U.S. patent application number 13/151317 was filed with the patent office on 2011-11-03 for crth2 receptor ligands for medicinal uses.
This patent application is currently assigned to 7TM Pharma A/S. Invention is credited to Thomas Frimurer, Marie Grimstrup, Thomas Hogberg, Evi Kostenis, Jean-Marie Receveur, Oystein Rist, Trond Ulven.
Application Number | 20110269763 13/151317 |
Document ID | / |
Family ID | 34993084 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269763 |
Kind Code |
A1 |
Ulven; Trond ; et
al. |
November 3, 2011 |
CRTH2 receptor ligands for medicinal uses
Abstract
Compounds of formula (I) are useful for the treatment of disease
responsive to modulation of CRTH2 receptor activity, such as
asthma, rhinitis, allergic airway syndrome, and allergic
rhinobronchitis: ##STR00001## wherein A represents a carboxyl group
--COOH, or a carboxyl bioisostere; A.sub.1 is hydrogen or methyl;
ring Ar.sup.1 is an optionally substituted phenyl ring or 5- or
6-membered monocyclic heteroaryl ring, in which AA.sub.1CHO-- and
L2 are linked to adjacent ring atoms; rings Ar.sup.2, Ar.sup.3 each
independently represent a phenyl or 5- or 6-membered monocyclic
heteroaryl ring, or a bicyclic ring system consisting of a 5- or
6-membered carbocyclic or heterocyclic ring which is benz-fused or
fused to a 5- or 6-membered monocyclic heteroaryl ring, said ring
or ring system being optionally substituted; t is 0 or 1; L2 and L3
are linker radicals as defined in the description.
Inventors: |
Ulven; Trond; (Hoersholm,
DK) ; Frimurer; Thomas; (Hoersholm, DK) ;
Rist; Oystein; (Hoersholm, DK) ; Kostenis; Evi;
(Hoersholm, SE) ; Hogberg; Thomas; (Hoersholm,
DK) ; Receveur; Jean-Marie; (Hoersholm, DK) ;
Grimstrup; Marie; (Hoersholm, DK) |
Assignee: |
7TM Pharma A/S
Hoersholm
DK
|
Family ID: |
34993084 |
Appl. No.: |
13/151317 |
Filed: |
June 2, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11597873 |
Sep 24, 2008 |
8022063 |
|
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PCT/EP2005/005884 |
May 30, 2005 |
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13151317 |
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Current U.S.
Class: |
514/242 ;
514/313; 514/340; 514/341; 514/342; 514/364; 514/365; 514/369;
514/374; 514/381; 514/384; 514/389; 514/406 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
3/10 20180101; A61P 43/00 20180101; A61P 25/06 20180101; A61P 37/08
20180101; C07D 277/24 20130101; C07D 277/34 20130101; A61P 9/10
20180101; A61P 17/06 20180101; A61P 37/06 20180101; A61P 13/12
20180101; A61P 19/04 20180101; A61P 27/16 20180101; A61P 25/28
20180101; A61P 27/02 20180101; C07D 261/08 20130101; A61P 37/02
20180101; A61P 11/02 20180101; C07D 263/32 20130101; A61P 17/02
20180101; A61P 25/14 20180101; A61P 3/00 20180101; C07D 231/12
20130101; A61P 29/00 20180101; A61P 17/00 20180101; C07D 271/06
20130101; A61P 11/06 20180101; A61P 11/08 20180101; A61P 11/00
20180101; A61P 19/06 20180101; A61P 1/04 20180101; A61K 31/454
20130101; A61P 37/00 20180101; A61K 31/415 20130101; A61P 19/02
20180101 |
Class at
Publication: |
514/242 ;
514/406; 514/381; 514/341; 514/374; 514/365; 514/364; 514/340;
514/389; 514/369; 514/342; 514/313; 514/384 |
International
Class: |
A61K 31/415 20060101
A61K031/415; A61K 31/4439 20060101 A61K031/4439; A61K 31/421
20060101 A61K031/421; A61K 31/426 20060101 A61K031/426; A61K
31/4152 20060101 A61K031/4152; A61K 31/47 20060101 A61K031/47; A61K
31/53 20060101 A61K031/53; A61K 31/4196 20060101 A61K031/4196; A61P
29/00 20060101 A61P029/00; A61P 37/00 20060101 A61P037/00; A61P
11/00 20060101 A61P011/00; A61P 37/08 20060101 A61P037/08; A61P
11/06 20060101 A61P011/06; A61P 11/08 20060101 A61P011/08; A61P
11/02 20060101 A61P011/02; A61P 3/00 20060101 A61P003/00; A61P
27/02 20060101 A61P027/02; A61P 17/00 20060101 A61P017/00; A61P
25/28 20060101 A61P025/28; A61P 25/14 20060101 A61P025/14; A61P
25/06 20060101 A61P025/06; A61P 19/04 20060101 A61P019/04; A61P
1/04 20060101 A61P001/04; A61P 1/00 20060101 A61P001/00; A61P 19/02
20060101 A61P019/02; A61P 17/06 20060101 A61P017/06; A61P 19/06
20060101 A61P019/06; A61P 9/10 20060101 A61P009/10; A61P 3/10
20060101 A61P003/10; A61P 13/12 20060101 A61P013/12; A61P 37/06
20060101 A61P037/06; A61K 31/41 20060101 A61K031/41 |
Foreign Application Data
Date |
Code |
Application Number |
May 29, 2004 |
GB |
0412198.4 |
Jun 24, 2004 |
GB |
0414196.6 |
Oct 29, 2004 |
GB |
0424018.0 |
Claims
1. A method of treatment of disease responsive to modulation of
CRTH2 receptor activity comprising administering to a subject
suffering such disease a compound of formula (I) or a salt, hydrate
or solvate thereof: ##STR00223## wherein A represents a carboxyl
group --COOH, or a carboxyl bioisostere; A.sub.1 is hydrogen or
methyl; ring Ar.sup.1 is an optionally substituted phenyl ring or
5- or 6-membered monocyclic heteroaryl ring, in which AA.sub.1CHO--
and L2 are linked to adjacent ring atoms; rings Ar.sup.2, Ar.sup.3
each independently represent a phenyl or 5- or 6-membered
monocyclic heteroaryl ring, or a bicyclic ring system consisting of
a 5- or 6-membered carbocyclic or heterocyclic ring which is
benz-fused or fused to a 5- or 6-membered monocyclic heteroaryl
ring, said ring or ring system being optionally substituted; t is 0
or 1; L2 and L3 each independently represent a divalent radical of
formula --(Alk.sup.1).sub.m--(Z).sub.n--(Alk.sup.2).sub.p wherein
m, n and p are independently 0 or 1, Alk.sup.1 and Alk.sup.2 are
independently optionally substituted straight or branched chain
C.sub.1-C.sub.3 alkylene or C.sub.2-C.sub.3 alkenylene radicals
which may contain a compatible --O--, --S-- or --NR-- link wherein
R is hydrogen or C.sub.1-C.sub.3 alkyl, and Z is --O--; --S--;
--C(.dbd.O)--; --SO.sub.2--; --SO--; --NR--, --NRSO.sub.2--,
--SO.sub.2NR--, --C(.dbd.O)NR--, --NRC(.dbd.O)--, --NRCONH--,
--NHCONR--, --NRC(.dbd.NR)NH--, --NHC(.dbd.NR)NR--,
--C(R).dbd.N--NR--, or --NR--N.dbd.C(R)-- wherein R is hydrogen or
C.sub.1-C.sub.3 alkyl; or a divalent 5- or 6-membered monocyclic
carbocyclic or heterocyclic radical, PROVIDED THAT (A) the total
length of L2 and L3 does not exceed that of an unbranched saturated
chain of 10 carbon atoms; and (B) L2 is not --C(.dbd.O)--,
--C(.dbd.O)NR--, or --NRC(.dbd.O)-- when Ar.sup.2 is optionally
substituted phenyl; and (C) (a) L2 is not a bond and (b) p in L2 is
not 0 when n is 1 and Z is aryl or heteroaryl, and (D) (a) L2 is
not --O--, --SO.sub.2--, --NR--, --CHR.sup.XR.sup.Y-- or
--CH(R.sup.X)(OR.sup.Y)--, wherein R.sup.x and R.sup.Y are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl, or join to form a ring, and (b) when p
is 1 and n is 1 and Z is aryl or heteroaryl then Alk.sup.2 is not
--CHR.sup.XR.sup.Y-- or --CH(R.sup.X)(OR.sup.Y)--, wherein R.sup.X
and R.sup.Y are independently hydrogen, halogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl, or join to form a ring.
2. A method as claimed in claim 1, wherein, in the compound (I),
(i) the length of each of L2 and L3 does not exceed that of an
unbranched saturated chain of 5 carbon atoms and (ii) the total
length of L2 and L3 does not exceed that of an unbranched saturated
chain of 7 carbon atoms, and (iii) neither of L2 and L3 includes
more than two R substituents different from hydrogen,
3. A method as claimed in claim 1 wherein, in the compound (I),
A.sub.l is hydrogen and Z is --O--; --S--; --C(.dbd.O)--;
--SO.sub.2--; --SO--; --NR--, --NRSO.sub.2-- --C(.dbd.O)NR--,
--NRCONH--, --NRC(.dbd.NR)NH--, or --C(R).dbd.N--NR--, wherein R is
hydrogen or C.sub.1-C.sub.3 alkyl; or a divalent 5- or 6-membered
monocyclic carbocyclic or heterocyclic radical.
4. A method as claimed in claim 1 wherein, in the compound (I), L2
is --N.dbd.CR--, --OCR.sub.2C(.dbd.O)NR--N.dbd.CR--,
--C(.dbd.O)NR--, --N.dbd.CR--, --C(.dbd.O)--,
--CH.dbd.CHC(.dbd.O)--, --(CH.sub.2).sub.0-3NRC(.dbd.O)--,
--NRC(.dbd.O)(CH.sub.2).sub.0-3--, --O--N.dbd.CH--,
--CH.sub.2NRCH.sub.2--, --NR(CH.sub.2).sub.1-3--,
--(CH.sub.2).sub.1-3NR--, --S--, --CH.sub.2OCH.sub.2--,
--O(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3O--,
--CH.sub.2SCH.sub.2--, --S(CH.sub.2).sub.0-3--,
--(CH.sub.2).sub.0-3S--, a divalent (C.sub.2-C.sub.6)alkylene
radical, a divalent (C.sub.2-C.sub.6)alkenylene radical, or a
divalent (C.sub.2-C.sub.6)alkynylene radical, wherein R is hydrogen
or C.sub.1-C.sub.3 alkyl.
5. A method as claimed in claim 1 wherein, in the compound (I), L2
is --NRN.dbd.CH--, --ON.dbd.CH--, or --N.dbd.CH--.
6. A method as claimed in claim 1 wherein, in the compound (I), L2
is --C(.dbd.O)--.
7. A method as claimed in claim 1 wherein, in the compound (I), L2
is --NHC(.dbd.O)-- or --C(.dbd.O)NH--.
8. A method as claimed in claim 1 wherein, in the compound (I), L2
is a divalent radical selected from one of the following formulae,
wherein either (i) the bond marked * is attached to Ar.sup.2 while
the bond marked ** is attached to Ar.sup.1, or (ii) the bond marked
* is attached to Ar.sup.1 while the bond marked ** is attached to
Ar.sup.2: ##STR00224## ##STR00225## wherein R is hydrogen or
C.sub.1-C.sub.3 alkyl.
9. A method as claimed in claim 8 wherein, in the compound (I), A1
is hydrogen and L2 has one of the following formulae wherein the
bond marked * is attached to Ar.sup.2 while the bond marked ** is
attached to Ar.sup.1: ##STR00226## wherein R is hydrogen or
C.sub.1-C.sub.3 alkyl.
10. A method as claimed in claim 1 wherein the disease is one
associated with elevated levels of prostaglandin D2 (PGD2) or one
or more active metabolites thereof.
11. A method as claimed in claim 1 wherein the disease is an
inflammatory, autoimmune, respiratory or allergy disease.
12. A method as claimed in claim 1 wherein the disease is selected
from asthma, rhinitis, allergic airway syndrome, allergic
rhinobronchitis, bronchitis, chronic obstructive pulmonary disease
(COPD), nasal polyposis, sarcoidosis, farmer's lung, fibroid lung,
cystic fibrosis, chronic cough, conjunctivitis, atopic dermatitis,
Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia
complex, Huntington's disease, frontotemporal dementia, Lewy body
dementia, vascular dementia, Guillain-Barre syndrome, chronic
demyelinating polyradiculoneurophathy, multifocal motor neuropathy,
plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis,
cerebellar degeneration and encephalomyelitis, CNS trauma,
migraine, stroke, rheumatoid arthritis, ankylosing spondylitis,
Behcet's Disease, bursitis, carpal tunnel syndrome, inflammatory
bowel disease, Crohn's disease, ulcerative colitis,
dermatomyositis, Ehlers-Danlos Syndrome (EDS), fibromyalgia,
myofascial pain, osteoarthritis (OA), osteonecrosis, psoriatic
arthritis, Reiter's syndrome (reactive arthritis), sarcoidosis,
scleroderma, Sjogren's Syndrome, soft tissue disease, Still's
Disease, tendinitis, polyarteritis Nodossa, Wegener's
Granulomatosis, myositis (polymyositis dermatomyositis), gout,
atherosclerosis, lupus erythematosus, systemic lupus erythematosus
(SLE), type I diabetes, nephritic syndrome, glomerulonephritis,
acute and chronic renal failure, eosinophilia fascitis, hyper IgE
syndrome, sepsis, septic shock, ischemic reperfusion injury in the
heart, allograft rejection after transplantations, and graft versus
host disease.
13. A method as claimed in claim 1 wherein the disease is selected
from asthma, rhinitis, allergic airway syndrome, and allergic
rhinobronchitis,
14. A method as claimed in claim 1 wherein, in the compound (I),
ring Ar.sup.2 is (i) an optionally substituted phenyl or naphthyl
ring; (ii) a phenyl ring fused to a 5- or 6-membered
nitrogen-containing heterocyclic ring, either or both of such rings
being optionally substituted; (iii) an optionally substituted
nitrogen-containing 5- or 6-membered heteroaryl ring; or (iv) a
nitrogen-containing 5- or 6-membered heterocyclic ring fused to a
phenyl ring, either of which rings being optionally
substituted.
15. A method as claimed in claim 14 wherein, in the compound (I),
ring Ar.sup.2 is optionally substituted phenyl, pyridyl, pyrimidyl,
diazolyl, thiazolyl, oxazolyl, triazinyl, quinolinyl, pyrrollyl,
furanyl, thiazolyl.
16. A method as claimed in claim 15 wherein, in the compound (I),
optional substituents in Ar.sup.2 are selected from fluoro, chloro,
bromo, (C.sub.1-C.sub.3)alkyl, trifluoromethyl,
(C.sub.1-C.sub.3)alkoxy, trifluoromethoxy, trifluoromethylthio,
dimethylamino, cyano, (C.sub.1-C.sub.3alkyl)SO.sub.2--,
NH.sub.2SO.sub.2--, (C.sub.1-C3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, and nitro.
17. A method as claimed in claim 1 wherein, in the compound (I),
Ar.sup.1 is a 5- or 6-membered nitrogen-containing heteroaryl ring,
optionally substituted.
18. A method as claimed in claim 1 wherein in the compound (I),
Ar.sup.1 is a phenyl ring and L3 is linked to the 4-position
thereof relative to the ACHA.sub.1O-- radical.
19. A method as claimed in claim 1 wherein in compound (I), t is 1
and Ar.sup.3 is a 5- or 6-membered heteroaryl ring, optionally
substituted.
20. A method as claimed in claim 1 wherein in compound (I), t is 1
and Ar.sup.3 is a phenyl ring, optionally substituted.
21. A method as claimed in claim 1 wherein in compound (I), any
optional substituents in ring Ar.sup.1 or Ar.sup.3 are selected
from fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl,
trifluoromethoxy, trifluoromethylthio,
(C.sub.1-C.sub.3alkyl)SO.sub.2--, NH.sub.2SO.sub.2--,
(C.sub.1-C.sub.3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, cycloalkyl, aryl, aryloxy,
aryl(C.sub.1-C.sub.6)-- or aryl(C.sub.1-C.sub.6 alkoxy)-.
22. A method as claimed in claim 1 wherein in compound (I), t is 0
and L3 is a bond.
23. A method as claimed in claim 1 wherein, in the compound (I), A
is --COOH.
24. A method as claimed in claim 1 wherein, in the compound (I), A
is a carboxyl bioisostere selected from --SO.sub.2NHR and
--P(.dbd.O)(OH)(OR) wherein R is hydrogen methyl or ethyl,
--SO.sub.2OH, --P(.dbd.O)(OH)(NH.sub.2), --C(.dbd.O)NHCN and groups
of formulae: ##STR00227##
25. A method as claimed in claim 1 wherein, in the compound (I),
A.sub.1 is hydrogen.
Description
[0001] This application is a divisional of U.S. Ser. No. 11/597,873
filed Nov. 29, 2006, now allowed, entitled CRTH2 Receptor Ligands
For Medicinal Uses, whereby U.S. Ser. No. 11/597,873 is a U.S.
National Stage application of co-pending PCT application
PCT/EP2005/005884, filed May 30, 2005, which claims the priority of
Great Britain Patent Application No. 0412198.4, filed May 29, 2004,
Great Britain Patent Application No. 0414196.6, filed Jun. 24, 2004
and Great Britain Patent Application No. 0424018.0, filed Oct. 29,
2004. These applications are incorporated herein by reference in
their entireties.
[0002] This invention relates to the use of a class of compounds
which are ligands of the CRTH2 receptor (Chemoattractant
Receptor-homologous molecule expressed on T Helper cells type 2),
in the treatment of diseases responsive to modulation of CRTH2
receptor activity, principally diseases having a significant
inflammatory component. The invention also relates to novel members
of that class of ligands and pharmaceutical compositions containing
them.
[0003] Many classes of antiinflammatory agents are known, including
the non-steroidal antiinflammatory compounds known as NSAIDs and
the inhibitors of cyclooxygenase (COX-1 and COX-2).
Benzoylphenylacetic acid and some benzophenone derivatives with
carboxymethoxy substituents in one of the rings have been
identified as antiinflammatory agents (see, for example, Khanum et.
al. Bioorganic Chemistry Vol 32, No. 4, 2004, pages 211-222 and the
references cited therein). Some o-phenyl carbamoyl-phenoxyacetic
acids and o-benzamido-phenoxymethyl tetrazoles have been reported
as potential antiinflammatory agent, see for example Drain et. al.
J. Pharm. Pharmac., 1971, 23, 857-864, and ibid 1970, 22, 684-693.
WO 99/15520 discloses a few benzophenone derivatives with
carboxymethoxy or tetrazolylmethoxy substituents in one of the
rings, synthesised as members of a group of compounds said to have
activity as inhibitors of peroxisome proliferator-activated
receptor (PPAR), and utility in a variety of disease states
including diabetes, cardiac disease, and circulatory disease.
[0004] The natural ligand of the G-protein coupled receptor CRTH2
is prostaglandin D2. As its name implies, CRTH2 is expressed on T
helper cells type 2 (Th2 cells) but it is also known to be
expressed on eosinophils and basophil cells. Cell activation as a
result of binding of PGD2 to the CRTH2 receptor results in a
complex biological response, including release of inflammatory
mediators. Elevated levels of PGD2 are therefore associated with
many diseases which have a strong inflammatory component, such as
asthma, rhinitis and allergies. Blocking binding of PGD2 to the
CRTH2 receptor is therefore a useful therapeutic strategy for
treatment of such diseases.
[0005] Some small molecule ligands of CRTH2, apparently acting as
antagonists of PGD2, are known, for example as proposed in the
following patent publications: WO 03/097042, WO 03/097598, WO
03/066046, WO 03/066047, WO 03/101961, WO 03/101981, GB 2388540, WO
04/089885 and WO 05/018529.
[0006] The structures of PGD2 antagonist compounds referred to in
some of the foregoing publications have a bicyclic or tricyclic
core ring system related to the indole core of indomethacin, a
known anti-inflammatory agent, now known to bind to CRTH2. The
present invention arises from the identification of a class of
compounds having a monocyclic core whose substituent moieties are
selected and orientated by the monocyclic core to interact with and
bind to CRTH2. The class of compounds with which this invention is
concerned are thus capable of modulating CRTH2 activity, and are
useful in the treatment of diseases which benefit from such
modulation, for example asthma, allergy and rhinitis.
[0007] According to the present invention, there is provided the
use of a compound of formula (I) or a salt, hydrate or solvate
thereof in the manufacture of a composition for the treatment of
disease responsive to modulation of CRTH2 receptor activity:
##STR00002##
[0008] wherein
[0009] A represents a carboxyl group --COOH, or a carboxyl
bioisostere;
[0010] A.sub.1 is hydrogen or methyl;
[0011] ring Ar.sup.1 is an optionally substituted phenyl ring or 5-
or 6-membered monocyclic heteroaryl ring, in which AA.sub.1CHO--
and L2 are linked to adjacent ring atoms;
[0012] rings Ar.sup.2, Ar.sup.3 each independently represent a
phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a
bicyclic ring system consisting of a 5- or 6-membered carbocyclic
or heterocyclic ring which is benz-fused or fused to a 5- or
6-membered monocyclic heteroaryl ring, said ring or ring system
being optionally substituted;
[0013] t is 0 or 1;
[0014] L2 and L3 each independently represents a divalent radical
of formula -(Alk.sup.1).sub.m-(Z).sub.n-(Alk.sup.2).sub.p wherein
[0015] m, n and p are independently 0 or 1, [0016] Alk.sup.1 and
Alk.sup.2 are independently optionally substituted straight or
branched chain C.sub.1-C.sub.3 alkylene or C.sub.2-C.sub.3
alkenylene radicals which may contain a compatible --O--, --S-- or
--NR-- link wherein R is hydrogen or C.sub.1-C.sub.3 alkyl, and
[0017] Z is --O--; --S--; --C(.dbd.O)--; --SO.sub.2--; --SO--;
--NR--, --NRSO.sub.2--, --SO.sub.2NR--, --C(.dbd.O)NR--,
--NRC(.dbd.O)--, --NRCONH--, --NHCONR--, --NRC(.dbd.NR)NH--,
--NHC(.dbd.NR)NR--, --C(R).dbd.N--NR--, or --NR--N.dbd.C(R)--
wherein R is hydrogen or C.sub.1-C.sub.3 alkyl; or a divalent 5- or
6-membered monocyclic carbocyclic or heterocyclic radical,
[0018] PROVIDED THAT [0019] (A) the total length of L2 and L3 does
not exceed that of an unbranched saturated chain of 10 carbon
atoms; and [0020] (B) L2 is not --C(.dbd.O)--, --C(.dbd.O)NR--, or
--NRC(.dbd.O)-- when Ar.sup.2 is optionally substituted phenyl; and
[0021] (C) (a) L2 is not a bond and (b) p in L2 is not 0 when n is
1 and Z is aryl or heteroaryl, and [0022] (D) (a) L2 is not --O--,
--SO.sub.2--, --NR--, --CHR.sup.XR.sup.Y-- or
--CH(R.sup.X)(OR.sup.Y)--, wherein R.sup.X and R.sup.Y are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl, or join to form a ring, and (b) when p
is 1 and n is 1 and Z is aryl or heteroaryl then Alk.sup.2 is not
--CHR.sup.XR.sup.Y-- or --CH(R.sup.X)(OR.sup.Y)--, wherein R.sup.X
and R.sup.Y are independently hydrogen, halogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or
C.sub.3-C.sub.7 cycloalkyl, or join to form a ring.
[0023] In one aspect of the invention, in compounds (I), the length
of each of L2 and L3 does not exceed that of an unbranched
saturated chain of 5 carbon atoms and (ii) the total length of L2
and L3 does not exceed that of an unbranched saturated chain of 7
carbon atoms, and (iii) neither of L2 and L3 includes more than two
R substituents different from hydrogen. In a narrower aspect of the
invention, compounds (I) as defined above wherein A.sub.1 is
hydrogen and Z is --O--; --S--; --C(.dbd.O)--; --SO.sub.2--;
--SO--; --NR--, --NRSO.sub.2--, --C(.dbd.O)NR--, --NRCONH--,
--NRC(.dbd.NR)NH--, or --C(R).dbd.N--NR--, wherein R is hydrogen or
C.sub.1-C.sub.3 alkyl; or a divalent 5- or 6-membered monocyclic
carbocyclic or heterocyclic radical, may be used
[0024] In another narrower aspect of the invention, compounds (I)
as defined above wherein L2 is --N.dbd.CR--,
--OCR.sub.2C(.dbd.O)NR--N.dbd.CR--, --C(.dbd.O)NR--, --N.dbd.CR--,
--C(.dbd.O)--,
--CH.dbd.CHC(.dbd.O)--(CH.sub.2).sub.0-3NRC(.dbd.O)--,
--NRC(.dbd.O)(CH.sub.2).sub.0-3--, --O--N.dbd.CH--,
--CH.sub.2NRCH.sub.2--, --NR(CH.sub.2).sub.1-3--,
--(CH.sub.2).sub.1-3NR--, --S--, --CH.sub.2OCH.sub.2--,
--O(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3O--,
--CH.sub.2SCH.sub.2--, --S(CH.sub.2).sub.0-3--,
--(CH.sub.2).sub.0-3S--, a divalent (C.sub.2-C.sub.6)alkylene
radical, a divalent (C.sub.2-C.sub.6)alkenylene radical, or a
divalent (C.sub.2-C.sub.6)alkynylene radical, wherein R is hydrogen
or C.sub.1-C.sub.3 alkyl, may be used
[0025] In further narrower aspects of the invention, compounds (I)
as defined above wherein L2 is --NRN.dbd.CH--, --ON.dbd.CH--, or
--N.dbd.CH--; or L2 is --C(.dbd.O)--; or L2 is --NHC(.dbd.O)-- or
--C(.dbd.O)NH--, may be used.
[0026] An independent aspect of the invention is the use of a
compound of formula (I) set out above or a salt, hydrate or solvate
thereof in the manufacture of a composition for the treatment of
disease responsive to modulation of CRTH2 receptor activity, in
which compound (I):
[0027] A represents a carboxyl group --COOH, or a carboxyl
bioisostere;
[0028] A.sub.1 is hydrogen or methyl;
[0029] ring Ar.sup.1 is an optionally substituted phenyl ring or 5-
or 6-membered monocyclic heteroaryl ring, in which AA.sub.1CHO--
and L2 are linked to adjacent ring atoms;
[0030] rings Ar.sup.2, Ar.sup.3 each independently represent a
phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a
bicyclic ring system consisting of a 5- or 6-membered carbocyclic
or heterocyclic ring which is benz-fused or fused to a 5- or
6-membered monocyclic heteroaryl ring, said ring or ring system
being optionally substituted;
[0031] t is 0 or 1;
[0032] L3 represents a divalent radical of formula
-(Alk.sup.1).sub.m-(Z).sub.n-(Alk.sup.2).sub.p wherein [0033] m, n
and p are independently 0 or 1, [0034] Alk.sup.1 and Alk.sup.2 are
independently optionally substituted straight or branched chain
C.sub.1-C.sub.3 alkylene or C.sub.2-C.sub.3 alkenylene radicals
which may contain a compatible --O--, --S-- or --NR-- link wherein
R is hydrogen or C.sub.1-C.sub.3 alkyl, and [0035] Z is --O--;
--S--; --C(.dbd.O)--; --SO.sub.2--; --SO--; --NR--, --NRSO.sub.2--,
--SO.sub.2NR--, --C(.dbd.O)NR--, --NRC(.dbd.O)--, --NRCONH--,
--NHCONR--, --NRC(.dbd.NR)NH--, --NHC(.dbd.NR)NR--,
--C(R).dbd.N--NR--, or --NR--N.dbd.C(R)-- wherein R is hydrogen or
C.sub.1-C.sub.3 alkyl; or a divalent 5- or 6-membered monocyclic
carbocyclic or heterocyclic radical,
[0036] L2 represents a divalent radical selected from one of the
following formulae (sometimes called "L2 set A" herein), wherein
either (i) the bond marked * is attached to Ar.sup.2 while the bond
marked ** is attached to Ar.sup.1, or (ii) the bond marked * is
attached to Ar.sup.1 while the bond marked ** is attached to
Ar.sup.2:
##STR00003## ##STR00004##
[0037] wherein R is hydrogen or C.sub.1-C.sub.3 alkyl; and
[0038] the total length of L2 and L3 does not exceed that of an
unbranched saturated chain of 10 carbon atoms.
[0039] In a narrower definition of this aspect of the invention, in
the compounds (I), (i) the length of L3 does not exceed that of an
unbranched saturated chain of 5 carbon atoms and (ii) the total
length of L2 and L3 does not exceed that of an unbranched saturated
chain of 7 carbon atoms, and (iii) L3 does not include more than
two R substituents different from hydrogen.
[0040] In the two immediately foregoing aspects of the invention,
in the compounds (I), A1 may be hydrogen and L2 may be one of the
following formulae (sometimes called "L2 set B" herein) wherein the
bond marked * is attached to Ar.sup.2 while the bond marked ** is
attached to Ar.sup.1:
##STR00005##
[0041] wherein R is hydrogen or C.sub.1-C.sub.3 alkyl.
[0042] The compounds with which the invention is concerned are
defined by reference to formula (I) as a result of studies towards
elucidation of the ligand binding site of CRTH2. Such studies led
to the overall conclusion that a general pharmacophore comprising
one negatively charged moiety, represented by AA.sub.1CHO--, and
two aromatic and/or hydrophobic moieties, represented by Ar.sup.2L2
and either H(Ar.sup.3).sub.tL3-Ar.sup.1 or only Ar.sup.1, oriented
in an approximate triangle, would form an arrangement for
interaction with the receptor binding site. It was concluded that
the substituent groupings AA.sub.1CHO-- and Ar.sup.2L2- should be
on adjacent ring atoms of Ar.sup.1. The linkers L2 and L3 provide
some flexibility to the molecule to facilitate optimum binding. The
restrictions on the lengths of, and substitutions in, the linkers
L2 and L3 are in order to restrict the total molecular size and
complexity of structures for use in accordance with the invention.
For the avoidance of doubt, the total length of L2 and L3 is, for
the purposes of this description and claims, the sum n2+n3, where
n2 is the number of connected atoms in the shortest chain of atoms
from terminal atom to terminal atom of linker L2, and n3 is the
number of connected atoms in the shortest chain of atoms from
terminal atom to terminal atom of linker L2. Preferably the
compounds with which the invention is concerned should have a
molecular weight of no more than 600. Optional substituents in any
element of the compounds (I) are permitted as in the definition of
compounds (I). Such substituents can modulate pharmacokinetic and
solubility properties, as well as picking up additional binding
interactions with the receptor.
[0043] In another aspect, the invention provides a method of
treatment of a subject suffering from a disease responsive to
modulation of CRTH2 receptor activity, which comprised
administering to the subject an amount of a compound (I) as defined
and described above effective to ameliorate the disease.
[0044] In particular, compounds with which the invention is
concerned are useful in the treatment of disease associated with
elevated levels of prostaglandin D2 (PGD2) or one or more active
metabolites thereof.
[0045] Examples of such diseases include asthma, rhinitis, allergic
airway syndrome, allergic rhinobronchitis, bronchitis, chronic
obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis,
farmer's lung, fibroid lung, cystic fibrosis, chronic cough,
conjunctivitis, atopic dermatitis, Alzheimer's disease, amyotrophic
lateral sclerosis, AIDS dementia complex, Huntington's disease,
frontotemporal dementia, Lewy body dementia, vascular dementia,
Guillain-Barre syndrome, chronic demyelinating
polyradiculoneurophathy, multifocal motor neuropathy, plexopathy,
multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar
degeneration and encephalomyelitis, CNS trauma, migraine, stroke,
rheumatoid arthritis, ankylosing spondylitis, Behcet's Disease,
bursitis, carpal tunnel syndrome, inflammatory bowel disease,
Crohn's disease, ulcerative colitis, dermatomyositis, Ehlers-Danlos
Syndrome (EDS), fibromyalgia, myofascial pain, osteoarthritis (OA),
osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactive
arthritis), sarcoidosis, scleroderma, Sjogren's Syndrome, soft
tissue disease, Still's Disease, tendinitis, polyarteritis Nodossa,
Wegener's Granulomatosis, myositis (polymyositis dermatomyositis),
gout, atherosclerosis, lupus erythematosus, systemic lupus
erythematosus (SLE), type I diabetes, nephritic syndrome,
glomerulonephritis, acute and chronic renal failure, eosinophilia
fascitis, hyper IgE syndrome, sepsis, septic shock, ischemic
reperfusion injury in the heart, allograft rejection after
transplantations, and graft versus host disease.
[0046] However, the compounds with which the invention is concerned
are primarily of value for the treatment asthma, rhinitis, allergic
airway syndrome, and allergic rhinobronchitis.
[0047] Many compounds of formula (I) above are novel in their own
right, and the invention includes such novel compounds per se.
[0048] As used herein, the term "(C.sub.2-C.sub.b)alkyl" wherein a
and b are integers refers to a straight or branched chain alkyl
radical having from a to b carbon atoms. Thus when a is 1 and b is
6, for example, the term includes methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and
n-hexyl.
[0049] As used herein the term "divalent (C.sub.a-C.sub.b)alkylene
radical" wherein a and b are integers refers to a saturated
hydrocarbon chain having from a to b carbon atoms and two
unsatisfied valences.
[0050] As used herein the term "(C.sub.2-C.sub.b)alkenyl" wherein a
and b are integers refers to a straight or branched chain alkenyl
moiety having from a to b carbon atoms having at least one double
bond of either E or Z stereochemistry where applicable. The term
includes, for example, vinyl, allyl, 1- and 2-butenyl and
2-methyl-2-propenyl.
[0051] As used herein the term "divalent
(C.sub.a-C.sub.b)alkenylene radical" means a hydrocarbon chain
having from a to a carbon atoms, at least one double bond, and two
unsatisfied valences.
[0052] As used herein the term "C.sub.a-C.sub.b alkynyl" wherein a
and b are integers refers to straight chain or branched chain
hydrocarbon groups having from two to six carbon atoms and having
in addition one triple bond. This term would include for example,
ethynyl, 1- and 2-propynyl, 1-, 2- and 3-butynyl, 1, 2-, 3- and
4-pentynyl, 1-, 2-, 3-, 4- and 5-hexynyl, 3-methyl-1-butynyl,
1-methyl-2-pentynyl.
[0053] As used herein the term "divalent
(C.sub.a-C.sub.b)alkynylene radical" wherein a and b are integers
refers to a divalent hydrocarbon chain having from 2 to 6 carbon
atoms, at least one triple bond, and two unsatisfied valences.
[0054] As used herein the term "carbocyclic" refers to a mono-, bi-
or tricyclic radical having up to 16 ring atoms, all of which are
carbon, and includes aryl and cycloalkyl.
[0055] As used herein the term "cycloalkyl" refers to a monocyclic
saturated carbocyclic radical having from 3-8 carbon atoms and
includes, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl.
[0056] As used herein the unqualified term "aryl" refers to a
mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes
radicals having two monocyclic carbocyclic aromatic rings which are
directly linked by a covalent bond. Illustrative of such radicals
are phenyl, biphenyl and napthyl.
[0057] As used herein the unqualified term "heteroaryl" refers to a
mono-, bi- or tri-cyclic aromatic radical containing one or more
heteroatoms selected from S, N and O, and includes radicals having
two such monocyclic rings, or one such monocyclic ring and one
monocyclic aryl ring, which are directly linked by a covalent bond.
Illustrative of such radicals are thienyl, benzthienyl, furyl,
benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl,
benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl,
benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl,
benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyridazinyl, triazinyl, indolyl and indazolyl.
[0058] As used herein the unqualified term "heterocyclyl" or
"heterocyclic" includes "heteroaryl" as defined above, and in
addition means a mono-, bi- or tri-cyclic non-aromatic radical
containing one or more heteroatoms selected from S, N and O, and to
groups consisting of a monocyclic non-aromatic radical containing
one or more such heteroatoms which is covalently linked to another
such radical or to a monocyclic carbocyclic radical. Illustrative
of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,
pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl,
piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl,
isoxazolyl, benzimidazolyl, methylenedioxyphenyl,
ethylenedioxyphenyl, maleimido and succinimido groups.
[0059] The term "carboxyl bioisostere" is a term familiar to
medicinal chemists (see for example "The Organic Chemistry of Drug
Design and Drug Action", by Richard B. Silverman, pub. Academic
Press, 1992), and refers to a group which has similar acid-base
characteristics to those of a carboxyl group. Well known carboxyl
bioisosteres include --SO.sub.2NHR or --P(.dbd.O)(OH)(OR) wherein R
is, for example, hydrogen methyl or ethyl, --SO.sub.2OH,
--P(.dbd.O)(OH)(NH.sub.2), --C(.dbd.O)NHCN and groups of
formulae:
##STR00006##
[0060] Unless otherwise specified in the context in which it
occurs, the term "substituted" as applied to any moiety herein
means substituted with up to four compatible substituents, each of
which independently may be, for example, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, hydroxy, hydroxy(C.sub.1-C.sub.6)alkyl,
mercapto, mercapto(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylthio, halo (including fluoro, bromo and
chloro), fully or partially fluorinated (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy or (C.sub.1-C.sub.3)alkylthio such as
trifluoromethyl, trifluoromethoxy, and trifluoromethylthio, nitro,
nitrile (--CN), oxo, phenyl, phenoxy, --COOR.sup.A, --COR.sup.A,
--OCOR.sup.A, --SO.sub.2R.sup.A, --CONR.sup.AR.sup.B,
--SO.sub.2NR.sup.AR.sup.B, --NR.sup.AR.sup.B, --OCONR.sup.AR.sup.B,
--NR.sup.BCOR.sup.A, --NR.sup.BCOOR.sup.A,
--NR.sup.BSO.sub.2OR.sup.A or --NR.sup.ACONR.sup.AR.sup.B wherein
R.sup.A and R.sup.B are independently hydrogen or a
(C.sub.1-C.sub.6)alkyl group or, in the case where R.sup.A and
R.sup.B are linked to the same N atom, R.sup.A and R.sup.B taken
together with that nitrogen may form a cyclic amino ring. Where the
substituent is phenyl or phenoxy, the phenyl ring thereof may
itself be substituted by any of the above substituents except
phenyl or phenoxy. An "optional substituent" may be one of the
foregoing substituent groups.
[0061] As used herein the term "salt" includes base addition, acid
addition and quaternary salts. Compounds of the invention which are
acidic can form salts, including pharmaceutically acceptable salts,
with bases such as alkali metal hydroxides, e.g. sodium and
potassium hydroxides; alkaline earth metal hydroxides e.g. calcium,
barium and magnesium hydroxides; with organic bases e.g.
N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane,
L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the
like. Those compounds (I) which are basic can form salts, including
pharmaceutically acceptable salts with inorganic acids, e.g. with
hydrohalic acids such as hydrochloric or hydrobromic acids,
sulphuric acid, nitric acid or phosphoric acid and the like, and
with organic acids e.g. with acetic, tartaric, succinic, fumaric,
maleic, malic, salicylic, citric, methanesulphonic,
p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and
mandelic acids and the like.
[0062] Compounds with which the invention is concerned which may
exist in one or more stereoisomeric form, because of the presence
of asymmetric atoms or rotational restrictions, can exist as a
number of stereoisomers with R or S stereochemistry at each chiral
centre or as atropisomeres with R or S stereochemistry at each
chiral axis. The invention includes all such enantiomers and
diastereoisomers and mixtures thereof.
[0063] Use of prodrugs, such as esters, of compounds (I) with which
the invention is concerned is also part of the invention.
[0064] For use in accordance with the above aspects of the
invention the following structural characteristics may be present,
in any compatible combination, in the compounds (I): [0065] L2 may
be a member of L2 set A above (and of course L2 set A includes L2
set B); [0066] L2 may be --N.dbd.CR--,
--OCR.sub.2C(.dbd.O)NR--N.dbd.CR--, --C(.dbd.O)NR--, --N.dbd.CR--,
--C(.dbd.O)--,
--CH.dbd.CHC(.dbd.O)--(CH.sub.2).sub.0-3NRC(.dbd.O)--,
--NRC(.dbd.O)(CH.sub.2).sub.0-3--, --O--N.dbd.CH--,
--CH.sub.2NRCH.sub.2--, --NR(CH.sub.2).sub.1-3--,
--(CH.sub.2).sub.1-3NR--, --S--, --CH.sub.2OCH.sub.2--,
--O(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.1-3O--,
--CH.sub.2SCH.sub.2--, --S(CH.sub.2).sub.0-3--,
--(CH.sub.2).sub.0-3S--, a divalent (C.sub.2-C.sub.6)alkylene
radical, a divalent (C.sub.2-C.sub.6)alkenylene radical, or a
divalent (C.sub.2-C.sub.6)alkynylene radical, wherein R is hydrogen
or C.sub.1-C.sub.3 alkyl; [0067] L2 may be --NRN.dbd.CH--,
--ON.dbd.CH--, --N.dbd.CH--, --C(.dbd.O)--, --NHC(.dbd.O)-- or
--C(.dbd.O)NH--; [0068] Ar.sup.2 may be an optionally substituted
phenyl or 5- or 6-membered nitrogen-containing heteroaryl ring, for
example pyridyl, pyrimidyl, diazolyl, thiazolyl, oxazolyl,
triazinyl, quinolinyl, pyrrollyl, furanyl, thiazolyl; [0069]
Optional substituents in Ar.sup.2 may be selected from fluoro,
chloro, bromo, (C.sub.1-C.sub.3)alkyl, trifluoromethyl,
(C.sub.1-C.sub.3)alkoxy, trifluoromethoxy, trifluoromethylthio,
dimethylamino, cyano, (C.sub.1-C.sub.3alkyl)SO.sub.2--,
NH.sub.2SO.sub.2--, (C.sub.1-C.sub.3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, and nitro; [0070] Ar.sup.1
may be an optionally substituted 5- or 6-membered
nitrogen-containing heteroaryl ring, for example pyridyl,
pyrimidyl, diazolyl, thiazolyl, oxazolyl, triazinyl, quinolinyl,
pyrrollyl, furanyl, thiazolyl, and wherein L3 may be linked to a
ring carbon in (for a 6-membered ring) the 4 position thereof
relative to the ACHA.sub.1O-- radical or (for a 5-membered ring)
the 4 position thereof counting the ACHA.sub.1O-- radical as in
position 1 and the Ar.sup.2L2-radical as in position 2 thereof;
[0071] Ar.sup.1 may be an optionally substituted phenyl ring
wherein L3 is linked to the 4 position thereof relative to the
ACHA.sub.1O-radical; [0072] when t is 1, Ar.sup.3 may be an
optionally substituted phenyl ring, or an optionally substituted 5-
or 6-membered heteroaryl ring, for example pyridyl, pyrimidyl,
diazolyl, thiazolyl, oxazolyl, triazinyl, quinolinyl, pyrrollyl,
furanyl, or thiazolyl; [0073] optional substituents in ring
Ar.sup.1 or Ar.sup.3 may be selected from fluoro, chloro, bromo,
iodo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, (C.sub.1-C.sub.3alkyl)SO.sub.2--,
NH.sub.2SO.sub.2--, (C.sub.1-C.sub.3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, cycloalkyl, aryl, aryloxy,
aryl(C.sub.1-C.sub.6)- or aryl(C.sub.1-C.sub.6 alkoxy)-; [0074]
when t is 0, L3 may be a bond; [0075] A may be --COOH or a carboxyl
bioisostere selected from --SO.sub.2NHR and --P(.dbd.O)(OH)(OR)
wherein R is hydrogen methyl or ethyl, --SO.sub.2OH,
--P(.dbd.O)(OH)(NH.sub.2), --C(.dbd.O)NHCN and groups of
formulae:
[0075] ##STR00007## [0076] It is currently preferred that A be
carboxyl; [0077] A.sub.1 may be hydrogen or methyl.
[0078] Compounds (I) for use in accordance with the invention
include those of formula (IV) and salts, hydrates or solvates
thereof, which are believed novel per se, and which form another
aspect of the invention:
##STR00008##
[0079] wherein A, A1, L3, Ar.sup.3, Ar.sup.2, and t are as defined
and discussed above in relation to formula (I), R13 represents
hydrogen or one or more optional substituents, and L2 is a member
of the L2 set A, as defined above. This includes the case where
A.sub.l is hydrogen and L2 is a member of the L2 set B as defined
above.
[0080] The following structural characteristics may be present in
compounds (IV), in any compatible combination:
[0081] A may be --COOH, or a carboxyl bioisostere selected from
--SO.sub.2NHR and --P(.dbd.O)(OH)(OR) wherein R is hydrogen methyl
or ethyl, --SO.sub.2OH, --P(.dbd.O)(OH)(NH.sub.2), --C(.dbd.O)NHCN
and groups of formulae:
##STR00009##
[0082] Currently it is preferred that A be carboxyl.
[0083] R.sub.13 may represent one or more substituents selected
from fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl,
trifluoromethoxy, trifluoromethylthio,
(C.sub.1-C.sub.3alkyl)SO.sub.2--, NH.sub.2SO.sub.2--,
(C.sub.1-C.sub.3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, cycloalkyl, aryl, aryloxy,
aryl(C.sub.1-C.sub.6)- or aryl(C.sub.1-C.sub.6 alkoxy)-.
[0084] A.sub.1 may be methyl or A.sub.1 may be hydrogen.
[0085] One preferred subset of the compounds (IV) has formula
(IVA)
##STR00010##
[0086] wherein A, A.sub.1 L3, t, Ar.sup.3, R.sub.13 are as defined
and discussed above in relation to compounds of formula (I) and
(IV) and R.sub.14 is optionally substituted phenyl or 5- or
6-membered heteroaryl.
[0087] Another preferred subset of the compounds (IV) has formula
(IVB):
##STR00011##
[0088] wherein A.sub.1, L3, t, and Ar.sup.3 are as defined and
discussed above in relation to formulae (I), (IV) and (IVA), and
R.sub.14 is optionally substituted phenyl or 5- or 6-membered
heteroaryl
[0089] Another preferred subset of the compounds (IV) has formula
(IVC):
##STR00012##
[0090] wherein R.sub.13 represents a substituent selected from
fluoro, chloro, bromo, iodo, (C.sub.1-C.sub.6)alkyl,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylmercapto, trifluoromethoxy,
trifluoromethylthio, dimethylamino, cyano,
(C.sub.1-C.sub.3alkyl)SO.sub.2--, NH.sub.2SO.sub.2--,
(C.sub.1-C.sub.3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, and nitro, and R.sub.14 is
optionally substituted phenyl or 5- or 6-membered heteroaryl. In
this subset, R.sub.14 may be a 2-substituted, 2,4-disubstituted,
2,6-disubstituted or 2,4,6-trisubstituted phenyl ring where the
substituents are selected from fluoro, chloro, bromo, iodo,
(C.sub.1-C.sub.6)alkyl, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylmercapto, trifluoromethoxy,
trifluoromethylthio, dimethylamino,
(C.sub.1-C.sub.3alkyl)SO.sub.2--, NH.sub.2SO.sub.2--,
(C.sub.1-C.sub.3alkyl)NHSO.sub.2--,
(C.sub.1-C.sub.3alkyl).sub.2NSO.sub.2--, and cyano. This subset
specifically includes compounds wherein A.sub.1 is hydrogen.
[0091] In any compound (I), (IV) (IVA), (IVB) or IVC) defined and
discussed above, wherein A1 is methyl, the carbon atom to which it
is attached preferably has the S stereochemical configuration.
[0092] Specific novel compounds of the invention are the
following:
[0093] 4-chloro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic
acid,
[0094] 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic
acid,
[0095]
[4-bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid,
[0096]
{4-bromo-2-[1-(2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid,
[0097]
{4-bromo-2-[1-(3-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid,
[0098]
{4-bromo-2-[1-(4-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}acetic
acid,
[0099]
{4-bromo-2-[1-(4-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid,
[0100]
{4-bromo-2-[1-(2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}acetic
acid,
[0101]
{4-bromo-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}acetic
acid,
[0102]
{4-bromo-2-[1-(2-fluorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid,
[0103]
{4-bromo-2-[1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}acetic acid,
[0104]
{4-bromo-2-[1-(3-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}acetic
acid,
[0105]
{4-bromo-2-[1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid,
[0106]
{2-[1-(2-chlorophenyl)-1H-pyrazole-4-carbonyl]-4-nitrophenoxy}aceti-
c acid,
[0107]
{4-bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid,
[0108]
{2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]-4-ethylphenoxy}acetic
acid,
[0109]
{4-bromo-2-[1-(2,4-dibromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}ac-
etic acid,
[0110]
{4-bromo-2-[1-(4-bromo-2-chlorophenyl)-1H-pyrazole-4-carbonyl]pheno-
xy}acetic acid,
[0111]
{4-bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phenox-
y}acetic acid,
[0112]
2-[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]propionic
acid,
[0113]
(S)-2-[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]propionic
acid,
[0114]
2-{4-Bromo-2-[1-(2-chlorophenyl)-1-H-pyrazole-4-carbonyl]phenoxy}pr-
opionic acid,
[0115]
(S)-2-{4-Bromo-2-[1-(2-chlorophenyl)-1-H-pyrazole-4-carbonyl]phenox-
y}propionic acid,
[0116]
2-{4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy-
}propionic acid,
[0117]
(S)-2-{4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phe-
noxy}propionic acid,
[0118]
{4-Bromo-2-[1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid,
[0119]
{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenox-
y}acetic acid,
[0120]
{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}acet-
ic acid,
[0121]
{4-Bromo-2-[1-(2-methylthiophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid,
[0122]
{4-Bromo-2-[1-(2-bromo-4-methylphenyl)-1H-pyrazole-4-carbonyl]pheno-
xy}acetic acid,
[0123]
2-{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}propionic acid,
[0124]
2-{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}pr-
opionic acid,
[0125]
(S)-2-{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenox-
y}propionic acid,
[0126]
2-{4-Bromo-2-[1-(2-methylthio)-1H-pyrazole-4-carbonyl]phenoxy}propi-
onic acid,
[0127]
(S)-2-{4-Bromo-2-[1-(2-methylthio)-1H-pyrazole-4-carbonyl]phenoxy}p-
ropionic acid,
[0128]
{4-Bromo-2-[1-(2,4-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid,
[0129]
{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}acetic acid,
[0130]
{4-Bromo-2-[1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid,
[0131]
2-{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]ph-
enoxy}propionic acid,
[0132]
2-{4-Bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}propionic acid,
[0133]
{4-Bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid,
[0134]
{4-Bromo-2-[1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid
[0135]
{4-Bromo-2-[1-(2-ethyl-6-methylphenyl)-1H-pyrazole-4-carbonyl]pheno-
xy}acetic acid,
[0136]
{4-Bromo-2-[1-(2-chloro-6-methylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}acetic acid,
[0137]
{4-Bromo-2-[1-(3,5-dichloropyridin-4-yl)-1H-pyrazole-4-carbonyl]phe-
noxy}acetic acid,
[0138]
[4-Bromo-2-(1-naphthalen-1-yl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid,
[0139] {4-Bromo-2-[2-(4-chlorobenzyl)thiazol-4-yl]phenoxy}acetic
acid,
[0140]
{4-Bromo-2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceti-
c acid,
[0141]
{4-Bromo-2-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acet-
ic acid,
[0142]
{4-Bromo-2-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acetic
acid,
[0143]
{4-Bromo-2-[3-(4-fluoro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ace-
tic acid,
[0144]
{4-Bromo-2-[3-(2,6-dichloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-
-acetic acid,
[0145]
{4-Bromo-2-[3-(2-trifluoromethylbenzyl)-[1,2,4]oxadiazol-5-yl]pheno-
xy}-acetic acid,
[0146]
4-Bromo-2-[3-(2,6-dichloro-phenyl)isoxazole-5-carbonyl]phenoxy}acet-
ic acid,
[0147]
{4-Bromo-2-[3-(1-phenylcyclopropyl)-[1,2,4]oxadiazol-5-yl]phenoxy}a-
cetic acid,
[0148]
{4-Bromo-2-[3-(2,4-dichlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}ac-
etic acid, [0149] and salts, hydrates and solvates thereof.
[0150] The invention also includes pharmaceutical compositions
comprising a compound belonging to the above described compounds of
formula (IV), (IVA), (IVB) or (IVC), together with a
pharmaceutically acceptable carrier.
[0151] Compositions
[0152] As mentioned above, the compounds with which the invention
is concerned are capable of modulating CRTH2 activity, and are
useful in the treatment of diseases which benefit from such
modulation. Examples of such diseases are referred to above, and
include asthma, allergy and rhinitis.
[0153] It will be understood that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, route of
administration, rate of excretion, drug combination and the
severity of the particular disease undergoing treatment. Optimum
dose levels and frequency of dosing will be determined by clinical
trial, as is required in the pharmaceutical art.
[0154] The compounds with which the invention is concerned may be
prepared for administration by any route consistent with their
pharmacokinetic properties. The orally administrable compositions
may be in the form of tablets, capsules, powders, granules,
lozenges, liquid or gel preparations, such as oral, topical, or
sterile parenteral solutions or suspensions. Tablets and capsules
for oral administration may be in unit dose presentation form, and
may contain conventional excipients such as binding agents, for
example syrup, acacia, gelatin, sorbitol, tragacanth, or
polyvinyl-pyrrolidone; fillers for example lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricant, for example magnesium stearate, talc, polyethylene
glycol or silica; disintegrants for example potato starch, or
acceptable wetting agents such as sodium lauryl sulphate. The
tablets may be coated according to methods well known in normal
pharmaceutical practice. Oral liquid preparations may be in the
form of, for example, aqueous or oily suspensions, solutions,
emulsions, syrups or elixirs, or may be presented as a dry product
for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, for example sorbitol, syrup, methyl cellulose,
glucose syrup, gelatin hydrogenated edible fats; emulsifying
agents, for example lecithin, sorbitan monooleate, or acacia;
non-aqueous vehicles (which may include edible oils), for example
almond oil, fractionated coconut oil, oily esters such as
glycerine, propylene glycol, or ethyl alcohol; preservatives, for
example methyl or propyl p-hydroxybenzoate or sorbic acid, and if
desired conventional flavouring or colouring agents.
[0155] For topical application to the skin, the drug may be made up
into a cream, lotion or ointment. Cream or ointment formulations
which may be used for the drug are conventional formulations well
known in the art, for example as described in standard textbooks of
pharmaceutics such as the British Pharmacopoeia.
[0156] For topical application to the eye, the drug may be made up
into a solution or suspension in a suitable sterile aqueous or non
aqueous vehicle. Additives, for instance buffers such as sodium
metabisulphite or disodium edeate; preservatives including
bactericidal and fungicidal agents such as phenyl mercuric acetate
or nitrate, benzalkonium chloride or chlorhexidine, and thickening
agents such as hypromellose may also be included.
[0157] The drug may also be formulated for inhalation, for example
as a nasal spray, or dry powder or aerosol inhalers.
[0158] The active ingredient may also be administered parenterally
in a sterile medium. Depending on the vehicle and concentration
used, the drug can either be suspended or dissolved in the vehicle.
Advantageously, adjuvants such as a local anaesthetic, preservative
and buffering agents can be dissolved in the vehicle.
[0159] The compounds with which the invention is concerned may be
administered alone, or as part of a combination therapy with other
drugs used for treatment of diseases with a major inflammatory
component. In the case of asthma, rhinitis, and allergic airway
syndrome such drugs include corticosteroids, long-acting inhaled
beta agonists, cromolyn, nedocromil, theophylline, leukotriene
receptor antagonists, antihistamines, and anticholinergics (e.g.
ipratropium), and are often administered as nasal sprays, dry
powder or aerosol inhalers.
[0160] In the case of arthritis and related inflammatory diseases
other known drugs include glucocorticoids, NSAIDs (Non Steroidal
Anti-Inflammatory Drugs--conventional prostaglandin synthesis
inhibitors, COX-2 inhibitors, salicylates), and DMARDs
(disease-modifying anti-rheumatic drugs such as methotrexate,
sulfasalazine, gold, cyclosporine).
[0161] Synthetic Routes
[0162] There are multiple synthetic strategies for the synthesis of
the compounds (I) with which the present invention is concerned,
but all rely on known chemistry, known to the synthetic organic
chemist. Thus, compounds according to Formula I can be synthesised
according to procedures described in the standard literature and
are well-known to the one skilled in the art. Typical literature
sources are "Advanced organic chemistry", 4.sup.th Edition (Wiley),
J March, "Comprehensive Organic Transformation", 2.sup.nd Edition
(Wiley), R. C. Larock , "Handbook of Heterocyclic Chemistry",
2.sup.nd Edition (Pergamon), A. R. Katritzky), review articles such
as found in "Synthesis", "Acc. Chem. Res.", "Chem. Rev", or primary
literature sources identified by standard literature searches
online or from secondary sources such as "Chemical Abstracts" or
"Beilstein".
[0163] In the discussion which follows, A represents a carboxylic
acid, a carboxyl bioisostere, or a protected carboxylic acid or
bioisostere, or a precursor of these. In the latter case, a
deprotection step is implied. A.sub.1 represents hydrogen or
methyl.
[0164] Many compounds claimed in this invention may be synthesized
by reacting a phenol precursor with LG-CH(A.sub.1)-A, where LG is a
leaving group and A is a carboxylic acid or a protected analog or
precursor, or a bioiosotere or a protected analog of this.
##STR00013##
[0165] The linker L2 can be formed by joining two appropriately
functionalised and, if needed, suitably protected fragments
containing La2 and Lb2 as reactive moieties as outlined below. La2
and Lb2 are defined as any moieties that can react by e.g. a
nucleophilic substitution, addition to multiple bonds or
cyclisation reaction to form a given L2 linker as exemplified
below.
##STR00014##
[0166] For example, the linker -L2- being
-Alk.sup.1-Z-(Alk.sup.2).sub.p- can be formed by reacting
Ar.sup.2-Alk.sup.1- "leaving group" with a nucleophilic derivative
H--Z-(Alk.sup.2).sub.p-Ar.sup.1(L1A)L3Ar.sup.3H wherein Z could be
O, S or NR and Alk.sup.1 could be an alkyl group. The reactions can
also be made by reversing the functionalisation of La2 and Lb2 to
make the connection between Z and Alk.sup.2. The linkers wherein Z
is SO or SO.sub.2 can be obtained by oxidations of the
corresponding -(Alk.sup.1).sub.m-S-(Alk.sup.2).sub.p- derivatives
during appropriate conditions.
[0167] Further representative examples, -L2- being
-Alk.sup.1-Z-(Alk.sup.2).sub.p- wherein Z is NH(CO) or NHSO.sub.2
can be formed by reacting Ar.sup.2-(Alk.sup.1)-NH.sub.2 with an
acylating derivative "leaving
group"-CO-(Alk.sup.2).sub.p-Ar.sup.1(L1A)L3Ar.sup.3H or "leaving
group"-SO.sub.2-(Alk.sup.2).sub.p-Ar.sup.1(L1A)L3Ar.sup.3H,
respectively. Alternatively, the conversion can be made directly
with the acids HO--CO-(Alk.sup.2).sub.p-Ar.sup.1(L1A)L3Ar.sup.3H
and HO--SO.sub.2-(Alk.sup.2).sub.p-Ar.sup.1(L1A)L3Ar.sup.3H,
respectively, using suitable coupling reagents such as
dicyclohexylcarbodiimide (DCC), and promoters such as
1-hydroxybenzotriazole. Analogously, -L2- being
-Alk.sup.1-Z-(Alk.sup.2).sub.p- wherein Z being NH(CO)NH can be
formed by reacting Ar.sup.2-(Alk.sup.1)-NH.sub.2 with an isocyanate
derivative OCN-(Alk.sup.2).sub.p-Ar.sup.1(L1A)L3Ar.sup.3H using
suitable acid or base catalysis. The reactions can also be made by
reversing the functionalisation of La2 and Lb2 to provide the
"retro-bonds" in the case of NH(CO) or NHSO.sub.2. Analogously, the
connections can be made between Z and Alk.sup.2.
[0168] A metal catalyzed coupling reaction like the Stille coupling
reaction, the Suzuki coupling reaction, the Heck reaction and the
Sonogashira reaction are useful in the synthesis of examples with
L2 being an divalent alkylene radical, a divalent alkenylene
radical or a divalent alkynylene radical.
[0169] Compounds with L2 being a hydrazone are usually conveniently
formed by a condensation reaction between the corresponding
hydrazines and aldehydes in ethanol or without solvent.
[0170] Likewise, L2 being -(Alk.sup.1).sub.m-Z-(Alk.sup.2).sub.p-
wherein Z is a 5-membered heterocyclic system exemplified by, for
example,
##STR00015##
[0171] can be made according to standard cyclisation procedures
using appropriate solvents, catalysts and temperatures. For
example, formation of 1,2,4-triazole can be made with La2 being
acylhydrazide and Lb2 being amide or thioamide or the reverse
orientation of La2 and Lb2. 1,2,4-Oxadiazole can be formed from La2
being amidoxime and Lb2 being carboxylic ester or the reverse
orientation of La2 and Lb2. 1,3,4-Oxadiazole can be formed from La2
being acylhydrazide and Lb2 being carboxylic ester or the reverse
orientation of La2 and Lb2. The thiazole can be made from La2 being
thioamide and Lb2 being an .alpha.-haloketone or the reverse
orientation of La2 and Lb2. The isoxazole can be made from La2
being alkyne and Lb2 being nitriloxide or the reverse orientation
in a cylcoaddition reaction.
[0172] In an analogous manner the compounds of formula I can be
made by forming the linker L3, according to procedures outlined for
L2, as depicted below. Thus, La and Lb are defined as any moieties
that can react by e.g. a nucleophilic substitution, addition to
multiple bonds or cyclisation reaction to form a given linker as
exemplified below.
##STR00016##
[0173] The Ar.sup.1 moiety can also be the central scaffold that is
used in connecting the L2 and L3 parts in a stepwise fashion. This
can be done via aromatic substitutions of the Ar.sup.1 core to
attach L2 and/or L3, which then can be further functionalised to
give the final Formula I compounds.
[0174] Furthermore, the Ar.sup.1 moiety can also be assemblied via
ring cyclisation reactions with reactants containing the L2 and L3
units either containing the full appendices as outlined below:
##STR00017##
[0175] or in forms that can be further functionalised into the
final Formula I structures as described previously. One such
illustration is given below
##STR00018##
[0176] For example, 1,2,4-triazoles can be made from acylhydrazides
and amides or thioamides; 1,2,4-Oxadiazoles from amidoximes and
carboxylic esters; 1,3,4-Oxadiazoles from acylhydrazides and
carboxylic esters; Thiazoles from thioamides and
.alpha.-haloketones; Pyridines via various cycloaddition
reactions.
[0177] The building blocks used in the reactions are either
commercially available or made according to standard procedures
well-know to one skilled in the art as described in "Advanced
organic chemistry", 4.sup.th Edition (Wiley), J March,
"Comprehensive Organic Transformation", 2.sup.nd Edition (Wiley),
R. C. Larock, "Handbook of Heterocyclic Chemistry', 2.sup.nd
Edition (Pergamon), A. R. Katritzky or other suitable literature
sources. The Examples herein describe specific strategies for the
synthesis of compounds wherein Ar.sup.1 is phenyl. Analogous
compounds are accessible by variation of the intermediates used in
the Examples.
[0178] The following Examples illustrate the preparation of
compounds with which this invention is concerned. Some compounds
were synthesised, and some were acquired from commercial sources.
In the Examples:
[0179] General Comments:
[0180] Microwave chemistry was performed in a Personal Chemistry
Emrys Optimizer. NMR spectra were obtained on a Bruker Avance AMX
300 MHz instrument. LC/MS was performed on an Agilent 1100-series
instrument. LC/MS methods are as follows: An10p8: Column: XTerra MS
C18; Flow: 1.0 mL/min; Gradient: 0-5 min: 15-100% MeCN in water,
5-71/2 min: 100% MeCN; Modifier: 5 mM ammonium formate;
MS-ionisation mode: API-ES (pos.). An10n8: Column: XTerra MS C18;
Flow: 1.0 mL/min; Gradient: 0-5 min: 15-100% MeCN in water, 5-71/2
min: 100% MeCN; Modifier: 5 mM ammonium formate; MS-ionisation
mode: API-ES (neg.).
[0181] General Synthetic Route I
##STR00019##
[0182] General Synthetic Route II
##STR00020##
[0183] General Procedure 1 (GP1):
[0184] Condensation of 3-formylchromone with arylhydrazine
[0185] The 3-formylchromone (1.0 mmol) and the arylhydrazine (1.0
mmol) in ethanol (3.0 mL) in a reaction tube was added 4.0 M aq.
KOH (1.0 mL, 4.0 mmol). The tube was sealed and heated by
microwaves to 120.degree. C. for 7 min (420 s). The reaction
mixture was added 3% HCl until pH<1 and left to precipitated.
The precipitate was filtered off and washed with a small amount of
ethanol. The product was used directly or purified by
recrystallisation from ethanol or by flash chromatography.
[0186] General Procedure 2 (GP2):
[0187] Alkylation of Phenol
[0188] The phenol (0.5 mmol) in acetone (1 mL) was added ethyl
bromoacetate (85 mg, 0.5 mmol) or ethyl 2-bromopropionate (91 mg,
0.5 mmol) and K.sub.2CO.sub.3 (75 mg, 0.54 mmol), and the reaction
mixture was stirred at room temperature for 12 h. The reaction
mixture was then concentrated in vacuo and the residue was
partitioned between water and ethyl acetate. The organic phase was
washed with brine, dried (MgSO.sub.4) and concentrated. The product
was used directly or purified by recrystallization from MeOH or by
flash chromatography.
[0189] General Procedure 3 (GP3):
[0190] Hydrolysis of Ester
[0191] The ester (0.10 mmol) in THF (0.5 mL) was added
LiOH.H.sub.2O (6.3 mg, 0.15 mmol) in water (0.5 mL). The reaction
was stirred at room temperature for >2 h, 3% HCl was added until
pH<1, and the mixture was extracted with CH.sub.2Cl.sub.2. The
organic phase was dried (MgSO.sub.4) and concentrated to give the
product.
[0192] General Procedure 4 (GP4):
[0193] Suzuki Coupling/Ester Hydrolysis
[0194] Aryl bromide (0.20 mmol), aryl boronic acid (0.21 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (9 mg, 0.01 mmol) was added MeCN (0.4
mL, degassed) and 1.0 M Na.sub.2CO.sub.3 (0.4 mL, degassed). The
reaction mixture was degassed by letting argon through for 1/2 min
and heated by microwaves (150.degree. C., 300 s), then added 3% HCl
until pH<1 and extracted with CH.sub.2Cl.sub.2. The extract was
filtered through celite and concentrated, and the residue was
purified by solid-phase extraction (pre-packed 1 g SAX columns), or
by flash chromatography.
INTERMEDIATE-1
##STR00021##
[0196] Ethyl
4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate. Prepared
from (5-bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone
and ethyl bromoacetate according to GP2 to give 215 mg (100%) white
crystals. The product was used without further purification: LC/MS
(an10p8): Rt 6.15 min, m/z 429 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 1.26 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz,
2H), 4.64 (s, 2H), 6.72 (d, J=8.9 Hz, 1H), 7.34 (m, 1H), 7.46 (m,
2H), 7.53 (dd, J=8.9, 2.5 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H),
7.73-7.78 (m, 2H), 8.17 (s, 1H), 8.58 (s, 1H); .sup.13C NMR
(CDCl.sub.3): .delta. 14.3, 61.9, 65.5, 114.0, 114.5, 119.8, 125.3,
127.7, 129.8, 131.8, 132.3, 132.7, 134.6, 139.6, 142.7, 154.1,
168.5, 186.9.
##STR00022##
[0197] 4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic
acid. Prepared from ethyl
4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate (31 mg,
0.072 mmol) according to GP3 to give 28.4 mg (99%) white solid:
LC/MS (an10p8): Rt 3.14 min, m/z 401; .sup.1H NMR (CDCl.sub.3):
.delta. 3.51 (s, 1H), 4.80 (s, 1H), 6.97 (d, J=8.7 Hz, 1H),
7.38-7.44 (m, 1H), 7.49-7.55 (m, 2H), 7.64-7.69 (m, 1H), 7.72-7.77
(m, 3H), 8.19 (s, 1H), 8.52 (s, 1H); .sup.13C NMR (CDCl.sub.3):
.delta. 67.2, 115.1, 116.6, 120.1, 124.5, 128.4, 130.0, 131.9,
133.3, 136.2, 139.2, 143.3, 155.2, 169.9, 187.6.
INTERMEDIATE-2
##STR00023##
[0199] Ethyl 2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate.
Prepared from (2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone
(264 mg, 1.0 mmol) and ethyl bromoacetate according to GP2 to give
235 mg (67%) of the title compound as white solid: .sup.1H NMR
(CDCl.sub.3): .delta. 1.26 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz,
2H), 4.67 (s, 2H), 6.84 (d, J=8.3 Hz, 1H), 7.10 (ts, J=7.4, 0.8 Hz,
1 Hz), 7.29-7.36 (m, 1H), 7.41-7.53 (m, 4H), 7.72-7.78 (m, 2H),
8.18 (s, 1H), 8.58 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta.
14.3, 61.7, 65.4, 112.2, 118.8, 119.3, 119.7, 120.0, 122.1, 125.8,
127.6, 129.7, 129.9, 130.1, 130.6, 131.8, 132.1, 136.3, 139.7,
142.8, 155.0, 168.9, 188.7.
##STR00024##
[0200] 2-(1-Phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid.
Prepared from ethyl
2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate according to GP3
and purified by column chromatography (SiO.sub.2, EtOAc:heptane,
1:1) to give 15 mg (56%) of the title compound as white solid:
LC/MS (an10n8): Rt 2.90 min, m/z 321.0 [M-H].sup.-; .sup.1H NMR
(CDCl.sub.3): .delta. 4.83 (s, 2H), 7.10 (d, J=8.3 Hz, 1H), 7.20
(t, J=7.5 Hz, 1H), 7.35-7.42 (m, 1H), 7.46-7.53 (m, 2H), 7.54-7.61
(m, 1H), 7.66 (dd, J=7.5, 1.5 Hz, 1H), 7.70-7.75 (m, 2H); .sup.13C
NMR (CDCl.sub.3): .delta. 67.7, 115.5, 120.1, 122.8, 124.7, 128.3,
128.6, 129.9, 131.0, 131.9, 134.0, 139.3, 143.5, 156.6, 170.4,
189.3.
INTERMEDIATE-3
##STR00025##
[0202] Ethyl
4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate.
Prepared from 4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenol
(282 mg) and ethyl bromoacetate according to GP2 to give 335 mg
(91%) yellow solid: LC/MS (an10n8): Rt 3.16, m/z 339.0 [M-H].sup.-;
.sup.1H NMR (CDCl.sub.3): .delta. 1.26 (t, J=7.0 Hz, 3H), 4.23 (t,
J=7.1 Hz, 2H), 4.63 (s, 2H), 6.81 (dd, J=9.0, 4.0 Hz, 1H), 7.13
(ddd, J=8.9, 4.5, 3.0 Hz, 1H), 7.21 (dd, J=8.1, 3.2 Hz, 1H),
7.31-7.37 (m, 1H), 7.24-7.50 (m, 2H), 7.72-7.78 (m, 2H), 8.18 (s,
1H), 8.58 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 14.3, 61.8,
66.1, 114.0 (d, J.sub.CF=7.6 Hz), 116.8 (d, J.sub.CF=24.5 Hz),
118.3 (d, J.sub.CF=23.5 Hz), 119.7, 125.2, 127.7, 129.7, 131.8,
139.6, 142.8, 151.1 (d, J.sub.CF=2.2 Hz), 157.6 (d, J.sub.CF=241.1
Hz), 168.7, 187.1.
##STR00026##
[0203] 4-Fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic
acid. Prepared from ethyl
4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate (31 mg)
according to GP3 to give 30 mg (100%) of a pale yellow solid: LC/MS
(an10n8): Rt 3.16, m/z 339.0 [M-H].sup.-; .sup.1H NMR (CDCl.sub.3):
.delta. 4.60 (s, 2H), 6.90 (dd, J=9.2 Hz, 1H), 7.08-7.17 (m, 1H),
7.21 (dd, J=7.9, 3.0 Hz, 1H), 7.28-7.35 (m, 1H), 7.38-7.46 (m, 2H),
7.65 (d, J=7.5 Hz, 2H), 8.06 (s, 1H), 8.44 (s, 1H).
INTERMEDIATE-4
##STR00027##
[0205]
4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetonitrile.
(5-Bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (342
mg) was added bromoacetonitrile (122 mg), acetone (2 mL) and
K.sub.2CO.sub.3 (140 mg), and the reaction was stirred for 24 h.
The reaction mixture was concentrated and the residue was
partitioned between water and EtOAc. The organic phase was washed
with brine, dried (MgSO4) and concentrated to give 383 mg (100%)
yellow solid, that was used directly in the next step: LC/MS
(an10p8): Rt 4.39 min, m/z 381.5 [M+1].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 4.80 (s, 2H), 7.07 (d, J=8.7 Hz, 1H),
7.35-7.42 (m, 1H), 7.45-7.54 (m, 2H), 7.60-7.69 (m, 2H), 7.69-7.75
(m, 2H), 8.03 (s, 1H), 8.31 (s, 1H); .sup.13C NMR (CDCl.sub.3):
.delta. 55.2, 114.7, 116.6, 116.7, 120.1, 125.1, 128.2, 129.9,
131.0, 132.6, 133.2, 135.0, 139.3, 142.7, 153.0, 186.0.
##STR00028##
[0206]
[5-Bromo-2-(2H-tetrazol-5-ylmethoxy)phenyl](1-phenyl-1H-pyrazol-4-y-
l)ketone.
[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]-acetonitril- e
(38 mg) was added NaN3 (66 mg), ZnBr.sub.2 (59 mg), isopropanol
(1.3 mL) and water (1.6 mL), and the reaction mixture was heated to
reflux for 1 h. The mixture was added 3% HCl (1 mL) and EtOAc (4
mL) and stirred until two clear phases appeared. The aqueous phase
was added 3% HCl until pH<1 and extracted with EtOAc. The
combined organic phases were washed with brine, dried (MgSO.sub.4)
and concentrated to give 47 mg white foam: LC/MS (an10n8): Rt 2.93,
m/z 243.0 [M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 5.69 (s,
2H), 7.13 (d, J=8.6 Hz, 1H), 7.39-7.45 (m, 1H), 7.49-7.56 (m, 2H),
7.62-7.71 (m, 2H), 7.71-7.79 (m, 1H), 8.13 (s, 1H), 8.45 (s, 1H);
.sup.13C NMR (CDCl.sub.3): .delta. 63.3, 115.6, 117.7, 120.3,
124.5, 128.6, 130.0, 131.2, 132.0, 132.9, 136.3, 139.1, 143.5,
154.7, 188.4.
##STR00029##
[0207] 3-(1-Phenyl-1H-pyrazole-4-carbonyl)biphenyl-4-yloxyacetic
acid. Prepared from ethyl
[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and
phenylboronic acid according to GP4: LC/MS (an10p8): Rt 1.05 min,
m/z 398.6 [M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 4.86 (s,
2H), 7.17 (d, J=8.6 Hz, 1H), 7.35-7.57 (m, 8H), 7.70-7.75 (m, 2H),
7.78 (dd, J=8.6, 2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 8.20 (s, 1H),
8.54 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 67.7, 115.8,
120.1, 124.8, 127.1, 128.0, 128.3, 129.1, 129.3, 129.4, 129.9,
132.3, 136.2, 139.3, 139.3, 143.5, 155.8, 170.4, 189.3.
INTERMEDIATE-5
##STR00030##
[0209]
(5-Bromo-2-hydroxyphenyl)-(1-pyridin-2-yl-1H-pyrazol-4-yl)ketone.
To a suspension of 6-bromo-3-formylchromone (253 mg) in isopropanol
(3 mL) and CH.sub.2Cl.sub.2 (2 mL) was added 2-hydrazinopyridine
(109 mg), and the mixture was stirred for 15 min to form a yellow
slurry. The slurry was added KOH (0.25 g) in water (0.25 mL), and
the reaction was heated to reflux for 1 h. The reaction mixture was
diluted with water, added 3% HCl until pH<1 and extracted with
CH.sub.2Cl.sub.2 (2.times.). The extract was washed with water and
brine, dried (MgSO.sub.4) and concentrated to give 342 mg orange
foam, which was purified by flash chromatography (SiO.sub.2,
EA:Hep, 1:1) to give 53 mg (15%) yellow solid: LC/MS (an10p8): Rt
5.0 min, m/z 343.5 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
6.98 (d, J=8.9 Hz, 1H), 7.31 (ddd, J=7.3, 4.9, 0.9 Hz, 1H), 7.60
(dd, J=8.9, 2.5 Hz, 1H), 7.87-7.93 (m, 1H), 8.03 (d, J=2.4 Hz, 1H),
8.04-8.09 (m, 1H), 8.02 (s, 1H), 8.47-8.51 (m, 1H), 9.13 (s, 1H),
11.94 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 110.9, 113.3,
120.8, 121.6, 122.8, 123.1, 130.5, 133.5, 138.9, 139.3, 143.3,
148.7, 161.9, 191.4.
INTERMEDIATE-6
##STR00031##
[0211] Ethyl
4-bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxyacetate.
Prepared from
(5-bromo-2-hydroxyphenyl)-(1-pyridin-2-yl-1H-pyrazol-4-yl)ketone
(43 mg) according to GP2 and purified by flash chromatography
(SiO.sub.2, EtOAc:heptane, 1:2) to give 34 mg (63%) of a pale
yellow solid: LC/MS (an10p8): Rt 4.9 min, m/z 429.5 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 1.23 (t, J=7.2 Hz, 3H), 4.20 (q,
J=7.2 Hz, 2H), 4.62 (s, 2H), 6.76 (d, J=8.6 Hz, 1H), 7.23-7.28 (m,
1H), 7.53 (ddd, J=8.9, 2.6, 1.0 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H),
7.82-7.99 (m, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.19 (s, 1H), 8.40-8.44
(m, 1H), 8.99 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 14.3,
61.8, 66.1, 114.5, 114.7, 131.6, 132.3, 132.4, 134.6, 139.1, 148.5,
154.4, 168.3, 187.1.
##STR00032##
[0212]
4-Bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxyacetic
acid. Prepared from
ethyl[4-bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxy]-acetate
(21 mg) according to GP3 to give 20 mg white foam: LC/MS (an10n8):
Rt 2.8 min, m/z 401.9 [M-H].sup.-; .sup.1H NMR (CDCl.sub.3):
.delta. 4.79 (s, 2H), 6.98 (d, J=8.9 Hz, 1H), 7.28-7.34 (m, 1H),
7.67 (dd, J=8.9, 2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.86-7.94 (m,
1H), 8.02-8.08 (m, 1H), 8.22 (s, 1H), 8. 43-8.48 (m, 1H), 9.04 (s,
1H).
INTERMEDIATE-7
##STR00033##
[0214]
(5-Bromo-2-hydroxy-phenyl)-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]ket-
one. To a suspension of 6-bromo-3-formylcromone (253 mg, 1.0 mmol)
in ethanol (5 mL) was added 4-methoxyphenylhydrazine (175 mg, 1.0
mmol), and the mixture was stirred under argon for 12 h an orange
slurry. The slurry was added KOH (260 mg) in water (0.25 mL), and
the reaction was heated to reflux for 11/2 h. The reaction mixture
was added 3% HCl until pH<1 and left on ice to precipitate. The
precipitate was filtered off and washed with a small amount of cold
ethanol to give 256 mg (69%) beige solid that was used without
further purification: LC/MS (an10p8): Rt 5.0 min, m/z 372.5
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 3.88 (s, 3H), 6.98
(d, J=8.9 Hz, 1H), 7.03 (d, J=9.1 Hz, 2H), 7.59 (dd, J=9.0, 2.5 Hz,
1H), 7.66 (d, J=9.1 Hz, 2H), 8.02 (d, J=2.4 Hz, 1H), 8.15 s, 1H),
8.39 (s, 1H), 11.92 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta.
55.9, 110.9, 115.0, 120.8, 121.6, 121.8, 122.9, 130.7, 133.5,
138.8, 142.3, 159.7, 161.8.
INTERMEDIATE-8
##STR00034##
[0216] Ethyl
4-bromo-2-[1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxyacetate.
Prepared from
(5-bromo-2-hydroxyphenyl)-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]ketone
and ethyl bromoacetate according to GP2: LC/MS (an10p8): Rt 4.59
min, m/z 458.4/460.4 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
1.26 (t, J=7.1 Hz, 3H), 3.84 (s, 3H), 4.23 (q, J=7.1 Hz, 2H), 4.62
(s, 2H), 6.72 (d, J=8.9 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 7.52 (dd,
J=8.9, 2.6 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H),
8.13 (s, 1H), 8.46 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta.
14.3, 55.8, 61.9, 65.6, 114.1, 114.4, 114.8, 121.4, 125.0, 131.6,
132.4, 132.6, 133.2, 134.5, 142.5, 154.1, 159.2, 168.5, 186.9.
##STR00035##
[0217]
4-Bromo-2-[1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from ethyl
4-bromo-2-[1-(4-methoxy-phenyl)-1H-pyrazole-4-carbonyl]phenoxyacetate
(23 mg) according to GP3 to give 21 mg (97%) white foam: LC/MS
(an10n8): Rt 5.76 min, m/z 428.9 [M-H].sup.-; .sup.1H NMR
(CDCl.sub.3): .delta. 3.86 (s, 3H), 4.77 (s, 2H), 6.94 (d, J=8.9
Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 7.59-7.66 (m, 3H), 7.71 (d, J=2.4
Hz, 1H), 8.14 (d, J=0.6 Hz, 1H), 8.40 (d, J=0.6 Hz, 1H).sup.13C NMR
(CDCl.sub.3): .delta. 55.9, 67.2, 115.0, 115.1, 116.6, 121.8,
124.2, 130.7, 131.8, 132.7, 133.2, 136.1, 143.2, 155.2, 159.7,
169.9, 187.6.
##STR00036##
[0218]
[3',5'-Difluoro-3-(1-phenyl-1H-pyrazole-4-carbonyl)biphenyl-4-yloxy-
]acetic acid. Prepared
ethyl[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate
and 3,5-difluorophenylboronic acid according to GP4: LC/MS
(an10n8): Rt 3.03 min, m/z 434.5 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 4.85 (s, 2H), 6.81 (td, J=8.9, 2.3 Hz, 1H),
7.07 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.9 Hz, 1H), 7.41 (d, J=6.6 Hz,
1H), 7.48 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.66-7.78 (m, 4H), 8.23
(s, 1H), 8.57 (s, 1H)
##STR00037##
[0219]
[4'-Chloro-3-(1-phenyl-1H-pyrazole-4-carbonyl)biphenyl-4-yloxy]acet-
ic acid. Prepared from
ethyl[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate
and 4-chlorophenylboronic acid according to GP4: LC/MS (an10n8): Rt
3.08 min, m/z 432.5 [M-H].sup.-.
##STR00038##
[0220] [4-Chloro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. Prepared from
(2-hydroxy-5-chlorophenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone and
ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt
3.08 min, m/z 356.6 [M+1].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
4.75 (s, 2H), 6.95 (d, J=8.9 Hz, 1H), 7.33-7.41 (m, 1H), 7.44-7.52
(m, 3H), 7.55 (d, J=2.6 Hz, 1H), 7.69-7.75 (m, 2H), 8.18 (s, 1H),
8.52 (s, 1H).
##STR00039##
[0221] [4-Methyl-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. Prepared from
(2-hydroxy-5-methylphenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone and
ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt
3.08 min, m/z 356.6 [M+1].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
2.37 (s, 3H), 4.78 (s, 2H), 6.97 (d, J=9.0 Hz, 1H), 7.33-7.51 (m,
5H), 7.73 (d, J=6 Hz, 2H), 8.16 (s, 1H), 8.51 (s, 1H), 11.21 (br s,
1H)
##STR00040##
[0222]
[4-Chloro-3-methyl-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]aceti-
c acid. Prepared from
(3-chloro-6-hydroxy-2-methyl-phenyl)-(1-phenyl-1H-pyrazol-4-yl)methanone
and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt
3.34 min, m/z 370.6 [M+1].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
2.44 (s, 3H), 4.77 (s, 2H), 6.92 (s, 1H), 7.39 (d, J=9.0 Hz, 1H),
7.46-7.51 (m, 2H), 7.59 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 8.19 (s,
1H), 8.52 (s, 1H), 10.39 (br s, 1H)
##STR00041##
[0223]
[2,4-Dichloro-6-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. Prepared from
(3,5-dichloro-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)methanone
and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt
3.27 min, m/z 390.5 [M+1].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
4.72 (s, 2H), 7.38-7.51 (m, 4H), 7.57-7.58 (m, 1H), 7.70 (d, J=8.1
Hz, 2H), 8.06 (s, 1H), 8.36 (s, 1H), 9.23 (br s, 1H).
##STR00042##
[0224]
4-Bromo-2-[1-(2-chloro-phenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
2-chlorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8) Rt 3.02 min, m/z 436.4 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.76 (s, 2H), 6.94 (d, J=8.9 Hz,
1H), 7.39-7.47 (m, 2H), 7.53-7.67 (m, 3H), 7.74 (dd, J=2.4, 0.9 Hz,
1H), 8.21 (s, 1H), 8.40 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta.
67.2, 115.0, 116.7, 123.9, 127.9, 128.2, 128.7, 130.55, 130.59,
131.1, 133.3, 136.2, 136.6, 137.1, 143.1, 155.2, 170.0, 187.5.
##STR00043##
[0225]
4-Bromo-2-[1-(3-chloro-phenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone and
3-chlorophenylhydrazine according to: LC/MS (an10p8) Rt 3.57 min,
m/z 436.4 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.76 (s,
2H), 6.90 (d, J=8.9 Hz, 1H), 7.34 (dm, J=6.8 Hz, 1H), 7.41 (t,
J=8.3 Hz, 1H), 7.58-7.66 (m, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.78 (m,
1H), 8.17 (s, 1H), 8.51 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta.
66.8, 115.1, 116.2, 117.9, 120.4, 124.9, 128.3, 130.7, 131.0,
132.0, 133.2, 135.8, 136.1, 140.2, 143.4, 155.0, 170.1, 187.4.
##STR00044##
[0226]
4-Bromo-2-[1-(4-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
4-bromophenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10p8) Rt 3.75 min, m/z 480.3 [M+H].sup.+; .sup.1H
NMR (CDCl.sub.3): .delta. 4.75 (s, 2H), 6.89 (d, J=8.9 Hz, 1H),
7.59-7.65 (m, 5H), 7.66-7.69 (m, 1H), 8.16 (s, 1H), 8.50 (s, 1H);
.sup.13C NMR (CDCl.sub.3): .delta. 66.5, 115.0, 115.9, 121.5,
121.8, 124.9, 130.8, 131.8, 133.0, 133.1, 135.9, 138.2, 143.4,
154.8, 170.6, 187.4.
##STR00045##
[0227]
4-Bromo-2-[1-(4-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
4-chlorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 3.53 min, m/z 436.4 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.74 (s, 2H), 6.88 (d, J=8.9 Hz,
1H), 7.44 (d, J=8.5 Hz, 2H), 7.61 (dd, J=8.9, 2.4 Hz, 1H),
7.63-7.70 (m, 3H), 8.17 (s, 1H), 8.49 (s, 1H); .sup.13C NMR
(CDCl.sub.3): .delta. 66.4, 114.9, 115.7, 121.2, 124.9, 130.0,
130.9, 131.9, 133.1, 133.9, 135.9, 137.7, 143.3, 154.7, 170.8,
187.4.
##STR00046##
[0228]
4-Bromo-2-[1-(2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
2-ethylphenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10n8): Rt 2.58 min, 427.0 m/z [M-H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 1.14 (t, J=7.5 Hz, 3H), 2.58 (q,
J=7.5, 2H), 4.76 (s, 2H), 6.93 (d, J=8.9 Hz, 1H), 7.28-7.34 (m,
2H), 7.37-7.48 (m, 2H), 7.62 (dd, J=8.9, 2.6 Hz, 1H), 7.72 (d,
J=2.5 Hz, 1H), 8.15 (s, 1H), 8.18 (s, 1H).
##STR00047##
[0229]
4-Nitro-2-[1-(4-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-nitro-3-formylchromone,
4-chlorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 2.44 min, m/z 401.7 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.84 (d, 2H), 7.1 (d, J=9.6 Hz,
1H), 7.44 (d, J=8.1 Hz, 2H), 7.67 (d, J=8.1 Hz, 2H), 8.22 (s, 1H),
8.36 (d, J=9.2 Hz, 1H), 8.41 (s, 1H), 8.53 (s, 1H); .sup.13C NMR
(CDCl.sub.3): .delta. 65.6, 112.9, 121.3, 124.9, 126.2, 128.2,
130.0, 130.1, 131.9, 134.1, 137.6, 142.4, 143.3, 159.7, 169.9,
186.2.
##STR00048##
[0230] 4-Nitro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic
acid. Prepared from 6-nitro-3-formylchromone,
2-ethylphenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10p8) Rt 2.05 min, m/z 367.8 [M+H].sup.+; .sup.1H
NMR (CDCl.sub.3): .delta. 4.83 (s, 2H), 7.01 (d, J=9.0 Hz, 1H),
7.34-7.42 (m, 1H), 7.44-7.53 (m, 1H), 7.65-7.72 (m, 1H), 8.26 (s,
1H), 8.34 (dd, J=9.0, 2.6 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H), 8.53 (s,
1H).
##STR00049##
[0231]
4-Bromo-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
2-bromophenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10p8): Rt 3.38 min, m/z 480.6 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.75 (s, 2H), 6.91 (d, J=9.0 Hz,
1H), 7.34-7.64 (m, 6H), 7.73-7.74 (m, 2H), 8.22 (s, 1H), 8.36 (s,
1H).
##STR00050##
[0232]
4-Bromo-2-[1-(2-fluorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
2-fluorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 3.36 min, m/z 418.7 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.75 (s, 2H), 6.91 (d, J=8.9 Hz,
1H), 7.21-7.42 (m, 3H), 7.62 (dd, J=8.9, 2.4 Hz, 1H), 7.70 (d,
J=2.5 Hz, 1H), 7.85-7.92 (m, 1H), 8.20 (s, 1H), 8.51 (d, J=2.3 Hz,
1H); .sup.13C NMR (CDCl.sub.3): .delta. 66.9, 115.0, 116.3, 117.1,
117.4, 124.62, 124.63, 125.0, 125.39, 125.44, 127.4, 127.5, 129.6,
129.7, 130.8, 133.2, 135.8, 136.8, 143.0, 152.3, 155.0, 155.6,
170.5, 187.4.
##STR00051##
[0233]
4-Bromo-2-[1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]pheno-
xyacetic acid. Prepared from 6-bromo-3-formylchromone,
2-trifluoromethylphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.44 min, m/z 468.7
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.72 (s, 2H), 6.89
(d, J=8.9 Hz, 1H), 7.53-7.75 (m, 5H), 7.84 (d, J=7.9 Hz, 1H), 8.20
(s, 2H); .sup.13C NMR (CDCl.sub.3): .delta. 66.8, 114.9, 116.2,
124.3, 126.3, 126.7, 127.58, 127.64, 129.2, 130.3. 130.7, 133.2,
136.0, 136.9, 143.1, 155.0, 170.3, 187.4.
##STR00052##
[0234]
4-Bromo-2-[1-(3-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
3-bromophenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10p8): Rt 4.29 min, m/z 480.5 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.79 (s, 2H), 6.95 (d, J=9.0 Hz,
1H), 7.28-7.40 (m, 1H), 7.53 (d, J=9 Hz, 1H), 7.65-7.73 (m, 3H),
7.96 (s, 1H), 8.18 (s, 1H); 8.51 (s, 1H).
##STR00053##
[0235]
4-Bromo-2-[1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]pheno-
xyacetic acid. Prepared from 6-bromo-3-formylchromone,
3-trifluoromethylphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10p8): Rt 4.54 min, m/z 468.7
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.76 (s, 2H), 6.89
(d, J=8.9 Hz, 1H), 7.57-7.66 (m, 3H), 7.68 (d, J=2.4 Hz, 1H),
7.89-7.96 (m, 1H), 8.04 (s, 1H), 8.20 (s, 1H), 8.59 (s, 1H), 9.15
(br s, 1H).
##STR00054##
[0236]
4-Bromo-2-[1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyace-
tic acid. Prepared from 6-bromo-3-formylchromone,
2,4-dichlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 4.35 min, m/z 468.6
[M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.76 (s, 2H), 7.03
(d, J=9.0 Hz, 1H), 7.52 (m, 1H), 7.57-7.69 (m, 3H), 7.89 (m, 1H),
8.19 (s, 1H), 8.69 (s, 1H); .sup.13C NMR (DMSO-d.sub.6): .delta.
55.8, 103.6, 106.2, 115.2, 119.5, 120.6, 120.7, 121.1, 122.4,
125.5, 125.6, 127.1, 128.3, 133.4, 145.1, 160.9, 177.4.
##STR00055##
[0237]
4-Nitro-2-[1-(2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-nitro-3-formylchromone
2-chlorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 2.42 min, m/z 401.8 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.83 (s, 2H), 7.01 (d, J=9.0 Hz,
2H), 7.42-7.48 (m, 2H), 7.56-7.63 (m, 2H), 8.34-8.40 (m, 2H), 8.5
(s, 2H).
##STR00056##
[0238]
4-Nitro-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-nitro-3-formylchromone,
2-bromophenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10p8): Rt 2.33 min, m/z 445.9 [M-H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.85 (s, 2H), 7.04 (d, J=9 Hz,
1H), 7.37-7.81 (m, 4H), 8.32-8.44 (m, 3H), 8.50 (s, 1H).
##STR00057##
[0239]
4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyace-
tic acid. Prepared from 6-bromo-3-formylchromone,
2,6-dichlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.56 min, m/z 468.6
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.72, 6.88 (d, J=8.9
Hz, 1H), 7.37-7.44 (m, 1H), 7.45-7.52 (m, 2H), 7.59 (d, J=8.7 Hz,
1H), 7.70 (m, 1H), 8.14 (s, 1H), 8.26 (s, 1H).
##STR00058##
[0240]
4-Ethyl-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-ethyl-3-formylchromone,
2-bromophenylhydrazine and ethyl bromoacetate according to GP1, GP2
and GP3: LC/MS (an10p8): Rt 2.88 min, m/z 428.8 [M+H].sup.+.
##STR00059##
[0241]
2-[1-(2-Chlorophenyl)-1H-pyrazole-4-carbonyl]-4-isopropylphenoxyace-
tic acid. Prepared from 6-isopropyl-3-formylchromone,
2-chlorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 2.83 min, m/z 398.8 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 1.28 (d, J=7.0 Hz, 6H), 2.93
(septet, J=6.9 Hz, 1H), 4.82 (s, 2H), 7.04 (d, J=8.5 Hz, 1H),
7.40-7.65 (m, 6H), 8.28 (s, 1H), 8.40 (s, 1H).
##STR00060##
[0242]
{4-Bromo-2-[1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carbonyl]phe-
noxyacetic acid. Prepared from 6-bromo-3-formylchromone,
4-trifluoromethoxyphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.24 min, m/z 484.6
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.75 (s, 2H), 6.89
(d, J=8.9 Hz, 1H), 7.34 (d, J=9.0 Hz, 2H), 7.61 (dd, J=8.9, 2.6 Hz,
1H), 7.67 (m, 1H), 7.72-7.80 (m, 2H), 8.17 (s, 1H), 8.51 (s, 1H);
.sup.13C NMR (CDCl.sub.3): .delta. 66.5, 115.0, 115.8, 121.4,
122.5, 125.0, 130.8, 132.0, 133.1, 136.0, 137.6, 143.4, 148.6,
148.7, 154.8, 170.8, 187.4.
##STR00061##
[0243]
4-Bromo-2-[1-(2,4-dibromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacet-
ic acid. Prepared from 6-bromo-3-formylchromone,
2,4-dibromophenylhydrazine according and ethyl bromoacetate to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 3.41 min, m/z 556.4 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 4.75 (s, 2H), 6.92 (d, J=9.0 Hz,
1H), 7.45 (d, J=8.5 Hz, 1H), 7.63 (m, 2H), 7.73 (d, J=2.5 Hz, 1H),
7.92 (d, J=2.1 Hz, 1H), 8.22 (s, 1H), 8.37 (s, 1H).
##STR00062##
[0244]
4-Bromo-2-[1-(4-bromo-2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenox-
yacetic acid. Prepared from 6-bromo-3-formylchromone,
4-bromo-2-chlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.34 min, m/z 512.5
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.78 (s, 2H), 6.95
(d, J=8.6 Hz, 1H), 7.51-7.76 (m, 5H), 8.21 (s, 1H), 8.42 (s,
1H).
##STR00063##
[0245]
4-Bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy-
acetic acid. Prepared from 6-bromo-3-formylchromone,
2,4,6-trichlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.35 min, m/z 502.6
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.91 (s, 2H), 7.05
(d, J=8.9 Hz, 1H), 7.68 (s, 2H), 7.78 (d, J=8.5 Hz, 1H), 7.88 (s,
1H), 8.31 (s, 1H), 8.43 (s, 1H), 9.03 (br s, 1H).
##STR00064##
[0246] 4-Methoxy-2-[1-phenyl-1H-pyrazole-4-carbonyl]phenoxyacetic
acid. Prepared from 6-bromo-3-formylchromone,
2,4-dichlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.46 min, m/z 350.9
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 3.81 (s, 3H), 4.77
(s, 2H), 7.02-7.16 (m, 3H), 7.41 (d, J=7.5 Hz, 1H), 7.50 (t, J=8.1
Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 8.17 (s, 1H), 8.52 (s, 1H).
##STR00065##
[0247]
2-[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]propionic
acid. Prepared from
(5-bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone and
ethyl 2-bromopropionate according to GP2 and GP3: LC/MS (an10p8) Rt
2.51 min, m/z 415 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
1.65 (d, J=6.8 Hz, 3H), 4.93 (q, J=6.8 Hz, 1H), 6.96 (d, J=8.9 Hz,
1H), 7.35-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.62 (dd, J=8.9, 2.5 Hz,
1H), 7.70-7.76 (m, 3H), 8.17 (s, 1H), 8.52 (s, 1H); .sup.13C NMR
(CDCl.sub.3): .delta. 18.8, 75.2, 114.8, 116.7, 120.1, 124.4,
128.3, 130.0, 133.3, 136.2, 139.2, 143.3, 155.0, 173.1, 187.8.
[0248]
2(S)-[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)-phenoxy]-propioni-
c acid. (5-Bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone
(100 mg, 0.29 mmol), (R)-(+)-bromoacetic acid (44 mg, 0.29 mmol)
ethyl 2-bromopropionate and K2CO3 (80 mg, 0.58 mmol) in acetone was
stirred at room temperature for 16 h. The reaction mixture was
concentrated and the residue was partitioned between EtOAc and
dilute HCl (pH.about.1). The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated, and the residue was purified
by flash chromatography (EtOAc:heptane, 1:1) to yield 55 mg (46%)
of the title compound: Chiral HPLC (Column: Ciracel OD (0.46
cm.times.24 cm); Eluent: isocratic, 85% hexane+15% 2-propanol+0.1%
TFA; Flow 0.5 mL/min) Rt 15.7 min, >90% e.e. (Racemic material
eluates with baseline separation of enantiomeres: Rt 15.7 and 16.7
min.) MS and NMR spectra correspond to racemic material.
##STR00066##
[0249]
2-{4-Bromo-2-[1-(2-chlorophenyl)-1-H-pyrazole-4-carbonyl]phenoxy}pr-
opionic acid. Prepared from 6-bromo-3-formylchromone,
2-chlorophenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.56 min, 448.9 m/z
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.65 (d, J=7.0 Hz,
3H), 4.93 (q, J=7.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 7.41-7.47 (m,
2H), 7.55-7.64 (m, 3H), 7.74 (s, 1H), 8.23 (s, 1H), 8.42 (s, 1H);
.sup.13C NMR (CDCl.sub.3): .delta. 18.9, 75.4, 115.0, 117.0, 124.1,
128.1, 128.4, 128.9, 130.7, 131.3, 133.6, 136.4, 136.8, 137.3,
143.3, 155.2, 173.5, 188.0.
##STR00067##
[0250]
2-{4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy-
}propionic acid. Prepared from 6-bromo-3-formylchromone,
2,6-dichlorophenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 min, 482.9 m/z
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.65 (d, J=6.8 Hz,
3H), 4.91 (q, J=6.8 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 7.41-7.53 (m,
3H), 7.62 (dd, J=8.9, 2.5 Hz, 1H), 7.74 (d, J=2.4, 1H), 8.17 (s,
1H), 8.28 (s, 1H); .sup.13C NMR (CDCl.sub.3): .delta. 18.9, 75.1,
114.9, 116.8, 124.2, 129.3, 130.7, 132.0, 133.6, 134.5, 135.6,
136.4, 137.6, 143.6, 155.1, 173.6, 187.8.
##STR00068##
[0251]
{4-Bromo-2-[1-(2-cyano-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid. Prepared from 6-bromo-3-formylchromone,
2-hydrazinobenzonitril (prepared according to van der Mey, et al.
J. Med. Chem. 2003, 2008-2016) and ethyl bromoacetate according to
GP1, GP2 and GP3: .sup.1H NMR (DMSO-d.sub.6): .delta. 4.72 (s, 2H),
7.17 (d, J=8.9 Hz, 1H), 7.36 (t, J=15.1, 7.3 Hz, 1H), 7.8 (m, 4H),
8.29 (d, J=8.3 Hz, 1H), 9.03 (s, 1H), 9.66 (s, 1H), 13.04 (br s,
1H).
##STR00069##
[0252]
{4-Bromo-2-[1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceti-
c acid. Prepared from 6-bromo-3-formylchromone,
2-ethoxyphenylhydrazine and ethyl 2-bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10p8): Rt 2.33 min, m/z 446.7 [M+H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 1.47 (t, J=7.0 Hz, 3H), 4.18 (q,
J=7.0 Hz, 2H), 4.78 (s, 2H), 6.97 (d, J=8.9 Hz, 1H), 7.09 (d, J=8.7
Hz, 2H), 7.36 (td, J=7.9, 1.8 Hz, 1H), 7.64 (dd, J=8.9, 2.5 Hz,
1H), 7.79 (d, J=2.5 Hz, 1H), 7.80 (dd, J=7.9, 1.6 Hz, 1H), 8.22 (s,
1H), 8.65 (s, 1H).
##STR00070##
[0253]
{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenox-
y}acetic acid. Prepared from 6-bromo-3-formylchromone,
4-bromo-2-ethylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.78 min, m/z 506.6
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.16 (td, J=7.8, 2.4
Hz, 3H), 2.58 (qd, J=7.8, 1.8 Hz, 2H), 4.77 (s, 2H), 6.94 (d, J=9.0
Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.56 (s,
1H), 7.65 (d, J=8.7 Hz, 1H), 7.72 (s,1H), 8.15 (s, 1H), 8.19 (s,
1H).
##STR00071##
[0254]
{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}acet-
ic acid. Prepared from 6-bromo-3-formylchromone,
4-bromo-2-ethylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.77 min, m/z 492.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 4.75 (s, 2H), 6.95
(d, J=8.6 Hz, 1H), 7.00-7.09 (m, 3H), 7.15 (t, J=7.5 Hz, 1H),
7.29-7.40 (m, 4H), 7.62-7.68 (m, 2H), 7.90 (d, J=9.0 Hz, 1H), 8.17
(s, 1H), 8.60 (s, 1H).
##STR00072##
[0255]
{4-Bromo-2-[1-(2-methylthiophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid. Prepared from 6-bromo-3-formylchromone,
2-methylthiophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.26 min, m/z 446.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 2.46 (s, 3H), 4.77
(s, 2H), 6.93 (d, J=8.9 Hz, 1H), 7.28-7.32 (m, 1H), 7.39-7.49 (m,
3H), 7.62 (dd, J=9.0, 2.5 Hz, 1H), 7.76 (s, 1H), 8.23 (s, 1H), 8.31
(s, 1H).
##STR00073##
[0256]
{4-Bromo-2-[1-(2-bromo-4-methylphenyl)-1H-pyrazole-4-carbonyl]pheno-
xy}acetic acid. Prepared from 6-bromo-3-formylchromone,
2-bromo-4-methylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.47 min, m/z 492.6
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 2.44 (s, 3H), 4.80
(s, 2H), 6.99 (d, J=8.9 Hz, 1H), 7.27-7.30 (m, 1H), 7.46 (d, J=8.1
Hz, 1H), 7.58 (s, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.80 (s, 1H), 8.20
(s, 1H), 8.33 (s, 1H).
##STR00074##
[0257]
2-{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}propionic acid. Prepared from 6-bromo-3-formylchromone,
4-bromo-2-ethylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.72 min, m/z 522.6
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.16 (t, J=7.7 Hz,
3H), 1.67 (d, J=6.8 Hz, 3H), 2.59 (q, J=7.5 Hz, 2H), 4.95 (q, J=7.0
Hz,1H), 6.96 (d, J=9.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.47 (d,
J=8.7 Hz, 1H), 7.55 (s, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.73 (s, 1H),
8.17 (s, 1H), 8.18 (s, 1H).
##STR00075##
[0258]
2-{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}pr-
opionic acid. Prepared from 6-bromo-3-formylchromone,
2-phenoxyphenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.68 min, m/z 508.7
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.65 (d, J=6.8 Hz,
3H), 4.92 (q, J=7.3 Hz,1H), 6.96-7.18 (m, 5H), 7.26-7.39 (m, 4H),
7.62 (d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 8.17
(s, 1H), 8.61 (s, 1H).
##STR00076##
[0259]
2-{4-Bromo-2-[1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}pro-
pionic acid. Prepared from 6-bromo-3-formylchromone,
2-ethoxyphenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.39 min, m/z 458.7
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.49 (t, J=7.1 Hz,
3H), 1.86 (d, J=7.1 Hz, 3H), 4.19 (m,2H), 4.98 (q, J=6.9 Hz, 1H),
7.02-7.12 (m,3H), 7.37 (t, J=8.2 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H),
7.78 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 8.20 (s, 1H), 8.67 (s,
1H).
##STR00077##
[0260]
2-{4-Bromo-2-[1-(2-methylthio)-1H-pyrazole-4-carbonyl]phenoxy}propi-
onic acid. Prepared from 6-bromo-3-formylchromone,
2-ethoxyphenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.56 min, 460.9 m/z
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.71 (d, J=6.8 Hz,
3H), 2.46 (s, 3H), 4.96 (q, J=7.0 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H),
7.29-7.34 (m, 1H), 7.40-7.50 (m, 3H), 7.64 (dd, J=8.9, 2.5 Hz, 1H),
7.80 (s, 1H), 8.22 (s, 1H), 8.32 (s, 1H).
##STR00078##
[0261]
2-{4-Bromo-2-[1-(2-bromo-4-methylphenyl)-1H-pyrazole-4-carbonyl]phe-
noxy}propionic acid. Prepared from 6-bromo-3-formylchromone,
2-bromo-4-methylphenylhydrazine and ethyl 2-bromopropionate
according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.74 min, 506.8
m/z [M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.72 (d, J=7.0
Hz, 3H), 2.45 (s, 3H), 4.98 (q, J=7.0 Hz, 1H), 7.03 (d, J=8.9 Hz,
1H), 7.28-7.30 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.59 (s, 1H), 7.67
(dd, J=8.9, 2.43 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 8.19 (s, 1H),
8.34 (s, 1H).
##STR00079##
[0262]
2-{4-Bromo-2-[1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy-
}propionic acid. Prepared from 6-bromo-3-formylchromone,
2,4-dichlorophenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.83 min, 482.8 m/z
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.50 (d, J=6.0 Hz,
3H), 4.75 (q, J=4.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 7.40 (dd,
J=8.5, 1.9 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.54-7.57 (m, 2H), 7.61
(s, 1H), 8.16 (s, 1H), 8.32 (s, 1H).
##STR00080##
[0263]
{4-Bromo-2-[1-(2-trifluoromethoxyphenyl)-1H-pyrazole-4-carbonyl]phe-
noxy}acetic acid. Prepared from 6-bromo-3-formylchromone,
2-trifluoromethoxyphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.43 min, m/z 482.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 4.77 (s, 2H), 6.95
(d, J=8.6 Hz, 1H), 7.45-7.50 (m, 3H), 7.65 (dd, J=8.9, 2.5 Hz, 1H),
7.73 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 8.23 (s, 1H), 8.40 (s,
1H).
##STR00081##
[0264]
{2-[1-(2,6-Dichlorophenyl)-1H-pyrazole-4-carbonyl]-4-ethylphenoxy}a-
cetic acid. Prepared from 6-ethyl-3-formylchromone,
2,6-dichlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.25 min, m/z 416.8
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.26 (t, J=7.5 Hz,
3H), 2.69 (q, J=7.7 Hz, 2H), 4.82 (s, 2H), 7.04 (d, J=8.7 Hz, 1H),
7.39-7.44 (m, 1H), 7.46-7.54 (m, 4H), 8.14 (s, 1H), 8.25 (s,
1H).
##STR00082##
[0265]
{4-Bromo-2-[1-(2,4-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid. Prepared from 6-bromo-3-formylchromone,
2,4-dimethylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.41 min, m/z 428.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 2.26 (s, 3H), 2.40
(s, 3H), 4.75 (s, 2H), 6.91 (d, J=8.9 Hz, 1H), 7.11 (d, J=8.1 Hz,
1H), 7.17 (s, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.9, 2.46
Hz, 1H), 7.71 (s, 1H), 8.15 (s, 1H), 8.22 (s, 1H).
##STR00083##
[0266]
2-{4-Bromo-2-[1-(2,4-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy-
}propionic acid. Prepared from 6-bromo-3-formylchromon,
2,4-dimethylphenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.40 min, m/z 442.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.67 (d, J=6.9 Hz,
3H), 2.25 (s, 3H), 2.40 (s, 3H), 4.93 (q, J=6.8 Hz, 1H), 6.97 (d,
J=8.9 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.25 (d, J=8.1
Hz, 1H), 7.62 (dd, J=8.7, 1.52 Hz, 1H), 7.73 (s, 1H), 8.15-8.16 (m,
2H).
##STR00084##
[0267] [2-(1-Benzyl-1H-pyrazole-4-carbonyl)-4-bromophenoxy]acetic
acid. Prepared from 6-bromo-3-formylchromone, benzylhydrazine and
ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8):
Rt 2.14 min, m/z 414.7 [M-H].sup.-; .sup.1H NMR (CDCl.sub.3):
.delta. 4.70 (s, 2H), 5.36 (s, 2H), 6.88 (d, J=8.7 Hz, 1H),
7.28-7.30 (m, 2H), 7.40-7.46 (m, 3H), 7.57 (d, J=8.9 Hz, 1H), 7.63
(s, 1H), 8.01 (s, 1H), 8.04 (s, 1H).
##STR00085##
[0268]
2-[2-(1-Benzyl-1H-pyrazole-4-carbonyl)-4-bromophenoxy]propionic
acid. Prepared from 6-bromo-3-formylchromone, benzylhydrazine and
ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS
(an10n8): Rt 2.16 min, m/z 428.8 [M-H].sup.-; .sup.1H NMR
(CDCl.sub.3): .delta. 1.59 (d, J=6.8 Hz, 3H), 4.88 (q, J=7.1 Hz,
1H), 5.35 (s, 2H), 6.91 (d, J=8.9 Hz, 1H), 7.30-7.42 (m, 5H),
7.53-7.71 (m, 2H), 8.01 (s, 2H).
##STR00086##
[0269]
{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}acetic acid. Prepared from 6-bromo-3-formylchromone,
4-chloro-2-methylphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.49 min, m/z 448.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 2.27 (s, 3H), 4.75
(s, 2H), 6.91 (d, J=8.9 Hz, 1H), 7.31 (s, 2H), 7.36 (s, 1H), 7.63
(d, J=8.7 Hz, 1H), 7.70 (s, 1H), 8.17 (s, 1H), 8.21 (s, 1H).
##STR00087##
[0270]
{4-Bromo-2-[1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid. Prepared from 6-bromo-3-formylchromone,
2,5-dichlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.46 min, m/z 468.6
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 4.78 (s, 2H), 6.92
(d, J=8.9 Hz, 1H), 7.39 (dd, J=8.7, 2.44 Hz, 1H), 7.50 (d, J=8.7
Hz, 1H), 7.61 (dd, J=8.9, 2.53 Hz, 1H), 7.70 (dd, J=8.1, 2.36 Hz,
2H), 8.22 (s, 1H), 8.45 (s, 1H).
##STR00088##
[0271]
{4-Bromo-2-[1-(2-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}acet-
ic acid. Prepared from 6-bromo-3-formylchromone,
2-methylphenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10n8): Rt 2.20 min, m/z 430.7 [M-H].sup.-;
.sup.1H NMR (CDCl.sub.3): .delta. 3.96 (s,3H), 4.79 (s, 2H), 6.96
(d, J=8.9 Hz, 1H), 7.11 (t, J=8.2 Hz, 2H), 7.40 (t.d, J=8.1, 1.5
Hz, 1H), 7.65 (dd, J=8.9, 2.5 Hz, 1H), 7.76 (d, J=2.5 Hz, 2H), 8.18
(s, 1H), 8.60 (s, 1H).
##STR00089##
[0272]
{4-Bromo-2-[1-(3,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid. Prepared from 6-bromo-3-formylchromone,
3,4-chlorophenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10n8): Rt 2.77 min, m/z 468.6 [M-H].sup.-;
.sup.1H NMR (CDCl.sub.3): .delta. 4.78 (s, 2H), 6.90 (d, J=8.7 Hz,
1H), 7.59 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.69 (d,
J=2.43 Hz, 2H), 7.91 (d, J=2.46 Hz, 1H), 8.18 (s, 1H), 8.53 (s,
1H).
##STR00090##
[0273]
2-{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]ph-
enoxy}propionic acid. Prepared from 6-bromo-3-formylchromone,
4-chloro-2-methylphenylhydrazine and ethyl 2-bromopropionate
according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 min, m/z
462.7 [M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.65 (d, J=6.9
Hz, 3H), 2.28 (s, 3H), 4.92 (d, J=6.8 Hz, 1H), 6.95 (d, J=8.9 Hz,
1H), 7.30 (s, 2H), 7.37 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.72 (s,
1H), 8.19 (s, 2H).
##STR00091##
[0274]
2-{4-Bromo-2-[1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy-
}propionic acid. Prepared from 6-bromo-3-formylchromone,
2,5-dichlorophenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.51 min, m/z 482.6
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.70 (d, J=6.8 Hz,
3H), 4.90 (q, J=6.9 Hz, 1H), 6.93 (d, J=9.1 Hz, 1H), 7.40 (dd,
J=8.7, 2.5 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.9, 2.5
Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 8.22 (s,
1H) 8.45 (s, 1H).
##STR00092##
[0275]
2-{4-Bromo-2-[1-(3,4-dichloro-phenyl)-1H-pyrazole-4-carbonyl]phenox-
y}propionic acid. Prepared from 6-bromo-3-formylchromon,
3,4-dichlorophenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.83 min, m/z 482.6
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.63 (d, J=6.8 Hz,
3H), 4.93 (q, J=6.9 Hz, 1H), 6.92 (d, J=9.03 Hz, 1H), 7.55-7.65 (m,
3H), 7.70 (s,1H), 7.93 (d, J=2.25 Hz, 1H), 8.20 (s, 1H), 8.57 (s,
1H).
##STR00093##
[0276]
2-{4-Bromo-2-[1-(2-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}pr-
opionic acid. Prepared from 6-ethyl-3-formylchromone,
2,6-dichlorophenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.23 min, m/z 444.7
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 1.68 (d, J=7.0 Hz,
3H), 3.95 (s, 3H), 4.95 (d, J=7.0 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H),
7.10 (d, J=8.5 Hz, 1H), 7.14 (s, 1H), 7.37-7.43 (m,1H), 7.63 (dd,
J=8.9, 2.6 Hz, 1H), 7.77 (s, 1H), 7.79 (s,1H), 8.19 (s, 1H), 8.62
(s, 1H).
##STR00094##
[0277] [4-Amino-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. A mixture of ethyl
4-nitro-2-(phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate (190 mg,
0.48 mmol) and 10% Pd/C (100 mg) in MeOH (50 mL) was stirred under
an atmosphere of hydrogen of 12 h, then filtered through a pad of
celite and concentrated, and the product was hydrolyzed according
to GP3 to give the title compound.
##STR00095##
[0278]
{4-Bromo-2-[1-(4-bromo-2-chlorophenyl)-1H-pyrazole-4-carbonyl]pheno-
xy}acetic acid. Prepared from 6-bromo-3-formylchromone,
4-bromo-2-chlorophenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.57 min, m/z 526.6
[M-H].sup.-; .sup.1H NMR (DMSO): .delta. 1.31 (d, J=6.8 Hz, 3H),
4.94 (q, J=6.6 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H), 7.53 (d, J=2.5 Hz,
1H), 7.59 (d, J=8.5 Hz, 1H), 7.66 (dd, J=9.0, 2.5 Hz, 1H), 7.76
(dd, J=8.5, 2.3 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 8.22 (s, 1H), 8.77
(s, 1H).
##STR00096##
[0279]
2-{4-Bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}propionic acid. Prepared from 6-bromo-3-formylchromone,
2,4,6-trichlorophenylhydrazine and ethyl 2-bromopropionate
according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.61 min, m/z
516.6 [M-H].sup.+; .sup.1H NMR (DMSO): .delta. 1.33 (d, J=6.8 Hz,
3H), 4.94 (q, J=7.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 7.54 (d, J=2.4
Hz, 1H), 7.66 (dd, J=8.9, 2.5 Hz, 1H), 7.99 (s, 2H), 8.26 (s, 1H),
8.72 (s, 1H).
##STR00097##
[0280]
2-{4-Bromo-2-[1-(2,4-dibromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}-
propionic acid. Prepared from 6-bromo-3-formylchromone,
2,4-dibromophenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.87 min, m/z 572.7
[M+H].sup.+; .sup.1H NMR (DMSO): .delta. 1.32 (d, J=6.8 Hz, 3H),
4.93 (q, J=6.8 Hz,1H), 6.91 (d, J=8.9 Hz, 1H), 7.54 (dd, J=8.3, 2.3
Hz, 2H), 7.66 (dd, J=8.9, 2.5 Hz, 1H), 7.78 (dd, J=8.6, 2.2 Hz,
1H), 8.15 (d, J=2.1 Hz, 1H), 8.21 (s, 1H), 8.72 (s, 1H).
##STR00098##
[0281]
{4-Bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid. Prepared from 6-bromo-3-formylchromone,
2,6-diethylphenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10n8): Rt 2.54 min, m/z 457.0 [M-H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 1.27 (t, J=7.3 Hz, 6H), 2.35 (q,
J=7.3 Hz, 4H), 4.82 (s, 2H), 6.99 (d, J=8.9 Hz, 1H), 7.29 (d, J=7.5
Hz, 2H), 7.48 (m, 1H), 7.67 (m, 1H), 7.79 (s, 1H), 8.11 (s, 1H),
8.27 (s, 1H), 8.87 (br s, 1H).
##STR00099##
[0282]
{4-Bromo-2-[1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}a-
cetic acid. Prepared from 6-bromo-3-formylchromone,
2,6-diethylphenylhydrazine and ethyl bromoacetate according to GP1,
GP2 and GP3: LC/MS (an10n8): Rt 2.27 min, m/z 428.9 [M-H].sup.+;
.sup.1H NMR (CDCl.sub.3): .delta. 2.07 (s, 6H), 4.74 (s, 2H), 6.91
(d, J=8.7 Hz, 1H), 7.19 (d, J=7.3 Hz, 2H), 7.25-7.35 (m, 1H),
7.55-7.66 (m, 1H), 7.71 (s, 1H), 8.06 (s, 1H), 8.23 (s, 1H), 8.91
(br s, 1H).
##STR00100##
[0283]
{4-Bromo-2-[1-(2-ethyl-6-methylphenyl)-1H-pyrazole-4-carbonyl]pheno-
xy}acetic acid. Prepared from 6-bromo-3-formylchromone,
2-ethyl-6-methylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.43 min, m/z 443.0
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.12 (t, J=7.8 Hz,
3H), 2.05 (s, 3H), 2.33 (q, J=7.8 Hz, 2H), 4.76 (s, 2H), 6.94 (d,
J=8.7 Hz, 1H), 7.14-7.25 (m, 2H), 7.31-7.41 (m, 1H), 7.56-66 (m,
1H), 7.72 (s, 1H), 8.06 (s, 1H), 8.22 (s, 1H), 8.93 (br s, 1H).
##STR00101##
[0284]
{4-Bromo-2-[1-(2-isopropylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}ac-
etic acid. Prepared from 6-bromo-3-formylchromone,
2-ethyl-6-methylphenylhydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.76 min, m/z 444.9
[M+H].sup.+; .sup.1H NMR (CDCl3-d): .delta. 1.22 (d, J=6.5 Hz, 6H),
2.89 (septet, J=6.1 Hz, 1H), 4.76 (s, 2H), 6.92 (d, J=8.7 Hz, 1H),
7.30 (s, 2H), 7.49 (s, 2H), 7.62(d, 1H), 7.72 (s, 1H), 8.15 (s,
1H), 8.20 (s, 1H), 8.92 (br s, 1H).
##STR00102##
[0285] [4-Ethoxy-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. Prepared from 6-ethoxy-3-formylchromone, phenylhydrazine and
ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8):
Rt 1.97 min, m/z 367.1 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3):
.delta. 1.43 (t, J=6.8 Hz, 3H), 4.03 (q, J=6.9 Hz, 2H), 4.78 (s,
2H), 7.01-7.13 (m, 2H), 7.15 (s, 1H), 7.36-7.43 (m, 1H), 7.46-7.57
(m, 2H), 7.71-7.75 (m, 2H), 8.16 (s, 1H), 8.50 (s, 1H).
##STR00103##
[0286] [4-Butyl-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. A solution of
ethyl[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate
(472 mg, 1.1 mmol), 1-butylboronic acid (102 mg, 1.0 mmol) and Pd
(dppf)Cl.sub.2 (72 mg, 0.05 mmol) in THF (10 mL) and water (1 mL)
under argon was refluxed for 24 h. The reaction mixture was
extracted with CH.sub.2Cl.sub.2, the organic phase was filtered
through celite and concentrated, and the residue was purified by
flash chromatography (SiO2, EtOAc:heptane, 1:10 to 1:1). The purest
fraction was concentrated (.about.10 mg), and the residue was
hydrolysed according to GP3: LC/MS (an10p8): Rt 2.59 min, m/z 379.1
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 0.88 (t, J=7.5 Hz,
3H), 1.29 (m, 2H), 1.49 (m, 2H), 2.48 (m, 2H), 4.51 (s, 2H), 6.84
(m, 1H), 7.14 (m, 1H), 7.30 (m, 2H), 7.42 (m, 2H), 7.65 (m, 2H),
7.97 (s, 1H), 8.46 (s, 1H).
##STR00104##
[0287]
{4-Bromo-2-[1-(2-chloro-6-methylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}acetic acid. Prepared from 6-bromo-3-formylchromone,
2-chloro-6-methylphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.49 min, m/z 450.9
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 2.16 (s, 3H), 4.80
(s, 2H), 6.98 (d, J=9.1 Hz, 1H), 7.30 (m, 1H), 7.34-7.40 (m, 2H),
7.66 (d, 1H), 7.77 (m, 1H), 8.13 (s, 1H); 8.24 (s, 1H).
##STR00105##
[0288]
2-{4-Bromo-2-[1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy-
}propionic acid. Prepared from 6-bromo-3-formylchromone,
2,6-dimethylphenylhydrazine and ethyl 2-bromopropionate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 min, m/z 440.9
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.68(d, J=6.8 Hz,
3H), 2.11 (s, 6H), 4.94 (q, J=7.0 Hz 1H), 6.97 (d, J=8.9 Hz, 1H),
7.19 (d, J=7.5 Hz 2H), 7.28-7.32 (m, 1H), 7.63 (d, J=8.1 Hz, 1H),
7.75 (m, 1H), 8.05 (s, 1H), 8.22 (s, 1H).
##STR00106##
[0289]
2-{4-Bromo-2-[1-(2,6-diethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}-
propionic acid. Prepared from 6-bromo-3-formylchromone,
2,6-diethylphenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.85 min, m/z 469.0
[M-H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.08-1.21 (m, 6H),
1.69-1.76 (m, 3H), 2.18-2.48 (m, 4H), 2.67 (s,1H), 4.97 (q, J=6.8
Hz 1H), 6.84 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 7.24 (d,
J=7.7 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.77
(s, 1H), 7.86 (s, 1H), 8.06 (s, 1H), 8.22 (s, 1H).
##STR00107##
[0290]
2-{4-Bromo-2-[1-(2-isopropylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}-
propionic acid. Prepared from 6-bromo-3-formylchromone,
2,6-diethylphenylhydrazine and ethyl 2-bromopropionate according to
GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.54 min, m/z 459.0
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 1.19-1.27 (m, 7H),
1.67 (d, J=7.0 Hz, 2H), 4.92 (q, J=6.8 Hz, 1H), 6.96 (d, J=8.9 Hz,
1H), 7.27-7.53 (m, 4H), 7.58-7.67 (m, 1H), 7.73 (s, 1H), 8.17 (s,
1H), 8.20 (s,1H).
##STR00108##
[0291]
{4-Bromo-2-[1-(3,5-dichloropyridin-4-yl)-1H-pyrazole-4-carbonyl]phe-
noxy}acetic acid. Prepared from 6-bromo-3-formylchromone,
2,6-dichloropyridine-4hydrazine and ethyl bromoacetate according to
GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.08 min, m/z 469.8
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.75 (s, 2H), 7.05
(d, J=9.1 Hz, 1H), 7.56 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 8.32 (s,
1H), 8.77 (s, 1H), 8.93 (s, 2H).
##STR00109##
[0292]
{4-Bromo-2-[1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]phen-
oxy}acetic acid. Prepared from 6-bromo-3-formylchromone,
4-trifluoromethylphenylhydrazine and ethyl bromoacetate according
to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.88 min, m/z 468.9
[M-H].sup.-; .sup.1H NMR (CDCl.sub.3): .delta. 4.78 (s, 2H), 6.92
(d, J=8.9 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.71 (s, 1H), 7.79 (d,
J=8.9 Hz, 2H), 7.91 (d, J=8.9 Hz, 2H), 8.23 (s, 1H), 8.65 (s,
1H).
##STR00110##
[0293]
[4-Bromo-2-(1-naphthalen-1-yl-1H-pyrazole-4-carbonyl)phenoxy]acetic
acid. Prepared from 6-bromo-3-formylchromone, 1-naphtylhydrazine
and ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS
(an10p8): Rt 2.649 min, m/z 451.0 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 4.78 (s, 2H), 6.93 (d, J=8.85 Hz, 1H),
7.52-7.68 (m, 6H), 7.73-7.82 (m, 2H), 7.93-8.05 (m, 2H), 8.33 (s,
1H), 8.38 (s, 1H).
[0294] General Synthetic Route IV
##STR00111##
[0295] General Procedure 5 (GP5):
[0296] A mixture of ethyl 2-(2-bromoacetyl)phenoxyacetate (0.1
mmol) and amide (X.dbd.O) or thioamide (X.dbd.S) (2.5 mmol) was
heated neat in the microwave for 3 hours at 140.degree. C. After
cooling, the solid residue was partitioned between EtOAc and
saturated aq. NaHCO.sub.3. The phases were separated and the
organic phase was dried (MgSO.sub.4) and concentrated in vacuo. The
crude solid was purified by flash chromatography to give the
corresponding oxazole or thiazole derivative.
INTERMEDIATE-9
##STR00112##
[0298] (2-Acetyl-4-bromophenoxy)acetic acid ethyl ester Prepared
from 5'-bromo-2'-hydroxyacetophenone (2 g, 9.3 mmol) and ethyl
bromoacetate (1.03 mL, 9.3 mmol) according to GP2 to give the title
compound as a white solid (2.64 g, 8.7 mmol, 94%): LC/MS (an10p8)
Rt 3.3 min, m/z 301 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
1.32 (t, 3H), 2.71 (s, 3H), 4.30 (q, 2H), 4.72 (s, 2H), 6.76 (d,
1H), 7.55 (dd, 1H), 7.88 (s, 1H).
INTERMEDIATE-10
##STR00113##
[0300] [4-Bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester.
To a cooled (0.degree. C.) solution of
(2-acetyl-4-bromophenoxy)acetic acid ethyl ester (2.5 g, 8.3 mmol)
in CHCl.sub.3 (25 mL) was slowly added bromine (425 uL, 8.3 mmol).
After completion the reaction mixture was allowed to stir at room
temperature for 1 hour. The mixture was partitioned between
CH.sub.2Cl.sub.2 and brine. The organic phase was washed with
brine, dried (MgSO.sub.4) and concentrated in vacuo to give the
title compound as a white solid (2.97 g, 7.8 mmol, 94%): .sup.1H
NMR (CDCl.sub.3): .delta. 1.35 (t, 3H), 4.32 (q, 2H), 4.75 (s, 2H),
4.76 (s, 2H), 6.77 (d, 1H), 7.60 (dd, 1H), 7.97 (s, 1H)
##STR00114##
[0301] [4-Bromo-2-(2-phenyloxazol-4-yl)phenoxy]acetic acid. Title
compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic
acid ethyl ester and benzamide according to GP5 and GP3: LC/MS
(an10p8) Rt 2.6 min, m/z 374/376 [M+H].sup.+.
##STR00115##
[0302] {4-Bromo-2-[2-(4-methoxyphenyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
4-methoxybenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.61
min, m/z 404 [M+H].sup.+.
##STR00116##
[0303] {4-Bromo-2-[2-(4-chlorophenyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
4-chlorobenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.90
min, m/z 407.7 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 4.89
(s, 2H), 7.09 (d, 1H), 7.48 (d, 1H), 7.64 (d, 2H), 8.08 (d, 2H),
8.20 (s, 1H), 8.89 (s, 1H), 13.2 (br s, 1H).
##STR00117##
[0304] {4-Bromo-2-[2-(3-methoxyphenyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
3-methoxybenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.68
min, m/z 404 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 3.87
(s, 1H), 4.89 (s, 2H), 7.09 (m, 2H), 7.4-7.7 (m, 4H), 8.22 (s, 1H),
8.89 (s, 1H), 13.3 (br s, 1H).
##STR00118##
[0305] {4-Bromo-2-[2-(4-ethoxyphenyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
4-ethylbenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.80
min, m/z 418/420 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
1.36 (t, 3H), 4.10 (q, 2H), 4.88 (s, 2H), 7.07 (m, 3H), 7.47 (d,
1H), 8.00 (d, 2H), 8.20 (s, 1H), 8.82 (s, 1H), 13.4 (br s, 1H).
##STR00119##
[0306] [2-(2-Benzyloxazol-4-yl)-4-bromophenoxy]acetic acid. Title
compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic
acid ethyl ester and 2-phenylacetamide according to GP5 and GP3:
LC/MS (an10p8) Rt 2.47 min, m/z 388 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 4.22 (s, 2H), 4.84 (s, 2H), 7.04 (d, 1H),
7.25 (m, 5H), 7.43 (d, 1H), 8.06 (s, 1H), 8.69 (s, 1H), 13 (br s,
1H).
##STR00120##
[0307] {4-Bromo-2-[2-(3-methoxybenzyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
2-(3-methoxyphenyl)acetamide according to GP5 and GP3: LC/MS
(an10p8) Rt 2.45 min, m/z 418 [M +H].sup.+.
##STR00121##
[0308]
{4-Bromo-2-[2-(2-chloro-4-fluorobenzyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
2-(2-chloro-4-fluorophenyl)acetamide according to GP5 and GP3:
LC/MS (an10p8) Rt 2.75 min, m/z 440 [M+H].sup.+.
##STR00122##
[0309] {4-Bromo-2-[2-(2,6-dichlorobenzyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
2-(2,6-dichlorophenyl)acetamide according to GP5 and GP3: LC/MS
(an10p8) Rt 2.75 min, m/z 456/458/460 [M+H].sup.+.
##STR00123##
[0310] {4-Bromo-2-[2-(4-methoxybenzyl)oxazol-4-yl]phenoxy}acetic
acid. Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
2-(4-methoxyphenyl)acetamide according to GP5 and GP3: LC/MS
(an10p8) Rt 2.40 min, m/z 418 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 3.72 (s, 3H), 4.14 (s, 1H), 4.85 (s, 1H),
6.92 (m, 2H), 7.02 (d, 1H), 7.2 (d, 1H), 7.23 (d, 1H), 7.44 (d,
1H), 8.05 (s, 1H), 8.67 (s, 1H), 13.2 (br s, 1H).
##STR00124##
[0311] [4-Bromo-2-(2-phenylthiazol-4-yl)phenoxy]acetic acid. Title
compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic
acid ethyl ester and thiobenzamide according to GP5 and GP3: LC/MS
(an10p8) Rt 2.69 min, m/z 390 [M+H].sup.+.
##STR00125##
[0312] {4-Bromo-2-[2-(4-chlorobenzyl)thiazol-4-yl]phenoxy}acetic
acid Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
2-(4-chlorophenyl)thioacetamide according to GP5 and GP3: LC/MS
(an10p8) Rt 2.69 min, m/z 390 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 4.42 (s, 2H), 4.86 (s, 2H), 7.06 (d, 1H),
7.45 (m, 5H), 8.33 (s, 1H), 8.41 (s, 1H), 13.2 (br s, 1H).
[0313] General Synthetic Route V
##STR00126##
[0314] General Procedure 6 (GP6)
[0315] Synthesis of Carbonylthiazoles
[0316] A mixture of the thioamide (1.0 mmol) and
N,N-dimethylformamide dimethylacetal (1.2 mmol) was stirred for 1
hour at room temperature under argon. The volatile materials were
removed under reduced pressure without heating to give the
corresponding N'-thioaroylformamidine which was used without
further purification in the next step.
[0317] To a solution of the ethyl 2-(2-bromoacetyl)phenoxyacetate
(1 mmol) and the N'-thioaroylformamidine (1 mmol) in benzene (2.6
mL) was added an excess of triethylamine (5 mmol). After stirring
overnight at room temperature, solvent was removed in vacuo. The
residue was partitioned between EtOAc and satureated aq.
NaHCO.sub.3. The organic phase was dried (MgSO.sub.4) and
concentrated in vacuo. The crude material was purified by flash
chromatography to give the thioamide.
##STR00127##
[0318] [4-Bromo-2-(2-phenylthiazole-5-carbonyl)phenoxy]acetic acid.
Title compound was prepared from
[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and
thiobenzamide according to GP6 and GP3: LC/MS (an10p8) Rt 2.44 min,
m/z 418 [M+H].sup.+.
[0319] General Synthetic Route VI
##STR00128##
[0320] General Procedure 7 (GP7)
[0321] Synthesis of Oxazole
[0322] A mixture of benzamide (1.0 mmol) and 2-bromoacetophenone
(0.5 mmol) was heated neat in an Emrys Optimizer microwave oven for
3 hours at 140.degree. C. After cooling EtOAc and CH.sub.2Cl.sub.2
were added and the formed precipitate was filtered off. The
filtrate was concentrated in vacuo and purified by flash
chromatography to give the corresponding oxazole.
INTERMEDIATE-11
##STR00129##
[0324] (4-Bromo-2-carbamoylphenoxy)acetic acid ethyl ester.
Prepared from bromosalicylamide and ethyl bromoacetate according
GP2: .sup.1H NMR (CDCl.sub.3): .delta. 1.35 (t, 3H), 4.34 (q, 2H),
4.73 (s, 2H), 5.87 (br s, 1H), 6.76 (d, 1H), 7.56 (d, 1H), 8.33 (br
s, 1H), 8.39 (s, 1H).
##STR00130##
[0325] [4-Bromo-2-(4-phenyl-oxazol-2-yl)-phenoxy]acetic acid. Title
compound was prepared from (4-bromo-2-carbamoylphenoxy)acetic acid
ethyl ester and 2-bromoacetophenone according to GP7: LC/MS
(an10p8) Rt 2.32 min, m/z 374/376 [M+H].sup.+.
[0326] General Synthetic Route VII
##STR00131##
[0327] General Procedure 8 (GP8):
[0328] Synthesis of Hydroximic Acid Chloride
[0329] To a solution of the aldoxime (1.0 mmol) in CH.sub.2Cl.sub.2
(1.7 mL) was added N-chlorosuccinimide (1.0 mmol) in one portion.
The reaction mixture was stirred for 3 hours at room temperature
under an argon atmosphere. Water was added. The phases were
separated. The organic phase was dried (MgSO.sub.4) and
concentrated in vacuo to give the corresponding hydroximic acid
chloride derivative which was used without further
purification.
[0330] General Procedure 9 (GP9):
[0331] Synthesis of Isoxazole
[0332] To a solution of the hydroximic acid chloride (1.0 mmol) and
(4-bromo-2-propynoyl-phenoxy)acetic acid ethyl ester (1.0 mmol) in
dry CH.sub.2Cl.sub.2 (3.7 mL) was slowly added a solution of
Et.sub.3N (1.0 mmol) in dry CH.sub.2Cl.sub.2 (0.6 mL) over a period
of 4 hours (use of syringe-pump). After completion of the addition,
the reaction mixture was washed with water, brine, dried
(MgSO.sub.4) and concentrated in vacuo. The crude oil was purified
by flash chromatography to give the corresponding isoxazol
derivative.
SYNTHESIS OF INTERMEDIATE-12
##STR00132##
[0334] (4-Bromo-2-formylphenoxy)acetic acid ethyl ester. Prepared
from 5-bromo-2-hydroxybenzaldehyde according GP2: LC/MS (an10p8) Rt
3.45min, m/z 287 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.
1.29 (t, 3H), 4.25 (q, 2H), 4.74 (s, 2H), 6.79 (d, 1H), 7.60 (d,
1H), 7.94 (s, 1H), 10.46 (s, 1H)
[0335]
[4-Bromo-2-(1-hydroxy-3-trimethylsilanylprop-2-ynyl)phenoxy]acetic
acid ethyl ester. To a cooled (-78.degree. C.) solution of
(trimethylsilyl)acetylene (3.93 g, 40.0 mmol) in dry THF (40 mL)
was slowly added a 2.5 M solution of butyllithium in hexanes (14.54
mL, 36.36 mmol). After stirring for 30 minutes at -78.degree. C.,
the mixture was transferred to a cooled (-78.degree. C.) solution
of (4-bromo-2-formylphenoxy)acetic acid ethyl ester (10.44 g, 36.36
mmol) in dry THF (120 mL). Upon completion, the reaction mixture
was stirred at -78.degree. C. for 45 minutes. Saturated aq.
NH.sub.4Cl (40 mL) was slowly added to the reaction mixture
followed by Et.sub.2O (40 mL). The quenched reaction mixture was
allowed to warm up to room temperature. The phases were separated
and the aqueous phase was extracted with Et.sub.2O (2.times.). The
combined organic phases were washed with brine, dried (MgSO.sub.4)
and concentrated in vacuo. The crude oil was purified by column
chromatography (SiO.sub.2), then was stirred for 90 min with
polystyrene-supported trisamine (PS-Trisamine, 4.17 mmol/g, 8 g) in
CH.sub.2Cl.sub.2 (160 mL). The resin was filtered off and the
filtrate was concentrated in vacuo to give the title compound as
pale yellow oil (7.6 g, 19.7 mmol, 54%). LC/MS (an10p8) Rt 4.30
min, m/z 408 [M+Na].sup.+; .sup.1H NMR (CDCl.sub.3): .delta. 0.24
(s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79 (s, 1H),
6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H).
[0336] [4-Bromo-2-(3-trimethylsilanylpropynoyl)phenoxy]acetic acid
ethyl ester. To a solution of
[4-bromo-2-(1-hydroxy-3-trimethylsilanylprop-2-ynyl)phenoxy]acetic
acid ethyl ester (0.95 g, 2.46 mmol) in CH.sub.2Cl.sub.2 (10 mL)
was added activated MnO.sub.2 in 2 portions (1.5 g+1 g), and the
reaction was stirred for 90 min. The solid was filtered off through
a celite pad and the filtrate was concentrated in vacuo to give the
title compound as yellow oil (0.83 g, 2.16 mmol, 87%). LC/MS
(an10p8) Rt 4.70 min, m/z 383 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3): .delta. 0.30 (s, 9H), 1.30 (t, 3H), 4.27 (q, 2H),
4.72 (s, 2H), 6.81 (d, 1H), 7.58 (dd, 1H), 8.10 (s, 1H).
[0337] (4-Bromo-2-propynoylphenoxy)acetic acid ethyl ester. To a
solution of [4-bromo-2-(3-trimethylsilanylpropynoyl)phenoxy]acetic
acid ethyl ester (0.83 g, 2.16 mmol) in methanol (20 mL) was added
a 0.1M aqueous solution of Na.sub.2B.sub.4O.sub.7 (10 mL). After
stirring for 2-3 minutes at room temperature, Et.sub.2O and 1N aq.
HCl were added. The phases were separated, and the organic phase
was washed with brine, dried (MgSO.sub.4) and concentrated in vacuo
to give the title compound as yellow oil which crystallized upon
standing (0.65 g, 2.09 mmol, 96%). LC/MS (an10p8) Rt 3.58 min, m/z
311 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3): .delta.1.31 (t, 3H),
3.45 (s, 1H), 4.27 (q, 2H), 4.74 (s, 2H), 6.83 (d, 1H), 7.61 (dd,
1H), 8.14 (d, 1H).
##STR00133##
[0338] [4-Bromo-2-(3-phenylisoxazole-5-carbonyl)phenoxy]acetic acid
Title compound was prepared from benzalddoxime and
(4-bromo-2-propynoylphenoxy)acetic acid ethyl ester according to
GP8 and GP9: LC/MS (an10n8) Rt 3.07 min, m/z 400 [M-H].sup.-;
.sup.1H NMR (DMSO): .delta. 4.77 (s, 2H), 7.13 (d, 1H), 7.53 (m,
3H), 7.73-7.92 (m, 5H).
##STR00134##
[0339]
{4-Bromo-2-[3-(2,6-dichloro-phenyl)isoxazole-5-carbonyl]phenoxy}ace-
tic acid. Title compound was prepared from
2,6-dichlorobenzalddoxime and (4-bromo-2-propynoylphenoxy)acetic
acid ethyl ester according to GP8 and GP9: LC/MS (an10n8) Rt 2.74
min, m/z 471.9 [M+H].sup.+.
[0340] General Synthetic Route VIII
##STR00135##
[0341] General Procedure 10 (GP10)
[0342] Synthesis of Amidoximes
[0343] Sodium (1.25 mmol) was added to dry methanol (1 ml) to give
solution A. Hydroxylamine hydrochloride (1.2 mmol) was dissolved in
dry methanol (1 mL) to give solution B. Solution A and B were
mixed, cooled in an ice-bath and filtered. To the filtrate was then
added the nitrile (1 mmol) and the reaction mixture was stirred
over night at room temperature. The solvent was removed in vacuo to
give the corresponding amidoxime. The compound was purified over
silica gel chromatography (EtOAc/Heptane: 1/2) or used without
further purification.
[0344] General Procedure 11 (GP11)
[0345] Synthesis of Oxadiazoles
[0346] To a solution of sodium (3.3 mmol) in dry ethanol (10 mL)
were successively added the amidoxime (1.15 mmol), molecular sieves
(1 g) and methyl benzoate (1 mmol). After stirring for 12 h under
reflux, the reaction mixture was cooled and filtered through a
celite pad. The celite pad was washed with methanol and
CH.sub.2Cl.sub.2. The solvent was removed in vacuo and the residue
was stirred with water. The precipitate was filtered off and dried
to give the corresponding oxadiazole. The compound was purified
over silica gel chromatography (EtOAc:Heptane, 1:2) or used without
further purification in.
##STR00136##
[0347] [4-Bromo-2-(3-phenyl-[1,2,4]oxadiazol-5-yl)phenoxy]acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and benzonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8): Rt 2.41 min, m/z 373.4 [M-H].sup.-; .sup.1H
NMR (DMSO-d.sub.6): .delta. 4.97 (s, 2H), 7.2 (d, 1H), 7.62 (s,
3H), 7.82 (d, 2H), 8.10 (d, 1H), 8.2 (s, 1H).
##STR00137##
[0348]
{4-Bromo-2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceti-
c acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 4-fluorobenzonitrile according to GP10, GP11,
GP2 and GP3: LC/MS (an10n8) Rt 2.49, m/z 391.4 [M-H].sup.-.
##STR00138##
[0349]
{4-Bromo-2-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acet-
ic acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 4-methoxybenzonitrile according to GP10,
GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.44 min, m/z 403.4
[M-H].sup.-.
##STR00139##
[0350]
{4-Bromo-2-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 4-chlorobenzonitrile according to GP10, GP11,
GP2 and GP3: LC/MS (an10n8) Rt 2.68 min, m/z 407.4 [M-H].sup.-.
##STR00140##
[0351]
{4-Bromo-2-[3-(4-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-5-yl]phen-
oxy}acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
4-trifluoromethoxybenzonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.09 min, m/z 457.5 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 4.96 (s, 2H), 7.21 (d, 1H), 7.59 (d, 2H),
7.82 (d, 1H), 8.22 (d, 3H).
##STR00141##
[0352]
{4-Bromo-2-[3-(3-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceti-
c acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 3-methoxybenzonitrile according to GP10,
GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.47 min, m/z 403.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 3.86 (s, 3H), 4.96
(s, 2H), 7.20 (d, 2H), 7.5 (t, 1H), 7.6 (s, 1H), 7.67 (d,1H), 7.8
(d, 1H), 8.2 (s, 1H).
##STR00142##
[0353]
{4-Bromo-2-[3-(3-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 3-chlorobenzonitrile according to GP10, GP11,
GP2 and GP3: LC/MS (an10n8) Rt 2.69 min, m/z 407.4 [M-H].sup.-;
.sup.1H NMR (DMSO): .delta. 4.97 (s, 2H), 7.2 (d, 1H), 7.6 (m, 2H),
7.7 (d, 1H), 7.8 (d 2H), 8.2, (s, 1H).
##STR00143##
[0354]
{4-Bromo-2-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]phen-
oxy}-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
4-trifluoromethylbenzonitrile according to GP10, GP11, GP2 and GP3:
LC/MS (an10n8) Rt 2.83 min, m/z 441.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 4.97 (s, 2H), 7.2 (d, 1H), 7.8 (dd, 1H),
7.9 (d, 2H), 8.2 (d, 1H), 8.3 (d, 2H).
##STR00144##
[0355]
{4-Bromo-2-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceti-
c acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 2-methoxybenzonitrile according to GP10,
GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.31 min, m/z 403.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 2.5 (s, 3H), 4.94
(s, 2H), 7.2 (m, 3H), 7.5 (t, 1H), 7.7 (d, 1H), 7.9 (d, 1H), 8.1
(s, 1H).
##STR00145##
[0356]
{4-Bromo-2-[3-(2-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and 2-chlorobenzonitrile according to GP10, GP11,
GP2 and GP3: LC/MS (an10n8) Rt 2.50 min, m/z 407.4 [M-H].sup.-;
.sup.1H NMR (DMSO-d.sub.6): .delta. 4.94 (s, 2H), 7.2 (d, 1H),
7.5-7.7 (m, 3H), 7.8 (dd, 1H), 8.0 (d, 1H), 8.1 (s,1H).
##STR00146##
[0357]
{2-[3-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-4-bro-
mo-phenoxy}-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
3,5-bistrifluoromethoxybenzonitrile according to GP10, GP11, GP2
and GP3: LC/MS (an10n8) Rt 3,332 min, m/z 509.5 [M-H].sup.-;
.sup.1H NMR (DMSO-d.sub.6): .delta.4.96 (s, 2H), 7.2 (d, 1H), 7.8
(d, 1H), 8.2 (s, 1H), 8.4 (s,1H), 8.5 (s, 1H), 8.6 (s, 1H).
##STR00147##
[0358]
{4-Bromo-2-[3-(2,6-dichlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}ac-
etic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
2,6-Dicholoro-benzonitrile according to GP10, GP11, GP2 and GP3:
LC/MS (an10n8) Rt 2.59 min, m/z 441.4 [M-H].sup.-.
##STR00148##
[0359]
{4-Bromo-2-[3-(4-phenoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ac-
etic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
4-phenoxybenzonitrile according to GP10, GP11, GP2 and GP3: LC/MS
(an10n8) Rt 3.29 min, m/z 465.5 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 4.95 (s,2H), 7.2 (m, 6H), 7.4 (t, 2H), 7.8
(d, 1H), 8.0 (d, 2H), 8.1 (s, 1H).
##STR00149##
[0360]
{4-Bromo-2-[3-(3-trifluoromethylphenyl)-[1,2,4]oxadiazol-5-yl]pheno-
xy}-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
3-trifluoromethylbenzonitrile according to GP10, GP11, GP2 and GP3:
LC/MS (an10n8) Rt 2.96 min, m/z 441.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 4.97 (s,2H), 7.2 (d, 1H), 7.8 (m, 2H), 8.0
(d, 1H), 8.2 (s, 1H), 8.3 (s, 1H), 8.4 (d, 1H).
##STR00150##
[0361]
{4-Bromo-2-[3-(4-trifluoromethoxy-benzyl)-[1,2,4]oxadiazol-5-yl]-ph-
enoxy}-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(4-trifluoromethoxyphenyl)acetonitrile according to GP10, GP11, GP2
and GP3: LC/MS (an10n8) Rt 2.76 min, m/z 4715 [M-H].sup.-; .sup.1H
NMR (DMSO-d.sub.6): .delta. 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H),
7.3 (d, 2H), 7.5 (d, 2H), 7.7 (d, 1H), 8.0 (s, 1H).
##STR00151##
[0362]
{4-Bromo-2-[3-(4-chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ace-
tic acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and (4-chlorophenyl)acetonitrile according to
GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.54 min, m/z 421.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.2 (s, 2H), 4.9
(s, 2H), 7.1 (d, 1H), 7.4 (s, 4H), 7.8 (d, 1H), 8.0 (s, 1H).
##STR00152##
[0363] [2-(3-Benzyl-[1,2,4]oxadiazol-5-yl)-4-bromo-phenoxy]-acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and phenylacetonitrile according to GP10, GP11,
GP2 and GP3: LC/MS (an10n8) Rt 2.26 min, m/z 387.4 [M-H].sup.-;
.sup.1H NMR (DMSO-d.sub.6): .delta. 4.2 (s, 2H), 4.9 (s, 2H), 7.1
(d, 1H), 7.3 (m, 5H), 7.7 (d, 1H), 8.0 (s, 1H).
##STR00153##
[0364]
{4-Bromo-2-[3-(4-fluoro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ace-
tic acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and (4-fluorophenyl)acetonitrile according to
GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.38 min, m/z 405.4
[M-H].sup.-.
##STR00154##
[0365]
{4-Bromo-2-[3-(3,5-difluoro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-
-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(3,5-difluorophenyl)acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.44 min, m/z 423.4 [M-H].sup.-.
##STR00155##
[0366]
{4-Bromo-2-[3-(4-methoxy-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ac-
etic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(4-methoxyphenyl)acetonitrile according to GP10, GP11, GP2 and GP3:
LC/MS (an10n8) Rt 2.25 min, m/z 417.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 4.1 (s, 2H), 4.9 (s, 2H), 6.9 (d, 2H), 7.1
(d, 1H), 7.2 (d, 2H), 7.7 (d, 1H), 8.0 (s, 1H).
##STR00156##
[0367]
{4-Bromo-2-[3-(2-methoxy-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ac-
etic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(2-Methoxy-phenyl)-acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.25 min, m/z 417.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 3.7 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 6.9
(t, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (m, 2H), 7.7 (d, 1H), 8.0
(s, 1H).
##STR00157##
[0368]
{4-Bromo-2-[3-(2-chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-ace-
tic acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and (2-chlorophenyl)acetonitrile according to
GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.48 min, m/z 421.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.2 (s, 2H), 4.9
(s, 2H), 7.1 (d, 1H), 7.3 (m, 2H), 7.4 (m, 2H), 7.7 (dd, 1H), 8.0
(d, 1H).
##STR00158##
[0369]
{4-Bromo-2-[3-(2,6-dichloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-
-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(2,6-dichlorophenyl)acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.58 min, m/z 455/457/459 [M-H].sup.-;
.sup.1H NMR (DMSO-d.sub.6): .delta. 4.4 (s, 2H), 4.9 (s, 2H), 7.1
(d, 1H), 7.4 (t, 1H), 7.5 (d, 2H), 8.7-7.8 (dd, 1H), 8.0 (d,
1H).
##STR00159##
[0370]
{4-Bromo-2-[3-(2,4-dichloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-
-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(2,4-dichlorophenyl)acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2,78 min, m/z 455/457/459 [M-H].sup.-.
##STR00160##
[0371]
{4-Bromo-2-[3-(3,4-dichlorobenzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}a-
cetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(3,4-dichlorophenyl)acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.81 min, m/z 455/457/459 [M-H].sup.-;
.sup.1H NMR (DMSO-d.sub.6): .delta. 4.3 (s, 2H), 4.8 (s, 2H), 7.1
(d, 1H), 7.3 (dd, 1H), 7.6 (d, 1H), 7.6 (d, 1H), 7.7 (dd, 1H), 8.0
(d, 1H).
##STR00161##
[0372]
{4-Bromo-2-[3-(3,4-dimethoxybenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}--
acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(3,4-bismethoxyphenyl)acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.20 min, m/z 447.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 3.72 (s, 3H), 3.74 (s, 3H), 4.1 (s, 2H),
4.9 (s, 2H), 6.8 (m, 2H), 6.9 (s, 1H), 7.1 (d, 1H), 7.7 (dd, 1H),
8.0 (d, 1H).
##STR00162##
[0373]
{4-Bromo-2-[3-(3-methoxybenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceti-
c acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and (3-methoxyphenyl)acetonitrile according to
GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.38 min, m/z 417.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.1 (s, 2H), 4.9
(s, 2H), 6.8 (d, 1H), 6.9 (m, 2H), 7.1 (d, 1H), 7.2 (t, 1H), 7:8
(m, 1H), 8.0 (d, 1H).
##STR00163##
[0374]
{4-Bromo-2-[3-(4-methylbenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and (4-methylphenyl)acetonitrile according to
GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.72 min, m/z 401.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 3.3 (s, 3H), 4.1
(s, 2H), 4.9 (s, 2H), 7.1 (m, 3H), 7.2 (d, 2H), 7.7 (dd, 1H), 8.0
(d, 1H).
##STR00164##
[0375]
{4-Bromo-2-[3-(2-trifluoromethylbenzyl)-[1,2,4]oxadiazol-5-yl]pheno-
xy}-acetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(2-trifluoromethylphenyl)acetonitrile according to GP10, GP11, GP2
and GP3: LC/MS (an10n8) Rt 2.77 min, m/z 455.5 [M-H].sup.-; .sup.1H
NMR (DMSO-d.sub.6): .delta. 4.3 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H),
7.5-7.6 (m, 2H), 7:6-7.7 (t, 1H), 7.7-7.8 (m, 2H), 8.0 (d, 1H).
##STR00165##
[0376]
{4-Bromo-2-[3-(3,5-dimethoxybenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}a-
cetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
(3,5-bismethoxyphenyl)acetonitrile according to GP10, GP11, GP2 and
GP3: LC/MS (an10n8) Rt 2.61 min, m/z 447.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 3.7 (s, 6H), 4.1 (s, 2H), 4.9 (s, 2H), 6.4
(d, 1H), 6.5 (d, 2H), 7.1 (d, 1H), 7.8 (dd, 1H), 8.0 (d, 1H).
##STR00166##
[0377]
{4-Bromo-2-[3-(2,4-dichlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}ac-
etic acid. Title compound was prepared from
5-bromo-2-hydroxy-benzoic acid methyl ester and
2,4-dichlorobenzonitrile according to GP10, GP11, GP2 and GP3:
LC/MS (an10n8) Rt 2.93 m/z 441/443/445 [M-H].sup.-; .sup.1H NMR
(DMSO): .delta. 4.7 (s, 1H), 6.95-6.98 (d, 1H), 7.42-7.44 (d, 1H),
7.58-7.60 (d, 1H), 7.67 (s, 1H), 7.82-7.85 (d, 1H), 7.94-7.95 (s,
1H).
##STR00167##
[0378]
{4-Bromo-2-[3-(3-chlorobenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}acetic
acid. Title compound was prepared from 5-bromo-2-hydroxy-benzoic
acid methyl ester and 3-chlorophenylacetonitrile according to GP10,
GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.79 m/z 421.4 [M-H].sup.-;
.sup.1H NMR (DMSO): .delta. 4.21 (s, 2H), 4.92 (s, 2H),
7.15-7.18(d, 1H), 7.32-7.39(m, 3H), 7.45 (s, 1H), 7.76-7.80 (dd,
1H), 8.03-8.04 (d, 1H).
##STR00168##
[0379]
{2-[3-(4-Acetylaminobenzyl)-[1,2,4]oxadiazol-5-yl]-4-bromophenoxy}a-
cetic acid. Title compound was prepared from
5-bromo-2-hydroxybenzoic acid methyl ester and
4-acetamidophenylacetonitrile according to GP10, GP11, GP2 and GP3:
LC/MS (an10n8) Rt 2.15 m/z 444.4 [M-H].sup.-; .sup.1H NMR (DMSO):
.delta. 2.02 (s, 3H), 4.10 (s, 2H), 4.92 (s, 2H), 7.14-7.17(d, 1H),
7.25-7.27(d, 2H), 7.52-7.54 (d, 2H), 7.76-7.78 (d, 1H), 8.03 (s,
1H).
##STR00169##
[0380]
{4-Bromo-2-[3-(1-phenylcyclopropyl)-[1,2,4]oxadiazol-5-yl]phenoxy}a-
cetic acid. Title compound was prepared from
5-bromo-2-hydroxy-benzoic acid methyl ester and
1-phenyl-1-cyclopropanecarbonitrile according to GP10, GP11, GP2
and GP3: LC/MS (an10n8) Rt.2.756 m/z 413.4 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.92 (m, 2H), 1.11 (m, 2H), 4.38 (s, 2H),
6.63-6.66 (d, 1H), 6.79-6.88 (m, 3H), 6.93-6.95 (m, 2H), 7.25-7.29
(dd, 1H), 7.50-7.51 (d, 1H).
##STR00170##
[0381] [4-Bromo-2-(3-pyridin-[1,2,4]oxadiazol-5-yl)phenoxy]acetic
acid. Title compound was prepared from 5-bromo-2-hydroxybenzoic
acid methyl ester and Pyridine-2-carbonitrile according to GP10,
GP11, GP2 and GP3: LC/MS (an10n8) Rt 1.89 min, m/z 374.4
[M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.9 (s, 2H), 7.2
(d, 1H), 7.6 (m, 1H), 7.8 (d, 1H), 8.0 (t, 1H), 8.2 (m, 2H), 8.8
(d, 1H).
[0382] General Synthetic Route IX
##STR00171##
##STR00172##
[0383]
{4-Bromo-2-[5-(4'-methoxybiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]pheno-
xy}acetic acid. Title compound was prepared from
2-hydroxy-5-bromo-benzonitrile and 4'-methoxy-biphenyl-4-carboxylic
acid methyl ester according to GP10, GP11, GP2 and GP3: LC/MS
(an10n8) Rt 2.96 min, m/z 479.5 [M-H].sup.-.
##STR00173##
[0384]
{4-Bromo-2-[5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-yl]phenoxy}acetic
acid. Title compound was prepared from
2-hydroxy-5-bromo-benzonitrile and 4-chlorobenzoic acid methyl
ester according to GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.61
min, m/z 407.4 [M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.3
(s, 2H), 6.9 (d, 1H), 7.6 (dd, 1H), 7.7 (d, 2H), 8.0 (d, 1H), 8.2
(d, 2H).
##STR00174##
[0385]
{4-Bromo-2-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]phenoxy}acetic
acid. Title compound was prepared from
2-hydroxy-5-bromobenzonitrile and 3-chlorobenzoic acid methyl ester
according to GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.61 min,
m/z 407.4 [M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.4 (s,
2H), 6.9 (d, 1H), 7.6 (m, 2H), 7.8 (d, 1H), 8.0 (s, 1H), 8.2 (m,
2H).
##STR00175##
[0386]
{4-Bromo-2-[5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-yl]phenoxy}acetic
acid. Title compound was prepared from
2-hydroxy-5-bromobenzonitrile and 2-chlorobenzoic acid methyl ester
according to GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.45 min,
m/z 407.4 [M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.3 (s,
2H), 6.9 (d, 1H) 7.6-7.7 (m, 4H), 8.0 (s, 1H), 8.2 (d, 1H).
##STR00176##
[0387] [4-Bromo-2-(5-phenyl-[1,2,4]oxadiazol-3-yl)phenoxy]acetic
acid. Title compound was prepared from
2-hydroxy-5-bromobenzonitrile and benzoic acid methyl ester
according to GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.33 min,
m/z 373.4 [M-H].sup.-; .sup.1H NMR (DMSO-d.sub.6): .delta. 4.8 (s,
2H), 7.1 (d, 1H), 7.6-7.7 (m, 4H), 8.0 (d, 1H), 8.2 (d, 2H).
[0388] General Synthetic Route X
##STR00177##
INTERMEDIATE-13
##STR00178##
[0390] 4-Bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic
acid ethyl ester. 4-Bromo-2-formylphenoxyacetic acid ethyl ester
(1.44 g, 5 mmol) was dissolved in dichloromethane (50 mL) and
glycine ethyl ester hydrochloride (1.39 g, 10 mmol) as well as
Et.sub.3N (1.4 mL, 10 mmol) was added. The mixture was stirred at
room temperature for 4 h. Water and dichloromethane was added and
the organic phase was passed through a phase separation filter and
then evaporated to give
{4-bromo-2-[(E)-ethoxycarbonylmethylimino-methyl]phenoxy}acetic
acid ethyl ester, which was redissolved in dichloromethane (50 mL)
and treated with NaBH(OAc).sub.3 (2.11 g, 10 mmol) and AcOH (1 mL),
and then stirred at room temperature for 5 h. Saturated
Na.sub.2CO.sub.3, water and dichloromethane was added, and the
organic phase was passed through a phase separation filter and
evaporated to give the title compound (1.56 g, 84% overall
yield).
[0391] General Procedure 12 (GP12)
[0392] Reaction with Isocyanates Followed by
Ringclosure/Hydrolysis
[0393] The aldehyde (0.6 mmol) was dissolved in dichloromethane (6
mL), and the isocyanate (1.2 mmol) and Et.sub.3N (176 .mu.L, 1.26
mmol) was added. The mixture was stirred at room temperature
overnight. Then glycine (150 mg, 2 mmol) was added (as scavenger
for excess isocyanate) and the mixture was stirred for additional 2
h. Finally water and dichloromethane was added and the organic
phase was passed through a phase separation filter and then
evaporated to give the urea, which was dissolved in acetic acid
(3.5 mL) and placed in a sealed glass vial. Then 4 M HCl (3.5 mL)
was added and the mixture heated by microwaves to 100.degree. C.
for 900 s. After cooling to room temperature a white precipitate
was formed, and the hydantoin was obtained after filtration and
washing with water. In cases where the product did not precipitate
after the hydrolysis, dichloromethane and water was added to the
mixture, and the organic phase was passed through a phase
separation filter. Evaporation of the organic phase gave the
product, which in some cases was further purified on a 1 g SAX
Acetate SPE column (equilibrated with 100% MeOH and then eluted
with 10% AcOH in MeOH).
##STR00179##
[0394]
4-Bromo-2-[3-(4-chlorobenzyl)-2,4-dioxoimidazolidin-1-ylmethyl]phen-
oxyacetic acid. Prepared from
4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid
ethyl ester (235 mg, 0.63 mmol) and 4-chlorobenzylisocyanate (166
.mu.L, 1.26 mmol) according to GP12 (yield: 183.4 mg, 62%): LC/MS
(an10p8): Rt 2.3 min, m/z 465 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 4.05 (s, 2H), 4.48 (s, 2H), 4.55 (s, 2H),
4.73 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 7.25-7.45 (m, 6H), 13.11 (br.
s, 1H).
##STR00180##
[0395]
4-Bromo-2-(2,4-dioxo-3-phenethylimidazolidin-1-ylmethyl)phenoxyacet-
ic acid. Prepared from
4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid
ethyl ester and phenethylisocyanate according to GP12: LC/MS
(an10p8): Rt 2.2 min, m/z 445 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6): .delta. 2.84 (t, J=7.2 Hz, 2H), 3.59 (t, J=7.2 Hz,
2H), 3.94 (s, 2H), 4.45 (s, 2H), 4.76 (s, 2H), 6.93 (d, J=8.6 Hz,
1H), 7.17-7.46 (m, 7H), 12.45 (br. s, 1H).
[0396] General Synthetic Route XI
##STR00181##
[0397] General Procedure 13 (GP13)
[0398] N-Alkylation
[0399] The 2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic
acid ethyl ester (0.85 mmol), Cs.sub.2CO.sub.3 (326 mg, 1.0 mmol),
and acetonitrile (10 mL) was mixed in a sealed glass vial. Then the
alkylating agent (1.0 mmol) was added and the mixture heated by
microwaves to 120.degree. C. for 600 s. Water was added and the
mixture was extracted with dichloromethane. The organic phase was
passed through a phase separation filter and then evaporated. The
product was used directly in the next step or purified by column
chromatography (SiO.sub.2).
[0400] General Procedure 14 (GP14)
[0401] Hydrogenation
[0402] The 5-benzylidenylthiazolidine-2,4-dione (.about.0.8 mmol),
ammonium formate (1.0 g, 16 mmol), Pt/C (5 wt %, 500 mg, 0.13
mmol), and acetic acid (12 mL) was mixed in a sealed glass vial and
heated by microwaves to 135.degree. C. for 1800 s. Then methanol
(15 mL) was added and the mixture was filtered through a 20 .mu.m
PE filter and then through a 1 g SAX Acetate SPE column, which was
washed with additional methanol (10 mL). After evaporation of the
methanol, dichloromethane and water was added, and the organic
phase was passed through a phase separation filter and concentrated
to give the product, which was used directly or purified by column
chromatography on SiO.sub.2.
[0403] General Procedure 15 (GP15)
[0404] Alkylation of 5-Position of thiazolidine-2,4-diones
[0405] 3-Alkyl-5-arylmethylthiazolidine-2,4-dione (0.15 mmol),
methyl iodide (28 .mu.L, 0.45 mmol), Cs.sub.2CO.sub.3 (147 mg, 0.45
mmol), and acetonitrile (10 mL) was mixed in a sealed glass vial
and heated by microwaves to 120.degree. C. for 3600 s. Water and
dichloromethane was added and the organic phase was passed through
a phase separation filter and then evaporated to give the product,
which was used directly for the hydrolysis.
[0406] General Procedure 16 (GP16)
[0407] Acidic Ester Hydrolysis
[0408] The ethyl phenoxyacetate (0.02-0.2 mmol) was dissolved in
acetic acid (5 mL), 4M HCl (5 mL) was added and the mixture was
heated by microwaves to 100.degree. C. for 900 s. After cooling to
room temperature a white precipitate was formed, which was filtered
of, washed with water and dried to give the product. In cases where
the product did not precipitate after the hydrolysis,
dichloromethane was added, the organic phase was washed with water
and concentrated, and the residue was purified on a 1 g SAX Acetate
SPE column (equilibrated with 100% MeOH and then eluted with 10%
AcOH in MeOH) to give the product.
INTERMEDIATE-14
##STR00182##
[0410] 4-Bromo-2-[2,4-dioxothiazolidinylidenemethyl]phenoxyacetic
acid ethyl ester. 4-Bromo-2-formylphenoxyacetic acid ethyl ester
(2.47 g, 8.7 mmol), 2,4-thiazolidinedione (1.13 g (90%), 8.7 mmol),
and ammonium acetate (671 mg, 8.7 mmol) was mixed with toluene (9
mL) in a sealed vial and heated by microwaves to 120.degree. C. for
600 s. After cooling to room temperature and scratching the inside
of the glass, the product precipitated out. The precipitate was
filtered and washed with toluene to give the title compound as a
yellow solid (2.38 g, 71%).
##STR00183##
[0411]
4-Bromo-2-[3-(4-chlorobenzyl)-2,4-dioxothiazolidin-5-ylmethyl]pheno-
xyacetic acid. Prepared from 4-chlorobenzylbromide and
4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic
acid ethyl ester according to GP13, GP14 and GP16 to give 50.4 mg
(21% overall yield) of the title compound: LC/MS (an10p8): Rt 2.6
min, m/z 482 [M-H].sup.-. .sup.1H NMR (DMSO-d.sub.6): .delta. 3.05
(dd, J=13.8, 9.7 Hz, 1H), 3.57 (dd, J=13.8, 4.9 Hz, 1H), 5.11 (dd,
J=9.7, 4.9 Hz, 1H), 4.67 (s, 2H), 4.75 (s, 2H), 6.91 (d, J=8.7,
1H), 7.25-7.28 (m, 2H), 7.37-7.42 (m, 4H), 13.15 (br. s, 1H).
##STR00184##
[0412]
4-Bromo-2-[3-(4-methylbenzyl)-2,4-dioxothiazolidin-5-ylmethyl]pheno-
xyacetic acid. Prepared from 4-methylbenzylbromide and
4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic
acid ethyl ester according to GP13, GP14 and GP16 (yield: 14 mg,
21%): LC/MS (an10p8): Rt 2.5 min, m/z 462 [M-H].sup.-. .sup.1H NMR
(DMSO-d.sub.6): .delta. 2.98-3.07 (m, 1H), 3.53-3.59 (m, 1H), 4.63
(s, 2H), 4.74 (s, 2H), 5.07-5.13 (m, 1H), 6.89-6.91 (m, 1H),
7.11-7.16 (m, 4H), 7.38-7.43 (m, 2H), 13.11 (br s, 1H).
##STR00185##
[0413]
4-Bromo-2-{3-[2-(4-chlorophenyl)-2-oxoethyl]-2,4-dioxothiazolidin-5-
-ylmethyl}phenoxyacetic acid. Prepared from
2-bromo-1-(4-chlorophenyl)ethanone and
4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic
acid ethyl ester according to GP13, GP14 and GP16 (yield: 8.2 mg,
34%): LC/MS (an10p8): Rt 2.8 min, m/z 510 [M-H].sup.-. .sup.1H NMR
(DMSO-d6): .delta. 3.01-3.09 (m, 1H), 3.57-3.63 (m, 1H), 4.79 (s,
2H), 5.17 (s, 2H), 5.21-5.24 (m, 1H), 6.91-6.95 (m, 1H), 7.44 (m,
2H), 7.66-7.69 (m, 2H), 8.07-8.09 (m, 2H).
##STR00186##
[0414]
4-Bromo-2-[3-(3-chlorobenzyl)-2,4-dioxothiazolidin-5-ylmethyl]pheno-
xyacetic acid (7d). Prepared from 3-chlorobenzyl bromide and
4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic
acid ethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8):
Rt 2.6 min, m/z 484 [M+H].sup.+. .sup.1H NMR (DMSO-d6): .delta.
3.02-3.10 (m, 1H), 3.54-3.60 (m, 1H), 4.69 (s, 2H), 4.75 (s, 2H),
5.09-5.14 (m, 1H), 6.89-6.92 (m, 1H), 7.18 (m, 1H), 7.33-7.43 (m,
5H), 13.01 (br s, 1H).
##STR00187##
[0415]
4-Bromo-2-(2,4-dioxo-3-pyridin-4-ylmethylthiazolidin-5-ylmethyl)phe-
noxyacetic acid. Prepared from 4-bromomethylpyridine and
4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic
acid ethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8):
Rt 2.1 min, m/z 451 [M+H].sup.+.
##STR00188##
[0416]
4-Bromo-2-[3-(4-chlorobenzyl)-5-methyl-2,4-dioxothiazolidin-5-ylmet-
hyl]phenoxyacetic acid. Prepared from 4-bromomethylpyridine
according to GP13, GP14, GP15 and GP16 (yield: 29 mg, 15%): LC/MS
(an10p8): Rt 3.0 min, m/z 496 [M-H].sup.-; .sup.1H NMR (DMSO-d6):
1.71 (s, 3H), 3.24 (d, J=13.8 Hz, 1H), 3.39 (d, J=13.8 Hz, 1H),
4.63-4.68 (m, 4H), 6.86 (d, J=8.6 Hz, 1H), 7.13-7.43 (m, 6H), 13.08
(br s, 1H).
##STR00189##
[0417]
4-Bromo-2-[3-(2,6-dichlorobenzyl)-5-methyl-2,4-dioxothiazolidin-5-y-
lmethyl]phenoxyacetic acid. Prepared from 2,6-dichlorobenzylbromide
according to GP13, GP14, GP15 and GP16 to give 21.1 mg of the title
compound: LC/MS (an10n8): Rt 2.9 min, m/z 532 [M-H].sup.-; .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.63 (s, 3H), 3.16 (d, J=13.6 Hz, 1H),
3.40 (d, J=13.6 Hz, 1H), 4.65 (s, 2H), 4.92 (s, 2H), 6.86 (d, J=8.9
Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.35-7.48 (m, 4H), 12.38 (br s,
1H).
##STR00190##
[0418]
4-Bromo-2-[3-(2-chlorobenzyl)-5-methyl-2,4-dioxothiazolidin-5-ylmet-
hyl]phenoxyacetic acid. Prepared from 2-chlorobenzylbromide
according to GP13, GP14, GP15 and GP16 to give 22.0 mg of the title
compound: LC/MS (an10n8): Rt 2.8 min, m/z 498 [M-H].sup.-; .sup.1H
NMR (DMSO-d.sub.6): .delta. 1.76 (s, 3H), 3.28 (d, J=13.7 Hz, 1H),
3.43 (d, J=13.7 Hz, 1H), 4.67 (d, J=3.2 Hz, 2H), 4.73 (s, 2H), 6.81
(d, J=8.9 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 7.24-7.36 (m, 3H),
7.43-7.50 (m, 2H), 12.18 (br s, 1H).
[0419] Biological Assays
[0420] Materials and Methods
[0421] Generation/origin of the cDNA Constructs. The coding
sequence of the human CRTH2 receptor (genbank accession no
NM.sub.--004778) was amplified by PCR from a human hippocampus cDNA
library and inserted into the pcDNA3.1(+) expression vector
(invitrogen) via 5' HindIII and 3' EcoRI. To generate a
CRTH2-Renilla luciferase (CRTH2-Rluc) fusion protein, the CRTH2
coding sequence without a STOP codon and Rluc were amplified, fused
in frame by PCR and subcloned into the pcDNA3.1(+)Zeo expression
vector (invitrogen). Human .beta.-arrestin2 (.beta.-arr2)
N-terminally tagged with GFP.sup.2 (.beta.arr2-GFP.sup.2) and
Renilla luciferase were purchased from BioSignal Packard Inc,
(Montreal, Canada). The sequence identity of the construct was
verified by restriction endonuclease digests and sequencing in both
directions on an ABI Prism (Applied Biosystems, Foster City,
Calif.).
TABLE-US-00001 Sequence ID CRTH2 (protein sequence (SEQ ID NO: 1):
MSANATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVLLHGLASLLGLVEN
GVILFVVGCRMRQTVVTTWVLHLALSDLLASASLPFFTYFLAVGHSWELG
TTFCKLHSSIFFLNMFASGFLLSAISLDRCLQVVRPVWAQNHRTVAAAHK
VCLVLWALAVLNTVPYFVFRDTISRLDGRIMCYYNVLLLNPGPDRDATCN
SRQAALAVSKFLLAFLVPLAIIASSHAAVSLRLQHRGRRRPGREVRLVAA
VVAAFALCWGPYHVFSLLEARAHANPGLRPLVWRGLPFVTSLAFFNSVAN
PVLYVLTCPDMLRKLRRSLRTVLESVLVDDSELGGAGSSRRRRTSSTARS
ASPLALCSRPEEPRGPARLLGWLLGSCAASPQTGPLNRALSSTSS Sequence ID CRTH2
(nucleotide sequence (SEQ ID NO: 2): atgtcggc caacgccaca ctgaagccac
tctgccccat cctggagcag atgagccgtc tccagagcca cagcaacacc agcatccgct
acatcgacca cgcggccgtg ctgctgcacg ggctggcctc gctgctgggc ctggtggaga
atggagtcat cctcttcgtg gtgggctgcc gcatgcgcca gaccgtggtc accacctggg
tgctgcacct ggcgctgtcc gacctgttgg cctctgcttc cctgcccttc ttcacctact
tcttggccgt gggccactcg tgggagctgg gcaccacctt ctgcaaactg cactcctcca
tcttctttct caacatgttc gccagcggct tcctgctcag cgccatcagc ctggaccgct
gcctgcaggt ggtgcggccg gtgtgggcgc agaaccaccg caccgtggcc gcggcgcaca
aagtctgcct ggtgctttgg gcactagcgg tgctcaacac ggtgccctat ttcgtgttcc
gggacaccat ctcgcggctg gacgggcgca ttatgtgcta ctacaatgtg ctgctcctga
acccggggcc tgaccgcgat gccacgtgca actcgcgcca ggcggccctg gccgtcagca
agttcctgct ggccttcctg gtgccgctgg cgatcatcgc ctcgagccac gcggccgtga
gcctgcggtt gcagcaccgc ggccgccggc ggccaggccg cttcgtgcgc ctggtggcag
ccgtcgtggc cgccttcgcg ctctgctggg ggccctacca cgtgttcagc ctgctggagg
cgcgggcgca cgcaaacccg gggctgcggc cgctcgtgtg gcgcgggctg cccttcgtca
ccagcctggc cttcttcaac agcgtggcca acccggtgct ctacgtgctc acctgccccg
acatgctgcg caagctgcgg cgctcgctgc gcacggtgct ggagagcgtg ctggtggacg
acagcgagct gggtggcgcg ggaagcagcc gccgccgccg cacctcctcc accgcccgct
cggcctcccc tttagctctc tgcagccgcc cggaggaacc gcggggcccc gcgcgtctcc
tcggctggct gctgggcagc tgcgcagcgt ccccgcagac gggccccctg aaccgggcgc
tgagcagcac ctcgagttag
[0422] Cell Culture and Transfection. COS-7 cells were grown in
Dulbecco's modified Eagle's medium (DMEM) 1885 supplemented with
10% fetal bovine serum, 100 units/ml penicillin, 1000 .mu.g/ml
streptomycin, and kept at 37.degree. C. in a 10% CO.sub.2
atmosphere. HEK293 cells were maintained in Minimum Essential
medium (MEM) supplemented with 10% (v/v) heat inactivated fetal
calf serum (HIFCS), 2 mM Glutamax.TM.-I, 1% non essential amino
acids (NEAA), 1% sodium pyruvate and 10 .mu.g/ml gentamicin. For
binding experiments, COS7 cells were transiently transfected with
the CRTH2 receptor using a calcium phosphate-DNA coprecipitation
method with the addition of chloroquine (as described by Holst et
al., 2001.dwnarw.). To perform the functional Bioluminescence
Resonance Energy Transfer (BRET) assays, a HEK293 cell clone stably
expressing .beta.arr2-GFP.sup.2 and CRTH2-Rluc was generated
(CRTH2-HEK293 cells).
[0423] Binding assay. 24 h after transfection COS-7 cells were
seeded into 96 well plates at a density of 30.000 cells/well.
Competition binding experiments on whole cells were then performed
about 18-24 h later using 0.1 nM [.sup.3H]PGD2 (NEN, 172 Ci/mmol)
in a binding buffer consisting of HBSS (GIBCO) and 10 mM HEPES.
Competing ligands were diluted in DMSO which was kept constant at
1% (v/v) of the final incubation volume. Total and nonspecific
binding were determined in the absence and presence of 10 .mu.M
PGD2. Binding reactions were routinely conducted for 3 h at
4.degree. C. and terminated by 2 washes (100 .mu.l each) with ice
cold binding buffer. Radioactivity was determined by liquid
scintillation counting in a TOPCOUNTER (Packard) following over
night incubation in Microscint 20. Stable HEK293 cells were seeded
at a density of 30.000 cells/well 18-24 h prior to the binding
assay which was performed essentially as described for COS7 cells
above. Determinations were made in duplicates.
[0424] BRET assay. Functional BRET assays were performed on HEK293
cells stably expressing human CRTH2-Rluc and GFP.sup.2-.beta.-arr2.
Prior to their use in the BRET assay cells were detached and
re-suspended in D-PBS with 1000 mg/L L-Glucose at a density of
2.times.10.sup.6 cells/mL. DeepBlueC.TM. was diluted to 50 .mu.M in
D-PBS with 1000 mg/L L-Glucose (light sensitive). 100 .mu.L of cell
suspension was transferred to wells in a 96-well microplate (white
OptiPlate) and placed in the Mithras LB 940 instrument (BERTHOLD
TECHNOLOGIES, Bad Wildbad, Germany). 12 .mu.L/well agonist was then
injected by injector 1 and 10 .mu.L/well DeepBlueC.TM. was injected
simultaneously by injector 2. Five seconds after the injections the
light output from the well was measured sequentially at 400 nm and
515 nm, and the BRET signal (mBRET ratio) was calculated by the
ratio of the fluorescence emitted by GFP.sup.2-.beta.-arr2 (515 nm)
over the light emitted by the receptor-Rluc (400 nm). Antagonists
were added before placing the microplates into the Mithras LB 940
and allowed to incubate for 15 minutes prior to the addition of
agonist and DeepBlueC.TM.. Compounds were dissolved in DMSO and the
final DMSO concentration was kept constant at 1% in the assay.
[0425] Human eosinophil shape change assay. Blood was sampled from
healthy volunteers according to a protocol approved by the Ethics
Committee of the University of Graz and processed as described
previously (Bohm et al., 2004). Preparations of polymorphonuclear
leukocytes (containing eosinophils and neutrophils) were prepared
by dextran sedimentation of citrated whole blood and Histopaque
gradients. The resulting cells were washed and resuspended in assay
buffer (comprising PBS with Ca.sup.2+/Mg.sup.2+ supplemented with
0.1% BSA, 10 mM HEPES and 10 mM glucose, pH 7.4) at
5.times.10.sup.6 cells/mL. Cells were incubated with the
antagonists or vehicle (PBS or DMSO) for 10 min at 37.degree. C.
and then stimulated with various concentration of the agonists
(PGD2 or eotaxin) for 4 min at 37.degree. C. To stop the reaction,
samples were transferred to ice and fixed with 250 .mu.L of
fixative solution. Samples were immediately analyzed on a
FACSCalibur flow cytometer (Becton Dickinson) and eosinophils were
identified according to their autofluorescence in the FL-1 and FL-2
channels. Shape change responses were quantified as percentage of
the maximal response to PGD2 or eotaxin in the absence of an
antagonist.
[0426] Materials
[0427] Tissue culture media and reagents were purchased from the
Gibco invitrogen corporation (Breda, Netherlands). PGD2 was
obtained from Cayman and [3H]PGD2 from NEN.
[0428] Data Analysis
[0429] Curve analysis was performed with the GraphPadPrism software
3.0 (Graphpad Prism Inc., San Diego, USA) and IC.sub.50 values were
calculated as a measure of the antagonistic potencies.
[0430] References
[0431] Hoist B, Hastrup H, Raffetseder U, Martini L, Schwartz T W.
Two active molecular phenotypes of the tachykinin NK1 receptor
revealed by G-protein fusions and mutagenesis. J Biol Chem. 2001
Jun. 8; 276(23):19793-9. Epub 2001 Feb. 22.
[0432] Biological Data:
[0433] Compounds were tested in the receptor binding assay and the
functional antagonist assay described below, and their IC.sub.50
values were assessed. The compounds are grouped in three
classes:
[0434] A: IC.sub.50 value lower than 0.5 .mu.M
[0435] B: IC.sub.50 value between 0.5 .mu.M and 5 .mu.M
[0436] C: IC.sub.50 value higher than 5 .mu.M
[0437] Tables 1 to 7 give the biological test results for the
compounds synthesised above and for some additional compounds
acquired from commercial sources. The ability of the compounds
above to inhibit prostaglandin D2 induced eosihophil shape change
is demonstrated by the examples in FIG. 1.
TABLE-US-00002 TABLE 1 ##STR00191## Binding Antag. A R1 R2 R3 R4 R5
R6 R7 R8 R9 X Y IC.sub.50 IC.sub.50 D1 COOH Br H H H H H H H H C C
A A D2 COOH H H H H H H H H H C C A B D3 COOH F H H H H H H H H C C
A B D4 Tetrazole Br H H H H H H H H C C A C D5 COOH Ph H H H H H H
H H C C A A D6 COOH Br H H H H H H H -- N C A A D7 COOH Br H H H H
H OMe H H C C A A D8 COOH ##STR00192## H H H H H H H H C C A B D9
COOH ##STR00193## H H H H H H H H C C A A D10 COOH Cl H H H H H H H
H C C A B D11 COOH Me H H H H H H H H C C A B D12 COOH Cl Me H H H
H H H H C C B C D13 COOH Cl H Cl H H H H H H C C C C D14 COOH Br H
H H Cl H H H H C C C A D15 COOH Br H H H H Cl H H H C C A A D16
COOH Br H H H H H Br H H C C A A D17 COOH Br H H H H H Cl H H C C A
A D18 COOH Br H H H Et H H H H C C A A D19 COOH NO.sub.2 H H H H H
Cl H H C C A A D20 COOH NO.sub.2 H H H H H H H H C C A A D21 COOH
Br H H H Br H H H H C C A A D22 COOH Br H H H F H H H H C C A A D23
COOH Br H H H CF.sub.3 H H H H C C A A D24 COOH Br H H H H Br H H H
C C A A D25 COOH Br H H H H CF.sub.3 H H H C C A A D26 COOH Br H H
H Cl H Cl H H C C A A D27 COOH NO.sub.2 H H H Cl H H H H C C A A
D28 COOH NO.sub.2 H H H Br H H H H C C A A D29 COOH Br H H H Cl H H
H Cl C C A A D30 COOH Et H H H Br H H H H C C A A D31 COOH i-Pr H H
H Cl H H H H C C A A D32 COOH Br H H H H H OCF.sub.3 H H C C A A
D33 COOH Br H H H Br H Br H H C C A A D34 COOH Br H H H Cl H Br H H
C C A A D35 COOH Br H H H Cl H Cl H Cl C C A A D36 COOH OMe H H H H
H H H H C C A B D37 COOH Br H H Me H H H H H C C A A (S)-D37 COOH
Br H H Me H H H H H C C A A D38 COOH Br H H Me Cl H H H H C C A A
D39 COOH Br H H Me Cl H H H Cl C C A A D40 COOH Br H H H CN H H H H
C C A A D41 COOH Br H H H OEt H H H H C C A A D42 COOH Br H H H Et
H Br H H C C A A D43 COOH Br H H H OPh H H H H C C A A D44 COOH Br
H H H SMe H H H H C C A A D45 COOH Br H H H Br H Me H H C C A A D46
COOH Br H H Me Et H Br H H C C A A D47 COOH Br H H Me OPh H H H H C
C A A D48 COOH Br H H Me OEt H H H H C C A A D49 COOH Br H H Me SMe
H H H H C C A A D50 COOH Br H H Me Br H Me H H C C A A D51 COOH Br
H H Me OPh H H H H C C A A D52 COOH Br H H H OCF.sub.3 H H H H C C
A A D53 COOH Et H H H Me H H H Me C C A A D54 COOH Br H H H Me H Me
H H C C A A D55 COOH Br H H Me Me H Me H H C C A A D58 COOH Br H H
H Me H Cl H H C C A A D59 COOH Br H H H Cl H H Cl H C C A A D60
COOH Br H H H OMe H H H H C C A A D61 COOH Br H H H H Cl Cl H H C C
A A D62 COOH Br H H Me Me H Cl H H C C A A D63 COOH Br H H Me Cl H
Cl H H C C A A D64 COOH Br H H Me H Cl Cl H H C C A A D65 COOH Br H
H Me OMe H H H H C C A A D66 COOH NH.sub.2 H H H H H H H H C C B A
D67 COOH Br H H Me Cl H Br H H C C A A D68 COOH Br H H Me Cl H Cl H
Cl C C A A D69 COOH Br H H Me Br H Br H H C C A A D70 COOH Br H H H
Et H H H Et C C A A D71 COOH Br H H H Me H H H Me C C A A D72 COOH
Br H H H Et H H H Me C C A A D73 COOH Br H H H i-Pr H H H H C C A A
D74 COOH EtO H H H H H H H H C C B C D75 COOH n-Bu H H H H H H H H
C C A C D76 COOH Br H H H Cl H H H Me C C A A D77 COOH Br H H Me Me
H H H Me C C A A D78 COOH Br H H Me Et H H H Et C C A A D79 COOH Br
H H Me i-Pr H H H H C C A A D80 COOH Br H H H Cl H H H Cl C N A A
D81 COOH Br H H H H H CF.sub.3 H H C C A A
TABLE-US-00003 TABLE 2 ##STR00194## Binding Antag. n X R1 R2 R3 R4
R5 IC.sub.50 IC.sub.50 D83 0 O H H H H H A C D84 0 O H H OMe H H A
B D85 0 O H H Cl H H A C D86 0 O H OMe H H H A A D87 0 O H H OEt H
H A C D88 1 O H H H H H A A D89 1 O H OMe H H H A A D90 1 O Cl H F
H H A A D91 1 O Cl H H H Cl A A D92 1 O H H OMe H H A A D93 0 S H H
H H H A A D94 1 S H H Cl H H A A
TABLE-US-00004 TABLE 3 ##STR00195## Binding Antag. n R1 R2 R3 R4 R5
IC.sub.50 IC.sub.50 D99 0 H H H H H A A D100 0 H H F H H A A D101 0
H H OMe H H A A D102 0 H H Cl H H A A D103 0 H H OCF.sub.3 H H A A
D104 0 H OMe H H H A A D105 0 H Cl H H H A A D106 0 H H CF.sub.3 H
H A A D107 0 OMe H H H H A A D108 0 Cl H H H H A A D109 0 H
CF.sub.3 H CF.sub.3 H A C D110 0 Cl H H H Cl A A D111 0 H H OPh H H
A A D112 0 H CF.sub.3 H H H A A D113 1 H H OCF.sub.3 H H A A D114 1
H H Cl H H A A D115 1 H H H H H A A D116 1 H H F H H A A D117 1 H F
H F H A A D118 1 H H OMe H H A A D119 1 H OMe H H H A A D120 1 Cl H
H H H A A D121 1 Cl H H H Cl A A D122 1 Cl H Cl H H A A D123 1 H Cl
Cl H H A A D124 1 H OMe OMe H H A A D125 1 H OMe H H H A C D126 1 H
H Me H H A A D127 1 CF.sub.3 H H H H A A D128 1 H OMe H OMe H A B
D129 0 Cl H Cl H H A A D130 1 H Cl H H H A A D131 1 H H NHAc H H A
A
TABLE-US-00005 TABLE 4 ##STR00196## Binding Antag. n R1 R2 R3 R4 R5
Activity IC.sub.50 IC.sub.50 D134 0 H H 4-PhOMe H H A A A D135 0 H
H Cl H H A A A D136 0 H Cl H H H A A A D137 0 Cl H H H H A A A D138
0 H H H H H A A C
TABLE-US-00006 TABLE 5 Binding Antag. Structure IC.sub.50 IC.sub.50
D56 ##STR00197## A A D57 ##STR00198## A A D82 ##STR00199## A A D95
##STR00200## A A D96 ##STR00201## A B D97 ##STR00202## A A D98
##STR00203## A D132 ##STR00204## A A D133 ##STR00205## A C
TABLE-US-00007 TABLE 6 Binding Antag. Structure IC.sub.50 IC.sub.50
D139 ##STR00206## A A D140 ##STR00207## A B D141 ##STR00208## A A
D142 ##STR00209## A A D143 ##STR00210## A A D144 ##STR00211## A A
D145 ##STR00212## A A D146 ##STR00213## A A
TABLE-US-00008 TABLE 7 ##STR00214## Binding Antag. Cmp R1 R2
IC.sub.50 IC.sub.50 D149 H ##STR00215## A A D150 Br ##STR00216## A
C D151 Br ##STR00217## A C D152 Br ##STR00218## A B D153 H
##STR00219## B C D154 H ##STR00220## A A D155 H ##STR00221## A B
D156 H ##STR00222## A B
Sequence CWU 1
1
21395PRTHomo sapiens 1Met Ser Ala Asn Ala Thr Leu Lys Pro Leu Cys
Pro Ile Leu Glu Gln1 5 10 15Met Ser Arg Leu Gln Ser His Ser Asn Thr
Ser Ile Arg Tyr Ile Asp 20 25 30His Ala Ala Val Leu Leu His Gly Leu
Ala Ser Leu Leu Gly Leu Val 35 40 45Glu Asn Gly Val Ile Leu Phe Val
Val Gly Cys Arg Met Arg Gln Thr 50 55 60Val Val Thr Thr Trp Val Leu
His Leu Ala Leu Ser Asp Leu Leu Ala65 70 75 80Ser Ala Ser Leu Pro
Phe Phe Thr Tyr Phe Leu Ala Val Gly His Ser 85 90 95Trp Glu Leu Gly
Thr Thr Phe Cys Lys Leu His Ser Ser Ile Phe Phe 100 105 110Leu Asn
Met Phe Ala Ser Gly Phe Leu Leu Ser Ala Ile Ser Leu Asp 115 120
125Arg Cys Leu Gln Val Val Arg Pro Val Trp Ala Gln Asn His Arg Thr
130 135 140Val Ala Ala Ala His Lys Val Cys Leu Val Leu Trp Ala Leu
Ala Val145 150 155 160Leu Asn Thr Val Pro Tyr Phe Val Phe Arg Asp
Thr Ile Ser Arg Leu 165 170 175Asp Gly Arg Ile Met Cys Tyr Tyr Asn
Val Leu Leu Leu Asn Pro Gly 180 185 190Pro Asp Arg Asp Ala Thr Cys
Asn Ser Arg Gln Ala Ala Leu Ala Val 195 200 205Ser Lys Phe Leu Leu
Ala Phe Leu Val Pro Leu Ala Ile Ile Ala Ser 210 215 220Ser His Ala
Ala Val Ser Leu Arg Leu Gln His Arg Gly Arg Arg Arg225 230 235
240Pro Gly Arg Phe Val Arg Leu Val Ala Ala Val Val Ala Ala Phe Ala
245 250 255Leu Cys Trp Gly Pro Tyr His Val Phe Ser Leu Leu Glu Ala
Arg Ala 260 265 270His Ala Asn Pro Gly Leu Arg Pro Leu Val Trp Arg
Gly Leu Pro Phe 275 280 285Val Thr Ser Leu Ala Phe Phe Asn Ser Val
Ala Asn Pro Val Leu Tyr 290 295 300Val Leu Thr Cys Pro Asp Met Leu
Arg Lys Leu Arg Arg Ser Leu Arg305 310 315 320Thr Val Leu Glu Ser
Val Leu Val Asp Asp Ser Glu Leu Gly Gly Ala 325 330 335Gly Ser Ser
Arg Arg Arg Arg Thr Ser Ser Thr Ala Arg Ser Ala Ser 340 345 350Pro
Leu Ala Leu Cys Ser Arg Pro Glu Glu Pro Arg Gly Pro Ala Arg 355 360
365Leu Leu Gly Trp Leu Leu Gly Ser Cys Ala Ala Ser Pro Gln Thr Gly
370 375 380Pro Leu Asn Arg Ala Leu Ser Ser Thr Ser Ser385 390
39521188DNAHomo sapiens 2atgtcggcca acgccacact gaagccactc
tgccccatcc tggagcagat gagccgtctc 60cagagccaca gcaacaccag catccgctac
atcgaccacg cggccgtgct gctgcacggg 120ctggcctcgc tgctgggcct
ggtggagaat ggagtcatcc tcttcgtggt gggctgccgc 180atgcgccaga
ccgtggtcac cacctgggtg ctgcacctgg cgctgtccga cctgttggcc
240tctgcttccc tgcccttctt cacctacttc ttggccgtgg gccactcgtg
ggagctgggc 300accaccttct gcaaactgca ctcctccatc ttctttctca
acatgttcgc cagcggcttc 360ctgctcagcg ccatcagcct ggaccgctgc
ctgcaggtgg tgcggccggt gtgggcgcag 420aaccaccgca ccgtggccgc
ggcgcacaaa gtctgcctgg tgctttgggc actagcggtg 480ctcaacacgg
tgccctattt cgtgttccgg gacaccatct cgcggctgga cgggcgcatt
540atgtgctact acaatgtgct gctcctgaac ccggggcctg accgcgatgc
cacgtgcaac 600tcgcgccagg cggccctggc cgtcagcaag ttcctgctgg
ccttcctggt gccgctggcg 660atcatcgcct cgagccacgc ggccgtgagc
ctgcggttgc agcaccgcgg ccgccggcgg 720ccaggccgct tcgtgcgcct
ggtggcagcc gtcgtggccg ccttcgcgct ctgctggggg 780ccctaccacg
tgttcagcct gctggaggcg cgggcgcacg caaacccggg gctgcggccg
840ctcgtgtggc gcgggctgcc cttcgtcacc agcctggcct tcttcaacag
cgtggccaac 900ccggtgctct acgtgctcac ctgccccgac atgctgcgca
agctgcggcg ctcgctgcgc 960acggtgctgg agagcgtgct ggtggacgac
agcgagctgg gtggcgcggg aagcagccgc 1020cgccgccgca cctcctccac
cgcccgctcg gcctcccctt tagctctctg cagccgcccg 1080gaggaaccgc
ggggccccgc gcgtctcctc ggctggctgc tgggcagctg cgcagcgtcc
1140ccgcagacgg gccccctgaa ccgggcgctg agcagcacct cgagttag 1188
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