ZA200602181B - Benzimidazole derivatives: Preparation and pharmaceutical applications - Google Patents
Benzimidazole derivatives: Preparation and pharmaceutical applications Download PDFInfo
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- ZA200602181B ZA200602181B ZA200602181A ZA200602181A ZA200602181B ZA 200602181 B ZA200602181 B ZA 200602181B ZA 200602181 A ZA200602181 A ZA 200602181A ZA 200602181 A ZA200602181 A ZA 200602181A ZA 200602181 B ZA200602181 B ZA 200602181B
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- hydroxy
- acrylamide
- benzimidazol
- ethyl
- propyl
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- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title description 2
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title 1
- -1 heterocycloalkyloxy Chemical group 0.000 claims description 127
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 73
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 68
- 125000003118 aryl group Chemical group 0.000 claims description 68
- 125000001072 heteroaryl group Chemical group 0.000 claims description 68
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 60
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 59
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 56
- 125000002252 acyl group Chemical group 0.000 claims description 53
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 53
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 53
- 125000003342 alkenyl group Chemical group 0.000 claims description 48
- 125000000304 alkynyl group Chemical group 0.000 claims description 48
- 125000001188 haloalkyl group Chemical group 0.000 claims description 48
- 125000004442 acylamino group Chemical group 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 125000004104 aryloxy group Chemical group 0.000 claims description 44
- 125000003282 alkyl amino group Chemical group 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 32
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 32
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- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 32
- 125000001769 aryl amino group Chemical group 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
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- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 32
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- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 32
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- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 30
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 29
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 29
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 24
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
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- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 2
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- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 claims description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
BENZIMIDAZOLE DERIVATIVES: PREPARATION AND PHARMACEUTICAL
The present invention relates to hydroxamate compounds that are inhibitors of histone deacetylase. More particularly, the present invention relates to benzimidazole containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with dysregulation of histone deacetylase (HDAC).
Local chromatin architecture is generally recognized as an important factor in the regulation of gene expression. The architecture of chromatin, a protein-DNA complex, is strongly influenced by post-transiational modifications of the histones which are the 1s protein components. Reversible acetylation of histones is a key component in the regulation of gene expression by altering the accessibility of transcription factors to DNA.
In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels of acetylation are associated with repression of gene expression [Wadem P.A. Hum. Mol. Genet. 10, 693-698 (2001), De
Ruiter AJM. et al, Biochem. J., 370, 737-749 (2003)]. In normal cells, histone deacetylases (HDACs) and histone acetyftransferase together control the level of acetylation of histones to maintain a balance. Inhibition of HDACs results in the accumulation of acetylated histones, which results in a variety of cell type dependent cellular responses, such as apoptosis, necrosis, differentiation, cell survival, inhibition of proliferation and cytostasis.
Inhibitors of HDAC have been studied for their therapeutic effects on cancer cells. For example, suberoylanilide hydroxamic acid (SAHA) is a potent inducer of differentiation . and/or apoptosis in murine erythroleukemia, bladder, and myeloma cell lines [Richon V.M. et al, Proc. Natl. Acad. Sci. USA, 93: 5705-5708 (1996), Richon V.M. et al, Proc. Natl.
Acad. Sci. USA, 95: 3003-3007 (1998)]. SAHA has been shown to suppress the growth of prostate cancer cells in vitro and in vivo [Butler LM. et al, Cancer Res. 60, 5165-5170 (2000)]. Other inhibitors of HDAC that have been widely studied for their anti-cancer activities are trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J. Biol. Chem., 265, 17174 (19890), Kiima M. et al, J. Biol. Chem., 268, 22429 (1993)}. Trichostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC. However, due to the in vivo instability of these
FU compounds they are less desirable as anti-cancer drugs. Recently, other small molecule
HDAC inhibitors have become available for clinical evaluation [US6,552,065]. Additional
HDAC inhibiting compounds have been reported in the literature [Bouchain G. et al, J.
Med. Chem., 46, 820-830 (2003)] and patents [WO 03/066579A2, WO 01/38322 A1]. The in vivo activity of such inhibitors can be directly monitored by their ability to increase the amount of acetylated histones in the biological sample. HDAC inhibitors have been reported to interfere with neurodegenerative processes, for instance, HDAC inhibitors arrest polyglutamine-dependent neurodegeneration [Nature, 413(6857). 739-43, 18
October, 2001]. In addition, HDAC inhibitors have also been known to inhibit production of cytokines such as TNF, IFN, IL-1 which are known to be implicated in inflammatory diseases and/or immune system disorders. [ J. Biol. Chem. 1990; 265(18): 10230-10237;
Science, 1998; 281: 1001-1005; Dinarello C.A. and Moldawer L.L. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis. A primer for clinicians. 2" Edition,
Amergen Inc., 2000].
Nevertheless, there is still a need to provide further HDAC inhibitors that would be expected to have useful, improved pharmaceutical properties such as anti-cancer agents.
In one aspect the present invention provides compounds of the formula (1): fy,
N aE O—R*
NTS
R!
Formula wherein:
R' is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkeny!, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR® and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
Corrected sheet: 26 June 2007
: p heteroalkyl, cycloalkyl, cycloalkenyl, heterooycloalky, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C(O)OR®, -COR®, -SH, -SR®, -OR® and acyl; orR'=L;
R? is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalky!, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsuifonyl, alkylsulfinyl, arylsulfonyl, aryisulfinyl, aminosulfonyl, SR® and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF;3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalky!, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR®, -C(O)OR?®, -SH, -SR°®, -OR® and acyl; orR?=1L;
R’ is selected from the group consisting of H, C4 -Cg alkyl, and acyl; or a metal ion selected from sodium, calcium, magnesium;
X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -NO,, -CF; -OCF,, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
Corrected sheet: 26 June 2007
2 Y sulfonyl, alkylsulfonyl, arylsulfonyl, —_—— aminoalkyl, alkoxyalkyl, -COOH -
C(O)OR?, -COR?®, -SH, -SR®, -OR®, acyl and -NR'R?,
R* is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyi, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R’” and R® are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyi, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalky! and acyl;
L is selected from the group consisting of: a) L=Cy-L'-W-
Wherein
Cy is C4-Cy5 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =O, =8§, -CN, -NO,, -CF;, -OCF,, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyil, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloaikenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -
C(O)OR?®, -COR?®, -SH, -SR®, -OR® and acyl.
L' is selected from the group consisting of C; ~Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; alkyl, alkoxy, acylamino, and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0),-, -N(R%)-, -C(O)N(R®)-, -SO.N(R%)-, N(R®)C(O)-, N(R®)SO,-, and -N(R®)-C(O)-N(R"°)-;
Corrected sheet: 26 June 2007
" b b) L=Cy-L'-W-L? ’
Wherein,
Cy is C4-Cys alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH,
C(O)OR®, -COR?®, -SH, -SR?, -OR® and acyl;
L' and L? are the same or different and independently C,—Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; -CF3, -OCF;, alkyl, alkoxy, acylamino and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0)z-, -N(R®)-, -C(O)N(R®)-, -SO,N(R®)-, N(R®)C(O)-, N(R®)SO.-, and -N(R%)-C(O)-N(R")-;
Cc) L=Cy-(CH,;)m-W-
Wherein,
Cy is C4-Cys alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =O, =8, -CN, -NO,, -CF3, -OCF3;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH,
C(O)OR®, -COR®, -SH, -SR?, -OR® and acyl; mis 0, 1,2, 3,40r5;
Corrected sheet: 26 June 2007 a v
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0),-, -N(R®)-, -C(O)N(R®)-, -SO,N(R%)-, N(R®)C(O)-, N(R®)SO_, and —N(R®)-C(O)-N(R'%)-; d) L=L'-w-L?
L' and L? are the same or different and independently selected from
C,-Cs alkyl, which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN,; i -NO,; —CF3;, -OCF; alkyl, alkoxy, acylamino, alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -8(0)z-, -N(R%)-, -C(O)N(R®)-, -SO.N(R®)-, N(R®)C(O)-, N(R®)SO-, and —N(R®)-C(0O)-N(R"°)-;
R® and R'® are the same or different and are independently selected from H, C;-Cs alkyl, Cs4-Cs cycloalkyl, C,-Cy heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and acyl;
Z is selected from -CH,-, -CH,CH,-, -CH=CH- and C;-C; cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C4-C, alkyl; or a pharmaceutically acceptable salt thereof.
One suitable genus of hydroxamic compounds are those of formula la: fe 1
L wl 3 no"
N 2" R3
R1
Formula la wherein
R' is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycioalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR® and acyl, each of which may be unsubstituted or
Corrected sheet: 26 June 2007 substituted with one or more substituents independently selected from the group consisting of: halogen, =0, =S, -CN, -NO,, -CF3, -OCF,, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C(O)OR?®, -COR?®, -SH, -SR®, -OR® and acyl; orR'=L;
R? is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyi, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR® and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, =0, =S, -CN, -NO,, -CF3, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR®, -C(O)OR?, -SH, -SR?, -OR® and acyl; orR?=L;
R? is selected from the group consisting of: H, C4 -Cs alkyl, and acyl; or a metal ion selected from sodium, calcium, magnesium;
X and Y are the same or different and are independently selected from the group consisting of. H, halogen, -CN, -NO,, -CF;, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,
Corrected sheet: 26 June 2007 heteroarylalkyl, arylalkyloxy, amino, alkylamin, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -
C(O)OR?®, -COR?®, -SH, -SR®, -OR?, acyl and -NR'R?,
Each R® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R’ and R® are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
L is selected from the group consisting of: a) L=Cy-L'-W-
Wherein
Cy is C4-C45 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy, or heteroaryl any of which may be optionally substituted one or more substituents independently selected from the group consisting of. halogen, =0, =S, -CN, -NO,, -CF; -OCF, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -
C(O)OR?®, -CORS®, -SH, -SR?, -OR®, and acyl.
L' is selected from the group consisting of C, —Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; alkyl, alkoxy, acylamino, and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(O)-, -S(0)z-, -N(R%)-, -C(OIN(R®)-, -SO,N(R®)-, N(R®)C(O)-, N(R®)SO--, and -N(R®)-C(0)-N(R")-; b) L=Cy-L'-W-L?
Wherein,
Corrected sheet: 26 June 2007
Cy is C4-Cy5 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =0, =S, -CN, -NO,, -CF;, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH,
C(O)OR?®, -COR?®, -SH, -SR®, -OR® and acyl;
L' and L? are the same or different and independently C,—Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; -CF3, -OCF3, alkyl, alkoxy, acylamino and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0)-, -N(R®)-, -C(O)N(R®)-, -SO:N(R®)-, N(R°)C(O)-, N(R®)SO--, and -N(R®)-C(O)-N(R")-; c) L=Cy-(CH;)m-W-
Wherein,
Cy is C4-Cys alkyl, aminoalkyl, heterocycloalkyl!, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of halogen, =O, =S, -CN, -NO,, -CF3;, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulifonyl, aminoalkyl, alkoxyalkyl, -COOH,
C(O)ORS®, -COR?, -SH, -SR®, -OR® and acyl; mis 0,1,2,3,4o0r5;
Corrected sheet: 26 June 2007
W is selected from the aroun consisting of a single bond, -O-, -S-, -
S(O), -8(0)-, -N(R%-, -C(O)N(R®)-, -SO,N(R®)-, N(R®)C(O)-, N(R®)SO,-, and —N(R®)-C(O)-N(R")-; d) L=L"-W-L?
L' and L? are the same or different and independently selected from
C1—Cs alkyl, which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; —CF3, -OCF; alkyl, alkoxy, acylamino, alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0)z, N(R®)-, -C(OIN(R®)-, -SO,N(R®)-, N(R°)C(O)-, N(R")SO--, and -N(R®)-C(O)-N(R'%)-;
R® and R'® are the same or different and are independently selected from H, C-Ce alkyl, C4-Cy cycloalkyl, C4-Cgy heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl;
Z is selected from -CH,-, -CH,CH,-,-CH=CH-, C;-Cs cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C,4-C, alkyl, or a pharmaceutically acceptable salt thereof.
Another group of useful compounds are those of the formula Ib:
X 0)
N PS
4 AO: v
N Ay Hy
R?
Formula Ib wherein
R' is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsuifonyl, arylsulfinyl, aminosulfonyl, SR® and acyl, each of which may be unsubstituted or
Corrected sheet: 26 June 2007 substituted with one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyi, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -
COOH, -C(O)OR?®, -COR?, -SH, -SR®, -OR® and acyl; orR'=L;
R? is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR® and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR®, -C(O)OR?, -SH, -SR®, -OR® and acyl; orR?=L;
X and Y are the same or different and are independently selected from the group consisting of; H, halogen, -CN, -NO,, -CF; -OCF;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
Corrected sheet: 26 June 2007 sulfonyl, alkyisulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -
C(O)OR®, -COR®, -SH, -SR®, acyl and -NR'R?;
Each R® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R°® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R’ and R® are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
L is selected from the group consisting of: a) L=Cy-L'-w-
Wherein
Cy is C+-Cys alkyl, aminoalkyl, heterocycloalky!, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =0, =S, -CN, -NO,, -CF;, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkyisulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -
C(O)OR®, -COR?®, -SH, -SR®, -OR® and acyl.
L' is selected from the group consisting of C, —Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of. halogen; =O; =S; -CN; -NO,; alkyl, alkoxy, acylamino, and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0),-, -N(R%)-, -C(O)N(R®)-, -SO,N(R%-, N(R%)C(O)-, N(R®)SO.-, and ~N(R®%)-C(0)-N(R"°)-; b) L=Cy-L'-W-L?
Wherein,
Corrected sheet: 26 June 2007
Cy is C4-Cis alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3;, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH,
C(O)OR?, -COR?, -SH, -SR®, -OR®and acyl;
L' and L? are the same or different and independently C,—Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; -CF;, -OCF;, alkyl, alkoxy, acylamino and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0),-, -N(R®)-, -C(O)N(R®)-, -SO,N(R®)-, N(R®)C(O)-, N(R®)SO,-, and -N(R®)-C(O)-N(R'%)-; c) L=Cy-(CH;)m-W-
Wherein,
Cy is Cy-C45 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF;, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH,
C(O)OR?®, -CORS3, -SH, -SR®, -OR® and acyl mis 0,1,2,3,40r5;
Corrected sheet: 26 June 2007
W is selected from the group consisting of a single bond, -O-, -S-, -
S(0)-, -S(0)z, N(R), COIN(RY)-, -SON(R®)-, N(R)C(O}-, N(R®)SOx-, and —N(R®-C(0)-N(R*)-; ] d) L=L'-w-?
L' and LZ are the same or different and independently selected from
C,~C; alkyl, which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; —CF3, -OCF; alkyl, alkoxy, acylamino, alkylamino;
W is selected from the group consisting of a single bond, -0-, -S-, -
S(O)- -S(O)z-, -N(R®)-, -C(O)N(R®)-, -SO,N(R?)-, N(RH)C(O), N(R)SO-, and -N(R%)-C(0)-N(R")-;
R® and R' are the same or different and are independently selected from H, C+-Ce alkyl, C.-C cycloalkyl, C4-Co heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl;
Z is a single bond or is selected from -CHo-, -CH,CH,-,-CH=CH-, C3-C; cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C-C, alkyl; or a pharmaceutically acceptable sait thereof.
As with any group of structurally related compounds which possess a particular utility, certain groups are preferred for the compounds of the Formula (1), (Ia) and (Ib) in their end use application.
In certain preferred embodiments R' is selected from the group consisting of C4-Cso alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heteracycloalkyl, heteroaryl, C4-Cs heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl each of which may be substituted as previously stated.
In another embodiment it is preferred that R! is selected from the group consisting of H, hydroxyalkyl, alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aminoalkyl, and heterocycloatky! each of which may be substituted as previously stated. in another embodiment it is preferred that R' is selected from the group consisting of H, hydroxyalkyl, alkyl, alkoxyalkyl, and aminoalkyl each of which may be substituted as previously stated.
In another embodiment it is preferred that if R' is alkyl or heteroalkyl then it is not substituted by a cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
Particularly preferred values of R' are: 5H: methyl; (pyridin-2-yl)methyi; (pyridin-3-yl)methyl; ethyl; 2-hydroxy-ethyl, 2-(pyridin-2- yhethyl; 2-(pyridin-3-yl)ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl. 2-(morpholin-4-yl)-ethyl; 2- (piperidin-1-yl)-ethyl; 2-(pyrollidin-1-yl)-ethyl; 2-diethylamino-ethyl; propyl; 2,3-di-hydroxy- propyl; 3-hydroxy-propyl; 3-methoxy-propyt; 3-isopropoxy-propyl, 2,2-dimethyl-propyl; 3- dimethylamino-propyl; 3-dimethylamino-2,2-dimethyl-propy!; 3-(2-oxo-pyroliidin-1-yl)- : 10 propyl, 3-(morpholin-4-yl)-propyl; 3-(imadazol-1-yl)-propyl; 3-(4-methyl-piperidin-1-yf)- propyl; 3-(pyrollidin-1-yl)-propyl; 4-dimethylamino-butyl; 5-hydroxy-pentyl; allyl; benzyl; and 3,4,5-trimethoxybenzyl.
In certain preferred embodiments R? is selected from the group consisting of H, Halogen, 15 C4-Cso alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C, heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl each of which may be substituted as previously stated.
In another embodiment it is preferred that R? is selected from the group consisting of H, alkyl, arylalkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, and L, each of which may be substituted as previously stated. in another embodiment it is preferred that R? is selected from the group consisting of H, hydroxyalkyl, alkyl, alkoxyalkyl, and aminoalkyl each of which may be substituted as previously stated.
In another embodiment it is preferred that if R? is alkyl or heteroalkyl then it is not substituted by a cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
Particularly preferred values of R? are: H; methyl; benzylamino-methyl; dibenzylamino- methyl; [2-(4-fluoro-phenyl)-acetylamino}-methyl; [2-(4-methoxy-phenyl)-acetylamino}- methyl; 4-methoxy-benzylamino-methyl; benzyloxy-methyl; phenylacetylamino-methyl; 1- amino-2-phenyl-ethyl; 2-benzylamino-ethyl; 2-(3-methoxy-phenyl)-ethyl; 2-(pyridin-3- ylethyl; 2-(2-phenoxyacetylamino)-ethyl; 2-benzenesulphonylamino-ethyl; 2-phenyl-ethyl; isopropyl; 2-phenyl-propyl; 3-phenyl-propyl; 3-phenoxy-propyl; 3-(1H-indol-3-yl)-propyl; 4- methoxy-phenyl; 4-fluoro-phenyl; 4-benzyloxy-3-methoxy-phenyl; isobutyl, cyclohexyl;
Claims (55)
1. A compound of the formula (1): fy N wl] O—R* NTS R1 Formula wherein R' is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR* and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF,, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C(O)OR®, -COR?®, -SH, -SR®, -OR®and acyl; orR' = L; R? is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyil, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR® and acyl, each of which may be Corrected sheet: 26 June 2007
J) H unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, =O, =S, -CN, -NO,, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkyny!, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,
alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfony!, aminoalkyl, alkoxyalkyl, -COOH, -COR?®, -C(O)OR?, -SH, -SR®, -OR®and acyl;
orR2=L;
R® is selected from the group consisting of H, C, -C; alkyl, and acyl; or a metal ion selected from sodium, calcium, magnesium;
X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -NO,, -CF;, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH - C(O)OR?®, -CORS?, -SH, -SR®, -OR® acyl and -NR'R?;
Each R* is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R°® is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
Each R” and R® are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
L is selected from the group consisting of:
a) L=Cy-L'-W-
Wherein Corrected sheet: 26 June 2007
1} b}
Cy is Cy-Cys alkyl, kyl heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl any of which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen, =0, =S, -CN, -NO,, -CF,, -OCF;, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyi, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,
arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, - C(O)OR®, -COR?, -SH, -SR®, -OR® and acyl.
L' is selected from the group consisting of C; —Cs alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; alkyl, alkoxy, acylamino, and alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, - S(0)-, -S(0)z, -N(R®)-, -C(OIN(R®)-, -SON(R®)-, N(R*)C(O)-, N(R®)SO-, and —N(R®%)-C(O)-N(R)-;
b) L=Cy-L'-W-L? Wherein,
Cy is C4-C4s alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl any of which may be optionally substituted one or more substituents independently selected from the group consisting of:
halogen, =O, =S, -CN, -NO,, -CF;, -OCF3;, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,
heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C(O)ORS®, -COR?®, -SH, -SR®, -OR®and acyl;
L' and L? are the same or different and independently C,—Cs alkyl,
which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN; -NO,; -CF,, -OCF3, alkyl, alkoxy, acylamino and alkylamino;
Corrected sheet: 26 June 2007
W is selected from tive croup consisting of a single bond, -O-, -S-, - S(O)-, -S(0),~, -N(R®)-, -C(O)N(R%)-, -SO.N(R®)-, N(R®)C(O)-, N(R*)SO.-, and -N(R®)-C(O)-N(R°)-;
c) L=Cy-(CHz)m-W- Wherein,
Cy is C,4-Cys alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl any of which may be optionally substituted one or more substituents independently selected from the group consisting of: : halogen, =O, =S, -CN, -NO,, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, aryisuifonyl, aminosulfonyl, aminoalkyi, alkoxyalkyl, -COOH, C(O)OR?®, -COR?, -SH, -SR®, -OR®and acyl;
mis 0, 1,2, 3,40r5;
W is selected from the group consisting of a single bond, -O-, -S-, -
S(O), -S(0)z-, -N(R®)-, -C(OIN(R®)-, -SO:N(R®)-, N(R®)C(O)-, N(R%)SO,-,
and —-N(R°)-C(0O)-N(R'%)-; d) L=L"-w-L?
L' and L? are the same or different and independently selected from C,—Cs alkyl, which may be optionally substituted one or more substituents independently selected from the group consisting of: halogen; =O; =S; -CN;
-NO,; —CF3, -OCF; alkyl, alkoxy, acylamino, alkylamino;
W is selected from the group consisting of a single bond, -O-, -S-, - S(O), -S(0)z-, -N(R%)-, -C(O)N(R®)-, -SO2N(R°®)-, N(R®)C(O)-, N(R®)SO.-, and -N(R®)-C(O)-N(R")-;
R® and R' are the same or different and are independently selected from H, C;-Cs alkyl, C4-Cy cycloalkyl, C4-Cqy heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl;
Z is selected from -CH,-, -CH,CH,-, -CH=CH-, or C;-C¢ cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C{-C,4 alkyl; or a pharmaceutically acceptable salt thereof.
Corrected sheet: 26 June 2007
2. A compound of claim 1 wherein Z is -CH,-, -CH,CH,-, -CH=CH-, or C;-Cs cycloalkyl, and Z is attached at ring position 5 or 6.
3. A compound of claim 1 or 2 wherein Z is -CH=CH-, and is attached at ring position s 5.
4. A compound of any one of claims 1 to 3 wherein R® = H.
5. A compound of any one of claims 1 to 4 wherein X and Y = H.
6. A compound according to any one of claims 1 to 5 wherein R* = H.
7. The compound according to any one of claims 1 to 6 wherein R' is selected from the group consisting of: H, hydroxyalkyl, alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aminoalkyl, and heterocycloalkyl, each of which may be unsubstituted or substituted.
8. The compound according to any one of claims 1 to 7 wherein R' is selected from the group consisting of: H; methyl, (pyridin-2-yl)methyl; (pyridin-3-yl)methyl; ethyl; 2- hydroxy-ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl; 2- (morpholin-4-yl)-ethyl; 2-(piperidin-1-yl)-ethyl, 2-(pyrollidin-1-yl)-ethyl; 2-diethylamino- ethyl; propyl; 2,3-di-hydroxy-propyl; 3-hydroxy-propyl; 3-methoxy-propyl; 3-isopropoxy- propyl; 2,2-dimethyl-propyl; 3-dimethylamino-propyl; 3-dimethylamino-2,2-dimethyl-propyl; 3-(2-oxo-pyrollidin-1-yi)-propyl; 3-(morpholin-4-yl)-propyl; 3-(imadazol-1-yl)-propyl; 3-(4- methyl-piperidin-1-yl)-propyl; 3-(pyrollidin-1-yl)-propyl; 4-dimethylamino-butyl; 5-hydroxy- pentyl; allyl; benzyl; 3,4,5-trimethoxybenzyl.
9. A compound according to any one of claims 1 to 8 wherein R? is selected from the group consisting of H, alkyl, arylalkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, each of which may be unsubstituted or substituted.
10. A compound according to any one of claims 1 to 9 wherein R? is: H; methyl; benzylamino-methyl; dibenzylamino-methyl; [2-(4-fluoro-phenyl)-acetylamino]-methyl; [2- (4-methoxy-phenyl)-acetylamino]-methyl; ~~ 4-methoxy-benzylamino-methyl; benzyloxy- methyl; phenylacetylamino-methyl; 1-amino-2-phenyl-ethyl; 2-benzylamino-ethyl; 2-(3- methoxy-phenyl)-ethyl; 2-(pyridin-3-yl)ethyl; 2-(2-phenoxyacetylamino)-ethyl; 2- benzenesulphonylamino-ethyl; 2-phenyl-ethyl; isopropyl; 2-phenyl-propyl; 3-phenyl-propyl; 3-phenoxy-propyl; 3-(1H-indol-3-yl)-propyl; 4-methoxy-phenyl, 4-flucro-phenyl; 4- Amended sheet: 26 June 2007 benzyloxy-3-methoxy-phenyl; isobutyl; cyclohexyl; octyl; benzyl, pyridin-2-yl; pyridin-4-yl; thiophen-3-yl; benzylsulfanyl, and 2-phenylmethansulfanyl.
11. The compound of claim 1 wherein the compound is selected from compounds, and s their pharmaceutically acceptable salts, selected from the group consisting of Q Oey 4 N N-Hydroxy-3-[1-(3-hydroxy-propyl)-2-(2-phenyk- Y propyl)-1H-benzimidazol-5-yl}-acrylamide OH [o] Oey” N H N-Hydroxy-3-[1-(3,4,5-trimethoxybenzyl)-2-(2- or 0, phenyl-ethyl)-1H-benzimidazol-5-yl]-acrylamide 3 Pp d Oye ) N-Hydroxy-3-[2-(4-benzyloxy-3-methoxy-phenyl)- 1-methyl-1H-benzimidazole-5-yi}-acrylamide an d 1 on N-Hydroxy-3-[2-(4-benzyloxy-3-methoxy-phenyl)- AT 1-(3-hydroxy-propyl)-1H-benzimidazole-5-yl}- N acrylamide OH
\ . gt ey N-Hydroxy-3-[1-(2-hydroxy-ethyl)-2-(4-methoxy- oD I J phenyl)-1H-benzimidazole-5-yl}-acrylamide lo] \ x OH od )—~ ] N-Hydroxy-3-[1-(2,3-hydroxy-propyl)-2-(4- Na methoxy-phenyl)-1 H-benzimidazole-5-yl}- OK acrylamide 4 ° Oye OI H N-Hydroxy-3-[2-(4-benzyloxy-3-methoxy-phenyl)- Cr 1-(2,3-hydroxy-propyl)-1 H-benzimidazole-5-yi}- OH acrylamide Oe =" not < H N-Hydroxy-3-{1-(2,3-hydroxy-propy!)-2-(2-phenyl- N OH ethyl)-1H-benzimidazol-5-yl}-acrylamide r OH BN dl a <0 N-Hydroxy-3-[1-(2,3-hydroxy-propyl)-2-(2-pyridyl)- re 1H-benzimidazol-5-yi]-acrylamide OH [a] N NN OH OTT i N-Hydroxy-3-{1-(2-hydroxy-ethyl)-2-(4-pyridyl)- N 1H-benzimidazol-5-yl]-acrylamide HO Q Vi N x LOH OL N-Hydroxy-3-{1-(3-hydroxy-propyl)-2-(4-pyridyi)- N 1H-benzimidazol-5-yl}-acrylamide OH
Oy So = < n N-Hydroxy-3-[1 -(3-pyridylmethyl)-2-(2-phenyt- PEN ethyl)-1H-benzimidazol-5-yll-acrylamide N =! lo}
N. ™N JOH . ¢ hs < N N-Hydroxy-3-1-(3-hydroxy-propyl)-2-(2-pyridyl- y 1 H-benzimidazol-5-yl}-acrylamide “om fo] Oe SA yor - H N-Hydroxy-3-[1 .(3-hydroxy-propyt)-2-phenethyt- 3 1 H-benzimidazol-5-yl}-acrylamide OH 7 N ~ OH Q ~r™ ef N-Hydroxy-3-{1 {(3-methoxy-propyl)-2-phenethyl- { l 1 H-benzimidazol-5-yi}-acrylamide [¢} / Oy Soy = < H N-Hydroxy-3-(2-phenethyl-1-(pyridin-2-y)methyl- IS 1H-benzimidazol-5-yl)-acrylamide Oy Nn LOH ¢ R N-Hydroxy-3-{1-(3-Dimethylamino-2,2-dimethyl { [ proppyl)-2-phenethyl-1 H-benzimidazo}-5-yl}- ¥ acrylamide
$0 oO dH N Np OH — hd H N-Hydroxy-3-[2-phenethyl-1-(2-pyridin-2-yl-ethyl- 1H-benzimidazol-5-yl]-acrylamide ®, OQ o sone NOH N-Hydroxy-3-[2-Benzyloxymethyl-1-(3-hydroxy- ol H S = propyl-1H-benzimidazol-5yl]-acrylamide OH
[0] A N NN N-oN DO H N-Hydroxy-3-[1-(3-hydroxy-propyl)-2-thiophen-3- Y yl-1H-benzimidazol-5-yl]-acrylamide OH prs OH 4 N . A H N-Hydroxy-3-[1-(3-hydroxy-propyl)-2-isobutyl-1H- Y benzimidazol-5-yl]-acrylamide OH
[0] —_ A Na ‘ H N-Hydroxy-3-[2-isobutyl-1-(2-pyridin-2-yl-ethyl)- J 1H-benzimidazol-5-yl]-acrylamide “ON N\A Corrected sheet: 26 June 2007 ee N-Hydroxy-3-[1-(3-hydroxy-propyl)-2-octyl-1H- H { benzimidazol-5-yl}-acrylamide l OH 0 N Nn no =: H N-Hydroxy-[2-cyciohexyl-1-(3-hydroxy-prapyl)- N 1H-benzimidazok-5-yll-acrylamide oH N-Hydroxy-3-(2-isobutyl-1-phenethyl-1H- ~~ benzimidazol-5-yl]-acrylamide N A Oy J on N-Hydroxy-3-(1,2-Diphenethyl-14-benzimidazol- = - N 5-yl]-acrylamide ot aS N-Hydroxy-3-(2-phenethyl-1-(2-pyridin-3-yl-ethyl)- _ \ N Xx no" ae 1H-benzimidazol-5-yl}-acrylamide { ~ —N
Q N-Hydroxy-3-[2-Benzyloxymethyi-1-(2-pyridin-3- ) rr ethyl)-1H-benzimidazol-5-yl}-acrylamide \ N-Hydroxy-3-[1-(3-Hydroxy-propyl)-2-isobutyl-1 H- Cert on benzimidazol-5-yi}-propionamide ; N ) OH N-Hydroxy-3-{1-[3-(2-oxo-pyrrolidin-1-yl)-propyl}- Op 2 oH 2-phenethyl-1H-benzimidazol-5-yl}-acrylamide Ne SO Y N-Hydroxy-3-[1-(3-morpholin-4-propyl}-2- Op J on Phenethyl-1H-benzimidazol-5-yl}-acrylamide 2 NN d Oe on 3H5-(2-Hydrocarbamoykvinyl)-2-phenethyl-1H- S000 i benzimidazol-1-yf}-propionic acid 4 oA,
N-Hydroxy-3-(1-Benzyl-2-phenethyl-1H- [eo] . . . Oy re benzimidazol-5-yl}-acrylamide N 0 N-Hydroxy-3-(1-Benzyl-2-isobutyl-1H- ’ [o} PE . —¢ J on benzimidazol-5-yl}-acrylamide ’ N . N Oo N-Hydroxy-3-(1-benzyl-1 H-benzimidazol-5-yl}- ye acrylamide < H N O N-Hydroxy-3-(2-phenethyl-1-propyl-1H-
a . 8 o« benzimidazol-5-yl}-acrylamide Cd —< ORE r N-Hydroxy-3-(1-propyl-1H-benzimidazol-5-y(}- N J on acrylamide 7] = N N { / N-Hydroxy-3-(1-Ethyl-2-phenethyl-1H- Omer benzimidazol-5-yl}-acrylamide N H { N
[2 “J ® N-Hydroxy-3-(1-Ethyl-1H-benzimidazol-5-yl}- AG on acrylamide ¢ i H NF N N-Hydroxy-3-[2-(2-phenyl-propyl)-1-(2-pyridin-3- lo} I . J oH yl-ethyl)-1H-benzimidazol-5-yl]-acrylamide Oey NF 2 N-Hydroxy-3-[1-(2-pyridin-2-yl-ethyl)-1H-
[0] Lo. . N SS benzimidazol-5-yl}-acrylamide < | H 2 NJ N-Hydroxy-3-(1-Ethyi-2-methyl-1H-benzimidazol-
[0] . y Aon 5-yl]-acrylamide — H { N-Hydroxy-3-[1-(2-morpholin-4-yl-ethyl)-2- 0 Lo . phenethyl-1H-benzimidazol-5-yl}-acrylamide Oe { 0) Corrected sheet: 26 June 2007
[15 SEER ¢ N-Hydroxy-3-[2-phenethyl-1-(3,4,5-trimethoxy-
J i. benzyl)-1H-benzimidazol-5-yl]-propionamide N A a / N-hydroxy-3-[1-(3-hydroxy-propyl)-2-isopropyl- pen on 1H-benzimidazol-5-yl]-acrylamide yA N-Hydroxy-3-(1-methyl-2-phenethyl-1H- aN A om benzimidazol-5-yl)-acrylamide N / N-Hydroxy-3-(1-methyl-1H-benzimidazol-5-yl)- ye acrylamide < L H / N-Hydroxy-3-(2-phenethyl-1H-benzimidazol-5-yl)-
QO . / J on acrylamide N N-Hydroxy-3-(1H-benzimidazol-5-yl)-acrylamide
[0] N H Corrected sheet: 26 June 2007
- (ho N-Hydroxy-3-[1-methyl-2-(3-phenyl-propyl)-1H- W benzimidazol-5-yl]-acrylamide 0 — x OH h N-Hydroxy-3-(1,2-dimethyl-1H-benzimidazol-5-yl]- « Ton acrylamide 4 oS N” SAGAS / N-Hydroxy-3-[1-methyl-2-(phenylacetylamino- Oy 0 methyl)-1H-benzimidazol-5-yl]-acrylamide
—. p AY H h N-[5-(2-Hydroxycarbamoyi-vinyl)-1-methyl-1H- Q benzimidazol-2-ylmethyl]-isonicotinamide i" [0] NH N = LOH AA, Ty / N-Hydroxy-3-[1-(3-imidazol-1-yl-propyl)-2- aN y « 9 on phenethyl-1H-benzimidazol-5-yl]-acrylamide INT \ Ch N-Hydroxy-3-[1-(4-dimethylamino-butyl)-2- a y « Q on phenethyl-1H-benzimidazol-5-yl]-acrylamide N Uy N \ Corrected sheet: 26 June 2007
N-Hydroxy-3-(3-benzyl)-2-phenethyl-3H- je benzimidazol-5-yl}-acrylamide [s] Orie ‘
N . N-Hydroxy-3-(3-methyl-2-phenethyl-3H- ay! «J on benzimidazo-5-yll-acrylamide - SORE
N . N-Hydroxy-3-[2-(benzylamino-methyl)-1-methyl-
Q . 1H-benzimidazol-5-yi]-acrylamide NH WN x NCH \¢ N N / N-Hydroxy-3-{2-[(dibenzylamino)-methyl]}-1- _ methyl-1H-benzimidazol-5-yl}-acrylamide Cd N xR OH / N-Hydroxy-3-{2-{(4-methoxy-benzylamino)- 4 methyl}-1-methyl-1H-benzimidazol-5-yl}- Q o acrylamide MS SOReE N / N-Hydroxy-3-[1-(3-dimethyiamino-propy!)-2- Oe on phenethyl-1H-benzimidazol-5-yll-acrylamide : N N— /
N-Hydroxy-3-[2-(benzylamino-methyl)-ethyl-1H- Q o benzimidazol-5-yl}-acrylamide a; SORA N-Hydroxy-3-(2-(benzyl-1-methyl-3-oxo-1H- Li benzimidazol-5-yl)-acrylamide Sorte H N / N-Hydroxy-3-[1-(2-diethylamino-ethyl)-2- Op Sot on Phenethyl-1H-benzimidazol-5-ylj-acrylamide = 7 = TN N Ve " N-Hydroxy-3-[2-phenethy!-1-(piperidin-1-yl-ethy!)- CH lon 1H-benzimidazol-5-yll-acrylamide N [ ) O N-Hydroxy-3-{2-[(dibenzylamino)-methyl]- 1-ethyl- : NA 1H-benzimidazol-5-yl}-acrylamide Qs N x OH Cer N-Hydroxy-3-(2-{{2-(4-fluoro-phenyl)- WARN ino}- 1-methyl-1H4-benzimi l- F (a 2 on acetylamino]-methyl}-1-methy enzimidazo dd W 5-yl)-acrylamide /
» 4 LY N-Hydroxy-3-[1-ethyl-2-(2-phenylacetylamino- 9 ethyl)-1H-benzimidazol-5-yl]-acrylamide < i HN N nN, OH Nv ORS. N N N-Hydroxy-3-[2-(2-Benzenesulfonylamino-ethyl)- {Ho 0 1-ethyl-1H-benzimidazol-5-yl]-acrylamide — SY N N N-Hydroxy-3-[2-phenethyl-1-(2-pyrrolidin-1-yl-
[0] sl. . {)- Lg or ethyl)-1H-benzimidazol-5-yl]-acrylamide 9 _ H b N-Hydroxy-3-{1-ethyl-2-[2-(2-phenoxy-
7 . i» _ _ . . - _ _ Oe od acetylamino)-ethyl]-1H-benzimidazol-5-yl] HN NNO acrylamide = : N N-Hydroxy-3-[2-(2-benzylamino-ethyl)-1-ethyl-1H- {)- N 0 benzimidazol-5-yl]-acrylamide — HN— N xn OH \¢ ORE { N-Hydroxy-3-[1-(2,2-dimethyl-propyl)-2- as « ? om phenethyl-1H-benzimidazol-5-yl]-acrylamide . Corrected sheet: 26 June 2007
® .. & N-Hydroxy-3-[1-(1-Benzyl-piperidin-4-yl)-2- jo] I .
wo. Ar $<) phenethyl-1H-benzimiazo-5-yllacrylamide Ny >" Oo N-Hydroxy-3-[1-(2-hydroxyethyl)-2-phenethyl-1H- benzimidazol-5-yl}-acrylamide [o] RSs YAY ZN ( wo i -&) N-Hydroxy-3-[1-(5-hydroxy-pentyl)-2-phenthyl- ~ N AO, 1H-benzimidazol-5-yl]-acrylamide N-Hydroxy-3-(1-allyl-2-phenethyl-1H- i =~ benzimidazol-5-yl)-acrylamide eyes HK) NP —" 3 ¢ CH; N-Hydroxy-3-(1-(3-isopropoxy-propyl)-2- wo Ser a, phenethyl-1H-benzimidazol-5-yl)-acrylamide N = \ Von HC Corrected sheet: 26 June 2007
N-Hydroxy-3-{1-[3-(4-methyl-piperzin-1-yl)-2- = phenethyl-1 H-benzimidazol-5-yl}-acrylamide HO N No \ ~0) N ( § ho HC N-Hydroxy-3-[2-phenethyl-1-(3-pyrrolidin-1-yl- 2 propyh)-1H-benzimidazol-5-yl}-acrylamide Ory N { l N-Hydroxy-3-[1-(3-Dimethylamino-2,2-dimethyl- 4% p o propyl)-2-(3-phenyl-propyl)-1H-benzimidazol-5- OT yll-acrylamide ol Z c / N-Hydroxy-3-{1-(3-Dimethylamino-2,2-dimethyl- . ay oA propyl)-2-[2-(4-fluoro-phenyl)-ethyl}-1H- N H benzimidazol-5-yl]-acrylamide & / N-Hydroxy-3-{2-(4-fluoro-phenyl)-ethyl}-1H- yp One benzimidazol-5-yi}-acrylamide N
&.. a N-Hydroxy-3-[1-(3-Dimethylamino-2,2-dimethyl- a2 ye propyl)-2-(2-pyridin-3-yl-ethyl)-1H-benzimidazol- NT < H 5-yl}-acrylamide lo / N-Hydroxy-3-[2-(2-pyridin-3-yl-propyl)-1H- »N \ Bi on benzimidazol-5-yl]-acrylamide N= ¢ H N H 2-[2-Phenethyl-1-(3,4,5-trimethoxy-benzyl)-1H- aN f benzimidazol-5-yl]-cyclopropanecarboxylic acid DOL i 9 hydroxyamide or a / N-Hydroxy-3-[2-benzylsulfanyl-1-(3- a Ay dimethylamino-2,2-dimethyl-propyl)-1H- s< H benzimidazol-5-yl]-acrylamide ¢ / N-Hydroxy-3-[1-(2-piperidin-1-yl-ethyl)-1H-
[0] se . , OR benzimidazol-5-yl]-acrylamide <, | H A N-Hydroxy-3-[1-(3-dimethylamino-2,2-dimethyl- an Aye y propyl)-2-phenylimethanesulfonyl-1H- — — .e . & ¢ H benzimidazol-5-yl]-acrylamide ¥ / Corrected sheet: 26 June 2007
N-Hydroxy-3-(2-benzyl-1-ethyl-1H-benzimidazol- Q 5-yl)-acrylamide ore 4 H / N-Hydroxy-3-(1-ethyl-2-[3-(1H-indol-3-yi)-propyi}- ~~ N 1H-benzimidazol-5-yl)-acrylamide I 3 N AA on SOAS iN N-Hydroxy-3-{1-(3-dimethylamino-2,2-dimethyl- o 0 propyl)-2-{2-(3-methoxy-phenyl)-ethyl}-14- Opry benzimidazol-5-yl)-acrylamide N H ‘ / N-Hydroxy-3-{2-(3-methoxy-phenyl)-ethyi}-1 H- DS 0 benzimidazol-5-yl}-acrylamide {3 X AO Re NH
=. \— H N N-Hydroxy-3-[1 -ethyl-2-(3-phenoxy-propyl)-1H- ax benzimidazol-5-yl}-acrylamide == ere ¢ H J (L)-N-Hydroxy-3-[2-(1-amino-2-phenyl-ethyl)-1- oO n iP om methyl-1H-benzimidazol-5-yl}-acrylamide ye Hy Ng N-Hydroxy-3-(3-oxy-2-pyridin-2-yl-1H- ~ % gi benzimidazol-5-yl]-acrylamide 4 PA NH O-or™ OH
N-Hydroxy-3-(2-{[2-(4-methoxy-phenyl)- oH yw 8 ., acetylamino]-methyl}-1-methyl-1H-benzimidazol- A HN 5.yl)-acrylamide / [o] . . 7 2-(1-Methyl-2-phenethyl-1H-benzimidazol-5-yl)- @ AN , . Nu cyclopropanecarboxylic acid hydroxyamide /
12. A pharmaceutical composition including a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable diluent, excipient or carrier.
13. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis.
14. A use according to claim 13 wherein the disorder is a proliferative disorder.
15. A use according to claim 14 wherein the proliferative disorder is cancer.
16. A compound according to any one of claims 1 to 11 for use in the treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis.
17. A compound according to any one of claims 1 to 11 for use in the treatment of a proliferative disorder.
18. A compound according to any one of claims 1 to 11 for use in the treatment of cancer.
19. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for use in modifying deacetylase activity.
20. A use according to claim 19 wherein the deacetylase activity is histone deacetylase activity. Amended sheet: 26 June 2007
21. A use according to claim 19 wherein the deacetylase activity is class | histone deacetylase activity.
22. A use according to claim 20 or 21 wherein the histone deacetylase is HDAC1.
23. A use according to claim 20 or 21wherein the histone deacetylase is HDACS.
24. A pharmaceutical composition according to claim 12 for use in modifying deacetylase activity.
25. A composition according to claim 24, wherein the deacetylase activity is histone deacetylase activity.
26. A composition according to claim 24, wherein the deacetylase active is class 1 histone deacetylase active.
27. A composition according to claim 25 or 26, wherein the histone deacetylase is HDACH1.
28. A composition according to claim 25 or 26, wherein the histone deacetylase is HDACS.
29. A compound according to any one of claims 1 to 11 for use in the treatment of a disorder that can be treated by the inhibition of histone deacetylase.
30. A compound according to any one of claims 1 to 11 for use in the treatment of a disorder selected from the group consisting of proliferative disorders (including cancer); Neurodegenerative diseases including Huntington's Disease, Polyglutamine disease, Parkinson's Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Progressive supranuclear palsy, Pick’s disease, Intracerebral haemorrhage, Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-related Amended sheet: 26 June 2007 macular degeneration, Rubeotic glaucoma; Inflammatory diseases and/or Immune system disorders including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, psoriasis, Crohn's Disease, Inflammatory bowel disease , Colitis Ulcerosa, Alcoholic hepatitis, Diabetes |, Sjoegrens’s syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, Systemic Lupus Erythematosus, Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar disease, schizophrenia, mania, depression and dementia; Cardiovascular Diseases including Heart failure, restenosis and arteriosclerosis; Fibrotic diseases including liver fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including Fungal infections, selected from Candida Albicans, Bacterial infections, Viral infections, selected from Herpes Simplex, Protozoal infections, selected from Malaria,- Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
31. A compound according to any one of claims 1 to 11 for use in inhibiting cell proliferation.
32. A compound according to any one of claims 1 to 11 for use in treatment of a neurodegenerative disorder.
33. A compound according to any one of claims 1 to 11 for use in the treatment of Huntington's Disease.
34. A compound according to any one of claims 1 to 11 for use in treatment of an inflammatory disease and/or immune system disorder.
35. A compound according to any one of claims 1 to 11 for use in the treatment of rheumatoid arthritis.
36. A compound according to any one of claims 1 to 11 for use in the treatment of systemic lupus erythematosus.
37. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for the treatment of a disorder that can be treated by the inhibition of histone deacetylase in a patient. Amended sheet: 26 June 2007
38. A use according to claim 37, wherein the disorder is selected from the group consisting of proliferative disorders (including cancer); Neurodegenerative diseases including Huntington’s Disease, Polyglutamine disease, Parkinson’s Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Progressive supranuclear palsy, Pick’s disease, Intracerebral haemorrhage, Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-related macular degeneration, Rubeotic glaucoma; Inflammatory diseases and/or Immune system disorders including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, psoriasis, Crohn's Disease, Inflammatory bowel disease , Colitis Ulcerosa, Alcoholic hepatitis, Diabetes , Sjoegrens’s syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, Systemic Lupus Erythematosus; Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar disease, schizophrenia, mania, depression and dementia; Cardiovascular Diseases including Heart failure, restenosis and arteriosclerosis; Fibrotic diseases including liver fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including Fungal infections, selected from Candida Albicans, Bacterial infections, Viral infections, selected from Herpes Simplex, Protozoal infections, selected from Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
39. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for inhibiting cell proliferation.
40. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for the treatment of a neurodegenerative disorder in a patient.
41. A use according to claim 40 wherein the neurodegenerative disorder is Huntington's Disease. Amended sheet: 26 June 2007
42. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for the treatment of an inflammatory disease and/or immune system disorder.
43. A use according to claim 42 wherein the inflammatory disease and/or immune system disorder is rheumatoid arthritis.
44. A use according to claim 42 wherein the inflammatory disease and/or immune system disorder is systemic lupus erythematosus.
45, A method for measuring an acetylated histone concentration in a biological sample using an enzyme-linked immunosorbant assay, the enzyme-linked immunosorbant assay including a combination of a primary capture antibody, or a portion thereof, and secondary detection antibody, or a portion thereof.
46. A method according to claim 45, wherein the primary capture antibody is selected from the group consisting of: an anti-H3 monoclonal antibody, an anti-acetylated H3 polyclonal antibody, a goat anti-H3 polyclonal antibody, a goat anti-acetylated H3 polyclonal antibody and a combination thereof.
47. A method according to claim 45 or 46, wherein the secondary detection antibody is selected from the group consisting of. an anti-H3 monoclonal antibody, an anti-acetylated H3 polyclonal antibody, a goat anti-H3 polyclonal antibody, a goat anti-acetylated H3 polyclonal antibody and a combination thereof.
48. A method according to claim 45, wherein the primary capture antibody is a mouse anti-H3 monoclonal antibody and the secondary detection antibody is a rat anti-acetylated H3 polyclonal antibody.
49. A method for identifying the pharmacological effect of a histone deacetylase inhibitor in a cell, the method including the steps of: a) providing a cell that has been treated with a histone deacetylase inhibitor; b) measuring the acetylated histone concentration in the cell by a method according to any one of claims 45 to 48; and c) comparing the acetylated histone concentration with the acetylated histone concentration of a control sample. Amended sheet: 26 June 2007
50. A method according to claim 49, wherein the control sample is derived from a cell that has not been treated with a histone deacetylase inhibitor.
51. A method according to claims 49 or 50, wherein the cell is a tumour cell.
52. A method for identifying the pharmacological effect of a histone deacetylase inhibitor in a subject, the method including the steps of: a) obtaining a biological sample from a subject that has been treated with a histone deacetylase inhibitor; b) measuring the acetylated histone concentration in the biological sample in vitro by a method according to any one of claims 45 to 48; and c) comparing the acetylated histone concentration with the acetylated histone concentration of a control sample.
53. A method according to claim 52, wherein the control sample is a biological sample derived from a subject that has not been treated with a histone deacetylase inhibitor.
54. A method according to any one of claims 45 to 48, 52 to 53, wherein the biological sample is selected from the group consisting of tissue, blood, serum, plasma, urine, saliva and a combination thereof.
55. A method according to claim 49 or claim 52, wherein the histone deacetylase inhibitor includes a compound according to any one of claims 1 to 11. Amended sheet: 26 June 2007
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50421403P | 2003-09-22 | 2003-09-22 |
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|---|---|
| ZA200602181B true ZA200602181B (en) | 2007-06-27 |
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| ZA200602181A ZA200602181B (en) | 2003-09-22 | 2004-09-21 | Benzimidazole derivatives: Preparation and pharmaceutical applications |
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| CN (1) | CN100546980C (en) |
| AR (1) | AR104985A2 (en) |
| ES (1) | ES2348360T3 (en) |
| ZA (1) | ZA200602181B (en) |
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| TW201245115A (en) * | 2011-01-24 | 2012-11-16 | Chdi Foundation Inc | Histone deacetylase inhibitors and compositions and methods of use thereof |
| CN103755595A (en) * | 2012-12-25 | 2014-04-30 | 中南大学 | Hydroxamic acid derivative and application thereof |
| EP3394052B1 (en) * | 2015-12-22 | 2021-07-28 | Kancera AB | Bicyclic hydroxamic acids useful as inhibitors of mammalian histone deacetylase activity |
| CN106565823B (en) * | 2016-11-10 | 2020-09-11 | 珠海诺贝尔国际生物医药研究院有限公司 | Eph receptor small molecule inhibitor and preparation method thereof |
| CN106946873B (en) * | 2017-03-31 | 2020-03-27 | 牡丹江医学院 | Medicine for treating facial nerve injury and preparation method thereof |
| CN110511213B (en) * | 2018-05-22 | 2021-10-19 | 成都先导药物开发股份有限公司 | an immunomodulator |
| CN110950848B (en) * | 2018-09-27 | 2024-03-26 | 徐诺药业 | Synthesis and application of novel aminopyrazole derivative |
| WO2021027722A1 (en) * | 2019-08-09 | 2021-02-18 | 成都先导药物开发股份有限公司 | Immunomodulator |
| CN112824398B (en) * | 2019-11-20 | 2022-10-21 | 成都先导药物开发股份有限公司 | an immunomodulator |
| AU2021299350B2 (en) * | 2020-07-03 | 2024-12-05 | Nihon Nohyaku Co., Ltd. | Anticoccidial agent and method for using the same |
| CN118459418B (en) * | 2024-04-26 | 2025-04-08 | 河北中医药大学 | Hydroxamic acid HDAC inhibitor and application thereof in preparation of antitumor drugs |
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| DK1233958T3 (en) * | 1999-11-23 | 2011-10-17 | Methylgene Inc | Inhibitors of histone deacetylase |
| US20040091951A1 (en) * | 2002-02-07 | 2004-05-13 | Axys Pharmaceuticals, Inc. | Assay for measuring acetylation or deacetylation activity of an enzyme |
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2004
- 2004-09-21 ES ES04775628T patent/ES2348360T3/en not_active Expired - Lifetime
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| AR104985A2 (en) | 2017-08-30 |
| CN100546980C (en) | 2009-10-07 |
| ES2348360T3 (en) | 2010-12-03 |
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