U.S. patent application number 11/524145 was filed with the patent office on 2007-03-29 for novel thiophene derivatives which are hm74a agonists.
Invention is credited to Henrietta Dehmlow, Uwe Grether, Nicole A. Kratochwil, Robert Narquizian, Constantinos Panousis.
Application Number | 20070072873 11/524145 |
Document ID | / |
Family ID | 37398750 |
Filed Date | 2007-03-29 |
United States Patent
Application |
20070072873 |
Kind Code |
A1 |
Dehmlow; Henrietta ; et
al. |
March 29, 2007 |
Novel thiophene derivatives which are HM74A agonists
Abstract
The invention is concerned with novel substituted thiophene
derivatives of formula (I) ##STR1## wherein R.sup.1 to R.sup.8, X,
m and n are as defined in the description and in the claims, as
well as physiologically acceptable salts and esters thereof. These
compounds are HM74A agonists and can be used as medicaments.
Inventors: |
Dehmlow; Henrietta;
(Grenzach-Wyhlen, DE) ; Grether; Uwe;
(Efringen-Kirchen, DE) ; Kratochwil; Nicole A.;
(Sool, CH) ; Narquizian; Robert; (St. Louis,
FR) ; Panousis; Constantinos; (Bottmingen,
CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
37398750 |
Appl. No.: |
11/524145 |
Filed: |
September 20, 2006 |
Current U.S.
Class: |
514/255.05 ;
514/269; 514/342; 514/447; 544/317; 544/405; 546/281.4; 549/68 |
Current CPC
Class: |
A61P 1/18 20180101; A61P
1/16 20180101; A61P 29/00 20180101; A61P 31/04 20180101; A61P 3/10
20180101; A61P 3/06 20180101; A61P 43/00 20180101; C07D 333/38
20130101; C07D 409/12 20130101; A61P 11/06 20180101; A61P 7/02
20180101; A61P 25/00 20180101; A61P 25/16 20180101; A61P 3/00
20180101; A61P 9/10 20180101; A61P 25/28 20180101; A61P 1/04
20180101 |
Class at
Publication: |
514/255.05 ;
514/269; 514/342; 514/447; 544/317; 544/405; 546/281.4;
549/068 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 31/497 20060101 A61K031/497; A61K 31/4436
20060101 A61K031/4436; A61K 31/381 20060101 A61K031/381; C07D
409/02 20060101 C07D409/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 27, 2005 |
EP |
05108907.6 |
Claims
1. A compound of formula (I): ##STR15## wherein X is O, S,
SO.sub.2, NR.sup.9, --C(O)NR.sup.9--, --NR.sup.9C(O)--,
--CH.sub.2--, --C.dbd.C-- or --C.ident.C--; R.sup.1 is hydrogen or
lower-alkyl; R.sup.2 is hydrogen, halogen, lower-alkyl or
fluoro-lower-alkyl; R.sup.3 is hydrogen, halogen, lower-alkyl or
fluoro-lower-alkyl; R.sup.4, R.sup.5, R.sup.6 and R.sup.7
independently from each other are hydrogen, halogen, lower-alkyl,
lower-alkoxy, fluoro-lower-alkyl or fluoro-lower-alkoxy, or R.sup.4
and R.sup.5 are bound together to form a cycloalkyl together with
the carbon atom to which they are attached and --R.sup.4--R.sup.5--
is --(CH.sub.2).sub.2-6--, or R.sup.6 and R.sup.7 are bound
together to form a cycloalkyl together with the carbon atom to
which they are attached and --R.sup.6--R.sup.7-- is
--(CH.sub.2).sub.2-6--; or; R.sup.4 and R.sup.6 are bound together
to form a ring and --R.sup.4--R.sup.6-- is --(CH.sub.2).sub.2-6--;
R.sup.8 is aryl or heteroaryl, which aryl or heteroaryl is
optionally substituted with 1 to 3 substituents selected from the
group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl,
lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,
lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,
R.sup.10R.sup.11NC(O), R.sup.10R.sup.11NC(O)-lower-alkyl,
fluoro-lower-alkyl, R.sup.10R.sup.11N-lower-alkyl,
lower-alkyl-SO.sub.2, lower-alkyl-SO.sub.2O,
lower-alkyl-SO.sub.2--NR.sup.10, R.sup.10R.sup.11NSO.sub.2, cyano,
NO.sub.2, cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl,
lower-alkinyl, fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl,
phenyl and heteroaryl, which phenyl or heteroaryl is optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O)
and lower-alkyl-C(O)N(R.sup.10); R.sup.9 is hydrogen, lower-alkyl
or fluoro-lower-alkyl; R.sup.10 and R.sup.11 independently from
each other are hydrogen or lower-alkyl; m is 0, 1, 2 or 3; n is 0,
1, 2 or 3; and pharmaceutically acceptable salts and
pharmaceutically acceptable esters thereof, with the proviso that
the compound of formula (I) is not
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester.
2. The compound according to claim 1, wherein R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 independently from each other are hydrogen,
lower-alkyl, lower-alkoxy, fluoro-lower-alkyl or
fluoro-lower-alkoxy, or R.sup.4 and R.sup.5 are bound together to
form a cycloalkyl together with the carbon atom to which they are
attached and --R.sup.4--R.sup.5-- is --(CH.sub.2).sub.2-6--, or
R.sup.6 and R.sup.7 are bound together to form a cycloalkyl
together with the carbon atom to which they are attached and
--R.sup.6--R.sup.7-- is --(CH.sub.2).sub.2-6--; and R.sup.8 is aryl
or heteroaryl, which aryl or heteroaryl is optionally substituted
with 1 to 3 substituents selected from the group consisting of
halogen, lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy,
fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,
lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,
R.sup.10R.sup.11NC(O), R.sup.10R.sup.11NC(O)-lower-alkyl,
fluoro-lower-alkyl, R.sup.10R.sup.11N-lower-alkyl,
lower-alkyl-SO.sub.2, lower-alkyl-SO.sub.2O,
lower-alkyl-SO.sub.2--NR.sup.10, R.sup.10R.sup.11NSO.sub.2, cyano,
cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,
fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl, phenyl and
heteroaryl, which phenyl or heteroaryl is optionally substituted
with 1 to 3 substituents selected from the group consisting of
halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and
lower-alkyl-C(O)N(R.sup.10), wherein R.sup.10 and R.sup.11 are as
defined in claim 1.
3. The compound according to claim 1, wherein X is O, --CH.sub.2--
or NR.sup.9 and R.sup.9 is as defined in claim 1.
4. The compound according to claim 1, wherein X is O or
--CH.sub.2--.
5. The compound according to claim 1, wherein X is O.
6. The compound according to claim 1, wherein R.sup.1 is
hydrogen.
7. The compound according to claim 1, wherein R.sup.2 is
hydrogen.
8. The compound according to claim 1, wherein R.sup.3 is hydrogen
or lower-alkyl.
9. The compound according to claim 1, wherein R.sup.3 is
hydrogen.
10. The compound according to claim 1, wherein R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 independently from each other are hydrogen,
halogen or lower-alkyl.
11. The compound according to claim 1, wherein R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 independently from each other are hydrogen or
lower-alkyl.
12. The compound according to claim 1, wherein R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 independently from each other are hydrogen or
methyl.
13. The compound according to claim 1, wherein R.sup.8 is aryl or
heteroaryl, which aryl or heteroaryl is optionally substituted with
1 to 3 substituents selected from the group consisting of halogen,
lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, fluoro-lower-alkyl,
cyano, NO.sub.2, cycloalkyl, pyrimidinyl, pyrazinyl, pyridinyl and
phenyl, which phenyl is optionally substituted with 1 to 3
substituents selected from the group consisting of halogen,
lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and
lower-alkyl-C(O)N(R.sup.10), and R.sup.10 is as defined in claim
1.
14. The compound according to claim 1, wherein R.sup.8 is aryl or
heteroaryl, which aryl or heteroaryl is optionally substituted with
1 to 3 substituents selected from the group consisting of halogen,
lower-alkyl, cycloalkyl and phenyl, which phenyl is optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O)
and lower-alkyl-C(O)N(R.sup.10).
15. The compound according to claim 1, wherein R.sup.8 is phenyl or
pyridinyl, which phenyl or pyridinyl is optionally substituted with
1 to 3 substituents selected from the group consisting of halogen,
lower-alkyl, cycloalkyl and phenyl, which phenyl is optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen and lower-alkoxy.
16. The compound according to claim 1, wherein R.sup.8 is
4'-fluoro-biphenyl-4-yl, biphenyl-4-yl, 2'-methoxy-biphenyl-4-yl,
5-(4-fluoro-phenyl)-pyridin-2-yl, 2-chloro-phenyl, phenyl,
3,4-dichloro-phenyl, 4-cyclopentyl-phenyl, 4-tert-butyl-phenyl or
5-(2-fluoro-phenyl)-pyridin-2-yl.
17. The compound according to claim 1, wherein R.sup.8 is
4-pyrimidin-2-yl-phenyl, 4-pyrazin-2-yl-phenyl,
4-pyridin-2-yl-phenyl, 4-pyridin-3-yl-phenyl or biphenyl-3-yl.
18. The compound according to claim 1, wherein m is 1, 2 or 3.
19. The compound according to claim 1, wherein m is 1 or 3.
20. The compound according to claim 1, wherein n is 0.
21. The compound according to claim 1, wherein R.sup.9 is
hydrogen.
22. The compound according to claim 1, wherein R.sup.10 and
R.sup.11 are hydrogen.
23. The compound according to claim 1, selected from the group
consisting of
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, 4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(2'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3'-Chloro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxy-
lic acid,
4-[2-(2'-Methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carb-
oxylic acid,
4-[2-(3'-Acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxyli-
c acid,
4-[2-(3'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carbo-
xylic acid,
4-[2-(3'-Acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, 4-(5-Phenyl-pentanoylamino)-thiophene-3-carboxylic acid,
4-{2-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carb-
oxylic acid,
4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid,
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,
4-[4-(3-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,
4-[4-(2-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,
4-[4-(3-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,
4-(4-Phenoxy-butyrylamino)-thiophene-3-carboxylic acid,
4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid,
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid,
4-[2-(4-Cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-sec-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, and
4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid, and pharmaceutically acceptable salts and esters
thereof.
24. The compound according to claim 1, selected from the group
consisting of
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid; 4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid;
4-[2-(2'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid;
4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene--
3-carboxylic acid;
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid;
4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid;
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid;
4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid;
4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid; and
4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carb-
oxylic acid; and pharmaceutically acceptable salts and esters
thereof.
25. The compound according to claim 1, selected from the group
consisting of
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyridin-3-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, 4-[2-(4-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3,5-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, 4-[2-(3-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, 4-(2-m-Tolyloxy-acetylamino)-thiophene-3-carboxylic acid,
4-[2-(3-Ethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
4-[2-(3-Nitro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
4-[2-(3-Ethoxy-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
4-[2-(3-Ethynyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic acid,
4-[2-(3-Chloro-4-cyano-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3-Trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3-Chloro-4-methyl-phenoxy)-acetylamino]-thiophene-3-carboxyl-
ic acid,
4-[2-(4-Chloro-3-fluoro-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid,
4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid,
4-[2-(2-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid,
4-[2-(3-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid,
4-[2-(3,5-Difluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Trifluoromethoxy-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3,5-Bis-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-ca-
rboxylic acid,
4-[2-(3-Chloro-5-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3,5-Dibromo-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3,5-Dichloro-phenylamino)-acetylamino]-thiophene-3-carboxyli-
c acid,
4-[2-(2-tert-Butyl-pyrimidin-5-yloxy)-acetylamino]-thiophene-3-ca-
rboxylic acid,
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-5-methyl-thiophene-3-carbo-
xylic acid,
4-[2-(3,4-Dichloro-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid,
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-propionylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-tert-Butyl-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid,
4-[2-Fluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene--
3-carboxylic acid,
4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(3,4-Dichloro-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carb-
oxylic acid, and
4-[2,2-Difluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-c-
arboxylic acid, and pharmaceutically acceptable salts and esters
thereof.
26. The compound according to claim 1, selected from the group
consisting of
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, 4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic
acid,
4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic
acid, and
4-[2,2-Difluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-c-
arboxylic acid and pharmaceutically acceptable salts and esters
thereof.
27. A process for the manufacture of compounds of formula (I)
according to claim 1, comprising the steps of: a) reacting a
compound of formula (II) ##STR16## with a compound of formula
(III), ##STR17## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, X, m and n are as defined in
claim 1 and R.sup.12 is OH, Cl, Br, or a carboxylic acid moiety to
form an anhydride; or b) hydrolysis of a compound of formula (Ia)
##STR18## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, X, m and n are as defined in claim 1 and R.sup.1
is lower-alkyl.
28. A pharmaceutical composition, comprising a therapeutically
effective amount of a compound according to claim 1 or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, and a pharmaceutically acceptable carrier and/or
adjuvant.
29. A method for the treatment and/or prevention of diseases which
are modulated by HM74A agonists, comprising the step of
administering a therapeuctically effective amount of a compound
according to claim 1 or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, to a human being or animal in need thereof.
30. The method according to claim 29, wherein said disease is
increased lipid levels, increased cholesterol levels,
atherosclerotic diseases, dyslipidemia, low HDL-cholesterol,
hypertriglyceridemia, thrombosis, angina pectoris, peripheral
vascular disease, stroke, diabetes, non-insulin dependent diabetes
mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's
disease, schizophrenia, impaired or improvable cognitive function,
sepsis, inflammatory diseases, asthma, colitis, pancreatitis or
cholestasisfibrosis of the liver.
Description
PRIORITY TO RELATED APPLICATIONS
[0001] This application claims the benefit of European Application
No. 05108907.6, filed Sep. 27, 2005, which is hereby incorporated
by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention is concerned with novel substituted thiophene
derivatives of the formula (I) ##STR2## and pharmaceutically
acceptable salts and pharmaceutically acceptable esters
thereof.
[0003] Further, the invention is concerned with a process for the
manufacture of the above compounds, pharmaceutical preparations
which contain such compounds as well as the use of these compounds
for the production of pharmaceutical preparations.
[0004] All documents cited or relied upon below are expressly
incorporated herein by reference.
BACKGROUND
[0005] Coronary heart disease (CHD) remains the leading cause of
death in Western countries. In the United States 13.2 million or
4.85% of the population is affected, with 1.2 million new or
recurrent attacks and around 500 thousand deaths per year (American
Heart Association, Statistics for 2001). The disease is influenced
by several well-established risk factors, such as age, sex, blood
lipids, blood pressure, smoking, diabetes, and body mass index
(BMI) as an indicator of overweight and obesity. The National
Cholesterol Education Program (NCEP) Adult Treatment Panel III
defines elevated plasma levels of low density lipoprotein (LDL)
cholesterol (LDL-C.gtoreq.160 mg/dL), and low levels of high
density lipoprotein (HDL) cholesterol (HDL-C.ltoreq.40 mg/dL) as
independent risk factors for CHD. Many prospective epidemiological
studies have indicated that a decreased HDL-C level is a
significant independent risk factor for heart disease, while
increased HDL-C levels.gtoreq.60 mg/dL (.gtoreq.1.55 mmol) have a
protective role against CHD.
[0006] Nicotinic acid (Niacin), a vitamin of the B complex, is used
for almost 40 years as a lipid-lowering drug with a favorable
profile for all lipoprotein classes. Numerous clinical studies have
shown the beneficial effects of niacin, demonstrating a reduction
of coronary artery disease and overall mortality. Niacin is the
most potent agent currently available to raise HDL. It has been
proposed that niacin's main mode of action is through inhibition of
lipolysis in the adipose tissue having as a result the reduction of
free fatty acids (FFA) in plasma and liver and consequently the
decreased production of very low density lipoproteins (VLDL),
accounting for the reduction of total cholesterol (TC),
triglycerides (TGs), and LDL-C. Due to the decreased TG rich
lipoproteins levels, less modification of HDL particles occurs upon
the action of cholesteryl ester transfer protein (CETP), resulting
in a decreased catabolism of HDL. A direct inhibition of
lipoprotein AI-HDL (LPAI-HDL) particle uptake by the liver has been
also proposed, accounting for the overall HDL raising properties of
niacin (Jin et al Arterioscler. Thromb. Vasc. Biol. 1997, 17,
2020-2028).
[0007] Niacin also has anti-diabetic, anti-thrombotic and
anti-inflammatory properties that contribute to the overall
cardioprotective effects. Through a variety of mechanisms niacin
reduces thrombosis, such as the reduction of lipoprotein (a)
(Lp(a)) which is a potent inhibitor of fibrinolytic activity, and
it is the only currently approved drug that effectively reduces the
serum levels of Lp(a) (Carlson et al. J. Intern. Med. 1989, 226,
271-6). Inflammation is a critical component of atherosclerosis,
leading to recruitment of macrophages which both promote plaque
development and decrease plaque stability thus increasing
cardiovascular risk. Niacin has been suggested to have
anti-inflammatory properties, such as the reduction of C-reactive
protein (CRP) levels (Grundy et al. Arch. Intern. Med. 2002, 162,
1568-76). Several prospective studies have established a strong and
direct correlation between cardiovascular risk and CRP levels, a
measure of vascular inflammation. Extensive use of niacin has been
hampered due to side effects, mainly intense cutaneous
flushing.
[0008] Recently HM74A/HM74, a G-protein coupled receptor (GPCR),
was identified as a receptor for niacin and proposed as the
mediator of the niacin effects (Wise et al. J. Biol. Chem. 2003,
278 (11) 9869-9874 and Soga et al Biochem Biophys Res Commun 2003
303 (1) 364-369). In support, deletion of the PUMA-G (HM74A
orthologue) in mice abrogated the niacin effects on reduction of
plasma free fatty acids and triglycerides (Tunaru et al Nature
Medicine 2003, (3) 352-255).
SUMMARY OF THE INVENTION
[0009] In one embodiment of the present invention, provided is a
compound of formula (I): ##STR3## wherein [0010] X is O, S,
SO.sub.2, NR.sup.9, --C(O)NR.sup.9--, --NR.sup.9C(O)--,
--CH.sub.2--, --C.dbd.C-- or --C.ident.C--; [0011] R.sup.1 is
hydrogen or lower-alkyl; [0012] R.sup.2 is hydrogen, halogen,
lower-alkyl or fluoro-lower-alkyl; [0013] R.sup.3 is hydrogen,
halogen, lower-alkyl or fluoro-lower-alkyl; [0014] R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 independently from each other are
hydrogen, halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl or
fluoro-lower-alkoxy, or R.sup.4 and R.sup.5 are bound together to
form a cycloalkyl together with the carbon atom to which they are
attached and --R.sup.4--R.sup.5-- is --(CH.sub.2).sub.2-6--, or
R.sup.6 and R.sup.7 are bound together to form a cycloalkyl
together with the carbon atom to which they are attached and
--R.sup.6--R.sup.7-- is --(CH.sub.2).sub.2-6--; [0015] or; [0016]
R.sup.4 and R.sup.6 are bound together to form a ring and
--R.sup.4--R.sup.6-- is --(CH.sub.2).sub.2-6--; [0017] R.sup.8 is
aryl or heteroaryl, which aryl or heteroaryl is optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, lower-alkyl, hydroxy-lower-alkyl,
lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,
lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,
R.sup.10R.sup.11NC(O), R.sup.10R.sup.11NC(O)-lower-alkyl,
fluoro-lower-alkyl, R.sup.10R.sup.11N-lower-alkyl,
lower-alkyl-SO.sub.2, lower-alkyl-SO.sub.2O,
lower-alkyl-SO.sub.2--NR.sup.10, R.sup.10R.sup.11NSO.sub.2, cyano,
NO.sub.2, cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl,
lower-alkinyl, fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl,
phenyl and heteroaryl, which phenyl or heteroaryl is optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O)
and lower-alkyl-C(O)N(R.sup.10); [0018] R.sup.9 is hydrogen,
lower-alkyl or fluoro-lower-alkyl; [0019] R.sup.10 and R.sup.11
independently from each other are hydrogen or lower-alkyl; [0020] m
is 0, 1, 2 or 3; [0021] n is 0, 1, 2 or 3; and pharmaceutically
acceptable salts and pharmaceutically acceptable esters thereof,
with the proviso that the compound of formula (I) is not
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester.
[0022] In another embodiment of the present invention, provided is
a process for the manufacture of a compound of formula (I),
comprising the steps of: [0023] reacting a compound of formula (II)
##STR4## [0024] with a compound of formula (III), ##STR5## [0025]
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, X, m and n are as defined above and R.sup.12 is
OH, Cl, Br, or a carboxylic acid moiety to form an anhydride; or
[0026] hydrolysis of a compound of formula (Ia) ##STR6## [0027]
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, X, m and n are as defined above and R.sup.1 is
lower-alkyl.
[0028] In a further embodiment of the present invention, provided
is a pharmaceutical composition, comprising a therapeutically
effective amount of a compound according to formula I or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, and a pharmaceutically acceptable carrier and/or
adjuvant.
[0029] In a yet another embodiment of the present invention,
provided is a method for the treatment and/or prevention of
diseases which are modulated by HM74A agonists, comprising the step
of administering a therapeuctically effective amount of a compound
according to formula I or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester to a human being or animal in need thereof.
DETAILED DESCRIPTION
[0030] The novel compounds of the present invention exceed the
compounds known in the art, inasmuch as they bind to and activate
HM74A. The compounds of the present invention are selective for
HM74A by which is meant that they show greater affinity for HM74A
than for HM74. The compounds of the present invention are expected
to have an enhanced therapeutic potential and exhibit reduced side
effects compared to nicotinic acid. The compounds of the present
invention can be used as medicaments for the treatment and/or
prevention of diseases which are modulated by HM74A agonists.
Examples of such diseases are increased lipid and cholesterol
levels, particularly dyslipidemia, low HDL-cholesterol,
atherosclerotic diseases, hypertriglyceridemia, thrombosis, angina
pectoris, peripheral vascular disease, stroke, diabetes,
particularly non-insulin dependent diabetes mellitus, metabolic
syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia,
sepsis, inflammatory diseases (such as e.g. asthma, colitis,
pancreatitis, cholestasis/fibrosis of the liver, and diseases that
have an inflammatory component such as e.g. Alzheimer's disease or
impaired/improvable cognitive function).
[0031] Unless otherwise indicated, the following definitions are
set forth to illustrate and define the meaning and scope of the
various terms used to describe the invention herein.
[0032] In this specification the term "lower" is used to mean a
group consisting of one to seven, preferably of one to four carbon
atom(s).
[0033] The term "halogen" refers to fluorine, chlorine, bromine and
iodine, with fluorine, chlorine and bromine being preferred.
[0034] The term "alkyl", alone or in combination with other groups,
refers to a branched or straight-chain monovalent saturated
aliphatic hydrocarbon radical of one to twenty carbon atoms,
preferably one to sixteen carbon atoms, more preferably one to ten
carbon atoms. Alkyl groups can be substituted as described below
for lower-alkyl. Lower-alkyl groups as described below also are
preferred alkyl groups.
[0035] The term "lower-alkyl", alone or in combination with other
groups, refers to a branched or straight-chain monovalent alkyl
radical of one to seven carbon atoms, preferably one to four carbon
atoms. This term is further exemplified by such radicals as methyl,
ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
Lower-alkyl groups can optionally be substituted, e.g. by hydroxy
or cyano. Such substituted lower-alkyl-groups are referred to as
"hydroxy-lower-alkyl" or "cyano-lower-alkyl" respectively.
[0036] The term "fluoro-lower-alkyl" refers to lower-alkyl groups
which are mono- or multiply substituted with fluorine. Examples of
fluoro-lower-alkyl groups are e.g. CFH.sub.2, CF.sub.2H, CF.sub.3,
CF.sub.3CH.sub.2, CF.sub.3(CH.sub.2).sub.2, (CF.sub.3).sub.2CH and
CF.sub.2H--CF.sub.2.
[0037] The term "alkenyl", alone or in combination with other
groups, stands for a straight-chain or branched hydrocarbon residue
comprising an olefinic bond and up to 20, preferably up to 16
carbon atoms. The term "lower-alkenyl" refers to a straight-chain
or branched hydrocarbon residue comprising an olefinic bond and up
to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl.
[0038] The term "alkinyl", alone or in combination with other
groups, stands for a straight-chain or branched hydrocarbon residue
comprising a triple bond and up to 20, preferably up to 16 carbon
atoms. The term "lower-alkinyl" refers to a straight-chain or
branched hydrocarbon residue comprising a triple bond and up to 7,
preferably up to 4 carbon atoms, such as e.g. 2-propinyl.
[0039] The term "amino", alone or in combination, signifies a
primary, secondary or tertiary amino group bonded via the nitrogen
atom, with the secondary amino group carrying an alkyl or
cycloalkyl substituent and the tertiary amino group carrying two
similar or different alkyl or cycloalkyl substituents or the two
nitrogen substitutents together forming a ring, such as, for
example, --NH.sub.2, methylamino, ethylamino, dimethylamino,
diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino
etc., preferably primary amino, dimethylamino and diethylamino and
particularly dimethylamino.
[0040] The term "cycloalkyl" refers to a monovalent carbocyclic
radical of 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms,
more preferably 3 to 6 carbon atoms, such as cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl.
[0041] The term "alkoxy" refers to the group R'--O--, wherein R' is
an alkyl. The term "lower-alkoxy" refers to the group R'--O--,
wherein R' is a lower-alkyl.
[0042] The term "fluoro-lower-alkoxy" refers to the group R''--O--,
wherein R'' is fluoro-lower-alkyl. Examples of fluoro-lower-alkoxy
groups are e.g. CFH.sub.2--O, CF.sub.2H--O, CF.sub.3--O,
CF.sub.3CH.sub.2--O, CF.sub.3(CH.sub.2).sub.2--O,
(CF.sub.3).sub.2CH--O, and CF.sub.2H--CF.sub.2--O.
[0043] The term "aryl", alone or in combination, relates to the
phenyl or naphthyl group, preferably the phenyl group, which can
optionally be substituted by 1 to 5, preferably 1 to 3 substituents
independently selected from the group consisting of halogen,
lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy,
fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,
lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,
H.sub.2NC(O), (H,lower-alkyl)NC(O), (lower-alkyl).sub.2NC(O),
H.sub.2NC(O)-lower-alkyl, (H,lower-alkyl)NC(O)-lower-alkyl,
(lower-alkyl).sub.2NC(O)-lower-alkyl, fluoro-lower-alkyl,
H.sub.2N-lower-alkyl, (H,lower-alkyl)N-lower-alkyl,
(lower-alkyl).sub.2N-lower-alkyl, lower-alkyl-SO.sub.2,
lower-alkyl-SO.sub.2O, lower-alkyl-SO.sub.2--NH,
lower-alkyl-SO.sub.2--N(lower-alkyl), H.sub.2NSO.sub.2,
(H,lower-alkyl)NSO.sub.2, (lower-alkyl).sub.2NSO.sub.2, cyano,
cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,
fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl, optionally
substituted phenyl and optionally substituted heteroaryl. Other
possible substituents are e.g. hydroxy, amino, NO.sub.2,
dioxo-lower-alkylene (forming e.g. a benzodioxyl group),
lower-alkylcarbonyl, lower-alkylcarbonyloxy,
lower-alkylcarbonyl-NH, cycloalkyl, phenyl and phenyloxy. Preferred
substituents are halogen, lower-alkyl, cycloalkyl and optionally
substituted phenyl. Furthermore, aryl groups can preferably be
substituted as described in the description and claims below.
[0044] The term "heteroaryl" refers to an aromatic 5 to 6 membered
monocyclic ring or 9 to 10 membered bicyclic ring which can
comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or
sulphur, such as furyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl,
pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,
isothiazolyl, 1,2,3-thiadiazolyl, benzoimidazolyl, indolyl,
indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and
quinolinyl. A preferred heteroaryl group is pyridinyl. Other
preferred heteroaryl groups are pyrimidinyl and pyrazinyl. A
heteroaryl group may optionally have a substitution pattern as
described earlier in connection with the term "aryl". Furthermore,
heteroaryl groups can preferably be substituted as described in the
description and claims below.
[0045] The term "pharmaceutically acceptable esters" embraces
derivatives of the compounds of formula (I), in which a carboxy
group has been converted to an ester. Lower-alkyl,
hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl,
mono- or di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,
pyrrolidino-lower-alkyl, piperidino-lower-alkyl,
piperazino-lower-alkyl, lower-alkyl-piperazino-lower-alkyl and
aralkyl esters are examples of suitable esters. The methyl, ethyl,
propyl, butyl and benzyl esters are preferred esters. The methyl
and ethyl esters are especially preferred. The term
"pharmaceutically acceptable esters" furthermore embraces compounds
of formula (I) in which hydroxy groups have been converted to the
corresponding esters with inorganic or organic acids such as,
nitric acid, sulphuric acid, phosphoric acid, citric acid, formic
acid, maleic acid, acetic acid, succinic acid, tartaric acid,
methanesulphonic acid, p-toluenesulphonic acid and the like, which
are non toxic to living organisms.
[0046] Compounds of formula (I) in which a COOH group is present
can form salts with bases. Examples of such salts are alkaline,
earth-alkaline and ammonium salts such as e.g. Na--, K--, Ca--,
Mg-- and trimethylammonium-salt. The compounds of formula (I) can
also be solvated, e.g. hydrated. The solvation can be effected in
the course of the manufacturing process or can take place e.g. as a
consequence of hygroscopic properties of an initially anhydrous
compound of formula (I) (hydration). The term pharmaceutically
acceptable salts also includes pharmaceutically acceptable
solvates.
[0047] In detail, the present invention relates to compounds of
formula (I) ##STR7## wherein [0048] X is O, S, SO.sub.2, NR.sup.9,
--C(O)NR.sup.9--, --NR.sup.9C(O)--, --CH.sub.2--, --C.dbd.C-- or
--C.ident.C--; [0049] R.sup.1 is hydrogen or lower-alkyl; [0050]
R.sup.2 is hydrogen, halogen, lower-alkyl or fluoro-lower-alkyl;
[0051] R.sup.3 is hydrogen, halogen, lower-alkyl or
fluoro-lower-alkyl; [0052] R.sup.4, R.sup.5, R.sup.6 and R.sup.7
independently from each other are hydrogen, halogen, lower-alkyl,
lower-alkoxy, fluoro-lower-alkyl or fluoro-lower-alkoxy, or R.sup.4
and R.sup.5 are bound together to form a cycloalkyl together with
the carbon atom to which they are attached and --R.sup.4--R.sup.5--
is --(CH.sub.2).sub.2-6--, or R.sup.6 and R.sup.7 are bound
together to form a cycloalkyl together with the carbon atom to
which they are attached and --R.sup.6--R.sup.7-- is
--(CH.sub.2).sub.2-6--; [0053] or; [0054] R.sup.4 and R.sup.6 are
bound together to form a ring and --R.sup.4--R.sup.6-- is
--(CH.sub.2).sub.2-6--; [0055] R.sup.8 is aryl or heteroaryl, which
aryl or heteroaryl is optionally substituted with 1 to 3
substituents selected from the group consisting of halogen,
lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy,
fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,
lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,
R.sup.10R.sup.11NC(O), R.sup.10R.sup.11NC(O)-lower-alkyl,
fluoro-lower-alkyl, R.sup.10R.sup.11N-lower-alkyl,
lower-alkyl-SO.sub.2, lower-alkyl-SO.sub.2O,
lower-alkyl-SO.sub.2--NR.sup.10, R.sup.10R.sup.11NSO.sub.2, cyano,
NO.sub.2, cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl,
lower-alkinyl, fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl,
phenyl and heteroaryl, which phenyl or heteroaryl is optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O)
and lower-alkyl-C(O)N(R.sup.10); [0056] R.sup.9 is hydrogen,
lower-alkyl or fluoro-lower-alkyl; [0057] R.sup.10 and R.sup.11
independently from each other are hydrogen or lower-alkyl; [0058] m
is 0, 1, 2 or 3; [0059] n is 0, 1, 2 or 3; and pharmaceutically
acceptable salts and pharmaceutically acceptable esters thereof,
with the proviso that the compound of formula (I) is not
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester.
[0060] Compounds of formula (I) are individually preferred and
physiologically acceptable salts thereof are individually preferred
and pharmaceutically acceptable esters thereof are individually
preferred, with the compounds of formula (I) being particularly
preferred.
[0061] The compounds of formula (I) can have one or more asymmetric
C atoms and can therefore exist as an enantiomeric mixture,
diastereomeric mixture or as optically pure compounds.
[0062] Preferred compounds of formula (I) as described above are
those, wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently
from each other are hydrogen, lower-alkyl, lower-alkoxy,
fluoro-lower-alkyl or fluoro-lower-alkoxy, or R.sup.4 and R.sup.5
are bound together to form a cycloalkyl together with the carbon
atom to which they are attached and --R.sup.4--R.sup.5-- is
--(CH.sub.2).sub.2-6--, or R.sup.6 and R.sup.7 are bound together
to form a cycloalkyl together with the carbon atom to which they
are attached and --R.sup.6--R.sup.7-- is --(CH.sub.2).sub.2-6--;
and R.sup.8 is aryl or heteroaryl, which aryl or heteroaryl is
optionally substituted with 1 to 3 substituents selected from the
group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl,
lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl,
lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl,
R.sup.10R.sup.11NC(O), R.sup.10R.sup.11NC(O)-lower-alkyl,
fluoro-lower-alkyl, R.sup.10R.sup.11N-lower-alkyl,
lower-alkyl-SO.sub.2, lower-alkyl-SO.sub.2O,
lower-alkyl-SO.sub.2-NR.sup.10, R.sup.10R.sup.11NSO.sub.2, cyano,
cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl,
fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl, phenyl and
heteroaryl, which phenyl or heteroaryl is optionally substituted
with 1 to 3 substituents selected from the group consisting of
halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and
lower-alkyl-C(O)N(R.sup.10), wherein R.sup.10 and R.sup.11 are as
defined above.
[0063] In a preferred embodiment, X is O, --CH.sub.2-- or NR.sup.9
and R.sup.9 is as above. Preferred compounds of formula (I) as
defined above are those, wherein X is O or --CH.sub.2--, preferably
those, wherein X is O.
[0064] Furthemore, those compounds are preferred, wherein R.sup.1
is hydrogen. Other preferred compounds are those, wherein R.sup.2
is hydrogen. Other preferred compounds are those, wherein R.sup.3
is hydrogen or lower-alkyl, preferably wherein R.sup.3 is
hydrogen.
[0065] Another preferred embodiment of the present invention
relates to compounds of formula (I) as described above, wherein
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently from each other
are hydrogen, halogen or lower-alkyl. A preferred embodiment of the
present invention relates to compounds of formula (I) as described
above, wherein R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently
from each other are hydrogen or lower-alkyl, preferably wherein
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently from each other
are hydrogen or methyl. In cases, wherein m or n are larger than 1,
more than one R.sup.4, R.sup.5, R.sup.6 or R.sup.7 occur. In such
cases, the individual R.sup.4, R.sup.5, R.sup.6 or R.sup.7 can be
equal or different. For example, if m is 3 and R.sup.4 and R.sup.5
are hydrogen or lower-alkyl, the group --(CR.sup.4R.sup.5).sub.3--
can e.g. be --CH(CH.sub.3)--CH.sub.2--CH.sub.2--. Furthermore, in
cases wherein m or n are larger than 1, it is preferred that only
one R.sup.4 and R.sup.5 or R.sup.6 and R.sup.7 are bound together
to form a cycloalkyl.
[0066] Compounds as defined above, wherein R.sup.8 is aryl or
heteroaryl, which aryl or heteroaryl is optionally substituted with
1 to 3 substituents selected from the group consisting of halogen,
lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, fluoro-lower-alkyl,
cyano, NO.sub.2, cycloalkyl, pyrimidinyl, pyrazinyl, pyridinyl and
phenyl, which phenyl is optionally substituted with 1 to 3
substituents selected from the group consisting of halogen,
lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and
lower-alkyl-C(O)N(R.sup.10), and R.sup.10 is as defined above, are
preferred. In the compounds of the present invention, R.sup.8
preferably is aryl or heteroaryl, which aryl or heteroaryl is
optionally substituted with 1 to 3 substituents selected from the
group consisting of halogen, lower-alkyl, cycloalkyl and phenyl,
which phenyl is optionally substituted with 1 to 3 substituents
selected from the group consisting of halogen, lower-alkyl,
lower-alkoxy, lower-alkyl-C(O) and lower-alkyl-C(O)N(R.sup.10).
More preferably, R.sup.8 is phenyl or pyridinyl, which phenyl or
pyridinyl is optionally substituted with 1 to 3 substituents
selected from the group consisting of halogen, lower-alkyl,
cycloalkyl and phenyl, which phenyl is optionally substituted with
1 to 3 substituents selected from the group consisting of halogen
and lower-alkoxy. Even more preferably, R.sup.8 is
4'-fluoro-biphenyl-4-yl, biphenyl-4-yl, 2'-methoxy-biphenyl-4-yl,
5-(4-fluoro-phenyl)-pyridin-2-yl, 2-Chloro-phenyl, phenyl,
3,4-dichloro-phenyl, 4-Cyclopentyl-phenyl, 4-tert-butyl-phenyl or
5-(2-fluoro-phenyl)-pyridin-2-yl. Other particularly preferred
compounds are those, wherein R.sup.8 is 4-pyrimidin-2-yl-phenyl,
4-pyrazin-2-yl-phenyl, 4-pyridin-2-yl-phenyl, 4-pyridin-3-yl-phenyl
or biphenyl-3-yl.
[0067] Other preferred compounds of the present invention are
those, wherein m is 1, 2 or 3, more preferably 1 or 3. Other
preferred compounds of the present invention are those, wherein n
is 0.
[0068] Further preferred compounds of formula (I) as described
above are those, wherein R.sup.9 is hydrogen. Compounds as
described above, wherein R.sup.10 and R.sup.11 are hydrogen, are
also preferred.
[0069] In particular, preferred compounds are the compounds of
formula (I) described in the examples as individual compounds as
well as pharmaceutically acceptable salts as well as
pharmaceutically acceptable esters thereof.
[0070] Preferred compounds of formula (I) are those selected from
the group consisting of: [0071]
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0072]
4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,
[0073]
4-[2-(2'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0074]
4-[2-(3'-Chloro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0075]
4-[2-(2'-Methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0076]
4-[2-(3'-Acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxyli-
c acid, [0077]
4-[2-(3'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0078]
4-[2-(3'-Acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0079] 4-(5-Phenyl-pentanoylamino)-thiophene-3-carboxylic
acid, [0080]
4-{2-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophen-
e-3-carboxylic acid, [0081]
4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid, [0082]
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,
[0083] 4-[4-(3-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid, [0084]
4-[4-(2-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,
[0085] 4-[4-(3-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid, [0086] 4-(4-Phenoxy-butyrylamino)-thiophene-3-carboxylic
acid, [0087]
4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid,
[0088]
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0089]
4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid, [0090]
4-[2-(4-Cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0091]
4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0092]
4-[2-(4-Isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0093]
4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0094]
4-[2-(4-sec-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, and [0095]
4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-
-3-carboxylic acid, and pharmaceutically acceptable salts and
esters thereof.
[0096] Particularly preferred compounds of formula (I) are those
selected from the group consisting of [0097]
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid; [0098]
4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid;
[0099]
4-[2-(2'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid; [0100]
4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid; [0101]
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid;
[0102] 4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic
acid; [0103]
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid; [0104]
4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid; [0105]
4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid; and [0106]
4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid; and pharmaceutically acceptable salts and esters
thereof.
[0107] Other preferred compounds of formula (I) are those selected
from the group consisting of: [0108]
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0109]
4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxyli- c
acid, [0110]
4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0111]
4-[2-(4-Pyridin-3-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0112]
4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0113]
4-[2-(4-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
[0114]
4-[2-(3,5-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0115]
4-[2-(3-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
[0116] 4-(2-m-Tolyloxy-acetylamino)-thiophene-3-carboxylic acid,
[0117] 4-[2-(3-Ethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0118]
4-[2-(3-Nitro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
[0119] 4-[2-(3-Ethoxy-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0120]
4-[2-(3-Ethynyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,
[0121] 4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0122]
4-[2-(3-Chloro-4-cyano-phenoxy)-acetylamino]-thiophene-3-carboxy-
lic acid, [0123]
4-[2-(3-Trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0124]
4-[2-(3-Chloro-4-methyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0125]
4-[2-(4-Chloro-3-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0126]
4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid, [0127]
4-[2-(2-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid, [0128]
4-[2-(3-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid, [0129]
4-[2-(3,5-Difluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0130]
4-[2-(4-Trifluoromethoxy-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid, [0131]
4-[2-(3,5-Bis-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxyli-
c acid, [0132]
4-[2-(3-Chloro-5-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0133]
4-[2-(3,5-Dibromo-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0134]
4-[2-(3,5-Dichloro-phenylamino)-acetylamino]-thiophene-3-carboxyl-
ic acid, [0135]
4-[2-(2-tert-Butyl-pyrimidin-5-yloxy)-acetylamino]-thiophene-3-carboxylic
acid, [0136]
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-5-methyl-thiophene-3-carbo-
xylic acid, [0137]
4-[2-(3,4-Dichloro-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid, [0138]
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-propionylamino]-thiophene-3-car-
boxylic acid, [0139]
4-[2-(4-tert-Butyl-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid, [0140]
4-[2-Fluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-
-3-carboxylic acid, [0141]
4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic
acid, [0142]
4-[2-(3,4-Dichloro-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic
acid, and [0143]
4-[2,2-Difluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-c-
arboxylic acid, and pharmaceutically acceptable salts and esters
thereof.
[0144] Other particularly preferred compounds of formula (I) are
those selected from the group consisting of: [0145]
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0146]
4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxyli- c
acid, [0147]
4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0148]
4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid, [0149]
4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic acid,
[0150]
4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic
acid, and [0151]
4-[2,2-Difluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-c-
arboxylic acid and pharmaceutically acceptable salts and esters
thereof.
[0152] It will be appreciated that the compounds of general formula
(I) in this invention may be derivatised at functional groups to
provide derivatives which are capable of conversion back to the
parent compound in vivo.
[0153] The invention further relates to a process for the
manufacture of compounds of formula (I) as defined above, which
process comprises [0154] reacting a compound of formula (II)
##STR8## [0155] with a compound of formula (III), ##STR9## [0156]
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, X, m and n are as defined above and R.sup.12 is
OH, Cl, Br, or a carboxylic acid moiety to form an anhydride; or
[0157] hydrolysis of a compound of formula (Ia) ##STR10## [0158]
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, X, m and n are as defined above and R.sup.1 is
lower-alkyl.
[0159] If R.sup.12 is a carboxylic acid moiety, it is preferably
pivaloylic acid, p-nitrobenzoic acid, p-trifluoromethylbenzoic
acid, 2,4,6-trichloro benzoic acid, acetic acid, trifluoroacetic
acid, carbonic acid monoisobutyl ester, diphenyl phosphinic acid or
benzene sulfonic acid to form an asymmetric anhydride, or it is the
remainder of a second moiety of formula (III) bound via an oxygen
atom to form a symmetric anhydride. Preferably, R.sup.12 is Cl or
Br.
[0160] The reaction of a compound of formula (II) with a compound
of formula (III) or the reaction of a compound of formula (Ia) can
be performed under reaction conditions well known to the person
skilled in the art. Such reactions can conveniently be carried out
for amide bond formation (process a) with compounds of formula
(III) (R.sup.12=Cl, Br) or with mixed or symmetric anhydrides
(III), wherein R.sup.12 is a carboxylic acid moiety such as e.g.
pivaloylic acid, p-nitrobenzoic acid, p-trifluoromethylbenzoic
acid, 2,4,6-trichloro benzoic acid, acetic acid, trifluoroacetic
acid, carbonic acid monoisobutyl ester, diphenyl phosphinic acid or
benzene sulfonic acid or the remainder of a second moiety of
formula (III) bound via an oxygen atom to form a symmetric
anhydride, in a solvent such as dichloromethane, in the presence of
a base such as triethylamine, ethyl-diisopropyl-amine,
N-ethylmorpholine or DMAP (dimethyl-pyridin-4-yl-amine) at
temperatures between 0.degree. C. and reflux, with compounds of
formula (III) (R.sup.12=OH) in the presence of
N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride or
BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophoshate) in the presence of a base such as
ethyl-diisopropyl-amine, triethylamine, N-methylmorpholine
optionally in the presence of 4-dimethylamino-pyridine, HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate), TBTU
(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate)
or HOBt (1-hydroxybenzo-triazole) in solvents such as
dichloromethane, DMF (dimethyl formamide), DMA (dimethylacetamide)
or dioxane at temperatures between 0.degree. C. and ambient
temperature or for process (b) by treatment with an alkali
hydroxide like LiOH or NaOH in a polar solvent such as
tetrahydrofuran, methanol, ethanol or water or mixtures thereof. If
one of the starting materials of formula (II), (III) or (Ia)
contains one or more functional groups which are not stable or are
reactive under the reaction conditions, appropriate protecting
groups (PG) (as described e.g. in "Protective Groups in Organic
Chemistry" by T. W. Greene and P. G. M. Wutts, 2.sup.nd Ed., 1991,
Wiley N.Y.) can be introduced before the condensation step applying
methods well known in the art. Such protecting groups can be
removed at a later stage of the synthesis using standard methods
described in the literature.
[0161] Compounds of the general formula (Ia) can contain one or
more stereocenters and can optionally be separated into optically
pure enantiomers or diastereomers by methods well known in the art,
e. g. by HPLC chromatography, chromatography on a chiral HPLC
column, chromatography with a chiral eluant or by derivatization of
compound (Ib) (R.sup.1=H) with an optically pure alcohol to form
esters, which can be separated by conventional HPLC chromatography
and then converted back to the enantiomerically pure acids (Ib)
(R.sup.1=H). In addition, racemic compounds (Ib) can be separated
into their antipodes via diastereomeric salts by crystallization
with optically pure amines such as e. g. (R) or
(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,
brucine, quinine or quinidine.
[0162] The present invention also relates to compounds of formula
(I) as defined above, when prepared by a process as described
above.
[0163] The compounds of formula (I) can be prepared by methods
known in the art or as described below in schemes 1 to 4. All
starting materials are either commercially available, described in
the literature or can be prepared by methods well known in the art.
Unless otherwise indicated, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, X, m and n are as described above. ##STR11##
[0164] The preparation of compounds of formula (I) is described in
scheme 1. The starting materials, amino-thiophens (II) and
carboxylic acids (III) (R.sup.12=OH), carboxylic acid derivatives
(III) (R.sup.12=Cl, Br, etc.) or carboxylic acid anhydrides (III),
particularly unsymmetric anhydrides, wherein R.sup.12 is a
deprotonated carboxylic acid moiety such as e.g. pivaloylic acid,
p-nitrobenzoic acid, p-trifluoromethylbenzoic acid, 2,4,6-trichloro
benzoic acid, acetic acid, trifluoroacetic acid, carbonic acid
monoisobutyl ester, diphenyl phosphinic acid or benzene sulfonic
acid or the remainder of a second moiety of formula (III) bound via
an oxygen atom to form a symmetric anhydride, are either
commercially available, described in the literature or can be
prepared by methods well known to a person skilled in the art.
Reacting compounds of formula (III) with compounds of formula (II)
results in the formation of compounds of formula (Ia) or (Ib) (step
a). Such amide bond formation reactions are well known in the art.
E.g. if R.sup.12 is equal to chlorine or bromine such an amide bond
formation can be performed in a solvent such as dichloromethane, in
the presence of a base such as triethylamine,
ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures
between 0.degree. C. and ambient temperature. Alternatively,
compounds of formula (Ia) or (Ib) may be prepared by treatment of
anilines (II) with carboxylic acid anhydrides (III) in a solvent
such as dichloromethane, in the presence of a base such as
triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at
temperatures between 0.degree. C. and ambient temperature.
[0165] In addition, condensations of amines (II) with carboxylic
acids (III) (R.sup.12=OH) can be performed using well known
procedures for amide formation, such as the use of
N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride,
HATU, TBTU or BOP
(benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophoshate) in the presence of a base such as
ethyl-diisopropyl-amine, triethylamine, N-methylmorpholine
optionally in the presence of 4-dimethylamino-pyridine or HOBt
(1-hydroxybenzo-triazole) in solvents such as dichloromethane, DMF,
DMA or dioxane at temperatures between 0.degree. C. and reflux.
[0166] If one of the starting materials (II) or (III) contains one
or more functional groups which are not stable or are reactive
under the conditions of the amide bond formation, appropriate
protecting groups (as described e.g. in "Protective Groups in
Organic Chemistry" by T. W. Greene and P. G. M. Wutts, 2.sup.nd
Ed., 1991, Wiley N.Y.) can be introduced before the condensation
step applying methods well known in the art. Such protecting groups
can be removed at a later stage of the synthesis using standard
methods described in the literature.
[0167] Compounds of the general formula (Ia) and (Ib) can contain
one or more stereocenters and can optionally be separated into
optically pure enantiomers or diastereomers by methods well known
in the art, e. g. by HPLC chromatography, chromatography on a
chiral HPLC column, chromatography with a chiral eluant or by
derivatization of compound (Ib) with an optically pure alcohol to
form esters, which can be separated by conventional HPLC
chromatography and then converted back to the enantiomerically pure
acids (Ib) (R.sup.1=H). In addition, racemic compounds (Ib) can be
separated into their antipodes via diastereomeric salts by
crystallization with optically pure amines such as e. g. (R) or
(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,
brucine, quinine or quinidine. ##STR12##
[0168] The preparation of compounds of formula (Ib) with R.sup.1=H
from compounds of formula (Ia) with R.sup.1 not H is described in
scheme 2 (step a). These hydrolysis reactions can be performed
according to standard procedures, e. g. by treatment with an alkali
hydroxide like LiOH or NaOH in a polar solvent such as
tetrahydrofuran, methanol, ethanol or water or mixtures thereof to
give carboxylic acids (Ib). In case R.sup.1 is equal to tert-butyl,
treatment with e. g. trifluoroacetic acid, optionally in the
presence of anisole in a solvent like dichloromethane or
dichloroethane between room temperature and the reflux temperature
of the solvents yields carboxylic acids (Ib).
[0169] If the ester (Ia) contains one or more functional groups
which are not stable under the hydrolysis conditions, appropriate
protecting groups (as described e.g. in "Protective Groups in
Organic Chemistry" by T. W. Greene and P. G. M. Wutts, 2.sup.nd
Ed., 1991, Wiley N.Y.) can be introduced before the saponification,
applying methods well known in the art. Subsequent hydrolysis and
removal of the protecting group(s) provides carboxylic acid
(Ib).
[0170] Compounds of the general formula (Ib) can contain one or
more stereocenters and can optionally be separated into optically
pure enantiomers or diastereomers by methods well known in the art,
e. g. by HPLC chromatography, chromatography on a chiral HPLC
column, chromatography with a chiral eluant or by derivatization of
compound (Ib) with an optically pure alcohol to form esters, which
can be separated by conventional HPLC chromatography and then
converted back to the enantiomerically pure acids (Ib). In
addition, racemic compounds (Ib) can be separated into their
antipodes via diastereomeric salts by crystallization with
optically pure amines such as e. g. (R) or (S)-1-phenyl-ethylamine,
(R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or
quinidine. ##STR13##
[0171] Condensations of amino thiophene (II) with carboxylic acids
(IV) (R.sup.12=OH; R.sup.13=Cl, Br, I) or carboxylic acid
derivatives (IV) (R.sup.12=Cl, Br; R.sup.13=Cl, Br, I) or
carboxylic acid anhydrides (IV) to give amides (V) can be performed
using standard procedures described in the literature. E.g. if
R.sup.12 is equal to chlorine, bromine or for the carboxylic acid
anhydrides the reaction could be performed in a solvent such as
dichloromethane, in the presence of a base such as triethylamine,
ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures
between 0.degree. C. and ambient temperature (Scheme 3, step a). If
R.sup.12 is equal to OH activating reagents like e. g.
N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride,
HATU, TBTU or BOP
(benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophoshate) in the presence of a base such as
ethyl-diisopropyl-amine, triethylamine, N-methylmorpholine
optionally in the presence of 4-dimethylamino-pyridine or HOBt
(1-hydroxybenzotriazole) in solvents such as dichloromethane, DMF,
DMA or dioxane at temperatures between 0.degree. C. and ambient
temperature could be used.
[0172] Protected alcohols V (R.sup.13=OPG) can be deprotected by
methods well known to the person skilled in the art (as described
e.g. in "Protective Groups in Organic Chemistry" by T. W. Greene
and P. G. M. Wutts, 2.sup.nd Ed., 1991, Wiley N.Y.). They can then
be converted to the corresponding mesylate or tosylate V
(R.sup.13=OMs, OTs) by treatment with methanesulfonyl chloride or
para-toluenesulfonyl chloride, respectively, in dichloromethane in
the presence of DMAP (dimethylaminopyridine) at temperatures
between 0.degree. C. and ambient temperature (scheme 3, step
b).
[0173] OPG refers to protected alcohols which can be made by
methods well known to the person skilled in the art (as described
e.g. in "Protective Groups in Organic Chemistry" by T. W. Greene
and P. G. M. Wutts, 2.sup.nd Ed., 1991, Wiley N.Y.).
[0174] Nucleophilic substitution reactions between compounds of
formula V and compounds of formula VI to form compounds of formula
Ia (Scheme 3, step c) are well know in the art. For example such a
reaction can be carried out in a polar solvent such as
dimethylformamide in the presence of a base such as potassium
carbonate at room temperature or at elevated temperature.
[0175] Compounds of formula Ia can be transformed in compounds of
formula Ib according to methods described in Scheme 2.
##STR14##
[0176] An additional synthetic route towards compounds of formula
(Ia or Ib) is depicted in scheme 4, for compounds in which R.sup.8
is a substituted aryl or heteroaryl. Starting point are derivatives
(VII) in which R.sup.14 is an aryl or heteroaryl group, in analogy
to the definition of R.sup.8, which carries a substituent
R.sup.15.
[0177] Halides (VII) (R.sup.15=Cl, Br, I), phenols (VII)
(R.sup.15=OH) or triflates (VII) (R.sup.15=OTf) can be reacted with
alcohols to give ethers (I) using methods well known in the art
(scheme 4, step a). Phenols (VII) (R.sup.15=OH) may be generated
from the protected phenols (VII) (R.sup.15=OPG) prior to use by
methods well known to the person skilled in the art (as described
e.g. in "Protective Groups in Organic Chemistry" by T. W. Greene
and P. G. M. Wutts, 2.sup.nd Ed., 1991, Wiley N.Y.) and may be
converted to the corresponding triflates (VII) (R.sup.15=OTf) by
standard methods described in the literature, e. g. using
PhN(SO.sub.2Tf).sub.2 in the presence of a base like cesium
carbonate in a solvent like N,N-dimethylformamide at temperatures
around ambient temperature or in pyridine with
trifluoromethanesulfonic anhydride at 0.degree. C. to ambient
temperature. The alcohols are either commercially available,
described in the literature or can be prepared by methods well
known to a person skilled in the art. If halides (VII)
(R.sup.15=Cl, Br, I) are used as starting material, compounds (I)
can e. g. be prepared in the presence of Cul, cesium carbonate and
8-hydroxychinoline in a solvent like 1-methyl-2-pyrrolidone (see
for example Z. J. Song et al., Organic Letters, 4, 1623; 2002).
Starting from triflates (VII) (R.sup.15=OTf), ethers (Ia) or (Ib)
can be synthesized applying e. g. the procedure from Larock et al.
(R. C. Larock et al., Organic Letters, 6, 99; 2004) using CsF in
acetonitrile at ambient temperature. In addition, several
transition metal mediated procedures for the formation of aryl
ethers are reported in the literature (see e. g. J. F. Hartwig et
al., J. Am. Chem. Soc., 121, 3224; 1999).
[0178] Alternatively, phenols (VI) (R.sup.15=OH) may be treated
with alcohols using Mitsunobu (e.g. O. Mitsunobu, Synthesis 1981,
1.) conditions to yield compounds (I). This transformation is
preferably carried out with triphenylphosphine and di-tert-butyl-,
diisopropyl- or diethyl-azodicarboxylate as reagents, in a solvent
like toluene, dichloromethane or tetrahydrofuran at 0.degree. C. to
ambient temperature.
[0179] Alternatively, compounds (I) may be prepared from phenol
(VI) (R.sup.15=OH) by alkylation with compounds bearing a good
leaving group such as Br, Cl, I, MsO, TsO, TfO in solvents such as
acetone, acetonitrile, DMF (dimethyl formamide), DMA
(dimethacetamide) or THF (tetrahydrofuran) in the presence of bases
such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or ethyl-diisopropylamine
at temperatures ranging from ambient temperature to the reflux
temperature of the solvent.
[0180] Alternatively, compounds (I) may be prepared from aryl
halides (VI) (R.sup.15=Cl, Br, I) or aryl triflates (VI)
(R.sup.15=OTf) by Carbon-Carbon bond formation reactions. Such
reactions are well known in the art, like e. g. Suzuki, Stille or
Heck reactions (Suzuki, A. Acc. Chem. Res. 1982, 15, 178; Scott, W.
J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 4630;
Heck, R. F. Organic React. 1982, 27, 345 respectively). The
counterparts of such reactions are either commercially available,
described in the literature or can be prepared by methods well
known to a person skilled in the art.
[0181] If one of the starting materials (II), (IV), (V), or (VI)
contains one or more functional groups which are not stable or are
reactive under the conditions of the amide bond formation,
appropriate protecting groups (as described e.g. in "Protective
Groups in Organic Chemistry" by T. W. Greene and P. G. M. Wutts,
2.sup.nd Ed., 1991, Wiley N.Y.) can be introduced before the
condensation step, applying methods well known in the art. Such
protecting groups can be removed at a later stage of the synthesis
using standard methods described in the literature.
[0182] Compounds of the general formula (I) can contain one or more
stereocenters and can optionally be separated into optically pure
enantiomers or diastereomers by methods well known in the art, e.
g. by HPLC chromatography, chromatography on a chiral HPLC column,
chromatography with a chiral eluant or by derivatization with an
optically pure alcohol to form esters, which can be separated by
conventional HPLC chromatography and then converted back to the
enantiomerically pure acids (I). In addition, racemic compounds can
be separated into their antipodes via diastereomeric salts by
crystallization with optically pure amines such as e. g. (R) or
(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,
brucine, quinine or quinidine.
[0183] The conversion of a compound of formula (I) into a
pharmaceutically acceptable salt can be carried out by treatment of
such a compound with physiologically compatible bases. Examples of
such salts are alkaline, earth-alkaline and ammonium salts such as
e.g. Na--, K--, Ca-- and trimethylammonium-salt. One method to form
such a salt is e.g. by addition of 1/n equivalents of a basic salt
such as e.g. M(OH).sub.n, wherein M=metal or ammonium cation and
n=number of hydroxide anions, to a solution of the compound in a
suitable solvent (e.g. ethanol, ethanol-water mixture,
tetrahydrofuran-water mixture) and to remove the solvent by
evaporation or lyophilisation.
[0184] The conversion of compounds of formula (I) into
pharmaceutically acceptable esters can be carried out e.g. by
treatment of a suitable carboxy group present in the molecule with
a suitable alcohol using e.g. a condensating reagent such as
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP), N,N-dicylohexylcarbodiimide (DCC),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI)
or
O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluorbor-
ate (TBTU). Pharmaceutically acceptable esters can furthermore be
prepared by treatment of a suitable hydroxy group present in the
molecule with a suitable acid, optionally or if necessary in the
presence of a condensating agent as described above.
[0185] Insofar as their preparation is not described in the
examples, the compounds of formula (I) as well as all intermediate
products can be prepared according to analogous methods or
according to the methods set forth above. Starting materials are
commercially available or known in the art.
[0186] As described above, the compounds of formula (I) of the
present invention and
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, can be used as medicaments for the treatment
and/or prevention of diseases which are modulated by HM74A
agonists. Examples of such diseases are increased lipid and
cholesterol levels, particularly dyslipidemia, low HDL-cholesterol,
atherosclerotic diseases, hypertriglyceridemia, thrombosis, angina
pectoris, peripheral vascular disease, stroke, diabetes,
particularly non-insulin dependent diabetes mellitus, metabolic
syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia,
sepsis, inflammatory diseases (such as e.g. asthma, colitis,
pancreatitis, cholestasis/fibrosis of the liver, and diseases that
have an inflammatory component such as e.g. Alzheimer's disease or
impaired/improvable cognitive function). The use as medicament for
the treatment of atherosclerosis, low HDL cholesterol levels,
non-insulin dependent diabetes mellitus, and the metabolic syndrome
is preferred.
[0187] The invention therefore also relates to pharmaceutical
compositions comprising a compound as described above or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, and a pharmaceutically acceptable carrier and/or
adjuvant.
[0188] Further, the invention relates to compounds as described
above or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, for use as therapeutic active substances,
especially as therapeutic active substances for the treatment
and/or prevention of diseases which are modulated by HM74A
agonists, particularly as therapeutically active substances for the
treatment and/or prevention of increased lipid levels, increased
cholesterol levels, atherosclerotic diseases, dyslipidemia, low
HDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris,
peripheral vascular disease, stroke, diabetes, non-insulin
dependent diabetes mellitus, metabolic syndrome, Alzheimer's
disease, Parkinson's disease, schizophrenia, impaired or improvable
cognitive function, sepsis, inflammatory diseases, asthma, colitis,
pancreatitis and cholestasisfibrosis of the liver.
[0189] In another embodiment, the invention relates to a method for
the treatment and/or prevention of diseases which are modulated by
HM74A agonists, particularly for the treatment and/or prevention of
increased lipid levels, increased cholesterol levels,
atherosclerotic diseases, dyslipidemia, low HDL-cholesterol,
hypertriglyceridemia, thrombosis, angina pectoris, peripheral
vascular disease, stroke, diabetes, non-insulin dependent diabetes
mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's
disease, schizophrenia, impaired or improvable cognitive function,
sepsis, inflammatory diseases, asthma, colitis, pancreatitis and
cholestasisfibrosis of the liver, which method comprises
administering a compound as described above or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, to a human or animal.
[0190] The invention further relates to the use of compounds as
defined above or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxyli- c
acid methyl ester, for the treatment and/or prevention of diseases
which are modulated by HM74A agonists, particularly for the
treatment and/or prevention of increased lipid levels, increased
cholesterol levels, atherosclerotic diseases, dyslipidemia, low
HDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris,
peripheral vascular disease, stroke, diabetes, non-insulin
dependent diabetes mellitus, metabolic syndrome, Alzheimer's
disease, Parkinson's disease, schizophrenia, impaired or improvable
cognitive function, sepsis, inflammatory diseases, asthma, colitis,
pancreatitis and cholestasisfibrosis of the liver.
[0191] In addition, the invention relates to the use of compounds
as described above or
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester, for the preparation of medicaments for the
treatment and/or prevention of diseases which are modulated by
HM74A agonists, particularly for the treatment and/or prevention of
increased lipid levels, increased cholesterol levels,
atherosclerotic diseases, dyslipidemia, low HDL-cholesterol,
hypertriglyceridemia, thrombosis, angina pectoris, peripheral
vascular disease, stroke, diabetes, non-insulin dependent diabetes
mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's
disease, schizophrenia, impaired or improvable cognitive function,
sepsis, inflammatory diseases, asthma, colitis, pancreatitis and
cholestasisfibrosis of the liver. Such medicaments comprise a
compound as described above.
[0192] Prevention and/or treatment of atherosclerosis, low HDL
cholesterol levels, non-insulin dependent diabetes mellitus, and
the metabolic syndrome is preferred.
[0193] In the above mentioned compositions, uses and methods,
compounds of formula (I) as described above are preferred over
2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic
acid methyl ester.
[0194] The following tests were carried out in order to determine
the biological activity of the compounds of formula (I).
Primary Radiolabelled Ligand Competition Binding Assay
[0195] Nicotinic acid binding assays were performed with membrane
preparations. A cell pellet containing 1.times.10.sup.8 HEK-293
cells, stably transfected with the HM74A receptor, was resuspended
in 3 ml of ice cold Dounce Buffer (10 mM Tris-Cl pH 7.6, 0.5 mM
MgCl.sub.2) supplemented with Roche protease inhibitor cocktail and
homogenized at high speed on a Polytron homogenizer two times for
20 sec on ice. Nuclei and unbroken cells were removed by
centrifugation for 5 min at 1,000.times.g after the addition of 1
ml of tonicity restoration buffer (10 mM Tris pH 7.6, 0.5 mM
MgCl.sub.2, 600 mM NaCl). The homogenate was centrifuged at
60,000.times.g for 30 min and pellets were resuspended in Tris
buffer (50 mM Tris pH 7.4, containing protease inhibitors). Binding
reactions contained 20 .mu.g membranes as determined by BCA protein
assay (Pierce), 50 nM [.sup.3H]-nicotinic acid (Amersham) with or
without compound addition in 250 .mu.l of binding buffer (50 mM
Tris pH 7.4, 2 mM MgCl.sub.2, 0.02% CHAPS). Incubations were
carried out at room temperature for 2 hrs and terminated by
filtration using a Filtermate Harvester (PerkinElmer) onto GF/C
filter plates (Millipore). Bound [.sup.3H]-nicotinic acid was
determined by scintillation counting using Top Count NXT
(PerkinElmer). Compounds were dissolved in a concentration of
10.sup.-2 or 10.sup.-3 M in DMSO, further dilutions were performed
in binding buffer. The effects of compounds were expressed as %
inhibition of [.sup.3H]-nicotinic acid binding. Sigmoidal curves
were fitted using the XLfit3 program (ID Business Solutions Ltd.
UK) and IC.sub.50 values determined.
[0196] The compounds of the present invention exhibit IC.sub.50
values in a range of about 0.001 .mu.M to about 100 .mu.M in the
binding assay. Preferably, the compounds of the present invention
have IC.sub.50 values in a range of about 0.001 .mu.M to about 10.0
.mu.M, more preferably about 0.001 .mu.M to about 1 .mu.M.
Secondary Fluorescent Calcium Indicator Assay (FLIPR)
[0197] HEK-293 cells were grown in tissue culture medium (DMEM/Nut
mix F12 Medium with Glutamax I (Invitrogen), containing 10% FBS) at
37.degree. C. in a 5% CO.sub.2 atmosphere. These cells were
cultured in 6-well dishes at 3.times.10.sup.5 cells/well and double
transfected with DNA vectors (pcDNA3.1, Invitrogen) expressing
either HM74A or HM74 and the chimeric G protein Gqi9. Two days
after transfection the wells were combined and plated in 150
cm.sup.2 flasks, in the presence of 50 .mu.g/ml Hygromycin
(Invitrogen) and 500 .mu.g/ml Geneticin (Gibco). Fourteen days
after plating, colonies were picked, expanded and analyzed for
expression using a functional assay (FLIPR). Stable transfected
HEK-293 cells expressing either HM74A or HM74 and the chimeric G
protein Gqi9 were plated at 50,000 cells/well in black 96-well
plates with clear bottom (Costar) and cultured to confluency
overnight in growth media (DMEM/Nut mix F12 Medium with Glutamax I
(Invitrogen), containing 10% FBS) at 37.degree. C. in a humidified
cell incubator containing 5% CO.sub.2. Growth media was aspirated
and replaced with 100 .mu.l of 1.times.FLIPR Calcium Assay Dye
(Molecular Devices) in Hank's balanced salt solution (HBSS)
containing 10 mM HEPES, and 250 mM probenecid (Sigma), for 1 hour
at 37.degree. C. Cell plates were transferred to a FLIPR unit
(Molecular Devices), and 50 .mu.l of 3.times. compound dilution
were added. Fluorescence emissions were measured and the effects of
compounds were expressed as % stimulation of maximal nicotinic acid
response (100 .mu.M). Sigmoidal curves were fitted using the XLfit3
program (ID Business Solutions Ltd. UK) and EC.sub.50 values
determined.
[0198] The compounds of the present invention exhibit EC.sub.50
values in a range of about 0.001 .mu.M about 100 .mu.M in the FLIPR
assay. Preferably, the compounds of the present invention have
EC.sub.50 values in a range of about 0.001 .mu.M to about 10.0
.mu.M; more preferably about 0.001 .mu.M to about 1 .mu.M.
[0199] In the following table, EC.sub.50 values for some of the
compounds of the present invention are shown. TABLE-US-00001
Example EC.sub.50 HM74A [.mu.M] 2 0.0487 11 0.131 23 0.225
[0200] The compounds of formula I and/or their pharmaceutically
acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parenteral or topical
administration. They can be administered, for example, perorally,
e.g. in the form of tablets, coated tablets, dragees, hard and soft
gelatine capsules, solutions, emulsions or suspensions, rectally,
e.g. in the form of suppositories, parenterally, e.g. in the form
of injection solutions or suspensions or infusion solutions, or
topically, e.g. in the form of ointments, creams or oils. Oral
administration is preferred.
[0201] The production of the pharmaceutical preparations can be
effected in a manner which will be familiar to any person skilled
in the art by bringing the described compounds of formula I and/or
their pharmaceutically acceptable salts, optionally in combination
with other therapeutically valuable substances, into a galenical
administration form together with suitable, non-toxic, inert,
therapeutically compatible solid or liquid carrier materials and,
if desired, usual pharmaceutical adjuvants.
[0202] Suitable carrier materials are not only inorganic carrier
materials, but also organic carrier materials. Thus, for example,
lactose, corn starch or derivatives thereof, talc, stearic acid or
its salts can be used as carrier materials for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carrier
materials for soft gelatine capsules are, for example, vegetable
oils, waxes, fats and semi-solid and liquid polyols (depending on
the nature of the active ingredient no carriers might, however, be
required in the case of soft gelatine capsules). Suitable carrier
materials for the production of solutions and syrups are, for
example, water, polyols, sucrose, invert sugar and the like.
Suitable carrier materials for injection solutions are, for
example, water, alcohols, polyols, glycerol and vegetable oils.
Suitable carrier materials for suppositories are, for example,
natural or hardened oils, waxes, fats and semi-liquid or liquid
polyols. Suitable carrier materials for topical preparations are
glycerides, semi-synthetic and synthetic glycerides, hydrogenated
oils, liquid waxes, liquid paraffins, liquid fatty alcohols,
sterols, polyethylene glycols and cellulose derivatives.
[0203] Usual stabilizers, preservatives, wetting and emulsifying
agents, consistency-improving agents, flavour-improving agents,
salts for varying the osmotic pressure, buffer substances,
solubilizers, colorants and masking agents and antioxidants come
into consideration as pharmaceutical adjuvants.
[0204] The dosage of the compounds of formula I can vary within
wide limits depending on the disease to be controlled, the age and
the individual condition of the patient and the mode of
administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily
dosage of about 1 to 5000 mg, preferably about 1 to 1000 mg,
especially about 1 to 300 mg, comes into consideration. Depending
on severity of the disease and the precise pharmacokinetic profile
the compound could be administered with one or several daily dosage
units, e.g. in 1 to 3 dosage units.
[0205] The pharmaceutical preparations conveniently contain about
1-1000 mg, preferably 1-300 mg, more preferably 1-100 mg, of a
compound of formula I.
[0206] The following Examples serve to illustrate the present
invention in more detail. They are, however, not intended to limit
its scope in any manner.
EXAMPLES
General Remarks
[0207] The reactions were performed under argon where
appropriate.
Example 1
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
Step 1: 4-[2-(4-Iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester
[0208] To a solution of
4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl
ester ([51486-30-7], 2.0 g, 8.6 mmol) in dimethylformamide (30 mL)
was added potassium carbonate (1.77 g, 12.8 mmol) and 4-iodophenol
(2.26 g, 10.3 mmol) and the reaction mixture was then stirred
overnight at 90.degree. C. To the reaction mixture was added ethyl
acetate (approximately 30 mL). The solid was filtered and washed
with ethyl acetate. The filtrate was then reduced in vacuo and
dissolved in dichloromethane (approximately 50 mL). The solution
was filtered again over charcoal and to the filtrate was added
isopropylether. After reducing the solution slowly in vacuo the
solid was filtered to yield the title compound (3.57 g, 79%).
[0209] Mp=135-137.degree. C., MS (m/e): 415.9 (M-H).sup.-,
100%).
Step 2:
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carbo-
xylic acid methyl ester
[0210] To a solution of
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (0.1 g, 0.428 mmol) in a mixture of tetrahydrofuran
(21 mL) and water (5 mL) was added 4-fluorophenylboronic acid (40.3
mg, 0.288 mmol) and cesium carbonate (313 mg, 0.96 mmol). The
solution was then degassed by bubbling a flux of argon for 20
minutes before adding polymer bound
tetrakis(triphenylphosphine)palladium (Aldrich-511579, 12.86 mg,
0.009 mmol). The reaction mixture was then stirred for 90 min at
80.degree. C. under argon atmosphere before allowing to cool down
to room temperature and diluting with ethyl acetate. The reaction
mixture was then filtered; the filtrate was then washed twice with
brine and dried over sodium sulfate before being concentrated in
vacuo. The residue was then filtered through a pad of silica
(SiO.sup.2, EtOAc, 100%) to yield the title compound as a light
brown solid (138 mg, 99%).
[0211] Mp=127-130.degree. C., MS (m/e): 384.1 (M-H).sup.-,
100%).
Step 3:
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carbo-
xylic acid
[0212] To
4-[2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carb-
oxylic acid methyl ester (100 mg, 0.259 mmol) in ethanol (6 mL) was
added a solution of sodium hydroxide (1N, 0.39 mL, 0.39 mmol) and
the reaction was stirred at room temperature for 2 days. After such
time the reaction mixture was filtered through glass wool and the
filtrate was then neutralized by addition of a solution of
hydrochloric acid (1N, 0.39 mL). Additional water was added to the
solution (in excess of 10 mL) before the precipitate was filtered,
washed with water and dried in vacuo to yield the title compound as
a white solid (93 mg, 80%).
[0213] Mp=244-251.degree. C., MS (m/e): 370.1 (M-H).sup.1,
100%).
Example 2
4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
Step 1: 4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester
[0214] To a solution of
4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl
ester ([51486-30-7], 0.1 g, 0.43 mmol) in dimethylformamide (1.5
mL) was added potassium carbonate (0.88 g, 0.64 mmol) and
4-hydroxybiphenyl (0.087 g, 0.514 mmol) and the reaction mixture
was then stirred overnight at 90.degree. C. After such time the
reaction mixture was allowed to cool to room temperature, water was
added (in excess of 5 mL) leading to precipitation. The precipitate
was then filtered, washed with water and dried in vacuo to yield
the title compound as a white solid (0.16 g, 87%).
[0215] Mp=132-135.degree. C., MS (m/e): 368.1 (M+H.sup.+,
100%).
Step 2: 4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0216] To
4-[2-(biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (100 mg, 0.259 mmol) in ethanol (6 mL) was added a
solution of sodium hydroxide (1N, 0.41 mL, 0.41 mmol) and the
reaction was stirred at room temperature for 30 hours. After such
time the reaction mixture was filtered through glass wool and the
filtrate was then neutralized by addition of a solution of
hydrochloric acid (1N, 0.39 mL). The precipitate was filtered,
washed with water and dried in vacuo to yield the title compound as
a white solid (96 mg, 80%).
[0217] Mp=247-251.degree. C., MS (m/e): 352.2 (M-H).sup.-,
100%).
Example 3
4-[2-(2'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0218] In analogy to Example 1 (step 2), from
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (example 1, step 1) and 2-methoxybenzeneboronic acid
was prepared
4-[2-(2'-methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester.
[0219] Mp=148-152.degree. C., MS (m/e): 398.2 (M+H.sup.+,
100%).
[0220] In analogy to Example 1 (step 3), from
4-[2-(2'-methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was prepared
4-[2-(2'-methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0221] Mp=196-199.degree. C., MS (m/e): 382.3 (M-H).sup.-,
100%).
Example 4
4-[2-(3'-Chloro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0222] In analogy to Example 1 (step 2 and 3), from
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (example 1, step 1) and 3-chlorophenylboronic acid was
prepared
4-[2-(3'-chloro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0223] Mp=216-218.degree. C., MS (m/e): 385.8 (M-H).sup.-,
100%).
Example 5
4-[2-(2'-Methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0224] In analogy to Example 1 (step 2), from
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (example 1, step 1) and o-tolylboronic acid was
prepared
4-[2-(2'-methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester.
[0225] MS (m/e): 382.1 (M+H.sup.+, 100%).
[0226] In analogy to Example 1 (step 3), from
4-[2-(2'-methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was prepared
4-[2-(2'-methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0227] Mp=207-209.degree. C., MS (m/e): 366.0 (M-H).sup.-,
100%).
Example 6
4-[2-(3'-Acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0228] In analogy to Example 1 (step 2), from
.sup.4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (example 1, step 1) and 3-acetamidobenzeneboronic acid
was prepared
4-[2-(3'-acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3--
carboxylic acid methyl ester.
[0229] MS (m/e): 425.1 (M+H.sup.+, 100%).
[0230] In analogy to Example 1 (step 3), from
4-[2-(3'-acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxyli-
c acid methyl ester was prepared
4-[2-(3'-acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxyli-
c acid.
[0231] Mp=250-253.degree. C., MS (m/e): 409.0 (M-H).sup.-,
100%).
Example 7
4-[2-(3'-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0232] In analogy to Example 1 (step 2) from
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (example 1, step 1) and 3-methoxyphenyl boronic acid
was prepared
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester.
[0233] MS (m/e): 398.2 (M+H.sup.+, 100%).
[0234] In analogy to Example 1 (step 3), from
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester was prepared
4-[2-(3'-methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0235] Mp=187-189.degree. C., MS (m/e): 382.0 (M-H).sup.-,
100%).
Example 8
4-[2-(3'-Acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0236] In analogy to Example 1 (step 2) from
4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester (example 1, step 1) and 3-acetylbenzeneboronic acid
was prepared
4-[2-(3'-acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester.
[0237] MS (m/e): 410.1 (M+H.sup.+, 100%).
[0238] In analogy to Example 1 (step 3), from
4-[2-(3'-acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was prepared
4-[2-(3'-acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0239] Mp=212-214.degree. C., MS (m/e): 394.1 (M-H).sup.-,
100%).
Example 9
4-(5-Phenyl-pentanoylamino)-thiophene-3-carboxylic acid
Step 1: 4-(5-Phenyl-pentanoylamino)-thiophene-3-carboxylic acid
methyl ester
[0240] To a suspension of methyl 4-aminothiophene-3-carboxylate
hydrochloride (100 mg, 0.64 mmol) and triethylamine (200 .mu.l,
1.46 mmol) in dichloromethane (1 mL) was slowly added a solution of
benzenepentanoyl chloride (158 mg, 0.83 mmol; [20371-41-9]) in
dichloromethane (0.5 ml) at 0.degree. C. The reaction mixture was
allowed to warm up to room temperature and stirred for 72 h. The
suspension was diluted with dichloromethane, washed with water and
brine. The aqueous phase was extracted with dichloromethane. The
combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The residue was purified by column
chromatography (heptane-ethyl acetate: 0-40%) to yield
4-(5-phenyl-pentanoylamino)-thiophene-3-carboxylic acid methyl
ester (113 mg, 0.36 mmol, 58%) as colorless oil.
[0241] MS (m/e): 318.1 (M+H.sup.+, 100%).
Step 2: 4-(5-Phenyl-pentanoylamino)-thiophene-3-carboxylic acid
[0242] To a solution of
4-(5-phenyl-pentanoylamino)-thiophene-3-carboxylic acid methyl
ester (50 mg, 0.16 mmol) in tetrahydrofuran/methanol 2/1 (1.5 ml)
was added a 1 N aqueous LiOH solution (0.95 ml, 0.95 mmol). The
reaction mixture was stirred at room temperature for 2 h, acidified
with 1 N HCl and extracted two times with ethyl acetate. The
combined organic layers were washed with water and brine and dried
over sodium sulfate. The solvent was removed under reduced pressure
and the crude product was purified by thin layer chromatography
(SiO.sub.2, dichloromethane) to give the title compound as
colorless oil (20 mg, 0.07 mmol, 42%).
[0243] MS (m/e): 304.1 (M+H.sup.+, 100%).
Example 10
4-{2-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid
Step 1:
4-[2-(5-Bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxyl-
ic acid methyl ester
[0244] To a solution of 4-amino-thiophene-3-carboxylic acid methyl
ester (0.5 g, 2.58 mmol) in dimethylformamide (25 mL) was added
N-ethyldiisopropylamine (2.25 mL, 12.9 mmol),
(5-bromo-pyridin-2-yloxy)-acetic acid ([79674-66-1], 0.6 g, 2.58
mmol) and HATU (Acros 365312, 1.24 g, 3.23 mmol). The reaction
mixture was stirred for 2 hours at room temperature. After such
time water was added to the reaction mixture until precipitation
occurred (sonication was also used to ease precipitation). The
precipitate was then isolated by filtration and washed with a
mixture of water and ethanol (3:1) to yield the title compound as a
light brown solid (0.96 g, 73%).
[0245] Mp=138-140.degree. C., MS (m/e): 373 (M+H.sup.+, 73%), 370.3
(55%), 219.1 (100%).
Step 2:
4-{2-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophe-
ne-3-carboxylic acid methyl ester
[0246] To a solution of
4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (50 g, 0.135 mmol) in a mixture of
tetrahydrofuran (10.5 mL) and water (2.5 mL) was added
2-methoxyphenylboronic acid (24.5 mg, 0.162 mmol) and cesium
carbonate (175.3 mg, 0.54 mmol). The solution was then degassed by
bubbling a flux of argon for 20 minutes before adding
tetrakis(triphenylphosphine)palladium (4.24 mg, 0.0034 mmol). The
reaction mixture was then stirred overnight at 80.degree. C. under
argon atmosphere before allowing to cool down to room temperature
and diluting with ethyl acetate. The reaction mixture was then
filtered; the filtrate was then washed twice with water and dried
over sodium sulfate before being concentrated in vacuo. The residue
was then purified by column chromatography (SiO.sub.2,
EtOAc/Heptane, 0-60%) to yield the title compound as a light yellow
solid (42.5 mg, 79%).
[0247] MS (m/e): 399.1 (M+H.sup.+, 100%).
Step 3:
4-{2-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophe-
ne-3-carboxylic acid
[0248] To
4-{2-[5-(2-methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thioph-
ene-3-carboxylic acid methyl ester (93 mg, 0.233 mmol) in ethanol
(10 mL) was added a solution of sodium hydroxide (1N, 0.47 mL, 0.47
mmol) and the reaction was stirred at room temperature for 2 days.
After such time the reaction mixture was filtered through glass
wool and the filtrate was then neutralized by addition of a
solution of hydrochloric acid (1N, 0.46 mL). Additional water was
added to the solution (in excess of 10 mL) before the precipitate
was isolated by filtration, washed with water and dried in vacuo to
yield the title compound as a white solid (79 mg, 88%).
[0249] Mp=194-197.degree. C., MS (m/e): 383.1 (M-H).sup.-,
100%).
Example 11
4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbox-
ylic acid
[0250] In analogy to Example 2, from
4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (example 10, step 1) and 4-fluoroboronic acid was
prepared
4-{2-[5-(4-fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid methyl ester.
[0251] MS (m/e): 387.1 (M-H).sup.-, 100%).
[0252] In analogy to Example 2 (step 2), hydrolysis of
4-{2-[5-(4-fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid methyl ester yielded
4-{2-[5-(4-fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid.
[0253] MS (m/e): 371.0 (M-H).sup.-, 100%).
Example 12
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid
Step 1: 4-(2-Chloro-phenoxy)-butyric acid [5057-52-3]
[0254] To a solution of sodium (405 mg, 1.08 mmol) in ethanol (11.1
mL) was added 2-chlorophenol and the reaction mixture was stirred
for 5 minutes before adding dihydro-furan-2-one (1.4 g, 16.1 mmol).
The reaction mixture was stirred for 5 hours at 100.degree. C.
after which time the ethanol was slowly evaporated by continuous
heating to 150.degree. C. for another 12 hours. After such time the
residue was dissolved in water (7 mL) and aqueous hydrochloric acid
(1N) was added until precipitation occurred. The precipitate was
isolated by filtration, washed with water and dried in vacuo to
yield the title compound as yellow solid (2.79 g, 80.4%).
[0255] MS (m/e): 212.9 (M-H).sup.-, 100%).
Step 2: 4-(2-Chloro-phenoxy)-butyryl chloride
[0256] To 4-(2-chloro-phenoxy)-butyric acid (250 mg, 1.165 mmol)
was added portionwise thionyl chloride (1.69 mL), and the reaction
mixture was stirred for 3 hours at 90.degree. C. After such time
the excess of thionyl chloride was removed in vacuo to yield the
crude title compound which was used in the next step without any
further purification.
Step 3:
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid
methyl ester
[0257] To 4-amino-thiophene-3-carboxylic acid methyl ester
hydrochloride (199 mg, 0.994 mmol) in dichloromethane (1.9 mL) and
triethylamine (0.29 mL, 2.08 mmol), was slowly added a crude
solution of 4-(2-chloro-phenoxy)-butyryl chloride (271 mg,
approximately 1.16 mmol) in dichloromethane (1.9 mL). The reaction
mixture was stirred for 3 hours at room temperature. The reaction
mixture was then further diluted with dichloromethane (50 mL) and
washed with water. The aqueous phase was then extracted with
dichloromethane and the combined organic phases were dried with
sodium sulfate, and concentrated in vacuo. The residue was then
purified by column chromatography (SiO.sub.2, Heptane/EtOAc: 0-80%)
to yield the title compound as a white solid (281 mg, 80%).
[0258] MS (m/e): 354.1 (M+H.sup.+, 100%).
Step 4:
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid
[0259] 4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid methyl ester (270 mg, 0.763 mmol) was added to a solution of
lithium hydroxide monohydrate (71.1 mg, 1.68 mmol) in a mixture of
tetrahydrofuran (7.4 mL) and water (7.4 mL) and the reaction
mixture was stirred for 3 hours at room temperature. The
tetrahydofuran was evaporated and the solution was neutralized by
addition of a solution of hydrochloric acid (1N, 0.39 mL). The
precipitate was filtered, washed with water and dried in vacuo to
yield the title compound as a yellow solid (218 mg, 84%).
[0260] MS (m/e): 338.1 (M-H).sup.-, 100%).
Example 13
4-[4-(3-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid
[0261] In analogy to the synthesis of Example 12,
4-[4-(3-chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid
was prepared by replacing in step 1, 2-chlorophenol by
3-chlorophenol.
[0262] MS (m/e): 338.1 (M-H).sup.-, 100%).
Example 14
4-[4-(2-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid
[0263] In analogy to the synthesis of Example 12,
4-[4-(2-fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid
was prepared by replacing in step 1, 2-chlorophenol by
2-fluorophenol.
[0264] MS (m/e): 322.1 (M-H).sup.-, 100%).
Example 15
4-[4-(3-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic
acid
[0265] In analogy to the synthesis of Example 12,
4-[4-(3-fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid
was prepared by replacing in step 1, 2-chlorophenol by
3-fluorophenol.
[0266] MS (m/e): 322.1 (M-H).sup.-, 100%).
Example 16
4-(4-Phenoxy-butyrylamino)-thiophene-3-carboxylic acid
[0267] In analogy to the synthesis of Example 12,
4-(4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid was prepared
by replacing in step 1, 2-chlorophenol by phenol.
[0268] MS (m/e): 322.1 (M-H).sup.-, 100%).
Example 17
Rac-4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic
acid
[0269] In analogy to the synthesis of Example 12,
Rac-4-(2-methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid
was prepared by replacing in step 1, 2-chlorophenol and
dihydro-furan-2-one by phenol and rac-3-methyl-dihydro-furan-2-one
respectively.
[0270] MS (m/e): 318.1 (M-H).sup.-, 100%).
Example 18
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
Step 1:
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester
[0271] To a solution of methyl
4-(2-chloroacetamido)-3-thiophenecarboxylate ([51486-30-7], 100 mg,
0.428 mmol) in dimethylformamide (1.5 mL) was added potassium
carbonate (88.7 mg, 0.642 mmol) and 3,4-dichlorophenol (83.7 mg,
0.514 mmol) and the reaction mixture was stirred at 90.degree. C.
overnight. After such time water was added. The precipitate was
isolated by filtration, washed with water and dried in vacuo to
yield the title compound as a white solid (108.1 mg, 70%).
[0272] Mp=179-182.degree. C., MS (m/e): 360.1 (M-H).sup.-, 100%),
358.1 (62%).
Step 2:
4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0273] To
4-[2-(3,4-dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (80 mg, 0.222 mmol) in suspension in ethanol was
added an aqueous solution of sodium hydroxide (1N, 0.333 mL, 0.333
mmol) and the reaction mixture was stirred at room temperature for
48 hours. After such time the reaction mixture was filtered and the
filtrate was neutralized by addition of an aqueous solution of
hydrochloric acid (1N, 0.335 mL). The precipitate was then isolated
by filtration, washed with water and dried in vacuo to yield the
title compound as a white solid (62.1 mg, 80%).
[0274] Mp=258-264.degree. C., MS (m/e): 344.0 (M-H).sup.-,
100%).
Example 19
4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbox-
ylic acid
Step 1:
4-[2-(5-Bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxyl-
ic acid methyl ester
[0275] To a solution of methyl 4-amino-3-thiophenecarboxylate
hydrochloride (500 mg, 2.58 mmol) in dimethylformamide (25 mL) was
added N-ethyldiisopropylamine (2.26 mL, 12.9 mmol),
(5-bromo-pyridin-2-yloxy)-acetic acid ([79674-66-1], 600 mg, 2.58
mmol) and HATU (1.24 g, 3.23 mmol). The reaction mixture was
allowed to stir for 2 hours at room temperature. After such time,
water was added, and precipitation was eased by ultrasonication.
The precipitate was isolated by filtration and washed with a
mixture of water and ethanol (3: 1) to yield
4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (699 mg, 73%) as a light brown solid.
[0276] Mp=138-140.degree. C., MS (m/e): 373.1 (73%, M+H.sup.+),
370.9 (55%), 216.1 (100%), 241.1 (95%).
Step 2:
4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophen-
e-3-carboxylic acid methyl ester
[0277] To a solution of
4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (100 mg, 0.269 mmol), 2-chlorophenylboronic acid
(50.5 mg) and cesium carbonate (350 mg) in THF (10.5 mL) and
degassed water (2.5 mL) was added
tetrakis(triphenylphosphine)palladium (8.4 mg) and the reaction
mixture was stirred under argon for 2 hours at 80.degree. C. After
such time water was added and the precipitate was isolated, washed
with water and dried in vacuo to yield
4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid methyl ester.
[0278] Mp=151-155.degree. C., MS (m/e): 403.3 (M+H.sup.+).
Step 3:
4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophen-
e-3-carboxylic acid
[0279] To a suspension of
4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid methyl ester (79 mg) in ethanol (10 mL) was added a
solution of sodium hydroxide (1M, 0.392 mL) and THF (8 mL) and the
reaction mixture was stirred at room temperature over night. After
such time the reaction mixture was acidified by addition of a
solution of hydrochloric acid (1N, 0.395 mL) and then water was
added. The precipitate was isolated by filtration, washed with
water and dried in vacuo to yield
4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid (51 mg, 67%).
[0280] Mp=218-223.degree. C., MS (m/e): 387.1 (M-H).sup.-, 100%),
389.2 (51%).
Example 20
4-[2-(4-Cydohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
Step 1:
4-[2-(4-Cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester
[0281] To a solution of methyl
4-(2-chloroacetamido)-3-thiophenecarboxylate ([51486-30-7], 0.1 g)
in dimethylformamide (1.5 mL) was added 4-cyclohexyl-phenol (0.91
mg) and potassium carbonate (89 mg). The reaction mixture was then
stirred at 90.degree. C. overnight, after what water was added
yielding precipitation. The precipitate was isolated and dried in
vacuo to give
4-[2-(4-cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (96 mg, 60%) as a white solid.
[0282] MS (m/e): 376.3 (7%), 375.3 (25%), 374.2 (100%).
Step 2:
4-[2-(4-Cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0283] To a solution of
4-[2-(4-cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (75 mg) in 2.5 mL of a mixture of THF:water
(1.5:1) was added sodium hydroxide (0.442 mL, 1 M, 2.2 eq) and the
reaction mixture was stirred for 24 hours at room temperature. Then
the reaction mixture was acidified by addition of a solution of
aqueous HCl (0.442 mL, 1N, 2.2 eq). The precipitate was isolated,
washed with water and dried in vacuo to yield
4-[2-(4-cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid (51 mg, 71%) as a white solid.
[0284] MS (m/e): 359.2 (M-H).sup.-, 29%), 358.2 (100%), 300.2
(10%).
Example 21
4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0285] In analogy to Example 20 (step 1), from 4-cyclopentyl-phenol
and methyl 4-(2-chloroacetamido)-3-thiophenecarboxylate
([51486-30-7]) was prepared
4-[2-(4-cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester.
[0286] MS (m/e): 363.8 (M+H.sup.+, 8%), 361.3 (20%), 360.1
(100%).
[0287] In analogy to Example 20 (step 2),
4-[2-(4-cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was hydrolysed to
4-[2-(4-cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0288] MS (m/e): 346.2 (7%), 345.1 (14%), 344.2 (100%).
Example 22
4-[2-(4-Isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0289] In analogy to Example 20 (step 1), from 4-isopropyl-phenol
and methyl 4-(2-chloroacetamido)-3-thiophenecarboxylate
([51486-30-7]) was prepared
4-[2-(4-isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester.
[0290] MS (m/e): 335.3 (17%), 334.2 (83%).
[0291] In analogy to Example 20 (step 2),
4-[2-(4-isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
methyl ester was hydrolysed to
4-[2-(4-isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0292] MS (m/e): 320.2 (7%), 319.1 (10%), 318.1 (100%).
Example 23
4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0293] In analogy to Example 20 (step 1) from 4-tert-butyl-phenol
and methyl 4-(2-chloroacetamido)-3-thiophenecarboxylate
([51486-30-7]) was prepared
4-[2-(4-tert-butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester.
[0294] MS (m/e): 349.3 (17%), 348.2 (84%).
[0295] In analogy to Example 20 (step 2),
4-[2-(4-tert-butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was hydrolyzed to
4-[2-(4-tert-butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0296] MS (m/e): 334.2 (10%), 333.2 (32%), 332.3 (100%).
Example 24
rac-4-[2-(4-sec-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0297] In analogy to Example 20 (step 1) from 4-sec-butyl-phenol
and methyl 4-(2-chloroacetamido)-3-thiophenecarboxylate
([51486-30-7]) was prepared
rac-4-[2-(4-sec-butyl-phenoxy)-acetylamino]-thiophene-3-carboxyl-
ic acid methyl ester.
[0298] MS (m/e): 350.5 (5%), 349.3 (16%), 348.2 (83%).
[0299] In analogy to Example 20 (step 2),
rac-4-[2-(4-sec-butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was hydrolyzed to
rac-4-[2-(4-sec-butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid.
[0300] MS (m/e): 334.2 (9%), 333.3 (33%), 332.2 (100%).
Example 25
4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbox-
ylic acid
[0301] In analogy to Example 19 (step 2) from 2-fluorophenyl
boronic acid and
4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester was prepared
4-{2-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid methyl ester.
[0302] MS (m/e): 387.1 (M+H.sup.+).
[0303] In analogy to Example 19 (step 3)
4-{2-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid methyl ester was hydrolyzed into
4-{2-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carbo-
xylic acid.
[0304] MS (m/e): 371.0 (M+H.sup.-).
Example 26
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
Step 1:
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxy-
lic acid methyl ester
[0305] To 4-[2-(4-Iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid methyl ester (77.6 mg) in DMF (1 mL) was added
2-(tributylstannyl)pyrimidine (74.1 mg),
tris(dibenzylideneacetone)-di-Palladium, triphenylarsine (27 mg)
and copper (I) iodide (3.2 mg) and the reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then allowed
to cool to room temperature and was concentrated in vacuo. To the
residue was then added ethylacetate (4 mL) and an aqueous solution
of potassium fluoride (30%) and the mixture was stirred rigorously
for one hour. Then the solid was filtered off and the biphasic
filtrate was separated. The organic layer was dried with sodium
sulfate and concentrated in vacuo. The residue was then purified by
column chromatography to yield the title compound (41 mg, 59%).
[0306] MS (m/e): 369.9 (M+H.sup.+).
Step 2:
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxy-
lic acid
[0307] To
4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carbox-
ylic acid methyl ester (41 mg) in a 1:1 mixture of THF and water
(2.25 mL) was added lithium hydroxide monohydrate and the reaction
mixture was stirred for 20 hours at room temperature. After such
time the THF was evaporated off in vacuo and the remaining aqueous
phase was neutralized by addition of a 1N HCl solution. The
resulting precipitate was then isolated by filtration, washed with
water, and dried in vacuo to yield the title compound as a light
yellow solid. MS (m/e): 354.1 (M+H.sup.-).
Example 27
4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0308] In analogy to Example 26, the title compound was prepared
using 2-(tributylstannyl)pyrazin instead of
2-(tributylstannyl)pyrimidine. MS (m/e): 354.0 (M-H)).
Example 28
4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0309] In analogy to Example 26, the title compound was prepared
using 2-(tributylstannyl)pyridin instead of
2-(tributylstannyl)pyrimidine. MS (m/e): 353.3 (M-H)).
Example 29
4-[2-(4-Pyridin-3-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0310] In analogy to Example 26, the title compound was prepared
using 3-(tributylstannyl)pyridin instead of
2-(tributylstannyl)pyrimidine. MS (m/e): 353.0 (M-H)).
Example 30
4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0311] In analogy to Example 26, the title compound was prepared
using 4-(tributylstannyl)pyridin instead of
2-(tributylstannyl)pyrimidine. MS (m/e): 353.0 (M-H)).
Example 31
4-[2-(4-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0312] In analogy to Example 2, the title compound was prepared
using 4-chlorophenol. MS (m/e): 310.2 (M+H+).
Example 32
4-[2-(3,5-dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0313] In analogy to Example 2, the tide compound was prepared
using 3,5-dichlorophenol. MS (m/e): 344.0 (M+H+).
Example 33
4-[2-(3-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0314] In analogy to Example 2, the tide compound was prepared
using 3-chlorophenol. MS (m/e): 310.2 (M+H+).
Example 34
4-(2-m-Tolyloxy-acetylamino)-thiophene-3-carboxylic acid
[0315] In analogy to Example 2, the title compound was prepared
using 3-methylphenol. MS (m/e): 290.1 (M-H)).
Example 35
4-[2-(3-Ethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
[0316] In analogy to Example 2, the title compound was prepared
using 3-ethylphenol. MS (m/e): 304.1 (M-H)).
Example 36
4-[2-(3-Nitro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
[0317] In analogy to Example 2, the title compound was prepared
using 3-nitrophenol. MS (m/e): 304.1 (M-H)).
Example 37
4-[2-(3-Ethoxy-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0318] In analogy to Example 2, the title compound was prepared
using 3-ethoxyphenol. MS (m/e): 320.2 (M-H)).
Example 38
4-[2-(3-Ethynyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0319] In analogy to Example 2, the title compound was prepared
using 3-ethynylphenol. MS (m/e): 302.1 (M+H+).
Example 39
4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic
acid
[0320] In analogy to Example 2, the title compound was prepared
using biphenyl-3-ol. MS (m/e): 354.1 (M+H+).
Example 40
4-[2-(3-Chloro-4-cyano-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0321] In analogy to Example 2, the title compound was prepared
using 3-chloro-4-cyano phenol. MS (m/e): 335.2 (M-H)).
Example 41
4-[2-(3-Trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0322] In analogy to Example 2, the title compound was prepared
using 3-trifluoromethyl phenol. MS (m/e): 344.1 (M-H)).
Example 42
4-[2-(3-Chloro-4-methyl-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0323] In analogy to Example 2, the title compound was prepared
using 3-chloro-4-methyl phenol. MS (m/e): 324.2 (M-H)).
Example 43
4-[2-(4-Chloro-3-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0324] In analogy to Example 2, the title compound was prepared
using 4-chloro-3-fluoro phenol. MS (m/e): 328.1 (M-H)).
Example 44
4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxy-
lic acid
[0325] In analogy to Example 2, the title compound was prepared
using 4-chloro-3-trifluoromethyl phenol. MS (m/e): 378.2
(M-H)).
Example 45
4-[2-(2-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxy-
lic acid
[0326] In analogy to Example 2, the title compound was prepared
using 2-fluoro-3-trifluoromethyl phenol. MS (m/e): 362.2
(M-H)).
Example 46
4-[2-(3-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxy-
lic acid
[0327] In analogy to Example 2, the title compound was prepared
using 3-fluoro-3-trifluoromethyl phenol. MS (m/e): 362.0
(M-H)).
Example 47
4-[2-(3,5-Difluoro -phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0328] In analogy to Example 2, the title compound was prepared
using 3,5-difluoro phenol. MS (m/e): 312.1 (M-H)).
Example 48
4-[2-(4-Trifluoromethoxy
-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
[0329] In analogy to Example 2, the title compound was prepared
using 4-trifluoromethoxy phenol. MS (m/e): 360.1 (M-H)).
Example 49
4-[2-(4-Trifluoromethoxy
-phenoxy)-acetylamino]-thiophene-3-carboxylic acid
[0330] In analogy to Example 2, the title compound was prepared
using 4-trifluoromethoxy phenol. MS (m/e): 412.1 (M-H)).
Example 50
4-[2-(3-Chloro-5-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0331] In analogy to Example 2, the title compound was prepared
using 3-chloro-5-fluoro phenol. MS (m/e): 328.1 (M-H)).
Example 51
4-[2-(3,5-Dibromo-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0332] In analogy to Example 2, the title compound was prepared
using 3,5-dibromo phenol. MS (m/e): 433.9 (M-H)).
Example 52
4-[2-(3,5-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic
acid
[0333] In analogy to Example 2, the title compound was prepared
using 3,5-dichloro phenol. MS (m/e): 343.1 (M-H)).
Example 53
4-[2-(2-tert-Butyl-pyrimidin)-acetylamino]-thiophene-3-carboxylic
acid
[0334] In analogy to Example 2, the title compound was prepared
using 2-tert-pyrimidin-5-ol [85929-96-0]. MS (m/e): 334.3
(M-H)).
Example 54
4-[2-(4'-Fluoro-biphenyl-4-yloxy)-acetylamino]5-methyl-thiophene-3-carboxy-
lic acid
[0335] In analogy to Example 2, the title compound was prepared
using 4-(2-chloro-acetylamino)-5-methyl-thiophene-3-carboxylic acid
methyl ester [23964-99-0] and 4'-fluoro-biphenyl-4-ol. MS (m/e):
384.0 (M-H)).
Example 55
Rac-4-[2-(3,4-Dichloro-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid
First Step: rac-4-(2-Chloro-propionylamino)-thiophene-3-carboxylic
acid methyl ester
[0336] To a suspension of 4-amino-thiophene-3-carboxylic acid
methyl ester (2.0g) in dichloromethane (25 mL) was added
2-chloropropionyl chloride (1.13 mL). The reaction mixture was then
cooled down to -15.degree. C. and a solution of triethylamine (3.2
mL) in dichloromethane (5 mL) was slowly added over 30 minutes.
After such time the reaction mixture was allowed to warm up to room
temperature, and the solution was washed twice with water, dried
over sodium sulfate and then concentrated in vacuo. The residue was
purified by column chromatography to yield the title compound as a
light yellow solid (2.1g, 82%). MS (EI): 247.0.
Following Steps:
rac-4-[2-(3,4-Dichloro-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid
[0337] In analogy to Example 2, the title compound was prepared
using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid
methyl ester and 3,4-dichlorophenol. MS (m/e): 360.0 (M-H)).
Example 56
Rac-4-[2-(4'-Fluoro-biphenyl-4-yloxy)-propionylamino]-thiophene-3-carboxyl-
ic acid
[0338] In analogy to Example 2, the title compound was prepared
using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid
methyl ester and 4'-fluoro-biphenyl-4-ol. MS (m/e): 384.1
(M-H)).
Example 57
Rac-4-[2-(4-tertButyl-phenoxy)-propionylamino]-thiophene-3-carboxylic
acid
[0339] In analogy to Example 2, the title compound was prepared
using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid
methyl ester and 4-tert-butylphenol. MS (m/e): 346.2 (M-H)).
Example 58
Rac-4-[2-Fluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-ca-
rboxylic acid
Step 1: 4-(2-Chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic
acid methyl ester
[0340] To a suspension of 4-amino-thiophene-3-carboxylic acid
methyl ester (2 g) in dichloromethane (25 mL) was added
chlorofluoroacetyl chloride (1.16 mL) and the reaction mixture was
stirred to -15.degree. C. Then a solution of triethylamine (3.2 mL)
in dichloromethane (5 mL) was added-slowly to the cold reaction
mixture which was then allowed to warm up and stirred at room
temperature for one hour. The reaction mixture was then diluted
with further methylene chloride and washed several times with
water, dried with sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography to yield the title
compound as a light yellow solid. MS (EI): 251.1; mp=51-54.degree.
C.
Steps 2 and 3:
Rac-4-[2-Fluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-c-
arboxylic acid
[0341] In analogy to Example 2, the title compound was prepared
using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid
methyl ester and 4-fluoro-4'-hydroxybiphenyl. MS (m/e): 388.2
(M-H)).
Example 59
Rac-4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxyl-
ic acid
[0342] In analogy to Example 58, the title compound was prepared
using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid
methyl ester and 4-tert-butylphenol. MS (m/e): 350.3 (M-H).
Example 60
Rac-4-[2-(3,4-Dichloro-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxyl-
ic acid
[0343] In analogy to Example 58, the title compound was prepared
using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid
methyl ester and 3,4-dichlorophenol. MS (m/e): 362.0 (M-H).
Example 61
Rac-4-[2,2-Difluoro-2-(4'-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene--
3-carboxylic acid
[0344] In analogy to Example 58, the title compound was prepared
using 4-amino-thiophene-3-carboxylic acid methyl ester,
chlorodifluoroacetyl chloride and 4-fluoro-4'-hydroxybiphenyl. MS
(m/e): 406.1 (M-H)).
Example 62
[0345] Film coated tablets containing the following ingredients can
be manufactured in a conventional manner: TABLE-US-00002
Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg
200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous
60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch
glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel
Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose
3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg
2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg
1.6 mg
[0346] The active ingredient is sieved and mixed with
microcristalline cellulose and the mixture is granulated with a
solution of polyvinylpyrrolidone in water. The granulate is mixed
with sodium starch glycolate and magesiumstearate and compressed to
yield kernels of 120 or 350 mg respectively. The kernels are
lacquered with an aqueous solution/suspension of the above
mentioned film coat.
Example 63
[0347] Capsules containing the following ingredients can be
manufactured in a conventional manner: TABLE-US-00003 Ingredients
Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize
starch 20.0 mg Talc 5.0 mg
[0348] The components are sieved and mixed and filled into capsules
of size 2.
Example 64
[0349] Injection solutions can have the following composition:
TABLE-US-00004 Compound of formula (I) 3.0 mg Polyethylene Glycol
400 150.0 mg Acetic Acid q.s. ad pH 5.0 Water for injection
solutions ad 1.0 ml
[0350] The active ingredient is dissolved in a mixture of
Polyethylene Glycol 400 and water for injection (part). The pH is
adjusted to 5.0 by Acetic Acid. The volume is adjusted to 1.0 ml by
addition of the residual amount of water. The solution is filtered,
filled into vials using an appropriate overage and sterilized.
Example 65
[0351] Soft gelatin capsules containing the following ingredients
can be manufactured in a conventional manner: TABLE-US-00005
Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mg
Hydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils
34.0 mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg
Gelatin capsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0
mg (dry matter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1
mg
[0352] The active ingredient is dissolved in a warm melting of the
other ingredients and the mixture is filled into soft gelatin
capsules of appropriate size. The filled soft gelatin capsules are
treated according to the usual procedures.
Example 66
[0353] Sachets containing the following ingredients can be
manufactured in a conventional manner: TABLE-US-00006 Compound of
formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline
cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose
14.0 mg Polyvinylpyrrolidone K 30 10.0 mg Magnesium stearate 10.0
mg Flavoring additives 1.0 mg
[0354] The active ingredient is mixed with lactose,
microcrystalline cellulose and sodium carboxymethyl cellulose and
granulated with a mixture of polyvinylpyrrolidone in water. The
granulate is mixed with magnesium stearate and the flavouring
additives and filled into sachets.
[0355] It is to be understood that the invention is not limited to
the particular embodiments of the invention described above, as
variations of the particular embodiments may be made and still fall
within the scope of the appended claims.
* * * * *