of the general
formula (I) 1 The compounds are useful in the treatment and/or
prevention of conditions mediated by nuclear receptors, in
particular the Peroxisome Proliferator-Activated Receptors
(PPAR).
Inventors: |
Jeppesen, Lone; (Virum,
DK) ; Bury, Paul Stanley; (Kobenhavn NV, DK) ;
Sauerberg, Per; (Farum, DK) |
Correspondence
Address: |
Reza Green, Esq.
Novo Nordisk of North America, Inc.
Suite 6400
405 Lexington Avenue
New York
NY
10174-6401
US
|
Family ID: |
27221244 |
Appl. No.: |
09/995137 |
Filed: |
November 27, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09995137 |
Nov 27, 2001 |
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09420347 |
Oct 19, 1999 |
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60105913 |
Oct 28, 1998 |
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Current U.S.
Class: |
514/217 ;
514/224.8; 514/229.8; 514/250; 514/290; 540/586; 544/101; 544/32;
544/344; 546/79 |
Current CPC
Class: |
C07D 495/14 20130101;
C07D 471/14 20130101; C07D 491/14 20130101 |
Class at
Publication: |
514/217 ;
514/224.8; 514/229.8; 514/250; 514/290; 540/586; 544/32; 544/101;
544/344; 546/79 |
International
Class: |
A61K 031/55; A61K
031/5415; A61K 031/538; A61K 031/498; A61K 031/473; C07D 223/14;
C07D 241/36 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 21, 1998 |
DK |
PA 1998 01354 |
Claims
1. A compound of formula (Ia) 13wherein ring A fused to the ring
containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more halogen, perhalomethyl,
hydroxy, nitro, cyano, formyl, or C.sub.1-12alkyl,
C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl, C.sub.2-12-alkynyl,
C.sub.1-12alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
acyloxy, hydroxyC.sub.1-12alkyl, amino, acylamino,
C.sub.1-12alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, C.sub.1-12alkoxyC.sub.1-12alkyl,
aryloxyC.sub.1-12alkyl, aralkoxyC.sub.1-12alkyl,
C.sub.1-12alkylthio, thioC.sub.1-12alkyl,
C.sub.1-12alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, halogen, perhalomethyl, C.sub.1-6alkoxy or amino
optionally substituted with one or more C.sub.1-6alkyl,
perhalomethyl or aryl; optionally substituted with one or more
halogen, perhalomethyl, hydroxy, nitro or cyano; ring B fused to
the ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more halogen, perhalomethyl,
hydroxy, nitro, cyano, formyl, or C.sub.1-12alkyl,
C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl, C.sub.2-12-alkynyl,
C.sub.1-12alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
acyloxy, hydroxyC.sub.1-12alkyl, amino, acylamino,
C.sub.1-12alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, C.sub.1-12alkoxyC.sub.1-12alkyl,
aryloxyC.sub.1-12alkyl, aralkoxyC.sub.1-12alkyl,
C.sub.1-12alkylthio, thioC.sub.1-12alkyl,
C.sub.1-12alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12,
wherein, R.sup.11 and R.sup.12 independently of each other are
selected from hydroxy, halogen, perhalomethyl, C.sub.1-6alkoxy or
amino optionally substituted with one or more C.sub.1-6alkyl,
perhalomethyl or aryl; optionally substituted with one or more
halogen, perhalomethyl, hydroxy, nitro or cyano; X is a valence
bond, --(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--, --CH.dbd.CH',
--O--, --O--(CHR.sup.9)--, --S--(CHR.sup.9)--,
--(NR.sup.9)--CH.sub.2--, --(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--CH.sub.2--, --(C.dbd.O)--,
--O--CH.sub.2--O--, --(NR.sup.9)--, --(NR.sup.9)--S(O.sub.2)--,
--CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--,
--S--, --(SO)--, --(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, nitro, cyano, formyl, C.sub.1-12alkyl, C.sub.1-12alkoxy,
aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,
heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,
hydroxyalkyl, amino, acylamino, C.sub.1-12alkyl-amino, arylamino,
aralkylamino, aminoC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl,
aryloxycarbonyl, aralkoxycarbonyl, C.sub.1-12alkoxyC.sub.1-12alkyl,
aryloxyC.sub.1-12alkyl, aralkoxyC.sub.1-12alkyl,
C.sub.1-12alkylthio, thioC.sub.1-12alkyl,
C.sub.1-12alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, halogen, C.sub.1-6alkoxy, amino optionally substituted
with one or more C.sub.1-6alkyl, perhalomnethyl or aryl; Q is
--O--, --S--, >SO.sub.2, >NR.sup.13, wherein R.sup.13 is
hydrogen or C.sub.1-6alkyl, Ar represents arylene, heteroarylene,
or a divalent heterocyclic group optionally substituted with one or
more C.sub.1-6alkyl or aryl; R.sup.5 represents hydrogen, hydroxy,
halogen, C.sub.1-12alkoxy, C.sub.1-12alkyl, C.sub.4-12-alkenynyl,
C.sub.2-12-alkenyl, C.sub.2-12-alkynyl or aralkyl; optionally
substituted with one or more halogen, perhalomethyl, hydroxy, nitro
or cyano; or R.sup.5 forms a bond together with R.sup.6, R.sup.6
represents hydrogen, hydroxy, halogen, C.sub.1-12alkoxy,
C.sub.1-12alkyl, C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl,
C.sub.2-12-alkynyl, acyl or aralkyl; optionally substituted with
one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or
R.sup.6 forms a bond together with R.sup.5, R.sup.7 represents
hydrogen, C.sub.1-12alkyl, C.sub.1-12-alkenynyl,
C.sub.2-12-alkenyl, C.sub.2-12-alkynyl, aryl, aralkyl,
C.sub.1-12alkoxyC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl,
aryloxycarbonyl, C.sub.1-12alkylaminocarbonyl, arylamino-carbonyl,
acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally
substituted with one or more halogen, perhalomethyl, hydroxy, nitro
or cyano; R.sup.8 represents hydrogen, C.sub.1-12alkyl,
C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl, C.sub.2-12-alkynyl, aryl,
aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups;
optionally substituted with one or more halogen, perhalomethyl,
hydroxy, nitro or cyano; Y represents oxygen, sulphur or NR.sup.10,
where R.sup.10 represents hydrogen, C.sub.1-12alkyl, aryl,
hydroxyC.sub.1-12alkyl or aralkyl groups or when Y is NR.sup.10,
R.sup.8 and R.sup.10 may form a 5 or 6 membered nitrogen containing
ring, optionally substituted with one or more C.sub.1-6alkyl; n is
an integer ranging from 1 to 4 and m is an integer ranging from 0
to 1, provided that A or B does not represent phenyl; or a
pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein ring A fused to the ring
containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy, cyano, or C.sub.1-7alkyl,
C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,
C.sub.1-7alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
acyloxy, hydroxyC.sub.1-7alkyl, amino, acylamino,
C.sub.1-7alkyl-amino, arylamino, aralkylamino, aminoC.sub.1-7alkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl, aryloxyC.sub.1-7alkyl,
aralkoxyC.sub.1-7alkyl, C.sub.1-7,alkylthio, thioC.sub.1-7alkyl,
C.sub.1-7alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, perhalomethyl or amino optionally substituted with one or
more C.sub.1-6alkyl, perhalomethyl or aryl; optionally substituted
with one or more halogen, perhalomethyl, hydroxy or cyano.
3. A compound according to anyone of the preceding claims wherein
ring A fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy, cyano, or
C.sub.1-7alkyl, C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, C.sub.1-7alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, acyl, amino, acylamino, C.sub.1-7alkyl-amino,
arylamino, aralkylamino, aminoC.sub.1-7alkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl, aryloxyC.sub.1-7alkyl,
aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio, thioC.sub.1-7alkyl;
optionally substituted with one or more halogen or hydroxy;
4. A compound according to anyone of the preceding claims wherein
ring A fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy or C.sub.1-7alkyl,
C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, C.sub.1-7alkoxy, aryl,
aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaryloxy,
heteroaralkoxy, acyl, arylamino, aryloxyC.sub.1-7alkyl.
5. A compound according to anyone of the preceding claims wherein
ring A fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy or C.sub.1-7alkyl,
C.sub.2-7alkenyl, C.sub.2-7-alkynyl, C.sub.1-7alkoxy or aryl.
6. A compound according to anyone of the preceding claims wherein
ring A fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen or halogen.
7. A compound according to anyone of the preceding claims wherein
ring B fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy, cyano, or
C.sub.1-7alkyl, C.sub.4-7alkenynyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, C.sub.1-7alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, acyl, acyloxy, hydroxyC.sub.1-7alkyl, amino,
acylamino, C.sub.1-7alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-7alkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
aryloxyC.sub.1-7alkyl, aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio,
thioC.sub.1-7alkyl, C.sub.1-7alkoxycarbonylamino,
aryloxycarbonylamino, aralkoxycarbonylamino, --COR.sup.11, or
--SO.sub.2R.sup.12, wherein R.sup.11 and R.sup.12 independently of
each other are selected from hydroxy, perhalomethyl or amino
optionally substituted with one or more C.sub.1-6alkyl,
perhalomethyl or aryl; optionally substituted with one or more
halogen, perhalomethyl, hydroxy or cyano.
8. A compound according to anyone of the preceding claims wherein
ring B fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy, cyano, or
C.sub.1-7alkyl, C.sub.4-7alkenynyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, C.sub.1-7alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, acyl, amino, acylamino, C.sub.1-7alkyl-amino,
arylamino, aralkylamino, aminoC.sub.1-7alkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl, aryloxyC.sub.1-7alkyl,
aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio, thioC.sub.1-7alkyl;
optionally substituted with one or more halogen or hydroxy.
9. A compound according to anyone of the preceding claims wherein
ring B fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy or C.sub.1-7alkyl,
C.sub.2-7alkenyl, C.sub.2-7-alkynyl, C.sub.1-7alkoxy, aryl,
aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaryloxy,
heteroaralkoxy, acyl, arylamino, aryloxyC.sub.1-7alkyl.
10. A compound according to anyone of the preceding claims wherein
ring B fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen, halogen, perhalomethyl, hydroxy or C.sub.1-7alkyl,
C.sub.2-7alkenyl, C.sub.2-7-alkynyl,C.sub.1-7alkoxy or aryl.
11. A compound according to anyone of the preceding claims wherein
ring B fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
hydrogen or halogen.
12. A compound according to anyone of the preceding claims wherein
X is a valence bond, --(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--,
--CH.dbd.CH--, --O--, --O--(CHR.sup.9)--, --S--(CHR.sup.9)--,
--(NR.sup.9)--CH.sub.2--, --(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--CH.sub.2--, --(C.dbd.O)--,
--O--CH.sub.2--O--, --(NR.sup.9)--, --(NR.sup.9)--S(O.sub.2)--,
--CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--,
--S--, --(SO)--, --(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, cyano, C.sub.1-7alkyl, C.sub.1-7alkoxy, aryl, aryloxy,
aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,
heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,
acylamino, C.sub.1-7alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-7alkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
aryloxyC.sub.1-7alkyl, aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio,
thioC.sub.1-7alkyl.
13. A compound according to anyone of the preceding claims wherein
X is a valence bond, --(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--,
--CH.dbd.CH--, --O--, --O--(CHR.sup.9)--, --S--(CHR.sup.9)--,
--(NR.sup.9)--CH.sub.2--, --(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--CH.sub.2--, --(C.dbd.O)--,
--O--CH.sub.2--O--, --(NR.sup.9)--, --(NR.sup.9)--S(O.sub.2)--,
--CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--,
--S--, --(SO)--, --(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, aryl.
14. A compound according to anyone of the preceding claims wherein
X is a valence bond, --(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--,
--CH.dbd.CH--, --O--(CHR.sup.9)--, --S--(CHR.sup.9)--,
--(NR.sup.9)--CH.sub.2--, --(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--CH.sub.2--, --(C.dbd.O)--,
--O--CH.sub.2--O--, --(NR.sup.9)--S(O.sub.2)--,
--CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--,
--(SO)--, --(SO2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2-- wherein R.sup.9 is hydrogen, halogen,
hydroxy, C.sub.1-4alkyl, C.sub.1-4alkoxy.
15. A compound according to anyone of the preceding claims wherein
X is a valence bond, --(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--,
--CH.dbd.CH--, --O--(CHR.sup.9)--, --(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--- CH.sub.2--, --(C.dbd.O)--,
--O--CH.sub.2--O--, --CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--,
--CH.sub.2--(SO)--, --(SO)--, --(SO.sub.2)--,
--CH.sub.2--(SO.sub.2)--, --CH.sub.2--O--CH.sub.2--, wherein
R.sup.9 is hydrogen.
16. A compound according to anyone of the preceding claims wherein
Q is --O-- or --S--.
17. A compound according to anyone of the preceding claims wherein
Q is --O--.
18. A compound according to anyone of the preceding claims wherein
Ar represents arylene, heteroarylene, or a divalent heterocyclic
group optionally substituted with one or more C.sub.1-6alkyl or
aryl; R.sup.5 represents hydrogen, hydroxy, halogen,
C.sub.1-7alkoxy, C.sub.1-7alkyl, C.sub.4-7-alkenynyl,
C.sub.2-7-alkenyl, C.sub.2-7-; or R.sup.5 forms a bond together
with R.sup.6, R.sup.6 represents hydrogen, hydroxy, halogen,
C.sub.1-7alkoxy, C.sub.1-7alkyl, C.sub.4-7alkenynyl,
C.sub.2-7-alkenyl, C.sub.2-7-alkynyl; or R.sup.6 forms a bond
together with R.sup.5, R.sup.7 represents hydrogen, C.sub.1-7alkyl,
C.sub.4-7alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, aryl,
aralkyl, C.sub.1-7alkoxyC.sub.1-7alkyl, C.sub.1-7alkoxycarbonyl,
aryloxycarbonyl, C.sub.1-7alkylaminocarbonyl, arylaminocarbonyl,
acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R.sup.8
represents hydrogen, C.sub.1-7alkyl, C.sub.4-7-alkenynyl,
C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, aryl, aralkyl, heterocyclyl,
heteroaryl or heteroaralkyl; Y represents oxygen, sulphur or
NR.sup.10 , where R.sup.10 represents hydrogen, C.sub.1-7alkyl,
hydroxyC.sub.1-7alkyl; n is an integer ranging from 2 to 3 and m is
an integer ranging from 0 to 1.
19. A compound according to anyone of the preceding claims wherein
Ar represents arylene or heteroarylene, R.sup.5 represents
hydrogen, hydroxy, halogen; or R.sup.5 forms a bond together with
R.sup.6, R.sup.6 represents hydrogen, hydroxy, halogen; or R.sup.6
forms a bond together with R.sup.5, R.sup.7 represents hydrogen,
C.sub.1-7alkyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, aryl,
aralkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
C.sub.1-7alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl,
heteroaryl or heteroaralkyl groups; R.sup.8 represents hydrogen,
C.sub.1-7alkyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,; Y represents
oxygen or sulphur; n is an integer ranging from 2 to 3 and m is
1.
20. A compound according to anyone of the preceding claims wherein
Ar represents arylene or heteroarylene; R.sup.5 represents
hydrogen; R.sup.6 represents hydrogen; R.sup.7 represents hydrogen,
C.sub.1-7alkyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, aryl,
aralkyl, C.sub.1-7alkoxyC.sub.1-7alkyl; R.sup.8 represents
hydrogen, C.sub.1-7alkyl, C.sub.2-7-alkenyl, C.sub.2-7alkynyl,; Y
represents oxygen; n is an integer ranging from 2 to 3 and m is
1.
21. A compound according to anyone of the preceding claims wherein
Ar represents arylene R.sup.5 represents hydrogen; R.sup.8
represents hydrogen; R.sup.7 represents hydrogen, C.sub.1-4alkyl,
C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, R.sup.8 represents hydrogen,
C.sub.1-4alkyl, Y represents oxygen; n is an integer ranging from 2
to 3 and m is 1.
22. A compound according to anyone of the preceding claims wherein
Ar represents phenylene, R.sup.5 represents hydrogen; R.sup.6
represents hydrogen; R.sup.7 represents hydrogen, C.sub.1-4alkyl,
R.sup.8 represents hydrogen Y represents oxygen; n is an integer
ranging from 2 to 3 and m is 1.
23. A compound according to anyone of the preceding claims wherein
A is 5 membered cyclic ring containing S.
24. A compound according to anyone of the preceding claims wherein
B is 5 membered cyclic ring containing S.
25. A compound according to anyone of the preceding claims wherein
X is --CH.dbd.(CR.sup.9)--, wherein R.sup.9 is H.
26. A compound according to anyone of the preceding claims wherein
n is 2.
27. A compound according to anyone of the preceding claims wherein
Q is --O--.
28. A compound according to anyone of the preceding claims wherein
m is 1.
29. A compound according to anyone of the preceding claims wherein
Ar is phenylene. In another preferred embodiment, the present
invention is concerned with compounds of formula I wherein R.sup.5
is H.
30. A compound according to anyone of the preceding claims wherein
R.sup.6 is H.
31. A compound according to anyone of the preceding claims wherein
R.sup.7 is ethyl.
32. A compound according to anyone of the preceding claims wherein
Y is oxygen.
33. A compound according to anyone of the preceding claims wherein
R.sup.8 is H.
34. The compound according to claim 1 which is:
3-{4-[2(8,9-Dihydro-3,5-di-
thia-4-aza-cyclopenta[f]azulen-4-yl)ethoxy]-phenyl}-2-ethoxy-propionic
acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen4-yl)ethox-
y]-phenyl}-2-methoxy-propionic acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia4-aza--
cyclopenta[f]azulen-4-yl)ethoxy]-phenyl}-2-propoxy-propionic acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia4-aza-cyclopenta[f]azulen-4-yl)ethoxy]-phe-
nyl}-2-benzyloxy-propionic acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyc-
lopenta[f]azulen-4-yl)ethyl]-phenyl}-2-ethoxy-propionic acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)ethyl]-phe-
nyl}-2-methoxy-propionic acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia4-aza-cyclop-
enta[f]azulen-4-yl)ethyl]-phenyl}-2-propoxy-propionic acid,
3-{4-[2-(8,9-Dihydro-3,5-dithia4-aza-cyclopenta[f]azulen-4-yl)ethyl]-phen-
yl}-2-benzyloxy-propionic acid,
3-{4-[1-(8,9-Dihydro-3,5-dithia-4-aza-cycl-
openta[f]azulen-4-yl)methoxy]-phenyl}-2-ethoxy-propionic acid,
3-{4-[1-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)methoxy]-p-
henyl}-2-methoxy-propionic acid,
3-{4-[1-(8,9-Dihydro-3,5-dithia4-aza-cycl-
openta[f]azulen-4-yl)methoxy]-phenyl}-2-benzyloxy-propionic acid,
3-{4-[3-(8,9-Dihydro-3,5dithia4-aza-cyclopenta[f]azulen-4-yl)propoxy]-phe-
nyl}-2-ethoxy-propionic acid,
3-{4-[3-(8,9-Dihydra-3,5-dithia-4-aza-cyclop-
enta[f]azulen-4yl)propoxy]-phenyl}-2-methoxy-propionic acid,
3-{4-[3-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)propoxy]-p-
henyl}-2-benzyloxy-propionic acid,
3-{4-[3-(8,9-Dihydro-3,5dithia4-aza-cyc-
lopenta[f]azulen-4-yl)propyl]-phenyl}-2-ethoxy-propionic acid,
3-{4-[3-(8,9-Dihydro-3,5-dithia4-aza-cyclopenta[f]azulen-4-yl)propyl]-phe-
nyl}-2-methoxy-propionic acid,
3-{4-[3-(8,9-Dihydro-3,5dithia-4-aza-cyclop-
enta[f]azulen-4-yl)propyl]-phenyl}-2-benzyloxy-propionic acid,
2-Ethoxy-3(4-(2(9H-1, 8,
10-triaza-anthracen-10-yl)ethoxy)phenyl)propioni- c acid,
2-methoxy-3(4-(2(9H-1, 8, 10-triaza-anthracen-10-yl)ethoxy)phenyl)-
propionic acid, 2-propoxy-3-(4-(2-(9H-1, 8,
10-triaza-anthracen-10-yl)etho- xy)phenyl)propionic acid,
2-benzyloxy-3-(4-(2-(9H-1,
8,10-triaza-anthracen-10-yl)ethoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(1-(9H-1 ,8,
10-triaza-anthracen-10-yl)methoxy)phenyl)propi- onic acid,
2-methoxy-3-(4-(1-(9H-1, 8, 10-triaza-anthracen-10-yl)methoxy)p-
henyl)propionic acid, 2-benzyloxy-3-(4-(1-(9H-1, 8,
10-triaza-anthracen-10-yl)methoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(3-(9H-1 ,8,
10-triaza-anthracen-10-yl)propoxy)phenyl)propi- onic acid,
2-propoxy-3-(4-(3-(9H-1, 8, 10-triaza-anthracen-10-yl)propoxy)p-
henyl)propionic acid, 2-methoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-y- l)propoxy)phenyl)propionic acid,
2-benzyloxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)propoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)propyl)phenyl)propio- nic acid,
2-propoxy-3-(4-(3-(9H-1,8, 10-triaza-anthracen-10-yl)propyl)phen-
yl)propionic acid, 2-methoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)p- ropyl)phenyl)propionic acid,
2-benzyloxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)propyl)phenyl)propionic acid,
2-deoxy-3-(4-(3-(4, 5, 9H -triaza- anthracen-10-yl)propyl)proprin
acid, 2-methoxy-3-(4-(2-(4, 5,
9-triaza-fluoren-9-yl)ethoxy)phenyl)propionic acid,
2-propoxy-3-(.sup.4-(2-(4, 5,
9-triaza-fluoren-9-yl)ethoxy)phenyl)p- ropionic acid,
2-ethoxy-3-(4-(1-(4, 5, 9-triaza-fluoren-9-yl)methoxy)pheny-
l)propionic acid, 2-methoxy-3-(4-(1-(4, 5,
9-triaza-fluoren-9-yl)methoxy)p- henyl)propionic acid,
2-benzyloxy-3-(4-(1-(4, 5, 9-triaza-fluoren-9-yl)met-
hoxy)phenyl)-propionic acid, 2-ethoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)propoxy)phenyl)propionic acid,
2-methoxy-3-(4-(1-(4, 5,
9-triaza-fluoren-9-yl)methoxy)phenyl)propionic acid,
2-benzyloxy-3-(4-(1-(4, 5,
9-triaza-fluoren-9-yl)methoxy)phenyl)pro- pionic acid,
2-propoxy-3-(4-(3-(4, 5, 9-triaza-fluoren-9-yl)propoxy)phenyl-
)propionic acid, 2-ethoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)propyl)phen- yl)propionic acid,
2-ethoxy-3-(4-(3-(4, 5, 9-triaza-fluoren-9-yl)propyl)ph-
enyl)propionic acid, 2-benzyloxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)prop- yl)phenyl)propionic acid,
2-propoxy-3-(4-(3-(4, 5, 9-triaza-fluoren-9-yl)p-
ropyl)phenyl)propionic acid, 2-ethoxy-3-(4-(2-(4, 8,
9-triaza-fluoren-9-yl)ethoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(2-(1, 8,
9-triaza-fluoren-9-yl)ethoxy)phenyl)propionic acid,
2-propoxy-3-(4-(2-(1, 8,
9-triaza-fluoren-9-yl)ethoxy)phenyl)propionic acid,
2-benzyoxy-3-(4-(2-(1, 8,
9-triaza-fluoren-9-yl)ethoxy)phenyl)propi- onic acid,
2-methoxy-3-(4-(1-(1, 8, 9-triaza-fluoren-9-yl)methoxy)phenyl)p-
ropionic acid, 2-ethoxy-3-(4-(1-(1, 8,
9-triaza-fluoren-9-yl)methoxy)pheny- l)propionic acid,
2-propoxy-3-(4-(1-(1, 8, 9-triaza-fluoren-9-yl)methoxy)p-
henyl)propionic acid, 2-benzyloxy-3-(4-(1-(1, 8,
9-triaza-fluoren-9-yl)met- hoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)propoxy)phenyl)propionic acid,
2-methoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)propoxy)phenyl)propionic acid,
2-propoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)propoxy)phenyl)propi- onic acid,
2-benzyloxy-3-(4(3-(1, 8, 9-triaza-fluoren-9-yl)propoxy)phenyl)-
propionic acid, 2-ethoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)propyl)pheny- l)propionic acid,
2-methoxy-3-(4-(3-(1, 8, 9-triaza-fluoren-9-yl)propyl)ph-
enyl)propionic acid, 2-propoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)propyl- )phenyl)propionic acid,
2-benzyloxy-3-(4-(3-(1, 8, 9-triaza-fluoren-9-yl)p-
ropyl)phenyl)propionic acid, 3-(4-(2-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)ethoxy)phenyl)2-ethoxy-propionic acid,
3-(4-(2-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)ethoxy)phenyl)2-methoxy-prop- ionic acid,
3-(4-(2-(dithieno[2,3-b;3', 2'-d]pyrrol-7-yl)ethoxy)phenyl)2-p-
ropoxy-propionic acid, 3-(4-(2-(dithieno[2, 3-b;3',
2'-d]pyrrol-7-yl)ethoxy)phenyl)2-benzyloxy-propionic acid,
3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)methoxy)phenyl)2-methoxy-pro- pionic acid,
3-(4-(1-(dithieno[2,3-b; 3', 2'-d]pyrrol-7-yl)methoxy)phenyl)-
2-ethoxy-propionic acid, 3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)methoxy)phenyl)2-proxy-propionic acid,
3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)methoxy)phenyl)2-propoxy-pro- pionic acid,
3-(4-(1-(dithieno[2,3-b;3', 2'-d]pyrrol-7-yl)methoxy)phenyl)2-
-benzyloxy-propionic acid, 3-(4-(3-(dithienol2,3-b;3',
2'-d]pyrrol-7-yl)propoxy)phenyl)2-methoxy-propionic acid,
3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)propoxy)phenyl)2-ethoxy-prop- ionic acid,
3-(4-(3-(dithieno[2,3-b;3', 2'-d]pyrrol-7-yl)propoxy)phenyl)2--
benzoxy-propionic acid, 3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)propoxy)phenyl)2-ethoxy-propionic acid,
3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)propy)phenyl)2-methoxy-propi- onic acid,
3-(4-(3-(dithieno[2,3-b;3', 2'-d]pyrrol-7-yl)propyl)phenyl)2-et-
hoxy-propionic acid, 3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)propyl)p- henyl)2-benzoxy-propionic acid,
3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)propyl)phenyl)2-ethoxy-propionic acid,
3-(4-(2-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)ethoxy)phenyl)2-methoxy-prop- ionic acid,
3-(4-(2-(difurano[2,3-b;3', 2'-d]pyrrol-7-yl)ethoxy)phenyl)2-e-
thoxy-propionic acid, 3-(4-(2-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)ethoxy)- phenyl)2-benzoxy-propionic acid,
3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)ethoxy)phenyl)2-ethoxy-propionic acid,
3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)methoxy)phenyl)2-ethoxy-prop ionic acid,
3-(4-(1-(difurano[2,3-b;3', 2'-d]pyrrol-7-yl)methoxy)phenyl)2-
-propoxy-propionic acid, 3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)methoxy)phenyl)2-benzyloxy-propionic acid,
3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)propoxy)phenyl)2-ethoxy-prop- ionic acid,
3-(4-(3(difurano[2,3-b;3', 2'-d]pyrrol-7-yl)propoxy)phenyl)2-p-
ropoxy-propionic acid, 3-(4-(3(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)propoxy- )phenyl)2-methoxy-propionic acid,
3-(4-(3(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)propoxy)phenyl)2-benzyloxy-propionic acid,
3-(4-(3(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)propyl)phenyl)2-ethoxy-propio- nic acid,
3-(4-(3(difurano[2,3-b;3', 2'-d]pyrrol-7-yl)propyl)phenyl)2-prop-
oxy-propionic acid, 3-(4-(3(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)propyl)phe- nyl)2-methoxy-propionic acid,
3-(4-(3(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)propyl)phenyl)2-benzyloxy-propionic acid,
3-(4-(2(4H-1,7-dithia-8-aza-s-indacen-8-yl)ethoxy)phenyl)2-ethoxy-propion-
ic acid,
3-(4-(2(4H-1,7-dithia-8-aza-s-indacen-8-yl)ethoxy)phenyl)2-methox-
y-propionic acid,
3-(4-(2(4H-1,7-dithia-8-aza-s-indacen-8-yl)ethoxy)phenyl-
)2-propoxy-propionic acid,
3-(4-(2(4H-1,7-dithia-8-aza-s-indacen-8-yl)etho-
xy)phenyl)1-2-benzyloxy-propionic acid,
3-(4-(1(4H-1,7-dithia-8-aza-s-inda-
cen-8-yl)methoxy)phenyl)2-ethoxy-propionic acid,
3-(4-(1(4H-1,7-dithia-8-a-
za-s-indacen-8-yl)methoxy)phenyl)2-methoxy-propionic acid,
3-(4-(1(4H-1,7-dithia-8-aza-s-indacen-8-yl)methoxy)phenyl)1-2-propoxy-pro-
pionic acid,
3-(4-(1(4H-1,7-dithia-8-aza-s-indacen-8-yl)methoxy)phenyl)2-b-
enzyloxy-propionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s-indacen-8-yl)propox-
y)phenyl)2-ethoxy-propionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s-indacen-8--
yl)propoxy)phenyl)2-methoxy-propionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s--
indacen-8-yl)propoxy)phenyl)2-propoxy-propionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s-indacen-8-yl)propoxy)phenyl)2-benzyloxy-pro-
pionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s-indacen-8-yl)propyl)phenyl)2-et-
hoxy-propionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s-indacen-8-yl)propyl)phe-
nyl)2-methoxy-propionic acid,
3-(4-(3(4H-1,7-dithia-8-aza-s-indacen-8-yl)p-
ropyl)phenyl)2-propoxy-propionic acid, 3-(
4-(3(4H-1,7-dithia-8-aza-s-inda-
cen-8-yl)propyl)phenyl)2-benzoxy-propionic acid,
2-ethoxy-3-(4-(2(4-oxa-1,- 8-aza-s-indacen-8-yl)
ethoxy)phenyl)-propionic acid,
2-ethoxy-3-(4-(2(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)ethoxy)phenyl)prop-
ionic acid,
2-propoxy-3-(4-(2(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)ethoxy-
)phenyl)propionic acid,
2-propoxy-3-(4-(2(4-oxa-1,7-dithia-8-aza-s-indacen-
-8-yl)ethoxy)phenyl)propionic acid,
2-benzyloxy-3-(4-(2(4-oxa-1,7-dithia-8-
-aza-s-indacen-8-yl)ethoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(1-(4-oxa--
1,7-dithia-8-aza-s-indacen-8-yl)methoxy)phenyl)propionic acid,
2-methoxy-3-(4-(1-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)methoxy)phenyl)p-
ropionic acid, 3
2-propoxy-3-(4-(1-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-
methoxy)phenyl)propionic acid,
2-benzyloxy-3-(4-(1-(4-oxa-1,7-dithia-8-aza-
-s-indacen-8-yl)methoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(3-(4-oxa-1,7-
-dithia-8-aza-s-indacen-8-yl)propoxy)phenyl)propionic acid,
2-methoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)propoxy)phenyl)p-
ropionic acid,
2-propoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)pr-
opoxy)phenyl)propionic acid,
2-benzyloxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-
-indacen-8-yl)propoxy)phenyl)propionic acid,
2-ethoxy-3-(4-(3-(4-oxa-1,7-d-
ithia-8-aza-s-indacen-8-yl)propyl)phenyl)propionic acid,
2-methoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)propyl)phenyl)pr-
opionic acid,
2-propoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)pro-
pyl)phenyl)propionic acid,
2-benzyloxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-i-
ndacen-8-yl)propyl)phenyl)propionic acid; or a pharmaceutically
acceptable salt thereof.
35. The compound according to claim 1 which is:
3-{4-[2-(8,9-Dihydro-3,5-d-
ithia4-aza-cyclopenta[f]azulen-4-yl)ethoxy]-phenyl}-2-ethoxy-propionic
acid; or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising, as an active
ingredient, a compound according to any one of the preceding
compound claims or a pharmaceutically acceptable salt thereof
together with a pharmaceutically acceptable carrier or diluent.
37. A composition according to claim 36 in unit dosage form,
comprising from about 0.05 to about 100 mg, preferably from about
0.1 to about 50 mg of the compound according to anyone of the
preceding compound claims or a pharmaceutically acceptable salt
thereof.
38. A pharmaceutical composition useful in the treatment and/or
prevention of conditions mediated by nuclear receptors, in
particular the Peroxisome Proliferator-Activated Receptors (PPAR),
the composition comprising, as an active ingredient, a compound
according to anyone of the preceding compound claims or a
pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier or diluent.
39. A pharmaceutical composition useful in the treatment and/or
prevention of diabetes and/or obesity, the composition comprising,
as an active ingredient, a compound according to anyone of the
preceding compound claims or a pharmaceutically acceptable salt
thereof together with a pharmaceutically acceptable carrier or
diluent.
40. A pharmaceutical composition for diabetes and/or obesity, the
composition comprising, as an active ingredient, a compound
according to anyone of the preceding compound claims or a
pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier or diluent.
41. A pharmaceutical composition according to any one of the claims
36-40 for oral, nasal, transdermal, pulmonal, or parenteral
administration.
42. A method for the treatment of ailments, the method comprising
administering to a subject in need thereof an effective amount of a
compound according to anyone of the preceding compound claims or a
pharmaceutically acceptable salt thereof, or of a composition
according to any one of the preceding composition claims.
43. A method for the treatment and/or prevention of conditions
mediated by nuclear receptors, in particular the Peroxisome
Proliferator-Activated Receptors (PPAR), the method comprising
administering to a subject in need thereof an effective amount of a
compound according to any one of the preceding compound claims or a
pharmaceutically acceptable salt thereof, or of a composition
according to anyone of the preceding claims 36-41.
44. A method for the treatment and/or prevention of diabetes and/or
obesity, the method comprising administering to a subject in need
thereof an effective amount of a compound according to anyone of
the preceding compound claims or a pharmaceutically acceptable salt
thereof, or of a composition according to anyone of the preceding
claims 36-41.
45. The method according to claims 42-44, wherein the effective
amount of the compound according to anyone of the preceding
compound claims or a pharmaceutically acceptable salt or ester
thereof is in the range of from about 0.05 to about 100 mg per day,
preferably from about 0.1 to about 50 mg per day.
46. Use of a compound according to anyone of the preceding compound
claims or a pharmaceutically acceptable salt thereof for the
preparation of a medicament.
47. Use of a compound according to anyone of the preceding compound
claims or a pharmaceutically acceptable salt thereof for the
preparation of a medicament useful in the treatment and/or
prevention of conditions mediated by nuclear receptors, in
particular the Peroxisome Proliferator-Activated Receptors
(PPAR).
48. Use of a compound according to anyone of the preceding compound
claims or a pharmaceutically acceptable-salt thereof for the
preparation of a medicament for treatment and/or prevention of
diabetes and/or obesity.
49. Use of a compound according to anyone of the preceding compound
claims or a pharmaceutically acceptable salt thereof for the
preparation of a medicament for treatment and/or prevention of
diabetes and obesity.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel compounds,
pharmaceutical compositions containing them, methods for preparing
the compounds and their use as medicaments. More specifically,
compounds of the invention can be utilised in the treatment of
conditions mediated by nuclear receptors, in particular the
Peroxisome Proliferator-Activated Receptors (PPAR). The present
compounds reduce blood glucose and triglyceride levels and are
accordingly useful for the treatment of ailments and disorders such
as diabetes and obesity.
[0002] The present invention also relates to a process for the
preparation of the above said novel compounds, their derivatives,
their analogs, their tautomeric forms, their stereoisomers, their
polymorphs, their pharmaceutically acceptable salts,
pharmaceutically acceptable solvates and pharmaceutical
compositions containing them.
[0003] The compounds are useful for the treatment and/or
prophylaxis of insulin resistance (type 2 diabetes), impaired
glucose tolerance, dyslipidemia, disorders related to Syndrome X
such as hypertension, obesity, insulin resistance, hyperglycaemia,
atherosclerosis, hyperlipidemia, coronary artery disease and other
cardiovascular disorders. The compounds of the present invention
are also useful for the treatment of certain renal diseases
including glomerulonephritis, glomerulosclerosis, nephrotic
syndrome, hypertensive nephrosclerosis: These compounds may also be
useful for improving cognitive functions in dementia, treating
diabetic complications, psoriasis, polycystic ovarian syndrome
(PCOS) and prevention and treatment of bone loss, e.g.
osteoporosis.
BACKGROUND OF THE INVENTION
[0004] Coronary artery disease (CAD) is the major cause of death in
type 2 diabetic and metabolic syndrome patients (i.e. patients that
fall within the `deadly quartet` category of impaired glucose
tolerance, insulin resistance, hypertriglyceridaemia and/or
obesity).
[0005] The hypolipidaemic fibrates and antidiabetic
thiazolidinediones separately display moderately effective
triglyceride-lowering activities although they are neither potent
nor efficacious enough to be a single therapy of choice for the
dyslipidaemria often observed in type 2 diabetic or metabolic
syndrome patients. The thiazolidinediones also potently lower
circulating glucose levels of type 2 diabetic animal models and
humans. However, the fibrate class of compounds are without
beneficial effects on glycaemia. Studies on the molecular actions
of these compounds indicate that thiazolidinediones and fibrates
exert their action by activating distinct transcription factors of
the peroxisome proliferator activated receptor (PPAR) family,
resulting in increased and decreased expression of specific enzymes
and apolipoproteins respectively, both key-players in regulation of
plasma triglyceride content. Fibrates, on the one hand, are
PPAR.alpha. activators, acting primarily in the liver.
Thiazolidinediones, on the other hand, are high affinity ligands
for PPAR.gamma. acting primarily on adipose tissue.
[0006] Adipose tissue plays a central role in lipid homeostasis and
the maintenance of energy balance in vertebrates. Adipocytes store
energy in the form of triglycerides during periods of nutritional
affluence and release it in the form of free fatty acids at times
of nutritional deprivation. The development of white adipose tissue
is the result of a continuous differentiation process throughout
life. Much evidence points to the central role of PPAR.gamma.
activation in initiating and regulating this cell differentiation.
Several highly specialised proteins are induced during adipocyte
differentiation, most of them being involved in lipid storage and
metabolism. The exact link from activation of PPAR.gamma. to
changes in glucose metabolism, most notably a decrease in insulin
resistance in muscle, has not yet been clarified. A possible link
is via free fatty acids such that activation of PPAR.gamma. induces
Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and
Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle
tissue. This, in turn, reduces the concentration of free fatty
acids in plasma dramatically, and due to substrate competition at
the cellular level, skeletal muscle and other tissues with high
metabolic rates eventually switch from fatty acid oxidation to
glucose oxidation with decreased insulin resistance as a
consequence.
[0007] PPAR.alpha. is involved in stimulating .beta.-oxidation of
fatty acids. In rodents, a PPAR.alpha.-mediated change in the
expression of genes involved in fatty acid metabolism lies at the
basis of the phenomenon of peroxisome proliferation, a pleiotropic
cellular response, mainly limited to liver and kidney and which can
lead to hepatocarcinogenesis in rodents. The phenomenon of
peroxisome proliferation is not seen in man. In addition to its
role in peroxisome proliferation in rodents, PPAR.alpha. is also
involved in the control of HDL cholesterol levels in rodents and
humans. This effect is, at least partially, based on a
PPAR.alpha.-mediated transcriptional regulation of the major HDL
apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic
action of fibrates and fatty acids also involves PPAR.alpha. and
can be summarised as follows: (I) an increased lipolysis and
clearance of remnant particles, due to changes in lipoprotein
lipase and apo C-III levels, (II) a stimulation of cellular fatty
acid uptake and their subsequent conversion to acyl-CoA derivatives
by the induction of fatty acid binding protein and acyl-CoA
synthase, (III) an induction of fatty acid b-oxidation pathways,
(IV) a reduction in fatty acid and triglyceride synthesis, and
finally (V) a decrease in VLDL production. Hence, both enhanced
catabolism of triglyceride-rich particles as well as reduced
secretion of VLDL particles constitutes mechanisms that contribute
to the hypolipidemic effect of fibrates.
[0008] A number of compounds have been reported to be useful in the
treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia
(U.S. Pat. 5,306,726, PCT Publications nos. WO91/19702, WO
95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO
97/25042, WO 95/17394, WO 99/08501, WO 99/19313 and WO
99/16758).
SUMMARY OF THE INVENTION
[0009] It seems more and more apparent that glucose lowering as a
single approach does not overcome the macrovascular complications
associated with type 2 diabetes and metabolic syndrome. Novel
treatments of type 2 diabetes and metabolic syndrome must therefore
aim at lowering both the overt hypertriglyceridaemia associated
with these syndromes as well as alleviation of hyperglycaemia.
[0010] The clinical activity of fibrates and thiazolidinediones
indicates that research for compounds displaying combined PPAR
.alpha. and PPAR .gamma. activation should lead to the discovery of
efficacious glucose and triglyceride lowering drugs that have great
potential in the treatment of type 2 diabetes and the metabolic
syndrome (i.e. impaired glucose tolerance, insulin resistance,
hypertriglyceridaemia and/or obesity).
DETAILED DESCRIPTION OF THE INVENTION
[0011] Accordingly, the present invention relates to compounds of
the general formula (Ia): 2
[0012] wherein ring A fused to the ring containing X and N
represents a 5-6 membered cyclic ring, optionally substituted with
one or more halogen, perhalomethyl, hydroxy, nitro, cyano, formyl,
or C.sub.1-12alkyl, C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl,
C.sub.2-12-alkynyl, C.sub.1-12alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, acyl, acyloxy, hydroxyC.sub.1-12alkyl, amino,
acylamino, C.sub.1-12alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, C.sub.1-12alkoxyC.sub.1-12alkyl,
aryloxyC.sub.1-12alkyl, aralkoxyC.sub.1-12alkyl,
C.sub.1-12alkylthio, thioC.sub.1-12alkyl,
C.sub.1-12alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, halogen, perhalomethyl, C.sub.1-6alkoxy or amino
optionally substituted with one or more C.sub.1-6alkyl,
perhalomethyl or aryl; optionally substituted with one or more
halogen, perhalomethyl, hydroxy, nitro or cyano;
[0013] ring B fused to the ring containing X and N represents a 5-6
membered cyclic ring, optionally substituted with one or more
halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, or
C.sub.1-12alkyl, C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl,
C.sub.2-12-alkynyl, C.sub.1-12alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy,
heteroaralkoxy, acyl, acyloxy, hydroxyC.sub.1-12alkyl, amino,
acylamino, C.sub.1-12alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, C.sub.1-12alkoxyC.sub.1-12alkyl,
aryloxyC.sub.1-12alkyl, aralkoxyC.sub.1-12alkyl,
C.sub.1-12alkylthio, thioC.sub.1-12alkyl,
C.sub.1-12alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, halogen, perhalomethyl, C.sub.1-6alkoxy or amino
optionally substituted with one or more C.sub.1-6alkyl,
perhalomethyl or aryl; optionally substituted with one or more
halogen, perhalomethyl, hydroxy, nitro or cyano;
[0014] X is a valence bond, --(CHR.sup.9)--,
--(CHR.sup.9)--CH.sub.2--, --CH.dbd.CH--, --O--,
--O--(CHR.sup.9)--, --S--(CHR.sup.9)--, --(NR.sup.9--CH.sub.2--,
--(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--CH.sub.2--,--(C.dbd.O)--,
--O--CH.sub.2--O--, --(NR.sup.9)--, --(NR.sup.9)--S(O.sub.2)--,
--CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--,
--S--, --(SO)--, --(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, nitro, cyano, formyl, C.sub.1-12alkyl, C.sub.1-12alkoxy,
aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,
heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,
hydroxyalkyl, amino, acylamino, C.sub.1-12alkyl-amino, arylamino,
aralkylamino, aminoC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl,
aryloxycarbonyl, aralkoxycarbonyl, C.sub.1-12alkoxyC.sub.1-12alkyl,
aryloxyC.sub.1-12alkyl, aralkoxyC.sub.1-12alkyl,
C.sub.1-12alkylthio, thioC.sub.1-12alkyl,
C.sub.1-12alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, halogen, C.sub.1-6alkoxy, amino optionally substituted
with one or more C.sub.1-6alkyl, perhalomethyl or aryl; Q is --O--,
--S--, >SO.sub.2, >NR.sup.13, wherein R.sup.13 is hydrogen or
C.sub.1-6alkyl, Ar represents arylene, heteroarylene, or a divalent
heterocyclic group optionally substituted with one or more
C.sub.1-6alkyl or aryl; R.sup.5 represents hydrogen, hydroxy,
halogen, C.sub.1-12alkoxy, C.sub.1-12alkyl, C.sub.4-12-alkenynyl,
C.sub.2-12-alkenyl, C.sub.2-12-alkynyl or aralkyl; optionally
substituted with one or more halogen, perhalomethyl, hydroxy, nitro
or cyano; or R.sup.5 forms a bond together with R.sup.6, R.sup.6
represents hydrogen, hydroxy, halogen, C.sub.1-12alkoxy,
C.sub.1-12alkyl, C.sub.4-12alkenynyl, C.sub.2-12-alkenyl,
C.sub.2-12-alkynyl, acyl or aralkyl; optionally substituted with
one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or
R.sup.6 forms a bond together with R.sup.5, R.sup.7 represents
hydrogen, C.sub.1-12alkyl, C.sub.4-12-alkenynyl,
C.sub.2-12-alkenyl, C.sub.2-12-alkynyl, aryl, aralkyl,
C.sub.1-12alkoxyC.sub.1-12alkyl, C.sub.1-12alkoxycarbonyl,
aryloxycarbonyl, C.sub.1-12alkylaminocarbonyl, arylaminocarbonyl,
acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally
substituted with one or more halogen, perhalomethyl, hydroxy, nitro
or cyano; R.sup.8 represents hydrogen, C.sub.1-12alkyl,
C.sub.4-12-alkenynyl, C.sub.2-12-alkenyl, C.sub.2-12-alkynyl, aryl,
aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups;
optionally substituted with one or more halogen, perhalomethyl,
hydroxy, nitro or cyano; Y represents oxygen, sulphur or NR.sup.10,
where R.sup.10 represents hydrogen, C.sub.1-12alkyl, aryl,
hydroxyC.sub.1-12alkyl or aralkyl groups or when Y is NR.sup.10,
R.sup.8 and R.sup.10 may form a 5 or 6 membered nitrogen containing
ring, optionally substituted with one or more C.sub.1-6alkyl; n is
an integer ranging from I to 4 and m is an integer ranging from 0
to 1, provided that A or B does not represent phenyl; or a
pharmaceutically acceptable salt thereof.
[0015] In a preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring A fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy, cyano, or C.sub.1-7alkyl,
C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,
C.sub.1-7alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
acyloxy, hydroxyC.sub.1-7alkyl, amino, acylamino,
C.sub.1-7alkyl-amino, arylamino, aralkylamino, aminoC.sub.1-7alkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl, aryloxyC.sub.1-7alkyl,
aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio, thioC.sub.1-7alkyl,
C.sub.1-7alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, perhalomethyl or amino optionally substituted with one or
more C.sub.1-6alkyl, perhalomethyl or aryl; optionally substituted
with one or more halogen, perhalomethyl, hydroxy cyano;
[0016] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring A fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy, cyano, or C.sub.1-7alkyl,
C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,
C.sub.1-7alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
amino, acylamino, C.sub.1-7alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-7alkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
aryloxyC.sub.1-7alkyl, aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio,
thioC.sub.1-7alkyl; optionally substituted with one or more halogen
or hydroxy;
[0017] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring A fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy or C.sub.1-7alkyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, C.sub.1-7alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl,
arylamino, aryloxyC.sub.1-7alkyl.
[0018] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring A fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy or C.sub.1-7alkyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, C.sub.1-7alkoxy or aryl.
[0019] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring A fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen or halogen.
[0020] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring B fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy, cyano, or C.sub.1-7alkyl,
C.sub.4-7alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,
C.sub.1-7alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
acyloxy, hydroxyC.sub.1-7alkyl, amino, acylamino,
C.sub.1-7alkyl-amino, arylamino, aralkylamino, aminoC.sub.1-7alkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl, aryloxyC.sub.1-7alkyl,
aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio, thioC.sub.1-7alkyl,
C.sub.1-7alkoxycarbonylamino, aryloxycarbonylamino,
aralkoxycarbonylamino, --COR.sup.11, or --SO.sub.2R.sup.12, wherein
R.sup.11 and R.sup.12 independently of each other are selected from
hydroxy, perhalomethyl or amino optionally substituted with one or
more C.sub.1-6alkyl, perhalomethyl or aryl; optionally substituted
with one or more halogen, perhalomethyl, hydroxy or cyano.
[0021] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring B fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy, cyano, or C.sub.1-7alkyl,
C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,
C.sub.1-7alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,
heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,
amino, acylamino, C.sub.1-7alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-7alkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
aryloxyC.sub.1-7alkyl, aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio,
thioC.sub.1-7alkyl; optionally substituted with one or more halogen
or hydroxy.
[0022] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring B fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy or C.sub.1-7alkyl, C.sub.2-7-alkenyl,
C.sub.2-7alkynyl, C.sub.1-7alkoxy, aryl, aryloxy, aralkyl,
aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl,
arylamino, aryloxyC.sub.1-7alkyl.
[0023] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring B fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen, halogen,
perhalomethyl, hydroxy or C.sub.1-7alkyl, C.sub.2-7alkenyl,
C.sub.2-7alkynyl, C.sub.1-7alkoxy or aryl.
[0024] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein ring B fused to the
ring containing X and N represents a 5-6 membered cyclic ring,
optionally substituted with one or more hydrogen or halogen.
[0025] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein X is a valence bond,
--(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--, --CH.dbd.CH--, --O--,
--O--(CHR.sup.9)--, --S--(CHR.sup.9)--, --(NR.sup.9)--CH.sub.2--,
--(CHR.sup.9)--CH.dbd.CH--, --(CHR.sup.9)--CH.sub.2--CH.sub.2--,
--(C.dbd.O)--, --O--CH.sub.2--O--, --(NR.sup.9)--,
--(NR.sup.9)--S(O.sub.2)--, --CH.dbd.(CR.sup.9)--,
--(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--, --S--, --(SO)--,
--(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, cyano, C.sub.1-7alkyl, C.sub.1-7alkoxy, aryl, aryloxy,
aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,
heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,
acylamino, C.sub.1-7alkyl-amino, arylamino, aralkylamino,
aminoC.sub.1-7alkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
aryloxyC.sub.1-7alkyl, aralkoxyC.sub.1-7alkyl, C.sub.1-7alkylthio,
thioC.sub.1-7alkyl.
[0026] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein X is a valence bond,
--(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--, --CH.dbd.CH--, --O--,
--O--(CHR.sup.9)--, --S--(CHR.sup.9)--, --(NR.sup.9)--CH.sub.2--,
--(CHR.sup.9)--CH.dbd.CH--, --(CHR.sup.9)--CH.sub.2--CH.sub.2--,
--(C.dbd.O)--, --O--CH.sub.2--O--, --(NR.sup.9)--,
--(NR.sup.9)--S(O.sub.2)--, --CH.dbd.(CR.sup.9)--,
--(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--, --S--, --(SO)--,
--(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, aryl.
[0027] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein X is a valence bond,
--(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--, --CH.dbd.CH--,
--O--(CHR.sup.9)--, --S--(CHR.sup.9)--, --(NR.sup.9)--CH.sub.2--,
--(CHR.sup.9)--CH.dbd.CH--, --(CHR.sup.9)--CH.sub.2--CH.sub.2--,
--(C.dbd.O)--, --O--CH.sub.2--O--, --(NR.sup.9)--S(O.sub.2)--,
--CH.dbd.(CR.sub.9)--, --(CO)--(CHR.sup.9)--, --CH.sub.2--(SO)--,
--(SO)--, --(SO.sub.2)--, --CH.sub.2--(SO.sub.2)--,
--CH.sub.2--O--CH.sub.2--, wherein R.sup.9 is hydrogen, halogen,
hydroxy, C.sub.1-4alkyl, C.sub.1-4alkoxy.
[0028] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein X is a valence bond,
--(CHR.sup.9)--, --(CHR.sup.9)--CH.sub.2--, --CH.dbd.CH--,
--O--(CHR.sup.9)--, --(CHR.sup.9)--CH.dbd.CH--,
--(CHR.sup.9)--CH.sub.2--CH.sub.2--, --(C.dbd.O)--,
--O--CH.sub.2--O--, --CH.dbd.(CR.sup.9)--, --(CO)--(CHR.sup.9)--,
--CH.sub.2--(SO)--, --(SO)--, --(SO.sub.2)--,
--H.sub.2--(O.sub.2)--C--CH.sub.2--O--CH.sub.2--H wherein R.sup.9
is hydrogen.
[0029] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Q is --O-- or
--S--.
[0030] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Q is --O--.
[0031] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Ar represents
arylene, heteroarylene, or a divalent heterocyclic group optionally
substituted with one or more C.sub.1-6alkyl or aryl; R.sup.5
represents hydrogen, hydroxy, halogen, C.sub.1-7alkoxy,
C.sub.1-7alkyl, C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7;
or R.sup.5 forms a bond together with R.sup.6, R.sup.6 represents
hydrogen, hydroxy, halogen, C.sub.1-7alkoxy, C.sub.1-7alkyl,
C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl, C.sub.2-7alkynyl; or
R.sup.6 forms a bond together with R.sup.5, R.sup.7 represents
hydrogen, C.sub.1-7alkyl, C.sub.4-7-alkenynyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, aryl, aralkyl, C.sub.1-7alkoxyC.sub.1-7alkyl,
C.sub.1-7alkoxycarbonyl, aryloxycarbonyl,
C.sub.1-7alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl,
heteroaryl or heteroaralkyl groups; R.sup.8 represents hydrogen,
C.sub.1-7alkyl, C.sub.4-7alkenynyl, C.sub.2-7-alkenyl,
C.sub.2-7-alkynyl, aryl, aralkyl, heterocyclyl, heteroaryl or
heteroaralkyl; Y represents oxygen, sulphur or NR.sup.10, where
R.sup.10 represents hydrogen, C.sub.1-7alkyl,
hyrdroxyC.sub.1-7alkyl; n is an integer ranging from 2 to 3 and m
is an integer ranging from 0 to 1.
[0032] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Ar represents arylene
or heteroarylene; R.sup.5 represents hydrogen, hydroxy, halogen; or
R.sup.5 forms a bond together with R.sup.6, R.sup.6 represents
hydrogen, hydroxy, halogen; or R.sup.6 forms a bond together with
R.sup.5, R.sup.7 represents hydrogen, C.sub.1-7alkyl,
C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, aryl, aralkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl, C.sub.1-7alkylaminocarbonyl,
arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl
groups; R.sup.8 represents hydrogen, C.sub.1-7alkyl,
C.sub.2-7-alkenyl, C.sub.2-7alkynyl,; Y represents oxygen or
sulphur; n is an integer ranging from 2 to 3 and m is 1.
[0033] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Ar represents arylene
or heteroarylene; R.sup.5 represents hydrogen. R.sup.6 represents
hydrogen; R.sup.7 represents hydrogen, C.sub.1-7alkyl,
C.sub.2-7-alkenyl, C.sub.2-7-alkynyl, aryl, aralkyl,
C.sub.1-7alkoxyC.sub.1-7alkyl; R.sup.8 represents hydrogen,
C.sub.1-7alkyl, C.sub.2-7-alkenyl, C.sub.2-7-alkynyl,; Y represents
oxygen; n is an integer ranging from 2 to 3 and m is 1.
[0034] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Ar represents
arylene; R.sup.5 represents hydrogen; R.sup.6 represents hydrogen;
R.sup.7 represents hydrogen, C.sub.1-4alkyl, C.sub.2-4-alkenyl,
C.sub.2-4-alkynyl, R.sup.8 represents hydrogen, C.sub.1-4alkyl, Y
represents oxygen; n is an integer ranging from 2 to 3 and m is
1.
[0035] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Ar represents
phenylene; R.sup.5 represents hydrogen; R.sup.6 represents
hydrogen; R.sup.7 represents hydrogen, C.sub.1-4alkyl, R.sup.8
represents hydrogen Y represents oxygen; n is an integer ranging
from 2 to 3 and m is 1.
[0036] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein A is 5 membered
cyclic ring containing S.
[0037] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein B is 5 membered
cyclic ring containing S.
[0038] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein X is
--CH.dbd.(CR.sup.9)--, wherein R.sup.9 is H.
[0039] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein n is 2.
[0040] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Q is --O--.
[0041] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein m is 1.
[0042] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Ar is phenylene.
[0043] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein R.sup.5 is H.
[0044] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein R.sup.6 is H.
[0045] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein R.sup.7 is ethyl.
[0046] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein Y is oxygen.
[0047] In another preferred embodiment, the present invention is
concerned with compounds of formula I wherein R.sup.8 is H.
[0048] Preferred compounds of the invention are:
[0049]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
oxy]-phenyl}2-ethoxy-propionic acid,
[0050]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
oxy]-phenyl}-2-methoxy-propionic acid,
[0051]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
oxy]-phenyl}-2-propoxy-propionic acid,
[0052]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
oxy]-phenyl}-2-benzyloxy-propionic acid,
[0053]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
yl]-phenyl}2-ethoxy-propionic acid,
[0054]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
yl]-phenyl}-2-methoxy-propionic acid,
[0055]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
yl]-phenyl}-2-propoxy-propionic acid,
[0056]
3-{4-[2-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-eth-
yl]-phenyl}-2-benzyloxy-propionic acid,
[0057]
3-{4-[1-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-met-
hoxy]-phenyl}-2-ethoxy-propionic acid,
[0058]
3-{4-[1-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen4-yl)-meth-
oxy]-phenyl}-2-methoxy-propionic acid,
[0059]
3-{4-[1-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen4-yl)-meth-
oxy]-phenyl}-2-benzyloxy-propionic acid,
[0060]
3-{4-[3-(8,9-Dihydro-3,5-dithia4-aza-cyclopenta[f]azulen-4-yl)-prop-
oxy]-phenyl}-2-ethoxy-propionic acid,
[0061]
3-{4-[3-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-pro-
poxy]-phenyl}2-methoxy-propionic acid,
[0062]
3-{4-[3-(8,9-Dihydro-3,5-dithia4-aza-cyclopenta[f]azulen-4-yl)-prop-
oxy]-phenyl}-2-benzyloxy-propionic acid,
[0063]
3-{4-[3-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen-4-yl)-pro-
pyl]-phenyl}-2-ethoxy-propionic acid,
[0064]
3-{4-[3-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen4-yl)-prop-
yl]-phenyl}2-methoxy-propionic acid,
[0065]
3-{4-[3-(8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]azulen4-yl)-prop-
yl]-phenyl}2-benzyloxy-propionic acid,
[0066] 2-Ethoxy-3-(4-(2-(9H-1, 8,
10-triaza-anthracen-10-yl)-ethoxy)-pheny- l)-propionic acid,
[0067] 2-methoxy-3-(4-(2-(9H-1, 8,
10-triaza-anthracen-10-yl)-ethoxy)-phen- yl)-propionic acid,
[0068] 2-propoxy-3-(4-(2-(9H-1, 8,
10-triaza-anthracen-10-yl)-ethoxy)-phen- yl)-propionic acid,
[0069] 2-benzyloxy-3-(4-(2-(9H-1, 8,
10-triaza-anthracen-10-yl)-ethoxy)-ph- enyl)-propionic acid,
[0070] 2-ethoxy-3-(4-(1 -(9H-1, 8,
10-triaza-anthracen-10-yl)-methoxy)-phe- nyl)-propionic acid,
[0071] 2-methoxy-3-(4-(1 -(9H-1, 8,
10-triaza-anthracen-10-yl)-methoxy)-ph- enyl)-propionic acid,
[0072] 2-benzyloxy-3-(4-(1 -(9H-1, 8,
10-triaza-anthracen-10-yl)-methoxy)-- phenyl)-propionic acid,
[0073] 2-ethoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propoxy)-phen- yl)-propionic acid,
[0074] 2-propoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propoxy)-phe- nyl)-propionic acid,
[0075] 2-methoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propoxy)-phe- nyl)-propionic acid,
[0076] 2-benzyloxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propoxy)-p- henyl)-propionic acid,
[0077] 2-ethoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propyl)-pheny- l)-propionic acid,
[0078] 2-propoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propyl)-phen- yl)-propionic acid,
[0079] 2-methoxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propyl)-phen- yl)-propionic acid,
[0080] 2-benzyloxy-3-(4-(3-(9H-1, 8,
10-triaza-anthracen-10-yl)-propyl)-ph- enyl)-propionic acid,
[0081] 2-ethoxy-3-(4-(2-(4, 5,
9-triaza-fluoren-9-yl)-ethoxy)-phenyl)-prop- ionic acid,
[0082] 2-methoxy-3-(4-(2-(4, 5,
9-triaza-fluoren-9-yl)-ethoxy)-phenyl)-pro- pionic acid,
[0083] 2-propoxy-3-(4-(2-(4, 5,
9-triaza-fluoren-9-yl)-ethoxy)-phenyl)-pro- pionic acid,
[0084] 2-ethoxy-3-(4-(1-(4, 5,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)-pro- pionic acid,
[0085] 2-methoxy-3-(4-(1-(4, 5,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)-pr- opionic acid,
[0086] 2-benzyoxy-3-(4-(1-(4, 5,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)-p- ropionic acid,
[0087] 2-ethoxy-3-(4-(3-(4, 5,
9-tiaza-fluoren-9-yl)-propoxy)-phenyl)-prop- ionic acid,
[0088] 2-methoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)-propoxy)-phenyl)-pr- opionic acid,
[0089] 2-benzyloxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)-propoxy)-phenyl)-- propianic acid,
[0090] 2-propoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)-propoxy)-phenyl)-pr- opionic acid,
[0091] 2-ethoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-prop- ionic acid,
[0092] 2-methoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-pro- pionic acid,
[0093] 2-propoxy-3-(4-(3-(4, 5,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-pro- pionic acid,
[0094] 2-ethoxy-3-(4-(2-(1, 8,
9-triaza-fluoren-9-yl)-ethoxy)-phenyl)-prop- ionic acid,
[0095] 2-methoxy-3-(4-(2-(1, 8,
9triaza-fluoren-9-yl)-ethoxy)-phenyl)-prop- ionic acid,
[0096] 2-propoxy-3-(4-(2-(1, 8,
9-triaza-fluoren-9-yl)-ethoxy)-phenyl)-pro- pionic acid,
[0097] 2-betnzyoxy-3-(4-(2-(1, 8,
9-triaza-fluoren-91yl)-ethoxy)-phenyl)-p- ropionic acid,
[0098] 2-ethoxy-3-(4-(1-(1, 8,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)-pro- pionic acid,
[0099] 2-ethoxy-3-(4-(1-(1, 8,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)-pro- pionic acid,
[0100] 2-propoxy-3-(4-(1-(1, 8,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)-pr- opionic acid,
[0101] 2-benzyloxy-3-(4-(1-(1, 8,
9-triaza-fluoren-9-yl)-methoxy)-phenyl)p- ropionic acid,
[0102] 2-ethoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propoxy)-phenyl)-pro- pionic acid,
[0103] 2-ethoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propoxy)-phenyl)-pro- pionic acid,
[0104] 2-propoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propoxy)phenyl)prop- ionic acid,
[0105] 2-benzyloxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propoxy)-phenyl)-- propionic acid,
[0106] 2-ethoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-prop- ionic acid,
[0107] 2-methoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-pro- pionic acid,
[0108] 2-propoxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-pro- pionic acid,
[0109] 2-benzyloxy-3-(4-(3-(1, 8,
9-triaza-fluoren-9-yl)-propyl)-phenyl)-p- ropionic acid,
[0110] 3-(4-(2-(dithieno[2,3-b; 3',
2'-d]pyrrol-7-yl)-ethoxy)-phenyl)-2-et- hoxypropionic acid,
[0111] 2-metho[2,3-b;3', 2'-d]pyrrol-7-yl)-etoxy)-phenyl)
-propionic acid,
[0112] 3(4-(2-d(dithieno[2,3-3',
2'-d]pryrrol-7-yl)-ethoxy)-phenyl)2-propi- onic acid,
[0113] 3-(4-(2-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-ethoxy)-phenyl)-2-ben- zyloxy-propionic acid,
[0114] 3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-ethoxy)-phenyl)-2-met- hoxy-propionic acid,
[0115] 3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-methoxy)-phenyl)-2-et- hoxy-propionic acid,
[0116] 3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-methoxy)-phenyl)-2-pr- opoxy-propionic acid,
[0117] 3-(4-(1-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-methoxy)-phenyl)-2-be- nzytoxy-propionic
acid,
[0118] 3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-et- hoxy-propionic acid,
[0119] 3-(4-(3-(dithieno[2,3-b; 3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-m- ethoxy-propionic acid,
[0120] 3-(4-(3-(dithieno[2,3-b;3', 240
-d]pyrrol-7-yl)-propoxy)-phenyl)-2-- propoxy-propionic acid,
[0121] 3-(4-(3-(dithieno[2,3-b; 3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-b- enzytoxy-propionic
acid,
[0122] 3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-propyl)-phenyl)-2-eth- oxy-propionic acid,
[0123] 3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-propyl)-phenyl)-2-met- hoxy-propionic acid,
[0124] 3-(4-(3-(dithieno[2,3-b;3',
2'-d]pyrrol-7-yl)-propyl)-phenyl)-2-bez- yoxy-propionic acid,
[0125] 3-(4-(2-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-ethoxy)phenyl)-2-etho- xy-propionic acid,
[0126] 3-(4-(2-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-ethoxy)-phenyl)-2-eth- oxy-propionic acid,
[0127] 3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-methoxy)-phenyl)-2-et- hoxy-propionic acid,
[0128] 3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrol-7-yl)-ethoxy)-phenyl)-2-meth- oxy-propionic acid,
[0129] 3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-ethoxy)-phenyl)-2-pro- poxy-propionic acid,
[0130] 3-(4-(1-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-methoxy)-phenyl)-2-be- nzyloxy-propionic
acid,
[0131] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-et- hoxy-propionic acid,
[0132] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-pr- opoxy-propionic acid,
[0133] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-me- thoxy-propionic acid,
[0134] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propoxy)-phenyl)-2-be- nzyloxy-propionic
acid,
[0135] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propy)-phenyl)-2-etox- y-propionic acid,
[0136] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propy)-phenyl)-2-prop- oxy-propionic acid,
[0137] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propyl)-phenyl)-2-met- hoxy-propionic acid,
[0138] 3-(4-(3-(difurano[2,3-b;3',
2'-d]pyrrol-7-yl)-propyl)-phenyl)-2-ben- zyloxy-propionic acid,
[0139]
3-(4-(2-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-phenyl)-2-etho-
xy-propionic acid,
[0140]
3-(4-(2-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-phenyl)-2-meth-
oxy-propionic acid,
[0141]
3-(4-(2-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-phenyl)-2-prop-
oxy-propionic acid,
[0142] 3-(
4-(2-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-pheny)-2-etho-
xy-propionic acid,
[0143]
3-(4-(2-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-methoxy)-phenyl)-2-eth-
oxy-propionic acid,
[0144]
3-(4-(1-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-methoxy)-phenyl)-2-met-
hoxy-propionic acid,
[0145]
3-(4-(2-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-methoxy)-pheny)1-2-pro-
poxy-propionic acid,
[0146] 3-(4-(1-(4
H-1,7-dithia-8-aza-s-indacen-8-yl)-methoxy)-phenyl)-2-et- hoxy-prop
ionic acid,
[0147]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy)-phenyl)-2-eth-
oxy-propionic acid,
[0148] 3-(4-(3-(4H-1,7-dithia
8-aza-s-indacen-8-yl)-propoxy)-phenyl)-2-met- hoxy-propionic
acid,
[0149]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy)-phenyl)-2-pro-
poxy-propionic acid,
[0150]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy)-phenyl)-2-ben-
zyloxy-propionic acid,
[0151]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-phenyl)-2-etho-
xy-propionic acid,
[0152]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-phenyl)-2-meth-
oxy-propionic acid,
[0153]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-phenyl)-2-prop-
oxy-propionic acid,
[0154]
3-(4-(3-(4H-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-phenyl)-2-benz-
yloxy-propionic acid,
[0155]
2-ethoxy-3-(4-(2-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-ph-
enyl)-propionic acid,
[0156]
2-methoxy-3-(4-(2-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-p-
henyl)-propionic acid,
[0157]
2-propoxy-3-(4-(2-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-p-
henyl)-propionic acid,
[0158]
2-propoxy-3-(4-(2-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-p-
henyl)-propionic acid,
[0159]
2-benzyloxy-3-(4-(2-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-ethoxy)-
-phenyl)-propionic acid,
[0160]
2-ethoxy-3-(4-(1-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-methoxy)-p-
henyl)-propionic acid,
[0161]
2-methoxy-3-(4-(1-(4-oxa-1,.sub.17-dithia-8-aza-s-indacen-8-yl)-met-
hoxy)-phenyl)-propionic acid,
[0162] 2-propoxy-3-(4-(1-(4-oxa-1,7) acid,
[0163]
2-benzyloxy-3-(4-(1-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-methoxy-
)-phenyl)-propionic acid,
[0164]
2-ethoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy)-p-
henyl)-propionic acid,
[0165]
2-methoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy)--
phenyl)-propionic acid,
[0166]
2-propoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy)--
phenyl)-propionic acid,
[0167]
2-benzyloxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propoxy-
)-phenyl)-propionic acid,
[0168]
2-ethoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-ph-
enyl)-propionic acid,
[0169]
2-ethoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-ph-
enyl)-propionic acid,
[0170]
2-propoxy-3-(4-(3-(4-oxa-1,7-dithia-8-aza-s-indacen-8-yl)-propyl)-p-
henyl)-propionic acid,
[0171] 2-benzyloxy-3-(4-(3-(4-oxa-1
,7-dithia-8-aza-s-indacen-8-yl)-propyl- )-phenyl)-propionic
acid;
[0172] or a pharmaceutically acceptable salt thereof.
[0173] A further preferred compound of the invention is:
[0174]
3-{4-[2-*8,9-Dihydro-3,5-dithia-4-aza-cyclopenta[f]-azulen-4-yl)-et-
hoxy]-phenyl}-2-ethoxy-propionic acid;
[0175] or a pharmaceutically acceptable salt thereof.
[0176] In the above structural formulas and throughout the present
specification, the following terms have the indicated meaning:
[0177] The terms "C.sub.1-12-alkyl" as used herein, alone or in
combination is intended to include those alkyl groups of the
designated length in either a linear or branched or cyclic
configuration represents e.g. cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl and the like. Typical
C.sub.1-6-alkyl groups include, but are not limited to, methyl,
ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl,
tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and
the like.
[0178] The terms "C.sub.2-n-alkenyl" wherein n' can be from 3
through 15, as used herein, represents an olefinically unsaturated
branched or straight group having from 2 to the specified number of
carbon atoms and at least one double bond. Examples of such groups
include, but are not limited to, vinyl, 1-propenyl, 2-propenyl,
allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl,
and the like.
[0179] The terms "C.sub.2-n-alkynyl" wherein n' can be from 3
through 15, as used herein, represent an unsaturated branched or
straight group having from 2 to the specified number of carbon
atoms and at least one triple bond. Examples of such groups
include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 1-pentynyl, 2-pentynyl and the like.
[0180] The terms "C.sub.4-n-alkenynyl" wherein n' can be from 5
through 15,as used herein, represent an unsaturated branched or
straight hydrocarbon group having from 4 to the specified number of
carbon atoms and both at least one double bond and at least one
triple bond. Examples of such groups include, but are not limited
to, 1-penten4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the
like.
[0181] The term "C.sub.1-12-alkoxy" as used herein, alone or in
combination is intended to include those C.sub.1-12-alkyl groups of
the designated length in either a linear or branched or cyclic
configuration linked thorugh an ether oxygen having its free
valence bond from the ether oxygen. Examples of linear alkoxy
groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
Examples of branched alkoxy are isoprpoxy, sec-butoxy, tert-butoxy,
isopentoxy and isohexoxy. Example of cyclic alkoxy are
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and
cyclohexyloxy.
[0182] The term "C.sub.1-6-alkoxycarbonyloxy" is intended to
include the above defined C.sub.1-6-alkoxy groups attached to a
carbonyloxy moiety, eg. methoxycarbonyloxy, ethoxycarbonyloxy,
etc..
[0183] As used herein the term "C.sub.4-12-(cycloalkylalkyl)"
represents a branched or straight alkyl group substituted at a
carbon with a cycloalkyl group. Examples of such groups include,
but are not limited to, cyclopropylethyl, cyclobutylmethyl,
2-(cyclohexyl)ethyl, cyclohexylmethyl, 3-(cyclopentyl)-1-propyl,
and the like.
[0184] The term "C.sub.1-12-alkylthio" as used herein, alone or in
combination, refers to a straight or branched or cyclic monovalent
substituent comprising a C.sub.1-12-alkyl group linked through a
divalent sulfur atom having its free valence bond from the sulfur
atom and having 1 to 12 carbon atoms e.g. methylthio, ethylthio,
propylthio, butylthio, pentylthio. Example of cyclic alkylthio are
cyclopropylthio, cyclobutylthio, cyclopentylthio and
cyclohexylthio.
[0185] The term "C.sub.1-12alkylamino" as used herein, alone or in
combination, refers to a straight or branched or cyclic monovalent
substituent comprising a C.sub.1-12-alkyl group linked through
amino having a free valence bond from the nitrogen atom e.g.
methylamino, ethylamino, propylamino, butylamino, pentylamino.
Example of cyclic alkylamino are cyclopropylamino, cyclobutylamino,
cyclopentylamino and cyclohexylamino.
[0186] The term "hydroxyC.sub.1-12alkyl" as used herein, alone or
in combination, refers to a C.sub.1-12alkyl as defined herein
whereto is attached a hydroxy group, e.g. hydroxyethyl,
1-hydroxypropyl, 2-hydroxypropyl etc..
[0187] The term "arylamino" as used herein, alone or in
combination, refers to an aryl as defined herein linked through
amino having a free valence bond from the nitrogen atom e.g.
phenylamino, naphthylamino, etc..
[0188] The term "aralkylamino" as used herein, alone or in
combination, refers to an aralkyl as defined herein linked through
amino having a free valence bond from the nitrogen atom e.g.
benzylamino, phenethylamino, 3-phenylpropylamino,
1-naphtylmethylamino, 2-(1-naphtyl)ethylamino and the like.
[0189] The term "aminoC.sub.1-12alkyl" as used herein, alone or in
combination, refers to a C.sub.1-12alkyl as defined herein whereto
is attached an amino group, e.g. aminoethyl, 1-aminopropyl,
2-aminopropyl etc..
[0190] The term "aryloxycarbonyl" as used herein, alone or in
combination, refers to an aryloxy as defined herein linked through
a carbonyl having a free valence bond from the carbon atom, e.g.
phenoxycarbonyl, 1-naphthyloxycarbonyl or 2-naphthyloxycarbonyl,
etc..
[0191] The term "aralkoxycarbonyl" as used herein, alone or in
combination, refers to an aralkoxy as defined herein linked through
a carbonyl having a free valence bond from the carbon atom, e.g.
benzyloxycarbonyl, phenethoxycarbonyl, 3-phenylpropoxycarbonyl,
1-naphthylmethoxycarbonyl, 2-(1-naphtyl)ethoxycarbonyl, etc..
[0192] The term "C.sub.1-12alkoxyC.sub.1-12alkyl" as used herein,
alone or in combination, refers to a C.sub.1-12alkyl as defined
herein whereto is attached a C.sub.1-12alkoxy as defined herein,
e.g. methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,
etc..
[0193] The term "aryloxyC.sub.1-12alkyl" as used herein, alone or
in combination, refers to a C.sub.1-12alkyl as defined herein
whereto is attached an aryloxy as defined herein, e.g.
phenoxymethyl, phenoxydodecyl, 1-naphthyloxyethyl,
2-naphthyloxypropyl, etc..
[0194] The term "aralkoxyC.sub.1-12alkyl" as used herein, alone or
in combination, refers to a C.sub.1-12alkyl as defined herein
whereto is attached an aralkoxy as defined herein, e.g.
benzyloxymethyl, phenethoxydodecyl, 3-phenylpropoxyethyl,
1-naphthylmethoxypropyl, 2-(1-naphtyl)ethoxymethyl, etc..
[0195] The term "thioC.sub.1-12alkyl" as used herein, alone or in
combination, refers to a C.sub.1-12alkyl as defined herein whereto
is attached a group of formula --SR'" wherein R'" is hydrogen,
C.sub.1-6alkyl or aryl, e.g. thiomethyl, methylthiomethyl,
phenylthioethyl, etc..
[0196] The term "C.sub.1-12alkoxycarbonylamino" as used herein,
alone or in combination, refers to a C.sub.1-12alkoxycarbonyl as
defined herein linked through amino having a free valence bond from
the nitrogen atom e.g. methoxycarbonylamino, carbethoxyamino,
propoxycarbonylamino, isopropoxycarbonylamino,
n-butoxycarbonylamino, tert-butoxycarbonylamino, etc..
[0197] The term "aryloxycarbonylamino" as used herein, alone or in
combination, refers to an aryloxycarbonyl as defined herein linked
through amino having a free valence bond from the nitrogen atom
e.g. phenoxycarbonylamino, 1-naphthyloxycarbonylamino or
2-naphthyloxycarbonylamino, etc..
[0198] The term "aralkoxycarbonylamino" as used herein, alone or in
combination, refers to an aralkoxycarbonyl as defined herein linked
through amino having a free valence bond from the nitrogen atom
e.g. benzyloxycarbonylamino, phenethoxycarbonylamino,
3-phenylpropoxycarbonyla- mino, 1-naphthylmethoxycarbonylamino,
2-(1-naphtyl)ethoxycarbonylamino, etc..
[0199] The term "aryl" is intended to include aromatic rings, such
as carboxylic aromatic rings selected from the group consisting of
phenyl, naphthyl, (1-naphtyl or 2-naphtyl) optionally substituted
with halogen, amino, hydroxy, C.sub.1-6-alkyl or
C.sub.1-6-alkoxy.
[0200] The term "arylene" is intended to include divalent aromatic
rings, such as carboxylic aromatic rings selected from the group
consisting of phenylene, naphthylene, optionally substituted with
halogen, amino, hydroxy, C.sub.1-6-alkyl or C.sub.1-6alkoxy.
[0201] The term "halogen" means fluorine, chlorine, bromine or
iodine.
[0202] The term "perhalomethyl" means trifluoromethyl,
trichloromethyl, tribromomethyl or triiodomethyl.
[0203] The term "C.sub.1-6-dialkylamino" as used herein refers to
an amino group wherein the two hydrogen atoms independently are
substituted with a straight or branched, saturated hydrocarbon
chain having the indicated number of carbon atoms; such as
dimethylamino, N-ethyl-N-methylamino, diethylamino, dipropylamino,
N-(n-butyl)-N-methylamino, di(n-pentyl)amino, and the like.
[0204] The term "acyl" as used herein refers to a monovalent
substituent comprising a C.sub.1-6-alkyl group linked through a
carbonyl group; such as e.g. acetyl, propionyl, butyryl,
isobutyryl, pivaloyl, valeryl, and the like.
[0205] The term "acyloxy" as used herein refers to acyl as defined
herein linked to an oxygen atom having its free valence bond from
the oxygen atom e.g. acetyloxy, propionyloxy, butyryloxy,
isobutyryloxy, pivaloyloxy, valeryloxy, and the like.
[0206] The term "C.sub.1-12-alkoxycarbonyl" as used herein refers
to a monovalent substituent comprising a C.sub.1-12-alkoxy group
linked through a carbonyl group; such as e.g. methoxycarbonyl,
carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl,
n-hexoxycarbonyl and the like.
[0207] The term "a cyclic ring containing from 5 to 7 carbon atoms"
as used herein refers to a monocyclic saturated or unsaturated or
aromatic system, wherein the ring may be cyclopentyl,
cyclopentenyl, cyclohexyl, phenyl or cycloheptyl.
[0208] The term "bicycloalkyl" as used herein refers to a
monovalent substituent comprising a bicyclic structure made of 6-12
carbon atoms such as e.g. 2-norbornyl, 7-norbornyl, 2-bicyclo[2. 2.
2]octyl and 9-bicyclo[3. 3. 1]nonanyl.
[0209] The term "heteroaryl" as used herein, alone or in
combination, refers to a monovalent substituent comprising a 5-6
membered monocyclic aromatic system or a 9-10 membered bicyclic
aromatic system containing one or more heteroatoms selected from
nitrogen, oxygen and sulfur, e.g. furan, thiophene, pyrrole,
imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine,
pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,
thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline,
indole, benzimidazole, benzofuran, pteridine and purine.
[0210] The term "heteroarylene" as used herein, alone or in
combination, refers to a divalent group comprising a 5-6 membered
monocyclic aromatic system or a 9-10 membered bicyclic aromatic
system containing one or more heteroatoms selected from nitrogen,
oxygen and sulfur, e.g. furan, thiophene, pyrrole, imidazole,
pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine,
isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole,
quinoline, isoquinoline, quinazoline, quinoxaline, indole,
benzimidazole, benzofuran, pteridine and purine.
[0211] The term "heteroaryloxy" as used herein, alone or in
combination, refers to a heteroaryl as defined herein linked to an
oxygen atom having its free valence bond from the oxygen atom e.g.
pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,
pyrimidine, pyridazine, isothiazole, isoxazole, oxazole,
oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline,
quinoxaline, indole, benzimidazole, benzofuran, pteridine and
purine linked to oxygen.
[0212] The term "aralkyl" as used herein refers to a straight or
branched saturated carbon chain containing from 1 to 6 carbons
substituted with an aromatic carbohydride; such as benzyl,
phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and
the like.
[0213] The term "aryloxy" as used herein refers to phenoxy,
1-naphthyloxy or 2-naphthyloxy.
[0214] The term "aralkoxy" as used herein refers to a
C.sub.1-6-alkoxy group substituted with an aromatic carbohydride,
such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy,
2-(1-naphtyl)ethoxy and the like.
[0215] The term "heteroaralkyl" as used herein refers to a straight
or branched saturated carbon chain containing from 1 to 6 carbons
substituted with a heteroaryl group; such as (2-furyl)methyl,
(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,
(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.
[0216] The term "heteroaralkoxy" as used herein refers to a
heteroaralkyl as defined herein linked to an oxygen atom having its
free valence bond from the oxygen atom, e.g. (2-furyl)methyl,
(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,
(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl linked to
oxygen.
[0217] The term "C.sub.1-6-alkylsulfonyl" as used herein refers to
a monovalent substituent comprising a C.sub.1-6-alkyl group linked
through a sulfonyl group such as e.g. methylsulfonyl,
ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,
n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl,
tert-butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl,
3-methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl,
neopentylsulfonyl, n-hexylsulfonyl and
2,2-dimethylpropylsulfonyl.
[0218] The term "C.sub.1-6-monoalkylaminosulfonyl" as used herein
refers to a monovalent substituent comprising a
C.sub.1-6-monoalkylamino group linked through a sulfonyl group such
as e.g. methylaminosulfonyl, ethylaminosulfonyl,
n-propylaminosulfonyl, isopropylaminosulfonyl,
n-butylaminosulfonyl, sec-butylaminosulfonyl,
isobutylaminosulfonyl, tert-butylaminosulfonyl,
n-pentylaminosulfonyl, 2-methylbutylaminosulfony- l,
3-methylbutylaminosulfonyl, n-hexylaminosulfonyl,
4-methylpentylaminosulfonyl, neopentylaminosulfonyl,
n-hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
[0219] The term "C.sub.1-6-dialkylaminosulfonyl" as used herein
refers to a monovalent substituent comprising a
C.sub.1-6dialkylamino group linked through a sulfonyl group such as
dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl,
diethylaminosulfonyl, dipropylaminosulfonyl,
N-(n-butyl)-N-methylaminosulfonyl, di(n-pentyl)aminosulfonyl, and
the like.
[0220] The term "C.sub.1-6-alkylsulfinyl" as used herein refers to
a monovalent substituent comprising a straight or branched
C.sub.1-6alkyl group linked through a sulfinyl group
(--S(.dbd.O)--); such as e.g. methylsulfinyl, ethylsulfinyl,
isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, and the like.
[0221] The term "acylamino" as used herein refers to an amino group
wherein one of the hydrogen atoms is substituted with an acyl
group, such as e.g. acetamido, propionamido,
isopropylcarbonylamino, and the like.
[0222] The term "(C.sub.3-6-cycloalkyl)C.sub.1-6-alkyl" as used
herein, alone or in combination, refers to a straight or branched,
saturated hydrocarbon chain having 1 to 6 carbon atoms and being
monosubstituted with a C.sub.3-6-cycloalkyl group, the cycloalkyl
group optionally being mono- or polysubstituted with
C.sub.1-6-alkyl, halogen, hydroxy or C.sub.1-6-alkoxy; such as e.g.
cyclopropylmethyl, (1-methylcyclopropyl)me- thyl,
1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl, and the
like.
[0223] The term "arylthio" as used herein, alone or in combination,
refers to an aryl group linked through a divalent sulfur atom
having its free valence bond from the sulfur atom, the aryl group
optionally being mono- or polysubstituted with C.sub.1-6-alkyl,
halogen, hydroxy or C.sub.1-6-alkoxy; e.g. phenylthio,
(4-methylphenyl)- thio, (2-chlorophenyl)thio, and the like.
[0224] The term "arylsulfinyl" as used herein refers to an aryl
group linked through a sulfinyl group (--S(.dbd.O)--), the aryl
group optionally being mono- or polysubstituted with
C.sub.1-6-alkyl, halogen, hydroxy or C.sub.1-6-alkoxy; such as e.g.
phenylsulfinyl, (4-chlorophenyl)sulfinyl, and the like.
[0225] The term "arylsulfonyl" as used herein refers to an aryl
group linked through a sulfonyl group, the aryl group optionally
being mono- or polysubstituted with C.sub.1-6-alkyl, halogen,
hydroxy or C.sub.1-6-alkoxy; such as e.g. phenylsulfonyl, tosyl,
and the like.
[0226] The term "C.sub.1-6-monoalkylaminocarbonyl" as used herein
refers to a monovalent substituent comprising a
C.sub.1-6-monoalkylamino group linked through a carbonyl group such
as e.g. methylaminocarbonyl, ethylaminocarbonyl,
n-propylaminocarbonyl, isopropylaminocarbonyl,
n-butylaminocarbonyl, sec-butylaminocarbonyl,
isobutylaminocarbonyl, tert-butylaminocarbonyl,
n-pentylaminocarbonyl, 2-methylbutaminocarbonyl,
3-methylbutylaminocarbonyl, n-hexylaminocarbonyl,
4-methylpentylaminocarb- onyl, neopentylaminocarbonyl,
n-hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl.
[0227] The term "C.sub.1-6dialkylaminocarbonyl" as used herein
refers to a monovalent substituent comprising a
C.sub.1-6dialkylamino group linked through a carbonyl group such as
dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,
diethylaminocarbonyl, dipropylaminocarbonyl,
N-(n-butyl)-N-methylaminocarbonyl, di(n-pentyl)aminocarbonyl, and
the like.
[0228] The term ".sub.1-6C-monoalkylaminocarbonylamino" as used
herein refers to an amino group wherein one of the hydrogen atoms
is substituted with a C.sub.1-6monoalkygaminocarbonyl group, e.g.
methylaminocarbonylamino, ethylamino-carbonylamino,
n-propylaminocarbonylamino, isopropylaminocarbonylamino,
n-butylaminocarbonylamino, sec-butylaminocarbonylamino,
isobutylaminocarbonylamino, tert-butylaminocarbonylamino, and
2-methylbutylaminocarbonylamino.
[0229] The term "C.sub.1-6-dialkylaminocarbonylamino" as used
herein refers to an amino group wherein one of the hydrogen atoms
is substituted with a C.sub.1-6dialkylaminocarbonyl group, such as
di-methylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino,
diethylaminocarbonylamino, dipropylaminocarbonylamino,
N-(n-butyl)Nmethylaminocarbonylamino,
di(n-pentyl)aminocarbonylamino, and the like.
[0230] As used herein, the phrase "heterocyclyl" means a monovalent
saturated or. unsaturated group being monocyclic and containing one
or more, such as from one to four carbon atom(s), and from one to
four N, O or S atom(s) or a combination thereof. The phrase
"heterocyclyl" includes, but is not limited to, 5-membered
heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline);
5-membered heterocycles having two heteroatoms in 1,2 or 1,3
positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane,
imidazolidine, imidazorine, 4-oxazolone); 5-membered heterocycles
having three heteroatoms (e.g. tetrahydrofurazan); 5-membered
heterocycles having four heteroatoms; 6-membered heterocycles with
one heteroatom (e.g. piperidine); 6-membered heterocycles with two
heteroatoms (e.g. piperazine, morpholine); 6-membered heterocycles
with three heteroatoms; and 6-membered heterocycles with four
heteroatoms.
[0231] As used herein, the phrase "a divalent heterocyclic group"
means a divalent saturated or unsaturated system being monocyclic
and containing one or more, such as from one to four carbon
atom(s), and one to four N, O or S atom(s) or a combination
thereof. The phrase a divalent heterocyclic group includes, but is
not limited to, 5-membered heterocycles having one hetero atom
(e.g. pyrrolidine, pyrroline); 5-membered heterocycles having two
heteroatoms in 1,2 or 1,3 positions (e.g. pyrazoline, pyrazolidine,
1,2-oxathiolane, imidazolidine, imidazoline, 4-oxazolone);
5-membered heterocycles having three teteroatoms (e.g.
tetrahydrofurazan); 5-membered heterocycles having four
heteroatoms; 6-membered heterocycles with one heteroatom (e.g.
piperidine); 6-membered heterocycles with two heteroatoms (e.g.
piperazine, morpholine); 6-membered heterocycles with three
heteroatoms; and 6-membered heterocycles with four heteroatoms.
[0232] As used herein, the phrase "a 5-6 membered cyclic ring"
means an unsaturated or saturated or aromatic system containing one
or more carbon atoms and optionally from one to four N, O or S
atom(s) or a combination thereof. The phrase "a 5-6 membered cyclic
ring" includes, but is not limited to, e.g. cyclopentyl,
cyclohexyl, phenyl, cyclohexenyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiomorpholinyl,
isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,
1,3-dioxolanyl, 1,4-dioxolanyl, 5-membered heterocycles having one
hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered
heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g.
oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered
heterocycles having three heteroatoms (e.g. triazoles,
thiadiazoles); 5-membered heterocycles having four heteroatoms;
6-membered heterocycles with one heteroatom (e.g. pyridine,
quinoline, isoquinoline, phenanthridine, cyclohepta[b]pyridine);
6-membered heterocycles with two heteroatoms (e.g. pyridazines,
cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines,
morpholines); 6-membered heterocycles with three heteroatoms (e.g.
1, 3, 5-triazine); and 6-membered heterocycles with four
heteroatoms.
[0233] As used herein, the phrase "5- or 6-membered nitrogen
containing ring" refers to a monovalent substituent comprising a
monocyclic unsaturated or saturated or aromatic system containing
one or more carbon, nitrogen, oxygen or sulfur atoms or a
combination thereof and having 5 or 6 members, e.g. pyrrolidinyl,
pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl,
piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl,
triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, thiadiazolyl, 1,3-dioxolanyl and 1,4-dioxolanyl.
[0234] Certain of the above defined terms may occur more than once
in the above formula (Ia), and upon such occurence each term shall
be defined independently of the other.
[0235] Pharmaceutically acceptable salts forming part of this
invention include salts of the carboxylic acid moiety such as
alkali metal salts like Li, Na, and K salts, alkaline earth metal
salts like Ca and Mg salts, salts of organic bases such as lysine,
arginine, guanidine, diethanolamine, choline and the like, ammonium
or substituted ammonium salts, aluminum salts. Salts may include
acid addition salts where appropriate which are, sulphates,
nitrates, phosphates, perchlorates, borates, hydrohalides,
acetates, tartrates, maleates, citrates, succinates, palmoates,
methanesulplionates, benzoates, salicylates, hydroxynaphthoates,
benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates
and the like. Pharmaceutically acceptable solvates may be hydrates
or comprising other solvents of crystallization such as
alcohols.
[0236] The pharmaceutically acceptable salts are prepared by
reacting the compound of formula (Ia) with 1 to 4 equivalents of a
base such as sodium hydroxide, sodium methoxide, sodium hydride,
potassium t-butoxide, calcium hydroxide, magnesium hydroxide and
the like, in solvents lilke ether, THF, methanol, t-butanol,
dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
Organic bases like lysine, arginine, diethanolamine, choline,
guandine and their derivatives etc. may also be used.
Alternatively, acid addition salts whereever applicable are
prepared by treatment with acids such as hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,
p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric
acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic
acid, tartaric acid and the like in solvents like ethyl acetate,
ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may
also be used.
[0237] The stereoisomers of the compounds forming part of this
invention may be prepared by using reactants in their single
enantiomeric form in the process wherever possible or by conducting
the reaction in the presence of reagents or catalysts in their
single enantiomer form or by resolving the mixture of stereoisomers
by conventional methods. Some of the preferred methods include use
of microbial resolution, resolving the diastereomeric salts formed
with chiral acids such as mandelic acid, camphorsulfonic acid,
tartaric acid, lactic acid, and the like wherever applicable or
chiral bases such as brucine, cinchona alkaloids and their
derivatives and the like. Commonly used methods are compiled by
Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley
Interscience, 1981). More specifically the compound of formula (Ia)
may be converted to a 1:1 mixture of diastereomeric amides by
treating with chiral amines, aminoacids, aminoalcohols derived from
aminoacids; conventional reaction conditions may be employed to
convert acid into an amide; the diastereomers may be separated
either by fractional crystallization or chromatography and the
stereoisomers of compound of formula (la) may be prepared by
hydrolysing the pure diastereomeric amide.
[0238] Various polymorphs of compound of general formula (Ia)
forming part of this invention may be prepared by crystallization
of compound of formula (la) under different conditions. For
example, using different solvents commonly used or their mixtures
for recrystallization; crystallizations at different temperatures;
various modes of cooling, ranging from very fast to very slow
cooling during crystallizations. Polymorphs may also be obtained by
heating or melting the compound followed by gradual or fast
cooling. The presence of polymorphs may be determined by solid
probe nmr spectroscopy, ir spectroscopy, differential scanning
calorimetry, powder X-ray diffraction or such other techniques.
[0239] The invention also relates to a method of preparing the
above mentioned compounds.
[0240] A compound of formula (Ia) can be prepared either--when m is
equal to 1--as a compound of formula VI, or b)--when m is equal to
0--as a compound of formula XII:
[0241] By alkylating I with a suitable electrophilic reagent to II.
(Examples of the electrophilic reagent are: ethylene oxide, ethyl
bromoacetate followed by reduction of the ester to alcohol,
2-bromoethanol and 3-bromopropanol) 3
[0242] The hydroxy group can be converted to a suitable leaving
group (for example to a halogen, sulfonate, phosphor under
Mitsunobu conditions) and then reacted with HQ-Ar--R to give III
4
[0243] When R.dbd.CHO, then III can be converted to IV with a
Wittig reagent 5
[0244] Addition to the double bond of suitable reagents give V
6
[0245] V can either be hydrolysed to the corresponding carboxylic
acid or can be reacted further with a suitable reagent to give VI
7
[0246] The molecule VII mentioned under formation of II can be
synthesised in an analogous way starting from HQ-Ar--CHO.
[0247] VII can also be reacted with the proper alkylating reagent
to give VIII 8
[0248] which then can be reacted with I to give VI.
[0249] Yet another way to synthesise the compounds in this
invention is to react I with a proper propargyl analogue IX to give
X 9
[0250] X can then be cross coupled with I--Ar--R using a Pd
catalyst like Pd(PPh.sub.3).sub.4 or PdCl.sub.2(PPh).sub.2 to give
XI 10
[0251] If R.dbd.CHO the above synthesis sequence (reaction with a
Wittig reagent, hydrogenation followed by hydrolysis or
derivatisation of the carboxylic acid) will give the desired
product XII 11
[0252] The compound XIII can also be cross coupled to the propargyl
derivative IX using a Pd catalyst like Pd(PPh.sub.3).sub.4 or
PdCl.sub.2(PPh).sub.2 to give the product XIV 12
[0253] XIV can then reacted with I to give XI, which can be reacted
further as described above to give XII.
[0254] L is a leaving group and all other symbols are as defined
earlier.
PHARMACOLOGICAL METHODS
[0255] In vitro PPAR alpha and PPAR gamma activation activity.
[0256] Principle
[0257] The PPAR gene transcription activation assays were based on
transient transfection into human HEK293 cells of two plasmids
encoding a chimeric test protein and a reporter protein
respectively. The chimeric test protein was a fusion of the DNA
binding domain (DBD) from the yeast GAL4 transcription factor to
the ligand binding domain (LBD) of the human PPAR proteins. The
PPAR LBD harbored in addition to the ligand binding pocket also the
native activation domain (activating function 2=AF2) allowing the
fusion protein to function as a PPAR ligand dependent transcription
factor. The GAL4 DBD will force the fusion protein to bind only to
Gal4 enhancers (of which none existed in HEK293 cells). The
reporter plasmid contained a Gal4 enhancer driving the expression
of the firefly luciferase protein. After transfection, HEK293 cells
expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion protein
will in turn bind to the Gal4 enhancer controlling the luciferase
expression, and do nothing in the absence of ligand. Upon addition
to the cells of a PPAR ligand, luciferase protein will be produced
in amounts corresponding to the activation of the PPAR protein. The
amount of luciferase protein is measured by light emission after
addition of the appropriate substrate.
[0258] Methods
[0259] Cell culture and transfection: HEK293 cells were grown in
DMEM+10% FCS, 1% PS. Cells were seeded in 96-well plates the day
before transfection to give a confluency of 80% at transfection.
0,8 .mu.g DNA per well was transfected using FuGene transfection
reagent according to the manufacturers instructions
(Boehringer-Mannheim). Cells were allowed to express protein for 48
h followed by addition of compound.
[0260] Plasmids: Human PPAR .alpha. and .gamma. was obtained by PCR
amplification using cDNA templates from liver, intestine and
adipose tissue respectively. Amplified cDNAs were cloned into
pCR2.1 and sequenced. The LBD from each isoform PPAR was generated
by PCR (PPAR.alpha.: aa 167 - C-term; PPAR.gamma.: aa 165 - C-term)
and fused to GAL4-DBD by subcloning fragments in frame into the
vector pM1 generating the plasmids pM1.alpha.LBD and pM1.gamma.LBD.
Ensuing fusions were verified by sequencing. The reporter was
constructed by inserting an oligonucleotide encoding five repeats
of the Gal4 recognition sequence into the pGL2 vector
(Promega).
[0261] Compounds: All compounds were dissolved in DMSO and diluted
1:1000 upon addition to the cells. Cells were treated with compound
(1:1000 in 200 .mu.l growth medium including delipidated serum) for
24 h followed by luciferase assay.
[0262] Luciferase assay: Medium including test compound was
aspirated and 100 .mu.l PBS incl. 1 mM Mg.sup.++ and Ca.sup.++ was
added to each well. The luciferase assay was performed using the
LucLite kit according to, the manufacturers instructions (Packard
Instruments). Light emission was quantified by counting SPC mode on
a Packard Instruments top-counter.
PHARMACEUTICAL COMPOSITIONS
[0263] In another aspect, the present invention includes within its
scope pharmaceutical compositions comprising, as an active
ingredient, at least one of the compounds of the general formula
(Ia) or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier or diluent.
[0264] Pharmaceutical compositions containing a compound of the
present invention may be prepared by conventional techniques, e.g.
as described in Remington: The Science and Practise of Pharmacy,
19.sup.th Ed., 1995. The compositions may appear in conventional
forms, for example capsules, tablets, aerosols, solutions,
suspensions or topical applications.
[0265] Typical compositions include a compound of formula (Ia) or a
pharmaceutically acceptable acid addition salt thereof, associated
with a pharmaceutically acceptable excipient which may be a carrier
or a diluent or be diluted by a carrier, or enclosed within a
carrier which can be in the form of a capsule, sachet, paper or
other container. In making the compositions, conventional
techniques for the preparation of pharmaceutical compositions may
be used. For example, the active compound will usually be mixed
with a carrier, or diluted by a carrier, or enclosed within a
carrier which may be in the form of a ampoule, capsule, sachet,
paper, or other container. When the carrier serves as a diluent, it
may be solid, semi-solid, or liquid material which acts as a
vehicle, excipient, or medium for the active compound. The active
compound can be adsorbed on a granular solid container for example
in a sachet. Some examples of suitable carriers are water, salt
solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated
castor oil, peanut oil, olive oil, gelatine, lactose, terra alba,
sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin,
agar, pectin, acacia, stearic acid or lower alkyl ethers of
cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid
monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
Similarly, the carrier or diluent may include any sustained release
material known in the art, such as glyceryl monostearate or
glyceryl distearate, alone or mixed with a wax. The formulations
may also include wetting agents, emulsifying and suspending agents,
preserving agents, sweetening agents or flavouring agents. The
formulations of the invention may be formulated so as to provide
quick, sustained, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in
the art.
[0266] The pharmaceutical compositions can be sterilized and mixed,
if desired, with auxiliary agents, emulsifiers, salt for
influencing osmotic pressure, buffers and/or colouring substances
and the like, which do not deleteriously react with the active
compounds.
[0267] The route of administration may be any route, which
effectively transports the active compound to the appropriate or
desired site of action, such as oral, nasal, pulmonary, transdermal
or parenteral e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intranasal, ophthalmic solution or an
ointment, the oral route being preferred.
[0268] If a solid carrier is used for oral administration, the
preparation may be tabletted, placed in a hard gelatin capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. If a liquid carrier is used, the preparation may be in the
form of a syrup, emulsion, soft gelatin capsule or sterile
injectable liquid such as an aqueous or non-aqueous liquid
suspension or solution.
[0269] For nasal administration, the preparation may contain a
compound of formula (Ia) dissolved or suspended in a liquid
carrier, in particular an aqueous carrier, for aerosol application.
The carrier may contain additives such as solubilizing agents, e.g.
propylene glycol, surfactants, absorption enhancers such as
lecithin (phosphatidylcholine) or cyclodextrin, or preservatives
such as parabenes.
[0270] For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
[0271] Tablets, dragees, or capsules having talc and/or a
carbohydrate carrier or binder or the like are particularly
suitable for oral application. Preferable carriers for tablets,
dragees, or capsules include lactose, corn starch, and/or potato
starch. A syrup or elixir can be used in cases where a sweetened
vehicle can be employed.
[0272] A typical tablet which may be prepared by conventional
tabletting techniques may contain:
1 Core: Active compound (as free compound or salt thereof) 5 mg
Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst.
(Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium
stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx.
0.9 mg *Acylated monoglyceride used as plasticizer for film
coating.
[0273] The compounds of the invention may be administered to a
mammal, especially a human in need of such treatment, prevention,
elimination, alleviation or amelioration of diseases related to the
regulation of blood sugar. Such mammals include also animals, both
domestic animals, e.g. household pets, and non-domestic animals
such as wildlife.
[0274] The compounds of the invention are effective over a wide
dosage range. For example, in the treatment of adult humans,
dosages from about 0.05 to about 100 mg, preferably from about 0.1
to about 100 mg, per day may be used. A most preferable dosage is
about 0.1 mg to about 70 mg per day. In choosing a regimen for
patients it may frequently be necessary to begin with a dosage of
from about 2 to about 70 mg per day and when the condition is under
control to reduce the dosage as low as from about 0.1 to about 10
mg per day. The exact dosage will depend upon the mode of
administration, on the therapy desired, form in which administered,
the subject to be treated and the body weight of the subject to be
treated, and the preference and experience of the physician or
veterinarian in charge.
[0275] Generally, the compounds of the present invention are
dispensed in unit dosage form comprising from about 0.1 to about
100 mg of active ingredient together with a pharmaceutically
acceptable carrier per unit dosage.
[0276] Usually, dosage forms suitable for oral, nasal, pulmonal or
transdermal administration comprise from about 0.001 mg to about
100 mg, preferably from about 0.01 mg to about 50 mg of the
compounds of formula (Ia) admixed with a pharmaceutically
acceptable carrier or diluent.
[0277] In a further aspect, the present invention relates to a
method of treating and/or preventing type I or type II
diabetes.
[0278] In a still further aspect, the present invention relates to
the use of one or more compounds of the general formula (Ia) or
pharmaceutically acceptable salts thereof for the preparation of a
medicament for the treatment and/or prevention of type I or type II
diabetes.
[0279] Any novel feature or combination of features described
herein is considered essential to this invention.
* * * * *