U.S. patent application number 12/839874 was filed with the patent office on 2010-11-11 for novel 2-oxo-heterocyclic compounds and the pharmaceutical compositions comprising the same.
This patent application is currently assigned to Korea Research Institute of Bioscience and Biotechnology. Invention is credited to Hyo Kon CHUN, Tae Gyu CHUN, Gyoon Hee HAN, Sang Bae HAN, Yung Hee KHO, Hwan Mook KIM, Chang Woo LEE, Hee Yoon LEE, Ho Jae LEE, Jin Ha LEE, Ki Hoon LEE, Bum Woo PARK, Song Kyu PARK, Dong Kyu RYU.
Application Number | 20100286207 12/839874 |
Document ID | / |
Family ID | 33459359 |
Filed Date | 2010-11-11 |
United States Patent
Application |
20100286207 |
Kind Code |
A1 |
KHO; Yung Hee ; et
al. |
November 11, 2010 |
Novel 2-Oxo-Heterocyclic Compounds And The Pharmaceutical
Compositions Comprising The Same
Abstract
The present invention is related to new 2-oxo-cyclic compound,
the process for preparing them and a pharmaceutical composition
comprising the same. The present invention provides a
pharmaceutical composition for preventing and treating the
inflammatory disease comprising the pain or inflammation caused by
rheumatic disease, for example, rheumatoid arthritis,
spondyloarthopathies, gout, osteoarthritis, systemic lupus
erythematosus and juvenile arthritis, and inflammatory syndrome for
example, from myositis, gingivitis, synovitis, ankylosing
spondylitis, burstitis, burns and scar, inflammatory Crohn's
disease, Types I diabetes. therefore, it can be used as the
therapeutics for treating and preventing inflammatory diseases.
Inventors: |
KHO; Yung Hee; (Daejeon,
KR) ; HAN; Gyoon Hee; (Gyeonggi-do, KR) ; LEE;
Ho Jae; (Daejeon, KR) ; PARK; Bum Woo; (Seoul,
KR) ; CHUN; Hyo Kon; (Daejeon, KR) ; KIM; Hwan
Mook; (Daejeon, KR) ; PARK; Song Kyu;
(Daejeon, KR) ; HAN; Sang Bae; (Chungcheongbuk-do,
KR) ; RYU; Dong Kyu; (Daejeon, KR) ; CHUN; Tae
Gyu; (Daejeon, KR) ; LEE; Jin Ha; (Daejeon,
KR) ; LEE; Chang Woo; (Daejeon, KR) ; LEE; Ki
Hoon; (Daejeon, KR) ; LEE; Hee Yoon; (Daejeon,
KR) |
Correspondence
Address: |
HOGAN LOVELLS US LLP;IP GROUP, COLUMBIA SQUARE
555 THIRTEENTH STREET, N.W.
WASHINGTON
DC
20004
US
|
Assignee: |
Korea Research Institute of
Bioscience and Biotechnology
Daejeon
KR
|
Family ID: |
33459359 |
Appl. No.: |
12/839874 |
Filed: |
July 20, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10557085 |
Sep 19, 2006 |
|
|
|
PCT/KR2004/001169 |
May 17, 2004 |
|
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12839874 |
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Current U.S.
Class: |
514/336 ;
514/346; 514/422; 514/424; 546/280.4; 546/291; 548/527;
548/550 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 207/26 20130101; C07D 409/06 20130101; C07D 207/38 20130101;
A61P 19/02 20180101; C07D 211/86 20130101 |
Class at
Publication: |
514/336 ;
548/550; 514/424; 548/527; 514/422; 514/346; 546/291;
546/280.4 |
International
Class: |
A61K 31/4436 20060101
A61K031/4436; A61P 29/00 20060101 A61P029/00; A61P 19/02 20060101
A61P019/02; C07D 207/38 20060101 C07D207/38; A61K 31/4015 20060101
A61K031/4015; C07D 409/06 20060101 C07D409/06; A61K 31/4025
20060101 A61K031/4025; A61K 31/4412 20060101 A61K031/4412; C07D
211/86 20060101 C07D211/86 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 2003 |
KR |
10-2003-0031450 |
May 17, 2003 |
KR |
10-2003-0031451 |
May 6, 2004 |
KR |
10-2004-0031841 |
May 7, 2004 |
KR |
10-2004-0032263 |
May 12, 2004 |
KR |
10-2004-0033387 |
May 12, 2004 |
KR |
10-2004-0033388 |
Claims
1-15. (canceled)
16. A novel compound represented by the following general formula
(I), the pharmaceutically acceptable salt or the isomer thereof:
##STR00120## wherein X is a hydroxyl group, --NHOH,
--NHOCH.sub.2Ph, ##STR00121## A is an hydrogen, A1 group or
##STR00122## A1 is a lower alkyl, lower alkenyl, lower alkynyl,
lower allyl group having C1 to C5 carbon atoms, a heterocyclic
group or aromatic aryl group selected from thiophenyl group,
naphtyl group, pyrrolyl group, furyl group and biphenyl group,
wherein the Y in A2 substituted is a lower alkyl group, lower
alkoxy group, nitro, halogen, amine, acetamide, carbonamide or
sulfonamide group, M is a lower alkyl group or phenyl group
substituted with R', of which R' is a hydrogen, lower alkyl or
lower alkoxy group, m and r is independently an integer of 1 to 5
respectively; p is an integer of 0, 1 or 2; n is an integer of 1 to
5; and dotted line means single bond or double bond.
17. A novel compound represented by the following general formula
(IV), the pharmaceutically acceptable salt or the isomer thereof:
##STR00123## wherein X is a hydroxyl group, --NHOH, --NHOCH2Ph,
##STR00124## Y is a lower alkyl group, lower alkoxy group, nitro,
halogen, amine, acetamide, carbonamide or sulfonamide group; M is a
lower alkyl group or phenyl group substituted with R', of which R'
is a hydrogen, lower alkyl or lower alkoxy group; m and r is
independently an integer of 1 to 5 respectively; n is an integer of
1 to 5; and dotted line means single bond or double bond.
18. The compound according to claim 17, wherein said compound is
one selected from the group consisting of:
3-[1-(2,4-Dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-yl]N-hydrox-
ypropionamide,
N-hydroxy-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid,
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3--
yl)-propionamide,
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy
propionamide,
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pr-
opionamide,
N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionam-
ide,
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pro-
pionic acid,
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,
3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propio-
nic acid,
3-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-pr-
opionic acid,
3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid,
3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid,
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-pyridin-2-yl-p-
ropionamide,
N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pro-
pionamide,
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahy-
dro-pyridin-3-yl)-propionamide,
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridi-
n-3-yl)-propionamide,
N-benzyloxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propion-
amide,
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)--
N-hydroxy-propionamide,
N-4-[5-(2-hydroxycarbamoyl-ethyl)-6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl-
]-phenyl-benzamide,
N-hydroxy-3-[1-(4-dimethylsulfonylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro--
pyridin-3-yl]-propionamide,
N-hydroxy-3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl-1,2,5,6-tetrahydr-
o-pyridin-3-yl]-propionamide,
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propio-
nic acid,
3-[1-(4-benzoylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3--
yl]-propionic acid,
3-[2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2-oxo-1,2,5,6-tetrahydro--
pyridin-3-yl]-propionic acid,
N-hydroxy-3-(2-oxo-1-phenethyl-piperidine-3-yl)-propionamide,
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydr-
oxy-acetamide,
2-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-acetamide,
N-hydroxy-2-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N--
hydroxy-acetamide,
N-hydroxy-2-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N-
-hydroxy-acetamide,
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N--
hydroxy-acetamide,
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid, (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,
(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,
[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid,
[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid,
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-N-hydroxy-acetamide,
(2-oxo-1-phenethyl-piperidine-3-yl)-acetic acid,
[2-oxo-1-(3-phenyl-propyl)-piperidine-3-yl]-acetic acid,
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy--
butylamide,
4-(1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-butylamid-
e,
N-hydroxy-4-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-
-butylamide, and
N-hydroxy-4-[2-oxo-1-(3-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-bu-
tylamide.
19. A novel compound represented by the following general formula
(V), the pharmaceutically acceptable salt or the isomer thereof:
##STR00125## wherein X is a hydroxyl group, --NHOH,
--NHOCH.sub.2Ph, ##STR00126## R is a lower alkyl, lower alkenyl,
lower alkynyl, lower allyl group having C1 to C5 carbon atoms, a
heterocyclic group or aromatic aryl group selected from thiophenyl
group, naphtyl group, pyrrolyl group, furyl group and biphenyl
group; n is an integer of 1 to 5; and dotted line means single bond
or double bond.
20. The compound according to claim 19, wherein said compound is
one selected from the group consisting of:
3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,
N-Benzyloxy-3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,
3-(1-Allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-propionamide,
N-hydroxy-3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide-
,
N-hydroxy-3-(1-(naphthalene-2-yl-methyl)-2-oxo-1,2,5,6-tetrahydro-pyridi-
n-3-yl)-propionamide, and
N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-1,2,5,6-tetrahydro-pyridin-3-
-yl]-propionamide.
21. A pharmaceutical composition comprising an efficient amount of
the compound represented by general formula (I), (IV) or (V)
according to any one of claims 16 to 20 or the pharmaceutically
acceptable salt thereof as an active ingredient in amount effective
to treat or prevent inflammatory diseases together with
pharmaceutically acceptable carriers or diluents.
22. A method for treating an inflammatory disease comprising the
pain or inflammation caused by rheumatic disease and inflammatory
syndrome which comprises administering a therapeutically effective
amount of a compound represented by general formula (I), (IV) or
(V) according to any one of claims 16 to 20 or the pharmaceutically
acceptable salt thereof.
23. A method according to claim 22, wherein said rheumatic disease
is selected from rheumatoid arthritis, spondyloarthropathies, gout,
osteoarthritis, systemic lupus erythematosus and juvenile
arthritis.
24. A method according to claim 22, wherein said inflammatory
syndrome is selected from myositis, gingivitis, synovitis,
ankylosing spondylitis, burstitis, burns and scar, inflammatory
Crohn's disease, and Type I diabetes.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel 2-oxo-heterocyclic
compounds as a potent anti-inflammatory agent and the
pharmaceutical compositions comprising the same.
BACKGROUND ART
[0002] The inflammation caused by mechanical scars or various
infection of bacteria et al is a normal response of human body
associated with an edema, a pain etc. Generally, the syndrome of
arthritic inflammation occurs temporally, however, it causes to
long-term and eventual deformity if it is progressed to be severe.
The arthritic disease can be classified into several diseases
according to the respective disease such as rheumatoid arthritis
(RA), rheumatic inflammation related disease etc. Among them, in
particular, arthritic inflammation is the most frequently occurred
and chronic disease characterized in the inflammatory change at the
synovial membrane of the inner layer of articular capsule, which
may progress to effect on all the joints of human body and become
worse to be a disabled person. A progressive arthritic disease such
as rheumatic arthritis gives rise to joint obstacle such as a joint
aberrance and acampsia, which often results in severe physical
disorder caused by the absence of effective treatment and
continuous aggravation of the disease.
[0003] It has been known that osteoarthritis (OA) correlates with
complex and multi-factors, however, most important factor among
them is the inflammation of synovial fluid. The injury of synovial
fluid may promotes the dissociation of proteoglycan (PG) as a
result of the interaction between synovial cells and cartilage
cells. The activated synovial cells reproduce numerous factors
which may induce the loss of articular cartilage, for example,
interleukin-1, tumor necrosis factor (TNF-.alpha.) and
prostaglandins. The direct injury of cartilage cells further
accelerates the reproduction of matrix metalloprotease (MMP)
activating enzymes such as collagenase, stromelysin and gellatinase
and various inflammatory mediators. Wherever the function of joint
cartilage reduces, it gives rise to occurring OA diseases. The
decrease of PGs at OA joint tissue reduces the resilence of
cartilage, which endows cartilage cell, subcartilaginous osteocyte
and synovial cell with a mechanical stress.
[0004] Both of OA and rheumatic arthritis (RA) are representative
diseases destructing joint cartilage and being characterized in
topical erosion of cartilage surface. For example, it has been
reported that the introduction of radio-labeled sulfuric acid salt
into the femoral joint cartilage of OA patients is significantly
decreased compared with that of control group, which indicates that
the dissociating rate of cartilage in OA patient is increased
(Mankin et al., J. Bone Joint Surg., 52A, pp 424-434, 1970).
[0005] Four types of proteinase, i.e., serine, cystein, aspartic
acid and metalloprotease exist in mammarian cell. The
metalloprotease, one of the proteinase, has been reported to be an
important factor for the extra-cellular substrate hydrolyzing
action of joint cartilage in OA and PA patients and further the
increased activity of collagenase and stromelysin has been found in
the cartilage of OA patient, of which activity is closely
interrelated with the severity of OA or PA disease (Mankin et al.,
Arthritis Rheum., 21, pp 761-766, (1978); Woessner et al.,
Arthritis Rheum., 26, pp 63-68, (1983) and Ibid., 27, pp 305-312,
(1984)). Agrekanase has been also found in OA and PA patient
recently and it shows metalloprotease enzyme similar activity and
provides with the specific fragmented product of proteoglycans
(Lohmander L. S. et al., Arthrits Rheum., 36, pp 1214-1222,
1993).
[0006] TNF (Tumor Necrosis Factor), a cytokine bound to cells, is
processed from 36 kD precursor type to 17 kD activated or thereof.
It has been found that TNF is a first controlling factor of acute
phase response similar to the phenomenon occurred during
inflammation, fever, acute infection and shock in human and animal,
therefore the excess reproduction of TNF could be a cause of death.
At present, it has been reported that the prevention of TNF
reproduction could treat various diseases together with autoimmune
disease such as rheumatoid arthritis (R.sup.A), insulin-independent
diabetes and Crohn's disease (Lohmander L. S. et al., Arthritis
Rheum., 36, pp 1214-1222, 1993; Macdonald T. et al., Clin. Exp.
Immunol., 81, p 301, 1990).
[0007] Accordingly, the reproduction inhibitors of TNF have
potentially therapeutic importance in the treatment of inflammatory
diseases. Recently, matrix metalloprotease as well as other
metalloproteases known to be as TNF-C (Tumor Necrosis
Factor-Convertase, can be transformed from inactivated form thereof
into activated form thereof (Gearing et al., Nature, 370, p 555
1994), therefore the inhibiting either the transformation of MPs or
the release of activated TNF-a from the cell thereby may be an
important mechanism in the treatment of inflammatory diseases.
[0008] Since the overproduction of TNF is a distinguished
phenomenon in lots of diseases having characteristic of the tissue
lysis mediated by MMP, the inhibitor of both MMP and TNF has
favorable advantage in the treatment of specific inflammatory
diseases correlated with both mechanism.
[0009] PCT WO 92/213260 A1 discloses N-carboxyalkylpeptidyl
compounds useful as an enzyme inhibitor of hydroxamates and
carboxylates matrix MMP; PCT WO 90/05716 A1 and PCT WO 92/13831 A1
disclose an hydroxamate matrix colagenase inhibitor; PCT WO 94/2446
A1 discloses natural amino acid derivatives useful as an MMP
inhibitor; PCT WO 95/9841 A1 discloses hydroxamate derivatives
useful as a cytokine inhibitor; GB A 2,268,934 and PCT WO 94/24140
A1 disclose a hydroxamate inhibitor of MMP inhibiting TNF
reproduction, the disclosure of which cited documents are
incorporated herein by reference.
[0010] To treat RA or OA disease, conventional drugs for example,
steroids such as cortisone and other ACTH (adrenocorticotrophic
hormone); NSAID (Non-steroidal anti-inflammatory drug) such as
aspirin, piroxicam, indomethacin etc; gold agents such as
aurothioglucose, gold sodium thiomalate an auranofin etc;
anti-rheumatic drug such as chloroquinone, D-penicillamine etc;
gout inhibitors such as colchicines; and immuno-suppressing agents
such as cyclophosphamide, azathioprine, methotrexate, levamisole
etc have been prescribed till now. However, the treatment with
conventional drugs has not provided with satisfactory efficacy and
has various adverse effects, which limits the usage of conventional
drugs.
[0011] For example, anti-inflammatory drugs such as asprin or
butazolin have been used to alleviate the syndrome of OA and PAs,
however, the consistent administration of the drugs is difficult
because of their adverse effects, for example, i.e., severe stomach
irritation resulting in gastritis, stomach ulcer etc.
[0012] Accordingly, there have been studied and investigated to
develop new satisfactory anti-rheumatic agents which can solve the
problems of conventional drugs, in particular, which can improve
anti-inflammatory efficacy and provide with safe long-term
administration without adverse action till now.
[0013] Present inventors extensively investigated to find new
compounds showing strong inhibiting activity for the reproduction
of NO and TNF-.alpha., finally found new 2-oxo-heterocyclic
compounds showing potent inhibition effects on the reproduction of
NO and TNF-.alpha., and completed present invention.
SUMMARY OF THE INVENTION
[0014] The present invention provides a novel 2-oxo-heterocyclic
compound and the pharmacologically acceptable salt thereof showing
strong inhibiting activity for the reproduction of NO and
TNF-.alpha..
[0015] The present invention also provides a pharmaceutical
composition comprising a novel t-oxo-heterocyclic compound and the
pharmacologically acceptable salt thereof as an active ingredient
in an effective amount to treat and prevent inflammation
diseases.
[0016] The present invention also provides a use of novel
2-oxo-heterocyclic compound and the pharmacologically acceptable
salt thereof for the preparation of pharmaceutical composition to
treat and prevent inflammatory diseases.
DISCLOSURE OF THE INVENTION
[0017] Thus, the present invention provides a novel compound
represented by the following general formula (I), and the
pharmaceutically acceptable salt:
##STR00001##
[0018] wherein
##STR00002##
[0019] X is a hydroxyl group, --NHOH, --NHOCH.sub.2Ph,
##STR00003##
[0020] A is an hydrogen, A1 group or
[0021] A1 is a lower alkyl, lower alkenyl, lower alkynyl, lower
allyl group having C1 to C5 carbon atoms, a heterocyclic group or
aromatic aryl group, preferably, the group selected from thiopenyl
group, naphtyl group, pyrrolyl group, furyl group and biphenyl
group, wherein Y is a lower alkyl group, lower alkoxy group, nitro,
halogen, amine, acetamide, carbonamide or sulfonamide group, M is a
lower alkyl group or phenyl group substituted with R', of which R'
is a hydrogen, lower alkyl or lower alkoxy group, m and r is
independently an integer of 1 to 5 respectively in A2 residue;
[0022] p is an integer of 0, 1 or 2;
[0023] n is an integer of 1 to 5; dotted line means single bond or
double bond.
[0024] In preferred embodiment, the present invention also provides
the compounds represented by following general formula (II), the
pharmaceutically acceptable salt or the isomer thereof:
##STR00004##
[0025] wherein
[0026] X is a hydroxyl group, --NHOH, --NHOCH.sub.2Ph,
##STR00005##
[0027] Y is a lower alkyl group, lower alkoxy group, nitro,
halogen, amine, acetamide, carbonamide or sulfonamide group;
[0028] M is a lower alkyl group or phenyl group substituted with
R', of which R' is a hydrogen, lower alkyl or lower alkoxy
group;
[0029] m and r is independently an integer of 1 to 5
respectively;
[0030] n is an integer of 1 to 5; dotted line means single bond or
double bond.
[0031] The preferred compounds of general formula (II) is one
selected from the group consisting of; [0032]
3-[1-(2,4-Dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxypro-
pionamide, [0033]
3-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-propionamide,
[0034]
N-hydroxy-3-(2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl)-propion-
amide, [0035]
N-hydroxy-3-[2-oxo-1-(3-phenyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide, [0036]
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-2,5-dihydro-1H-pyrrol-3-yl]-propion-
amide, [0037]
N-hydroxy-3-[1-(2-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide, [0038]
N-hydroxy-3-[1-(3-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide, [0039]
N-hydroxy-3-[1-(4-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide, [0040]
N-hydroxy-3-[1-(2-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide, [0041]
N-hydroxy-3-[1-(3-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide, [0042]
N-hydroxy-3-[1-(4-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide, [0043]
3-[1-(4-bromo-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-propion-
amide, [0044]
3-[1-(4-chloro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-propio-
namide, [0045]
3-[1-(4-benzyloxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-pro-
pionamide, [0046]
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propion-
amide, [0047]
3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid, [0048]
3-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid,
[0049]
N-{4-[3-(2-hydroxycarbamoyl-ethyl)-2-oxo-2,5-dihydro-pyrrole-1-yl-methyl]-
-phenyl}-benzamide, [0050]
N-hydroxy-3-{2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2,5-dihydro-1H--
pyrrol-3-yl}-propionamide, [0051]
2-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-acetamide,
[0052]
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-a-
cetamide, [0053]
N-hydroxy-2-(2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl)-acetamide,
[0054]
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-2,5-dihydro-1H-pyrrol-3-yl]--
acetamide, [0055]
2-[1-(4-benzyloxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-ace-
tamide, [0056]
2-(1-benzyl-2-oxo-pyrrolidin-3-yl)-N-hydroxy-acetamide, [0057]
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-pyrrolidin-3-yl]-N-hydroxy-aceta-
mide, [0058]
N-hydroxy-2-(2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetamide, [0059]
3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-
-N-hydroxy-propionamide, [0060]
3-{1-[2-(3-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydr-
oxy-propionamide, [0061]
3-{1-[2-(4-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydr-
oxy-propionamide, [0062]
N-hydroxy-3-{1-[2-(2-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l}-propionamide, [0063]
N-hydroxy-3-{1-[2-(3-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l}-propionamide, [0064]
N-hydroxy-3-{1-[2-(4-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l}-propionamide, [0065]
3-{1-[2-(2-bromo-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydro-
xy-propionamide, [0066]
3-{1-[2-(4-bromo-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydro-
xy-propionamide, [0067]
N-hydroxy-3-{1-[2-(2-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl}-propionamide, [0068]
N-hydroxy-3-{1-[2-(3-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl}-propionamide, [0069]
N-hydroxy-3-{1-[2-(4-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl}-propionamide, [0070]
N-hydroxy-3-[2-oxo-1-(2-p-tolyl-ethyl)-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide, [0071]
N-hydroxy-3-{1-[3-(4-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl}-propionamide, [0072]
N-hydroxy-3-[2-oxo-1-(3-o-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide, [0073]
N-hydroxy-3-[2-oxo-1-(3-m-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide, [0074]
N-hydroxy-3-{1-[3-(4-isopropyl-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrro-
l-3-yl]-propionamide, [0075]
3-{1-[3-(4-bromo-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydr-
oxy-propionamide, [0076]
3-{1-[3-(4-chloro-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hyd-
roxy-propionamide, [0077]
N-hydroxy-3-{1-[3-(4-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl]-propionamide, [0078]
N-hydroxy-3-{1-[3-(2-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl]-propionamide, [0079]
N-hydroxy-3-{1-[3-(3-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl]-propionamide.
[0080] In preferred embodiment, the present invention also provides
the compounds represented by following general formula (III), the
pharmaceutically acceptable salt or the isomer thereof:
##STR00006##
[0081] wherein
[0082] X is a hydroxyl group, --NHOH, --NHOCH.sub.2Ph,
##STR00007##
[0083] R is a lower alkyl, lower alkenyl, lower alkynyl, lower
allyl group having C1 to C5 carbon atoms, a heterocyclic group or
aromatic aryl group, preferably, the group selected from thiopenyl
group, naphtyl group, pyrrolyl group, furyl group and biphenyl
group;
[0084] n is an integer of 1 to 5; dotted line means single bond or
double bond.
[0085] The preferred compounds of general formula (III) is one
selected from the group consisting of; [0086]
N-hydroxy-3-(1-naphthalene-2-ylmethyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-p-
ropionamide, [0087]
N-hydroxy-3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide,
[0088]
3-(1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-propionamid-
e, [0089]
N-hydroxy-3-[1-(2-naphthalene-1-yl-ethyl)-2-oxo-2,5-dihydro-1H-p-
yrrol-3-yl]-propionamide, [0090]
N-hydroxy-3-[1-(2-naphthalene-2-yl-ethyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l]-propionamide, [0091]
N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide, [0092]
3-[1-(3-biphenyl-4-yl-propyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-
-propionamide, [0093]
N-hydroxy-3-[1-(3-naphthalene-2-yl-propyl)-2-oxo-2,5-dihydro-1H-pyrrol-3--
yl]-propionamide.
[0094] In preferred embodiment, the present invention also provides
the compounds represented by following general formula (IV), the
pharmaceutically acceptable salt or the isomer thereof:
##STR00008##
[0095] wherein
[0096] X is a hydroxyl group, --NHOH, --NHOCH.sub.2Ph,
##STR00009##
[0097] Y is a lower alkyl group, lower alkoxy group, nitro,
halogen, amine, acetamide, carbonamide or sulfonamide group;
[0098] M is a lower alkyl group or phenyl group substituted with
R', of which R' is a hydrogen, lower alkyl or lower alkoxy
group;
[0099] m and r is independently an integer of 1 to 5
respectively;
[0100] n is an integer of 1 to 5; dotted line means single bond or
double bond.
[0101] The preferred compounds of general formula (IV) is one
selected from the group consisting of; [0102]
3-[1-(2,4-Dimethoxybenzyl)-2-oxo-1,2,5,6-tetragydropyridin-3-yl]N-hydroxy-
propionamide, [0103]
N-hydroxy-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid, [0104]
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pr-
opionamide, [0105]
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy
propionamide, [0106]
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pr-
opionamide, [0107]
N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionam-
ide, [0108]
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propion-
ic acid, [0109]
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid,
[0110]
3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid, [0111]
3-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid, [0112]
3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid, [0113]
3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid, [0114]
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-pyridin-2-yl--
propionamide, [0115]
N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pro-
pionamide, [0116]
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridi-
n-3-yl)-propionamide, [0117]
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridi-
n-3-yl)-propionamide, [0118]
N-benzyloxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propion-
amide, [0119]
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydr-
oxy-propionamide, [0120]
N-4-[5-(2-hydroxycarbamoyl-ethyl)-6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl-
]-phenyl-benzamide, [0121]
N-hydroxy-3-[1-(4-dimethylsulfonylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro--
pyridin-3-yl]-propionamide, [0122]
N-hydroxy-3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl-1,2,5,6-tetrahydr-
o-pyridin-3-yl]-propionamide, [0123]
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propio-
nic acid, [0124]
3-[1-(4-benzoylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propi-
onic acid, [0125]
3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2-oxo-1,2,5,6-tetrahydro-p-
yridin-3-yl]-propionic acid, [0126]
N-hydroxy-3-(2-oxo-1-phenethyl-piperidine-3-yl)-propionamide,
[0127]
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydr-
oxy-acetamide, [0128]
2-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-acetamide,
[0129]
N-hydroxy-2-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-
-yl)-N-hydroxy-acetamide, [0130]
N-hydroxy-2-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N-
-hydroxy-acetamide, [0131]
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N--
hydroxy-acetamide, [0132]
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid, [0133]
(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid,
[0134] (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid, [0135]
[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid, [0136]
[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid, [0137]
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-N-hydroxy-acetamide,
[0138] (2-oxo-1-phenethyl-piperidine-3-yl)-acetic acid, [0139]
[2-oxo-1-(3-phenyl-propyl)-piperidine-3-yl]-acetic acid, [0140]
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy--
butylamide, [0141]
4-(1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-butylamid-
e, [0142]
N-hydroxy-4-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridi-
n-3-yl]-butylamide, [0143]
N-hydroxy-4-[2-oxo-1-(3-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-bu-
tylamide.
[0144] In preferred embodiment, the present invention also provides
the compounds represented by following general formula (V), the
pharmaceutically acceptable salt or the isomer thereof:
##STR00010##
[0145] wherein
[0146] X is a hydroxyl group, --NHOH, --NHOCH.sub.2Ph,
##STR00011##
[0147] R is a lower alkyl, lower alkenyl, lower alkynyl, lower
allyl group having C1 to C5 carbon atoms, a heterocyclic group or
aromatic aryl group, preferably, the group selected from thiopenyl
group, naphtyl group, pyrrolyl group, furyl group and biphenyl
group;
[0148] n is an integer of 1 to 5; dotted line means single bond or
double bond.
[0149] The preferred compounds of general formula (V) is one
selected from the group consisting of; [0150]
3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid, [0151]
N-Benzyloxy-3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide,
[0152]
3-(1-Allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-propio-
namide, [0153]
N-hydroxy-3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide-
, [0154]
N-hydroxy-3-(1-(naphthalene-2-yl-methyl)-2-oxo-1,2,5,6-tetrahydro-
-pyridin-3-yl)-propionamide, [0155]
N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-1,2,5,6-tetrahydro-pyridin-3-
-yl]-propionamide.
[0156] It is another object of the present invention to provide the
pharmaceutical composition comprising an efficient amount of the
compound represented by general formula (I) to (V) or the
pharmaceutically acceptable salt thereof as an active ingredient in
amount effective to alleviate or treat pain diseases or
inflammatory diseases together with pharmaceutically acceptable
carriers or diluents.
[0157] The inventive compounds represented by general formula (I)
to (V) can be transformed into their pharmaceutically acceptable
salt and solvates by the conventional method well known in the art.
For the salts, acid-addition salt thereof formed by a
pharmaceutically acceptable free acid thereof is useful and can be
prepared by the conventional method. For example, after dissolving
the compound in the excess amount of acid solution, the salts are
precipitated by the water-miscible organic solvent such as
methanol, ethanol, acetone or acetonitrile to prepare acid addition
salt thereof and further the mixture of equivalent amount of
compound and diluted acid with water or alcohol such as glycol
monomethylether, can be heated and subsequently dried by
evaporation or filtrated under reduced pressure to obtain dried
salt form thereof. As a free acid of above-described method,
organic acid or inorganic acid can be used. For example, organic
acid such as methansulfonic acid, p-toluensulfonic acid, acetic
acid, trifluoroacetic acid, citric acid, maleic acid, succinic
acid, oxalic acid, benzoic acid, lactic acid, glycolic acid,
gluconic acid, galacturonic acid, glutamic acid, glutaric acid,
glucuronic acid, aspartic acid, ascorbic acid, carbonylic acid,
vanillic acid, hydroiodic acid and the like, and inorganic acid
such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric
acid, tartaric acid and the like can be used herein.
[0158] Further, the pharmaceutically acceptable metal salt form of
inventive compounds may be prepared by using base. The alkali metal
or alkali-earth metal salt thereof can be prepared by the
conventional method, for example, after dissolving the compound in
the excess amount of alkali metal hydroxide or alkali-earth metal
hydroxide solution, the insoluble salts are filtered and remaining
filtrate is subjected to evaporation and drying to obtain the metal
salt thereof. As a metal salt of the present invention, sodium,
potassium or calcium salt are pharmaceutically suitable and the
corresponding silver salt can be prepared by reacting alkali metal
salt or alkali-earth metal salt with suitable silver salt such as
silver nitrate.
[0159] The pharmaceutically acceptable salt of the compound
represented by general formula (I) to (V) comprise all the acidic
or basic salt which may be present at the compounds, if it does not
indicated specifically herein. For example, the pharmaceutically
acceptable salt of the present invention comprise the salt of
hydroxyl group such as the sodium, calcium and potassium salt
thereof; the salt of amino group such as the hydrogen bromide salt,
sulfuric acid salt, hydrogen sulfuric acid salt, phosphate salt,
hydrogen phosphate salt, dihydrophosphate salt, acetate salt,
succinate salt, citrate salt, tartarate salt, lactate salt,
mandelate salt, methanesulfonate(mesylate) salt and
p-toluenesulfonate (tosylate) salt etc, which can be prepared by
the conventional method well known in the art.
[0160] There may exist in the form of optically different
diastereomers since the compounds represented by general formula
(I) to (V) have unsymmetrical centers, accordingly, the compounds
of the present invention comprise all the optically active isomers,
R or S stereoisomers and the mixtures thereof. Present invention
also comprises all the uses of racemic mixture, more than one
optically active isomer or the mixtures thereof as well as all the
preparation or isolation method of the diastereomer well known in
the art.
[0161] The compounds of the invention of formula (I) to (V) may be
chemically synthesized by the methods which will be explained by
following reaction schemes hereinafter, which are merely exemplary
and in no way limit the invention. The reaction schemes show the
steps for preparing the representative compounds of the present
invention, and the other compounds also may be produced by
following the steps with appropriate modifications of reagents and
starting materials, which are envisaged by those skilled in the
art.
General Synthetic Procedures
##STR00012##
[0163] As depicted in above Scheme 1, the scheme explains the
process for preparing hydroxamine compound (e) consisting of 4
steps;
[0164] At 1.sup.st step, compound (a) is reacted with
1-bromo-3-butene under organic solvent in the presence of Hung base
to synthesize compound (b). In the step, an organic solvent such as
acetonitrile, dichloromethane etc are preferable and
diethylisopropylamine can be used as a Hung base in the amount of 2
to 3 equivalents to the compound (a). It is preferable the reaction
is performed at the temperature ranging from 0.degree. C. to R.
T.
[0165] At 2.sup.nd step, the compound (b) obtained in step 1 is
reacted with mono acid in the presence of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide(EDC) under an
organic solvent to synthesize the compound (c). In the step, an
organic solvent such as methylenechloride, THF etc are preferable
and a mono acid such as 2-methylene-pentandionic acis-5-methyl
ester in the amount of 1 to 1.2 equivalents to the compound (b) is
preferable. It is preferable the reaction is performed at the
temperature ranging from 0.degree. C. to R. T.
[0166] At 3.sup.rd step, the compound (c) obtained in step 2 is
converted into the compound (d) in the presence of Grubb's (I)
catalyst such as Ruthenium catalyst under organic solvent. In the
step, it is preferable to use the catalyst in the amount of 0.02 to
0.1 equivalents to the compound (c) at the temperature ranging from
0.degree. C. to R. T.
[0167] At 4.sup.th step, the compound (d) obtained in step 3 is
reacted with amine salt to synthesize hydroxamide compound (e) in
case that X is NHOH in general formula I compounds. In the step, it
is preferable to use potassium hydroxamide (KONH.sub.2) in the
amount of 2 to 3 equivalents to the compound (d) at the temperature
ranging from 0.degree. C. to R. T.
##STR00013##
[0168] As depicted in the above Scheme 2, the ester compounds (d)
is reacted with hydroxide metal salt under the organic solvent such
as THF to synthesize the carboxylic acid (f). In the reaction, it
is preferable to use LiOH in the amount of 2 to 3 equivalents to
the compound (d) at the temperature ranging from 0.degree. C. to R.
T.
##STR00014##
[0169] As depicted in the above Scheme 3, the carboxylic acid
compound (f) obtained in Scheme 2 is reacted with
benzyloxyamine(BnONH.sub.2), pyridylamine or diaminobenzene in the
presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC)
under organic solvent to synthesize the amide compounds of which X
is benzyloxyamine(BnONH.sub.2), pyridylamine or diaminobenzene
group. In the reaction, it is preferable to use
benzyloxyamine(BnONH.sub.2), pyridylamine or diaminobenzene in the
amount of 1 to 1.5 equivalents to the compound (f) at the
temperature ranging from 0.degree. C. to R. T.
##STR00015## ##STR00016##
[0170] As shown in the above Scheme 4, the amide compound (j) and
carboxylic acid compound (k) are prepared by following procedure
from the ester compounds (d):
[0171] At 1.sup.St step, the compound (d) prepared from Scheme 2 is
reacted with zinc under organic solvent to synthesize the compound
(h). In the step, it is preferable to use the zinc in the amount of
2 to 5 equivalents of the compound (h).
[0172] At 2.sup.nd step, the compound (h) obtained in step 1 is
reacted with (AcO).sub.2O, PhCOCl, MsCl or TsCL to synthesize the
compound (i). In the reaction, it is preferable to use
(AcO).sub.2O, PhCOCl, MsCl or TsCL in the amount of 1 to 3
equivalents to the compound (h).
[0173] At 3.sup.rd step, the compound (i) obtained in step 2 is
reacted with amine salt under the organic solvent such as methanol
to produce the hydroxamide compound (j), i.e., the general formula
I compound wherein X is NHOH where the amine salt is preferably
used in the amount of 2 to 3 equivalents to the compound (i), or
with hydroxide metal salt such as LiOH under the organic solvent
such as THF to produce the carboxylic acid compound (k), i.e., the
general formula I compound wherein X is OH where the metal salt is
preferably used in the amount of 2 to 3 equivalents to the compound
(i).
##STR00017##
[0174] As shown in Scheme 5, the 1,2,5,6-dihydropyridine compound
(d) is reduced to the piperidine compound (l) by reacting with
palladium-carbon (Pd/C) under alcohol solvent in the amount of 0.1
to 0.2 equivalents of compound (d) and further the piperidine
compound (l) is reacted with KONH.sub.2 under MeOH to synthesize
the compound (m). In the reaction, it is preferable to use the
amine salt in the amount of 2 to 3 equivalents to the compound (m)
at the temperature ranging from 0.degree. C. to R. T.
##STR00018##
[0175] As shown in Scheme 6, the benzyl compound (d) is reacted
with triethysilane(TES) in the amount of 1 to 1.5 equivalent of the
compound (d) under TFA solution to produce the compound (l). The
compound (l) is further reacted with hexamethyldisilylazidesodium
(NaHMDS) under THF solvent and subsequently reacted with R--X (R:
ally, methyl etc, X: halogen atom) to produce the compound (m). In
the reaction, it is preferable to use the NaHMDS in the amount of 1
to 1.5 equivalents to the compound (l).
##STR00019##
[0176] As shown in Scheme 7, the compound (b) as a starting
material is prepared by following procedure: At 1.sup.st step, the
compound (z) which can be procure by conventional market or
chemical company is reacted with Wittig reagent under the organic
solvent such as dichloromethane to synthesize to the compound (aa).
In the step, it is preferable to use the Wittig reagent in the
amount of 1.5 to 2 equivalents of the compound (z) at the
temperature ranging from 60 to 70.degree. C.
[0177] At 2.sup.nd step, the compound (aa) obtained in step 1 is
reacted with Pd/C in the amount of 0.1 to 0.2 equivalents of the
compound (aa) under ethyl alcohol solvent to synthesize the
compound (ab).
[0178] At 3.sup.rd step, the compound (ab) obtained in step 2 is
reacted with lithium aluminum hydride (LAH) under the organic
solvent such as THF to produce the compound (ac) at 0.degree.
C.
[0179] At 4.sup.th step, the compound (ac) substiteis reacted with
p-toluenesulfonylchloride, diisopropylethylamine or
4-(dimethylamino) pyridine in the amount of 0.1 to 0.2 equivalents
of the compound (aa) under ethyl alcohol solvent to synthesize the
compound (ab).
[0180] At 5.sup.th step, both of allyl amine and Hunig base, i.e.,
diisopropylethylamine are added to the compound (ad) dissolved in
acetonitrile, mixed and stirred for six hours at 80.degree. C. to
produce the compound (ae), one of the compound (b).
[0181] The present invention also provides a pharmaceutical
composition comprising an efficient amount of the compound
represented by general formula (I) to (V) or the pharmaceutically
acceptable salt thereof as an active ingredient in amount effective
to treat or prevent inflammatory diseases together with
pharmaceutically acceptable carriers or.
[0182] The compound of formula (I) to (V) according to the present
invention can be provided as a pharmaceutical composition
containing pharmaceutically acceptable carriers, adjuvants or
diluents. For example, the compounds of the present invention can
be dissolved in oils, propylene glycol or other solvents which are
commonly used to produce an injection. Suitable examples of the
carriers include physiological saline, polyethylene glycol,
ethanol, vegetable oils, isopropyl myristate, etc., but are not
limited to them. For topical administration, the compounds of the
present invention can be formulated in the form of ointments and
creams.
[0183] The pharmaceutical compositions comprising the compound of
the present invention can be treat and prevent the inflammatory
disease comprising the pain or inflammation caused by rheumatic
disease, for example, rheumatoid arthritis, spondyloarthopathies,
gout, osteoarthritis, systemic lupus erythematosus and juvenile
arthritis, and inflammatory syndrome for example, from myositis,
gingivitis, synovitis, ankylosing spondylitis, burstitis, burns and
scar, inflammatory Crohn's disease, Types I diabetes.
[0184] The compound of the present invention has potent
anti-inflammatory activity, and the pharmaceutical composition of
the present invention thus may be employed to treat or prevent the
inflammatory disease comprising the pain or inflammation caused by
rheumatic disease and inflammatory syndrome.
[0185] The present invention also provides a method of preventing
or treating the inflammatory disease comprising the pain or
inflammation caused by rheumatic disease and inflammatory syndrome
which comprises administering compound selected from the group
consisting of compounds of formula (I) to (V) or pharmaceutical
acceptable salts thereof in need of such prevention or treatment a
therapeutically effective amount of the salt or a pharmaceutically
acceptable hydrate thereof as an anti-inflammatory agent.
[0186] The present invention also provides a use of the compounds
as an active ingredient in medicines for treating or preventing the
inflammatory disease comprising the pain or inflammation caused by
rheumatic disease and inflammatory syndrome.
[0187] Hereinafter, the following formulation methods and
excipients are merely exemplary and in no way limit the
invention.
[0188] The compounds of the present invention in pharmaceutical
dosage forms may be used in the form of their pharmaceutically
acceptable salts, and also may be used alone or in appropriate
association, as well as in combination with other pharmaceutically
active compounds.
[0189] The compounds of the present invention may be formulated
into preparations for injections by dissolving, suspending, or
emulsifying them in aqueous solvents such as normal saline, 5%
Dextrose, or non-aqueous solvent such as vegetable oil, synthetic
aliphatic acid glycerides, esters of higher aliphatic acids or
propylene glycol. The formulation may include conventional
additives such as solubilizers, isotonic agents, suspending agents,
emulsifying agents, stabilizers and preservatives.
[0190] The desirable dose of the inventive compounds varies
depending on the condition and the weight of the subject, severity,
drug form, route and period of administration, and may be chosen by
those skilled in the art. However, in order to obtain desirable
effects, it is generally recommended to administer at the amount
ranging 0.0001-100 mg/kg, preferably 0.001-100 mg/kg by weight/day
of the inventive compounds of the present invention. The dose may
be administered in single or divided into several times per day. In
terms of composition, the compounds should be present between
0.0001 to 10% by weight, preferably 0.0001 to 1% by weight based on
the total weight of the composition.
[0191] The pharmaceutical composition of present invention can be
administered to a subject animal such as mammals (rat, mouse,
domestic animals or human) via various routes. All modes of
administration are contemplated, for example, administration can be
made orally, rectally or by intravenous, intramuscular,
subcutaneous, intrathecal, epidural or intracerebroventricular
injection.
[0192] The present invention is more specifically explained by the
following examples. However, it should be understood that the
present invention is not limited to these examples in any
manner.
BEST MODE FOR CARRYING OUT THE INVENTION
[0193] It will be apparent to those skilled in the art that various
modifications and variations can be made in the compositions, use
and preparations of the present invention without departing from
the spirit or scope of the invention.
[0194] The present invention is more specifically explained by the
following examples. However, it should be understood that the
present invention is not limited to these examples in any
manner.
EXAMPLES
[0195] The following Reference Example, Examples and Experimental
Examples are intended to further illustrate the present invention
without limiting its scope.
Example 1
Preparation of
3-[1-(2,4-Dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxypro-
pionamide (1e)
##STR00020##
[0196] Step 1. Preparation of allyl-(2,4-dimethoxybenzyl)amine
(1b)
[0197] 0.32 ml of allylbromide (3.66 mM) and 0.7 ml of diisopropyl
ethylamine (3.99 mM) were added to the reaction solution containing
500 mg of 2,4-dimethoxybenzylamine (3.33 mM) dissolved in methylene
chloride with stifling and the solution was left alone at room
temperature. After the reaction mixture was neutralized with 10%
NaOH solution, the mixture was extracted with chloroform, washed
with saturated NaCl solution, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The resulting compound was purified with
Silica gel column chromatography with a solvent mixture mixed with
methanol and chloroform (1:9) as an eluant to give 276 mg of
allyl-(2,4-dimethoxybenzyl)amine (1b) (yield: 40%).
[0198] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.12 (d, J=8.1 Hz,
1H), 6.44-6.39 (m, 2H), 5.99-5.86 (m, 1H), 5.21-5.09 (m, 2H), 3.79
(d, J=6.0 Hz, 6H), 3.74 (s, 2H), 3.23 (d, J=6.0 Hz, 2H)
Step 2. Preparation of
4-[allyl-(2,4-dimethoxy-benzyl)-carbamoyl]-pent-4-enoic acid methyl
ester (1c)
[0199] 253 mg of 2-methylene-pentane dionate-5-methyl ester (1.6
mM), 331 mg of [3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.73
mM) and 48 mg of 4-(dimethylamino)pyridine (0.39 mM) were added to
0.5 M of reaction solution dissolving the compound (1b) prepared by
above step 1 in methylene chloride and the mixture was stirred for
10 hrs at room temperature. After the resulting mixture was washed
with 5% HCl solution (10 ml), the mixture was extracted with
ethylacetate, washed with saturated NaCl. And then the extracts
were washed with saturated 10 ml of NaHCO.sub.3 solution and NaCl
solution to separate into an organic layer and water layer. The
organic layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resultant was purified by Silica gel
column chromatography with a solvent mixture mixed with EtOAc and
hexanes (1:2) as an eluant to give 324 mg of
4-[allyl-(2,4-dimethoxy-benzyl)-carbamoyl]-pent-4-enoic acid methyl
ester (1c) (yield: 70%).
[0200] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.14 (s, 1H), 6.44
(d, 2H), 5.72 (s, 1H), 5.12 (s, 4H), 4.56-4.81 (m 2H), 3.91-3.83
(m, 2H), 3.78 (d, J=5.3 Hz, 6H), 3.65 (d, J=1.4 Hz, 3H), 2.63 (t,
J=5.7 Hz, 2H), 2.54 (t, J=5.4 Hz, 2H)
Step 3. Preparation of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (1d)
[0201] 324 mg of the compound (1c) (0.933 mM) prepared by the above
Step 2 was added to the catalyst solution containing 74 mg of
ruthenium (0.09 mM) dissolved in 93 ml of CH.sub.2Cl.sub.2. Then
the mixture was stirred for 24 hrs at room temperature, filtered
and concentrated in vacuo. The resultant was purified by Silica gel
column chromatography with a solvent mixture mixed with EtOAc and
hexanes (1:1) as an eluant to give 268 mg of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrole-3-yl]-propionic
acid methyl ester (1d) (yield: 90%).
[0202] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.11 (d, J=9.0 Hz,
1H), 6.61 (br t, 1H), 6.43 (s, 1H), 6.40 (d, J=2.7 Hz, 1H), 4.56
(s, 2H), 3.78 (d, J=5.4 Hz, 9H), 3.65 (s, 2H), 2.61 (s, 4H)
Step 4. Preparation of
3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-p-
ropionamide (1e)
[0203] 100 mg of compound (d) prepared by the above Step 3 was
dissolved in methanol solution (0.313 mM) and then 1.7 M methanolic
suspension solution containing NH.sub.2OK (0.27 ml, 0.47 mM) was
added thereto at 0.degree. C. and the resulting mixture was stirred
for 4 hrs at room temperature. The resulting mixture was
neutralized with 0.02 ml of acetic acid, diluted with
methanol/chloroform solution, filtered and concentrated in vacuo.
The resulting compound was purified by Silica gel column
chromatography with a solvent mixture mixed with methanol and
chloroform (1:9) as an eluant to give 50 mg of
3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-p-
ropionamide (1e) (yield: 50%).
[0204] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.04 (d, J=8.1 Hz,
1H), 6.83 (s, 1H), 6.53-6.44 (m, 2H), 4.54 (s, 2H), 3.81 (t, J=2.0
Hz, 6H), 2.56 (t, J=7.2 Hz, 2H), 2.34 (t, J=7.4 Hz, 2H), 1.9 (s,
3H)
Example 2
Preparation of
3-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-propionamide
(2e)
[0205]
3-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-propionamid-
e (2e) was prepared by the similar procedure described in above
Example 1 (See Table 1).
Example 3
Preparation of
N-hydroxy-3-(2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl)-propionamide
(3e)
[0206]
N-hydroxy-3-(2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl)-propiona-
mide (3e) was prepared by the similar procedure described in above
Example 1 (See Table 1).
Example 4
Preparation of
N-hydroxy-3-[2-oxo-1-(3-phenyl-propyl)-2,5-dihydro-1H-pyrrol-3-A-propiona-
mide (4e)
[0207]
N-hydroxy-3-[2-oxo-1-(3-phenyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide (4e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 5
Preparation of
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-2,5-dihydro-1H-pyrrol-3-A-propionam-
ide (5e)
[0208]
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-2,5-dihydro-1H-pyrrol-3-yl]-p-
ropionamide (5e) was prepared by the similar procedure described in
above Example 1 (See Table 1).
Example 6
Preparation of
N-hydroxy-3-[1-(2-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide (6e)
[0209]
N-hydroxy-3-[1-(2-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide (6e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 7
Preparation of
N-hydroxy-3-[1-(3-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide (7e)
[0210]
N-hydroxy-3-[1-(3-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide (7e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 8
Preparation of
N-hydroxy-3-[1-(4-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide (8e)
[0211]
N-hydroxy-3-[1-(4-methyl-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide (8e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 9
Preparation of
N-hydroxy-3-[1-(2-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (9e)
[0212]
N-hydroxy-3-[1-(2-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-
-propionamide (9e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 10
Preparation of
N-hydroxy-3-[1-(3-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (10e)
[0213]
N-hydroxy-3-[1-(3-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-
-propionamide (10e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 11
Preparation of
N-hydroxy-3-[1-(4-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (11e)
[0214]
N-hydroxy-3-[1-(4-methoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-
-propionamide (11e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 12
Preparation of
3-[1-(4-bromo-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-propion-
amide (12e)
[0215]
3-[1-(4-bromo-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-p-
ropionamide (12e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 13
Preparation of
3-[1-(4-chloro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-propio-
namide (13e)
[0216]
3-[1-(4-chloro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy--
propionamide (13e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
Example 14
Preparation of
3-[1-(4-benzyloxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-pro-
pionamide (14e)
[0217]
3-[1-(4-benzyloxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydro-
xy-propionamide (14e) was prepared by the similar procedure
described in above Example 1 (See Table 1).
Example 15
Preparation of
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propion-
amide (15e)
[0218]
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-p-
ropionamide (15e) was prepared by the similar procedure described
in above Example 1 (See Table 1).
TABLE-US-00001 TABLE 1 Ex- ample Chemical structure NMR spectrum 2
##STR00021## 7.30-7.14(m, 5H), 6.71(d, J = 18.3 Hz, 1H), 4.59(d, J
= 7.8 Hz, 2H), 3.73(s, 2H), 2.63(s, 4H). 3 ##STR00022##
7.25-7.09(m, 5H), 6.64(s, 1H), 3.62(t, J = 6.1 Hz, 4H), 2.81(t, J =
7.3 Hz, 2H), 2.52(s, 2H), 2.30(d, J = 6.6 Hz, 2H) 4 ##STR00023##
7.21(d, J = 7.5 Hz, 2H), 7.12(d, J = 6.6 Hz, 3H), 6.72(s, 1H),
3.75(s, 2H), 3.41 (s, 2H), 2.57(d, J = 6.3 Hz, 6H), 2.44(s, 1H),
1.82(s, 2H) 5 ##STR00024## 7.28-7.12(m, 5H), 6.73(s, 1H), 3.78(d, J
= 9.0 Hz, 2H), 3.43(s, 2H), 2.61(s, 5H), 1.58(s, 5H) 6 ##STR00025##
7.12(s ,5H), 6.67(s, 1H), 4.58(d, J = 8.4 Hz, 2H), 3.64(s, 2H),
2.61(s, 4H), 2.34-2.22(m, 3H) 7 ##STR00026## 7.15(d, J = 6.9 Hz,
1H), 7.02-6.95(m, 3H), 6.74(s, 1H), 4.52(d, J = 8.4 Hz, 2H),
3.70(s, 2H), 2.60(s, 3H), 2.27(d, J = 4.8 Hz, 4H) 8 ##STR00027##
7.09-7.03(m, 4H), 6.70(d, J = 18.3 Hz, 1H), 4.54(d, J = 7.2 Hz,
2H), 3.70(s, 2H), 2.61(s, 3H), 2.45(s, 1H), 2.28(d, J = 13.5 Hz,
3H) 9 ##STR00028## 7.23-7.18(m, 1H), 7.08(d, J = 3.5 Hz, 1H),
6.84(dd, J = 5.8 Hz, 2H), 6.72(s, 1H), 4.59(s, 2H), 3.78(s, 3H),
3.75(s, 2H), 2.60 (s, 2H), 2.44(s, 2H) 10 ##STR00029## 7.16(t, J =
4.8 Hz, 1H), 6.73(t, J = 5.4 Hz, 3H), 6.68(s, 1H), 4.53(d, J = 10.5
Hz, 2H), 3.72(t, J = 5.2 Hz, 5H), 2.59(s, 2H), 2.43(s, 2H) 11
##STR00030## 7.06-7.014(m, 4H), 6.71(s, 1H), 4.49(s, 2H), 3.66(s,
2H), 2.59(s, 2H), 2.43(s, 2H), 2.25(s, 3H) 12 ##STR00031## 7.40(d,
J = 7.8 Hz, 2H), 7.05(d, J = 8.4 Hz, 2H), 6.78(s, 1H), 4.53(s, 2H),
4.39 (s, 2H), 3.76(s, 2H), 2.57(t, J = 5.7 Hz, 2H), 2.31(t, J = 7.2
Hz, 2H) 13 ##STR00032## 7.28-7.07(m, 2H), 6.95(t, J = 8.2 Hz, 2H),
6.74(s, 1H), 4.52(s, 2H), 3.60(s, 2H), 2.54(s, 2H), 2.31(d, J = 7.2
Hz, 2H) 14 ##STR00033## 7.41-7.30(m, 5H), 7.14(d, J = 8.4 Hz, 2H),
6.91(d, J = 8.4 Hz, 2H), 6.67(s, 1H), 5.02 (s, 2H), 4.55(s, 2H),
3.72(s, 2H), 2.65(2, 4H) 15 ##STR00034## RT: 3.82-4.54(Mass:
306.1)
Example 16
Preparation of
3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid (16f)
##STR00035##
[0220] 10.8 mg of LiOH.H.sub.2O solution (0.25 mM) was added to
0.86 ml of THF solution containing 55 mg of 3-[1-(2,4-dimethoxy
benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl
ester (0.17 mM) in a dropwise manner at 0.degree. C. The reaction
mixture was stirred for 2 hrs at 0.degree. C. adjust pH 1 with 5%
HCl was added to the mixture to pH 1. Then the mixture was
extracted three times with 10 ml of ethyl acetate, the organic
layer was washed with 15 ml of saturated NaCl solution, dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
resulting compound was purified with Silica gel column
chromatography with a solvent mixture mixed with methanol and
chloroform (1:9) as an eluant to give 41 mg of
3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid (16f) (yield: 80%).
[0221] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.11 (d, J=9.0 Hz,
1H), 6.65 (br t, 1H), 6.41 (ab, J=6.5 Hz, 1.1 Hz, 2H), 4.57 (s,
2H), 3.81-3.76 (m, 8H), 2.63 (s, 4H)
Example 17
Preparation of
3-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid
(17f)
[0222] 3-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid
(17f) was prepared by the similar procedure described in above
Example 16 (See Table 2).
TABLE-US-00002 TABLE 2 Example Chemical structure NMR spectrum data
17 ##STR00036## 7.33-7.19(m, 5H), 6.69(br t, 1H), 4.62(s, 2H),
3.74(s, 2H), 2.66(s, 4H)
Example 18
Preparation of
N-{4-[3-(2-hydroxycarbamoyl-ethyl)-2-oxo-2,5-dihydro-pyrrole-1-yl-methyl]-
-phenyl]-benzamide (18j)
Step 1. Preparation of
3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (h)
[0223] 90 mg of
3-[1-(4-nitro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (0.3 mM) was dissolved in methanol solution at
room temperature. And then 290 mg of Zn (4.44 mM) and 0.02 ml of
acetic acid (0.3 mM) were added thereto and the mixture was stirred
for 48 hrs at room temperature. The resulting compound was purified
by Silica gel column chromatography with ethylacetate as an eluant
to give 20 mg of
3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (h) (yield: 25%).
[0224] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.01 (d, J=8.4 Hz,
2H), 6.62 (d, J=1.8 Hz, 2H), 6.60 (br t, 1H) 4.48 (s, 2H), 3.68 (d,
J=1.2 Hz, 3H), 3.65 (s, 4H), 2.66-2.58 (m, 4H)
Step 2. Preparation of
3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (i)
[0225] 10 mg of
3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (h) prepared by above Step 1 was dissolved in
methylene chloride solution (0.04 mM) at room temperature. And then
8.5 .mu.l of benzoyl chloride (0.07 mM) and 19.1 .mu.l of
diisopropylamine (0.11 mM) were added thereto and the mixture was
stirred for 2 hrs at 0.degree. C. The reaction was stopped by
adding methanol and the mixture was extracted three times with 10
ml of ethyl acetate. The organic layer was washed with saturated
NaCl solution, dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resulting compound was purified with
Silica gel column chromatography with a solvent mixture mixed with
ethyl acetate and hexane (1:2) as an eluant to give 12 mg of
3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (i) (yield: 87%).
[0226] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.88-7.83 (m, 3H),
7.62-7.47 (m, 6H), 6.68 (br t, 1H), 4.62 (S, 2H), 3.75 (d, 2H),
3.68 (s, 3H), 2.67-2.64 (m, 4H)
Step 3. Preparation of
N-{4-[3-(2-hydroxycarbamoyl-ethyl)-2-oxo-2,5-dihydro-pyrrole-1-yl-methyl]-
-phenyl}-benzamide (j)
[0227] 7 mg of compound (i) prepared by the above Step 2 was
dissolved in methanol solution (0.02 mM) and then 1.7 M methanolic
suspension solution containing NH.sub.2OK (0.4 ml, 0.68 mM) was
added thereto at 0.degree. C. and the resulting mixture was stirred
for 8 hrs at room temperature. The resulting mixture was
neutralized with 0.01 ml of acetic acid, diluted with 10%
methanol/chloroform solution, filtered and concentrated in vacuo.
The resulting compound was purified by Silica gel column
chromatography with a solvent mixture mixed with methanol and
chloroform (1:9) as an eluant to give 3.2 mg of
N-{4-[3-(2-hydroxycarbamoyl-ethyl)-2-oxo-2,5-dihydro-pyrrole-1-yl-methyl]-
-phenyl}-benzamide (j) (yield: 46%).
[0228] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.86 (d, J=6.6 Hz,
2H), 7.62 (d, J=8.7 Hz, 2H), 7.53-7.39 (m, 4H), 7.17 (d, J=8.4 Hz,
2H), 6.77 (br t, 1H), 4.57 (s, 2H), 3.77 (s, 2H), 2.58 (t, J=7.3
Hz, 2H), 2.31 (t, J=7.2 Hz, 2H)
Example 19
Preparation of
N-hydroxy-3-[2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2,5-dihydro-1H--
pyrrol-3-yl]-propionamide (19j)
[0229]
N-hydroxy-3-{2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2,5-dihyd-
ro-1H-pyrrol-3-yl}-propionamide (19j) was prepared by the similar
procedure described in above Example 18 (See Table 3).
TABLE-US-00003 TABLE 3 Ex- ample Chemical structure NMR spectrum
data 19 ##STR00037## 7.61(t, J = 7.0 Hz, 3H), 7.05-6.89(m, 6H),
4.54(s, 3H), 3.74(s, 3H), 3.39(s, 3H), 2.37 (s, 3H), RT:
3.87-4.34(Mass: 430.0)
Example 20
Preparation of
2-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-acetamide
(20q)
Step 1. Preparation of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid
methyl ester (o)
[0230] 587 mg of 2-methylene-succinate 4-methyl ester (4.07 mM),
781 mg of 143-(dimethylamino)propyl]-3-ethylcarbodiimide (4.07 mM)
and 75 mg of 4-(dimethylamino)pyridine (0.61 mM) were added to the
reaction solution containing 300 mg of allylbenzylamine (2.04 mM)
dissolved in methylene chloride solution (0.5M) with stifling for
10 hrs at room temperature. After the resulting mixture was washed
with 5% HCl solution (10 ml), the mixture was diluted with ethyl
acetate, washed with 10 ml of solution mixture mixed with saturated
NaHCO.sub.3 solution and saturated NaCl solution to separate into
an organic layer and water layer. The organic layer was dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
resultant was purified by Silica gel column chromatography with a
solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to
give 272 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl
ester (o) (yield: 49%).
[0231] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.30-7.22 (m, 5H),
5.84-5.71 (m, 1H), 5.37-5.15 (m, 4H), 4.75-4.65 (m, 2H), 4.02 (s,
2H), 3.63 (s, 3H), 3.48 (s, 2H)
Step 2. Preparation of
(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl
ester (p)
[0232] 234 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl
ester (o) (0.1 mM) prepared by the above Step 1 was added to the
catalyst solution containing 36 mg of Grubb's (I) catalyst (0.04
mM) such as ruthenium dissolved in CH.sub.2Cl.sub.2 under Ar
atmosphere. Then the mixture was stirred for 24 hrs at room
temperature, filtered and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with a solvent mixture
mixed with EtOAc and hexanes (1:2) as an eluant to give 180 mg of
(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl
ester (p) (yield: 85%).
[0233] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.33-7.18 (m, 5H),
6.94 (t, J=1.5 Hz, 1H), 4.61 (s, 2H), 3.79 (d, J=0.7 Hz, 2H), 3.70
(s, 3H), 3.37 (d, J=1.5 Hz, 2H)
Step 3. Preparation of
2-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-acetamide
(q)
[0234] 24 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic
acid methyl ester (p) prepared by the above Step 2 was dissolved in
methanol solution (0.1 mM) and then 1.7 M methanolic suspension
solution containing NH.sub.2OK (0.4 ml, 0.68 mM) was added thereto
at 0.degree. C. and the resulting mixture was stirred for 4 hrs at
room temperature. The resulting mixture was neutralized with 0.02
ml of acetic acid, diluted with 10% methanol/chloroform solution,
filtered and concentrated in vacuo. The resulting compound was
purified by Silica gel column chromatography with a solvent mixture
mixed with methanol and chloroform (1:9) as an eluant to give 12 mg
of
2-(1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-acetamide
(q) (yield: 48%).
[0235] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.35-7.21 (m, 5H),
7.05 (br t, 1H), 4.63 (s, 2H), 3.90 (s, 2H), 3.30 (t, J=1.5 Hz,
1H), 3.13 (s, 2H)
Example 21
Preparation of
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-a-
cetamide (21q)
[0236]
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hyd-
roxy-acetamide (21q) was prepared by the similar procedure
described in above Example 20 (See Table 4).
Example 22
Preparation of
N-hydroxy-2-(2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl)-acetamide
(22q)
[0237]
N-hydroxy-2-(2-oxo-1-phenethyl-2,5-dihydro-1H-pyrrol-3-yl)-acetamid-
e (22q) was prepared by the similar procedure described in above
Example 20 (See Table 4).
Example 23
Preparation of
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-2,5-dihydro-1H-pyrrol-3-yl]-acetami-
de (23q)
[0238]
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-2,5-dihydro-1H-pyrrol-3-yl]-a-
cetamide (23q) was prepared by the similar procedure described in
above Example 20 (See Table 4).
Example 24
Preparation of
2-[1-(4-benzyloxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-ace-
tamide (24q)
[0239]
2-[1-(4-benzyloxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydro-
xy-acetamide (24q) was prepared by the similar procedure described
in above Example 20 (See Table 4).
TABLE-US-00004 TABLE 4 Ex- ample Chemical structure NMR spectrum
data 21 ##STR00038## 7.12(d, J = 8.4 Hz, 2H), 6.90(d, J = 20.7 Hz,
1H), 6.43(d, J = 6.0 Hz), 4.57(d, J = 2.7 Hz, 2H), 3.86(d, J = 15.9
Hz, 2H), 3.79(d, J = 3.0 Hz, 6H) 22 ##STR00039## 7.29-7.14(m, 5H),
6.90(br t, 1H), 3.75-3.65 (m, 4H), 3.23(s, 1H), 2.92-2.84(m, 2H) 23
##STR00040## 7.21(t, J = 7.4 Hz, 2H), 7.11(d, J = 7.8 Hz, 3H),
6.76(br t, 1H), 5.22(s, 1H), 3.30 (t, J = 3.3 Hz, 1H), 2.58(t, J =
7.0 Hz, 2H), 2.04(s, 3H), 1.82(s, 3H), 1.57(s, 4H) 24 ##STR00041##
7.39-7.31(m, 5H), 7.13(d, J = 8.4 Hz, 2H), 6.92(d, J = 8.7 Hz, 3H),
5.03(s, 2H), 4.56 (s, 2H), 3.82(d, J = 13.8 Hz, 2H), 3.53(s, 1H),
3.31(s, 1H)
Example 25
Preparation of
2-(1-benzyl-2-oxo-pyrrolidin-3-yl)-N-hydroxy-acetamide (25s)
##STR00042##
[0240] Step 1. Preparation of
(2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetic acid methyl ester
(25r)
[0241] 30 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic
acid methyl ester was dissolved in methanol solution (0.12 mM)
under nitrogen atmosphere. Then 2.6 mg of Pd--C (0.02 mM) was added
thereto, and hydrogenated under a hydrogen balloon for 1 to 2 hrs
at room temperature. The reaction mixture was filtered and
concentrated in vacuo. The resulting compound was purified with
Silica gel column chromatography with a solvent mixture mixed with
EtOAc and hexane (1:1) as an eluant to give
(2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetic acid methyl ester (25r)
(yield: 95%).
[0242] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.34-7.19 (m, 5H),
4.44 (ab, J=19.8 Hz, 7.4 Hz, 2H), 3.67 (s, 3H), 3.21-3.16 (m, 2H),
2.9 6(m, 2H), 2.43 (dd, J=8.7 Hz, 7.9 Hz, 1H), 2.34-2.23 (m, 1H),
1.76-1.65 (m, 1H)
Step 2. Preparation of
2-(1-benzyl-2-oxo-pyrrolidin-3-yl)-N-hydroxy-acetamide (25s)
[0243] 12 mg of (2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetic acid
methyl ester (25r) prepared by the above Step 1 was dissolved in
methanol solution (0.04 mM) and then 1.7 M methanolic suspension
solution containing NH.sub.2OK (0.07 ml, 0.12 mM) was added thereto
at 0.degree. C. and the resulting mixture was stirred for 4 hrs at
room temperature. The resulting mixture was neutralized with 0.02
ml of acetic acid, diluted with 10% methanol/chloroform solution,
filtered and concentrated in vacuo. The resulting compound was
purified by Silica gel column chromatography with a solvent mixture
mixed with methanol and chloroform (1:9) as an eluant to give 1.6
mg of 2-(1-benzyl-2-oxo-pyrrolidin-3-yl)-N-hydroxy-acetamide (25s)
(yield: 8%).
[0244] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.34-7.19 (m, 5H),
4.46 (d, J=8.1 Hz, 2H), 3.35-3.20 (m, 2H), 3.01-2.71 (m, 2H),
2.66-2.44 (m, 2H), 2.35-2.22 (m, 2H), 1.81-1.58 (m, 2H)
Example 26
Preparation of
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-pyrrolidin-3-yl]-N-hydroxy-acetamide
(26s)
[0245]
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-pyrrolidin-3-yl]-N-hydroxy-acetam-
ide (26s) was prepared by the similar procedure described in above
Example 25 (See Table 5).
Example 27
Preparation of
N-hydroxy-2-(2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetamide (27s)
[0246] N-hydroxy-2-(2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetamide
(27s) was prepared by the similar procedure described in above
Example 25 (See Table 5).
TABLE-US-00005 TABLE 5 Ex- ample Chemical structure NMR spectrum
data 26 ##STR00043## 7.10(t, J = 9.3 Hz, 1H), 6.44(t, J = 2.6 Hz,
2H), 4.43(dd, J = 14.3 Hz, 14.8 Hz, 2H), 3.78(s, 6H), 3.31-3.21(m,
2H), 2.88-2.68(m, 1H), 2.56-2.49(m, 1H), 2.26-2.22(m, 1H),
1.71-1.60(m, 1H) 27 ##STR00044## 7.30-7.15(m, 5H), 3.50(t, J = 7.11
Hz, 2H), 3.25-3.11(m, 2H), 2.86-2.66(m, 3H), 2.57-2.44(m, 1H),
2.32-2.21(m, 2H), 1.77-1.62(m, 1H)
Example 28
Preparation of
3-[1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydr-
oxy-propionamide (28y)
##STR00045##
[0247] Step 1. Preparation of
toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u)
[0248] 1.02 g of p-toluensulfonyl chloride (5.35 mM), 1.24 ml of
diisopropyl ethylamine (7.13 mM) and 86 mg of
4-(dimethylamino)pyridine (0.71 mM) were added to the reaction
solution (3.57 mM) containing 500 mg of 2-(2-fluoro-phenyl)-ethanol
(3.57 mM) dissolved in methylene chloride solution with stifling
for 6 hrs at 0.degree. C. under Ar atmosphere, and then the
reaction mixture was stirred for 12 hrs at room temperature. The
resulting mixture was neutralized with ammonium chloride, extracted
with ethyl acetate and washed with saturated NaCl solution to
separate into an organic layer and water layer. The organic layer
was dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo. The resultant was purified by Silica gel column
chromatography with a solvent mixture mixed with methanol and
chloroform (1:7) as an eluant to give 740 mg of
toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) (yield:
70%).
Step 2. Preparation of allyl-[2-(2-fluoro-phenyl)-ethyl]-amine
(v)
[0249] 0.89 ml of allylamine (11.89 mM) and 0.31 ml of diisopropyl
ethylamine (1.78 mM) were added to the reaction solution (1.19 mM)
containing 350 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl
ester (u) prepared by above Step 1 dissolved in acetonitrile
solution with stifling for 6 hrs at 80.degree. C. After the
reaction mixture was neutralized with 10% NaOH solution, the
mixture was extracted with chloroform, washed with saturated NaCl
solution, dried over MgSO.sub.4, filtered, and concentrated in
vacuo. The resultant was purified by Silica gel column
chromatography with a solvent mixture mixed with methanol and
chloroform (1:9) as an eluant to give 141 mg of
allyl-[2-(2-fluoro-phenyl)-ethyl]-amine (v) (yield: 66%).
Step 3. Preparation of
4-{allyl-[2-(3-fluoro-phenyl)-ethyl]-carbamoyl}-pent-4-enoic acid
methyl ester (w)
[0250] 106 mg of 2-methylene-pentane dionate-5-methyl ester (0.67
mM), 139 mg of 143-(dimethylamino)propyl]-3-ethylcarbodiimide (0.73
mM) and 20 mg of 4-(dimethylamino)pyridine (0.17 mM) were added to
reaction solution (0.56 mM) dissolving 100 mg of
allyl-[2-(2-fluoro-phenyl)-ethyl]-amine (v) prepared by above step
2 in methylene chloride and the mixture was stirred for 10 hrs at
room temperature. After the resulting mixture was washed with 5%
HCl solution (10 ml), the mixture was extracted with ethylacetate,
washed with saturated NaCl. And then the extracts were washed with
10 ml of saturated NaHCO.sub.3 solution and NaCl solution to
separate into an organic layer and water layer. The organic layer
was dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo. The resultant was purified by Silica gel column
chromatography with a solvent mixture mixed with EtOAc and hexanes
(1:2) as an eluant to give 128 mg of
4-{allyl-[2-(3-fluoro-phenyl)-ethyl]-carbamoyl}-pent-4-enoic acid
methyl ester (w) (yield: 72%).
[0251] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.19-7.09 (m, 1H),
7.04-6.94 (m, 3H), 5.84-5.57 (m, 1H), 5.13 (t, J=10.7 Hz, 4H),
5.06-4.94 (m, 2H), 3.79 (s, 2H), 3.62 (s, 4H), 3.53 (d, J=5.4 Hz,
3H), 2.89 (d, J=6.0 Hz, 3H)
Step 4. Preparation of
3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propio-
nic acid methyl ester (x)
[0252] 100 mg of
4-{allyl-[2-(3-fluoro-phenyl)-ethyl]-carbamoyl}-pent-4-enoic acid
methyl ester (w) (0.31 mM) prepared by the above Step 3 was added
to the catalyst solution containing 27 mg of ruthenium catalyst
(0.03 mM) dissolved in 31.3 ml of CH.sub.2Cl.sub.2 under Ar
atmosphere. Then the mixture was stirred for 24 hrs at room
temperature, filtered and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with a solvent mixture
mixed with EtOAc and hexanes (1:1) as an eluant to give 69 mg of
3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-propio-
nic acid methyl ester (x) (yield: 75%).
[0253] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.16-7.12 (m, 2H),
7.03-6.93 (m, 2H), 6.59 (br t, 1H), 3.67-3.65 (m, 4H), 3.62 (s,
3H), 2.89 (t, J=7.3 Hz, 2H), 2.56 (s, 4H)
Step 5. Preparation of
3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydr-
oxy-propionamide (28y)
[0254] 38 mg of
3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-propio-
nic acid methyl ester (x) prepared by the above Step 4 was
dissolved in methanol solution (0.13 mM) and then 1.7 M methanolic
suspension solution containing NH.sub.2OK (0.38 ml, 0.65 mM) was
added thereto at 0.degree. C. and the resulting mixture was stirred
for 8 hrs at room temperature. The resulting mixture was
neutralized with 0.02 ml of acetic acid, diluted with 10%
methanol/chloroform solution, filtered and concentrated in vacuo.
The resulting compound was purified by Silica gel column
chromatography with a solvent mixture mixed with methanol and
chloroform (1:9) as an eluant to give 25 mg of
3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydr-
oxy-propionamide (28y) (yield: 65%).
[0255] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.19-7.08 (m, 2H),
7.02-6.92 (m, 2H), 6.69 (br t, 1H), 3.69 (s, 2H), 3.63 (t, J=7.0
Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H), 2.25 (t,
J=7.3 Hz, 2H)
Example 29
Preparation of
3-{1-[2-(3-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydr-
oxy-propionamide (29y)
[0256]
3-{1-[2-(3-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}--
N-hydroxy-propionamide (29y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 30
Preparation of
3-{1-[2-(4-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydr-
oxy-propionamide (30y)
[0257]
3-{1-[2-(4-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}--
N-hydroxy-propionamide (30y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 31
Preparation of
N-hydroxy-3-{1-[2-(2-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l}-propionamide (31y)
[0258]
N-hydroxy-3-{1-[2-(2-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrr-
ol-3-yl}-propionamide (31y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 32
Preparation of
N-hydroxy-3-{1-[2-(3-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l}-propionamide (32y)
[0259]
N-hydroxy-3-{1-[2-(3-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrr-
ol-3-yl}-propionamide (32y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 33
Preparation of
N-hydroxy-3-{1-[2-(4-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l]-propionamide (33y)
[0260]
N-hydroxy-3-[1-[2-(4-nitro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrr-
ol-3-yl}-propionamide (33y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 34
Preparation of
3-{1-[2-(2-bromo-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydro-
xy-propionamide (34y)
[0261]
3-{1-[2-(2-bromo-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-
-hydroxy-propionamide (34y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 35
Preparation of
3-{1-[2-(4-bromo-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydro-
xy-propionamide (35y)
[0262]
3-{1-[2-(4-bromo-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-
-hydroxy-propionamide (35y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 36
Preparation of
N-hydroxy-3-{1-[2-(2-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl}-propionamide (36y)
[0263]
N-hydroxy-3-[1-[2-(2-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-py-
rrol-3-yl}-propionamide (36y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 37
Preparation of
N-hydroxy-3-[1-[2-(3-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl]-propionamide (3'7y)
[0264]
N-hydroxy-3-[1-[2-(3-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-py-
rrol-3-yl}-propionamide (37y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 38
Preparation of
N-hydroxy-3-{1-[2-(4-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl}-propionamide (38y)
[0265]
N-hydroxy-3-[1-[2-(4-methoxy-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-py-
rrol-3-yl}-propionamide (38y) was prepared by the similar procedure
described in above Example 28 (See Table 6).
Example 39
Preparation of
N-hydroxy-3-[2-oxo-1-(2-p-tolyl-ethyl)-2,5-dihydro-1H-pyrrol-3-yl]-propio-
namide (39y)
[0266]
N-hydroxy-3-[2-oxo-1-(2-p-tolyl-ethyl)-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide (39y) was prepared by the similar procedure described
in above Example 28 (See Table 6).
TABLE-US-00006 TABLE 6 Ex- ample Chemical structure NMR spectrum
data 29 ##STR00046## 7.25-7.18(m, 1H), 6.90(ab, J = 18.3 Hz, 4.3
Hz, 3H), 6.71(br t, 1H), 3.65(t, J = 6.9 Hz, 4H), 2.85(t, J = 6.9
Hz, 2H), 2.61 (s, 2H), 2.45(s, 2H) 30 ##STR00047## 7.11-6.94(m,
4H), 6.70(br t, 1H), 3.65 (s, 4H), 2.82(s, 3H), 2.68-2.60(m, 3H) 31
##STR00048## 7.93(d, J = 7.8 Hz, 1H), 7.56(t, J = 6.7 Hz, 1H),
7.44-7.36(m, 2H), 6.81(br t, 1H), 3.85(s, 2H), 3.76(t, J = 7.3 Hz,
2H), 3.15(t, J = 7.1 Hz, 2H), 2.54(t, J = 7.1 Hz, 2H), 2.30(t, J =
7.4 Hz, 2H) 32 ##STR00049## 8.00(d, J = 7.2 Hz, 2H), 7.49-7.38(m,
2H), 6.70(br t, 1H), 3.72(s, 2H), 3.64(t, J = 7.2 Hz, 2H), 2.93(t,
J = 7.4 Hz, 2H), 2.48(t, J = 7.3 Hz, 2H), 2.22(t, J = 7.7 Hz, 2H)
33 ##STR00050## 8.09(d, J = 8.4 Hz, 2H), 7.36(d, J = 9.6 Hz, 2H),
6.74(br t, 1H), 3.76(d, J = 1.2 Hz, 1H), 3.69(t, J = 7.1 Hz, 1H),
3.29(d, J = 7.8 Hz, 1H), 3.26(dd, J = 1.8 Hz, 1.5 Hz, 1H), 2.97(t,
J = 7.3 Hz, 2H), 2.49(t, J = 6.9 Hz, 2H), 2.25(t, J = 7.6 Hz, 2H)
34 ##STR00051## 7.48(d, J = 8.1 Hz, 2H), 7.21-7.13(m, 2H),
7.07-7.02(m, 1H), 6.71(br t, 1H), 3.70-3.62(m, 4H), 2.98(t, J = 7.3
Hz, 2H), 2.52(t, J = 7.3 Hz, 2H), 2.27(t, J = 7.6 Hz, 2H) 35
##STR00052## 7.40(d, J = 8.4 Hz, 2H), 7.10(d, J = 8.1 Hz, 2H),
6.79(br t, 1H), 3.78(d, J = 1.2 Hz, 2H), 3.66(t, J = 7.3 Hz, 2H),
2.85(t, J = 7.1 Hz, 2H), 2.54(t, J = 7.1 Hz, 2H), 2.30(t, J = 7.4
Hz, 2H) 36 ##STR00053## 7.19-7.13(m, 1H), 7.03-7.01(m, 1H), 6.81(t,
J = 7.4 Hz, 2H), 6.70(br t, 1H), 3.78(s, 3H), 3.69(s, 2H), 3.63(t,
J = 7.0 Hz, 2H), 2.85(t, J = 7.1 Hz, 2H), 2.52(t, J = 7.7 Hz, 2H),
2.27(t, J = 7.6 Hz, 2H) 37 ##STR00054## 7.14(t, J = 7.6 Hz, 1H),
6.72-6.67(m, 4H), 3.72(s, 3H), 3.65(s, 2H), 3.60(br t, 2H), 2.80(t,
J = 7.1 Hz, 2H), 2.51(t, J = 7.3 Hz, 2H), 2.25(t, J = 7.3 Hz, 2H)
38 ##STR00055## 7.02(d, J = 8.7 Hz, 2H), 6.76(d, J = 8.4 Hz, 2H),
6.66(br t, 1H), 3.72(s, 3H), 3.62-3.56(m, 4H), 2.76(t, J = 7.3 Hz,
2H), 2.51(t, J = 7.3 Hz, 2H), 2.25(t, J = 7.6 Hz, 2H) 39
##STR00056## 7.05(s, 4H), 6.74(br t, 1H), 3.72(d, J = 1.2 Hz, 2H),
3.64(t, J = 7.3 Hz, 2H), 3.31-3.29(m, 2H), 2.82(t, J = 7.3 Hz, 2H),
2.54(t, J = 7.1 Hz, 2H), 2.31(d, J = 7.8 Hz, 2H), 2.27(s, 3H).
Example 40
Preparation of
N-hydroxy-3-{1-[3-(4-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl}-propionamide (40ah)
Step 1. Preparation of 3-p-tolyl-acrylic acid methyl ester
(40aa)
[0267] 1 g of p-tolualdehyde (8.3 mM) and 4.16 g of triphenyl
phosphanyliden-acetic acid methyl ester (12.45 mM) were dissolved
in methylene chloride, the reaction solution was stirred at
90.degree. C. for overnight. After the resluting mixture was
concentrated under reduced pressure, a solvent mixture mixed with
EtOAc and hexane(1:7) was added thereto with stirring for 1 hr. And
then white solid was removed on filter, the residue was filtered
and concentrated in vacuo to give 1.39 g of 3-p-tolyl-acrylic acid
methyl ester (40aa) (yield: 95%).
Step 2. Preparation of 3-p-tolyl-propionic acid methyl ester
(40ab)
[0268] 1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa)
prepared by above Step 1 was dissolved in methanol solution (7.9
mM) under nitrogen atmosphere. Then Pd--C was added thereto,
hydrogenated under a hydrogen balloon for 1 to 2 hrs at room
temperature. The reaction mixture was filtered and concentrated in
vacuo. The resulting compound was purified with Silica gel column
chromatography with a solvent mixture mixed with EtOAc and hexane
(1:10) as an eluant to give 1.24 g of 3-p-tolyl-propionic acid
methyl ester (40ab) (yield: 95%).
Step 3. Preparation of 3-p-tolyl-propane-1-ol (40ac)
[0269] 1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab)
prepared by above Step 2 was dissolved in 100 ml of tetrahydrofuran
under Ar atmosphere. Then 27 ml of lithium alluminium-hydride was
added thereto with stifling for 2 hrs at 0.degree. C. After 3 ml of
distilled water, 3 ml of NaOH (1N) and 9 ml of distilled water were
added to the reaction mixture sequentially, the mixture was stirred
for 30 min and filtered using cellite in glass filter and
concentrated in vacuo. The resultant was purified by Silica gel
column chromatography with a solvent mixture mixed with methanol
and chloroform (1:2) as an eluant to give 971 mg of
3-p-tolyl-propane-1-ol (40ac) (yield: 93%).
Step 4. Preparation of toluene-4-sulfonate-3-p-tolyl-propyl ester
(40ad)
[0270] 2.46 g of tosyl chloride (13 mM), 3.4 ml of diisopropylamine
(19.4 mM) and 158 mg of 4-(dimethylamino)pyridine (1.29 mM) were
added to reaction solution (6.46 mM) dissolving 971 mg of
3-p-tolyl-propane-1-ol (40ac) prepared by above step 3 in methylene
chloride at 0.degree. C. under Ar atmosphere with stifling for 6
hrs, and the reaction mixture was stirred for 12 hrs at room
temperature. After the reaction mixture was neutralized with
ammonium chloride, the mixture was extracted with ethyl acetate,
washed with saturated NaCl solution, dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The resultant was purified by
Silica gel column chromatography with a solvent mixture mixed with
methanol and chloroform (1:7) as an eluant to give 1.3 g of
toluene-4-sulfonate-3-p-tolyl-propyl ester (40ad) (yield: 70%).
Step 5. Preparation of allyl-(3-p-tolyl-propyl)-amine (40ae)
[0271] 1.6 ml of allylamine (21.4 mM) and 0.97 ml of diisopropyl
ethylamine (5.5 mM) were added to the reaction solution (4.27 mM)
containing 1.3 g of allyl-(3-p-tolyl-propyl)-amine (40ae) prepared
by above Step 4 dissolved in acetonitrile solution with stifling
for 6 hrs at 100.degree. C. After the reaction mixture was
neutralized with 10% NaOH solution, the mixture was extracted with
chloroform, washed with saturated NaCl solution, dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with a solvent mixture
mixed with methanol and chloroform (1:9) as an eluant to give 687
mg of allyl-(3-p-tolyl-propyl)-amine (40ae) (yield: 85%).
Step 6. Preparation of
4-[allyl-(3-p-tolyl-propyl)-carbamoyl]-pent-4-enoic acid methyl
ester
[0272] 683 mg of 2-methylene-pentane dionate-5-methyl ester (4.3
mM), 902 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (4.7
mM) and 133 mg of 4-(dimethylamino)pyridine (1.09 mM) were added to
reaction solution (3.62 mM) dissolving 687 mg
allyl-(3-p-tolyl-propyl)-amine (40ae) prepared by above step 5 in
0.5M of methylene chloride solution under Ar atmosphere and the
mixture was stirred for 10 hrs at room temperature. After the
resulting mixture was washed with 5% HCl solution (10 ml), the
mixture was extracted with ethylacetate, washed with saturated
NaCl. And then the extracts were washed with saturated 10 ml of
NaHCO.sub.3 solution and NaCl solution to separate into an organic
layer and water layer. The organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with a solvent mixture
mixed with EtOAc and hexanes (1:2) as an eluant to give 797 mg of
4-[allyl-(3-p-tolyl-propyl)-carbamoyl]-pent-4-enoic acid methyl
ester (40af) (yield: 73%).
[0273] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.05 (s, 4H), 5.70
(s, 1H), 5.16-5.07 (m, 4H), 3.94 (s, 2H), 3.64 (t, J=3.3 Hz, 3H),
3.36 (s, 2H), 2.67-2.51 (m, 6H), 2.28 (s, 3H), 1.83 (t, J=7.7 Hz,
2H)
Step 7. Preparation of
3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (40ag)
[0274] 797 mg of
4-[allyl-(3-p-tolyl-propyl)-carbamoyl]-pent-4-enoic acid methyl
ester (40af) (2.6 mM) prepared by the above Step 6 was added to the
catalyst solution containing 180 mg of ruthenium catalyst (0.1 mM)
dissolved in 200 ml of CH.sub.2Cl.sub.2 under Ar atmosphere. Then
the mixture was stirred for 24 hrs at room temperature, filtered
and concentrated in vacuo. The resultant was purified by Silica gel
column chromatography with a solvent mixture mixed with EtOAc and
hexanes (1:1) as an eluant to give 391 mg of
3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (40ag) (yield: 50%).
[0275] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 6.96 (s, 4H), 6.56
(s, 1H), 3.67 (s, 2H), 3.55 (s, 3H), 3.37 (t, J=7.2 Hz, 2H), 2.48
(t, J=8.2 Hz, 6H), 2.19 (s, 3H), 1.76 (t, J=7.6 Hz, 2H)
Step 8. Preparation of
N-hydroxy-3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (40ah)
[0276] 100 mg of
3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (40ag) prepared by the above Step 7 was dissolved
in methanol solution (0.33 mM) and then 1.7 M methanolic suspension
solution containing NH.sub.2OK (0.82 ml, 5.0 mM) was added thereto
at 0.degree. C. and the resulting mixture was stirred for 8 hrs at
room temperature. The resulting mixture was neutralized with 0.02
ml of acetic acid, diluted with 10% methanol/chloroform solution,
filtered and concentrated in vacuo. The resulting compound was
purified by Silica gel column chromatography with a solvent mixture
mixed with methanol and chloroform (1:9) as an eluant to give 50 mg
of
N-hydroxy-3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (40ah) (yield: 50%).
[0277] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.21 (s, 4H), 6.95
(s, 1H), 3.96 (s, 2H), 3.60 (s, 2H), 2.72 (s, 5H), 2.45 (s, 3H),
1.99 (s, 2H)
Example 41
Preparation of
N-hydroxy-3-[2-oxo-1-(3-o-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (41ah)
[0278]
N-hydroxy-3-[2-oxo-1-(3-o-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-
-propionamide (41ah) was prepared by the similar procedure
described in above Example 40 (See Table 7).
Example 42
Preparation of
N-hydroxy-3-[2-oxo-1-(3-m-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propi-
onamide (42ah)
[0279]
N-hydroxy-3-[2-oxo-1-(3-m-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-
-propionamide (42ah) was prepared by the similar procedure
described in above Example 40 (See Table 7).
Example 43
Preparation of
N-hydroxy-3-{1-[3-(4-isopropyl-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrro-
l-3-yl]-propionamide (43ah)
[0280]
N-hydroxy-3-[1-[3-(4-isopropyl-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-
-pyrrol-3-yl]-propionamide (43ah) was prepared by the similar
procedure described in above Example 40 (See Table 7).
Example 44
Preparation of
3-[1-[3-(4-bromo-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydr-
oxy-propionamide (44ah)
[0281]
3-{1-[3-(4-bromo-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]--
N-hydroxy-propionamide (44ah) was prepared by the similar procedure
described in above Example 40 (See Table 7).
Example 45
Preparation of
3-{1-[3-(4-chloro-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hyd-
roxy-propionamide (45ah)
[0282]
3-{1-[3-(4-chloro-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-
-N-hydroxy-propionamide (45ah) was prepared by the similar
procedure described in above Example 40 (See Table 7).
Example 46
Preparation of
N-hydroxy-3-{1-[3-(4-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl]-propionamide (46ah)
[0283]
N-hydroxy-3-[1-[3-(4-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-p-
yrrol-3-yl]-propionamide (46ah) was prepared by the similar
procedure described in above Example 40 (See Table 7).
Example 47
Preparation of
N-hydroxy-3-{1-[3-(2-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol--
3-yl]-propionamide (47ah)
[0284]
N-hydroxy-3-[1-[3-(2-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-p-
yrrol-3-yl]-propionamide (47ah) was prepared by the similar
procedure described in above Example 40 (See Table 7).
Example 48
Preparation of
N-hydroxy-3-1143-(3-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-
-yl]-propionamide (48ah)
[0285]
N-hydroxy-3-[1-[3-(3-methoxy-phenyl)-propyl]-2-oxo-2,5-dihydro-1H-p-
yrrol-3-yl]-propionamide (48ah) was prepared by the similar
procedure described in above Example 40 (See Table 7).
TABLE-US-00007 TABLE 7 Example Chemical structure NMR spectrum data
41 ##STR00057## 7.08 (d, J = 4.2 Hz, 4H), 6.69 (s, 1H), 3.80 (s,
2H), 3.48 (d, J = 6.6 Hz, 2H), 2.57 (d, J = 9.0 Hz, 6H), 2.25 (d, J
= 6.3 Hz, 4H), 1.79 (s, 2H) 42 ##STR00058## 7.02-6.97 (m, 1H), 6.81
(d, J = 8.4 Hz, 3H), 6.64 (s, 1H), 4.07 (s, 2H), 3.71 (s, 2H), 3.32
(t, J = 7.4 Hz, 2H), 2.43 (t, J = 7.7 Hz, 5H), 2.17 (t, J = 6.5 Hz,
4H), 1.78-1.68 (m, 2H) 43 ##STR00059## 10.23 (s, 1H), 7.09 (dd, J =
6.0 Hz, 4H), 6.73 (s, 1H), 3.79 (s, 2H), 3.45 (t, J = 5.1 Hz, 2H),
2.87-2.80 (m, 1H), 2.61 (s, 1H), 2.56 (t, J = 5.9 Hz, 2H), 2.46 (s,
2H), 1.88-1.81 (m, 2H), 1.26-1.19 (m, 6H) 44 ##STR00060## 7.23 (t,
J = 5.5 Hz, 1H), 7.14 (t, J = 5.5 Hz, 2H), 6.73 (s, 1H), 3.77 (s,
2H), 3.43 (t, J = 5.0 Hz, 2H), 2.58 (t, J = Hz, 4H), 2.45 (s, 2H),
1.88-1.81 (m, 2H) 45 ##STR00061## 7.23-7.04 (m, 4H), 6.73 (s, 1H),
3.77 (s, 2H), 3.43 (t, J = 5.7 Hz, 2H), 2.56 (t, J = 12.9 Hz, 3H),
2.42 (s, 2H), 1.83 (t, J = 6.7 Hz, 2H) 46 ##STR00062## 7.03 (d, J =
8.7 Hz, 2H), 6.79-6.75 (m, 2H), 6.72 (s, 1H), 3.71 (d, J = 9.9 Hz,
5H), 3.40 (t, J = 7.3 Hz, 2H), 2.58-2.42 (m, 6H), 1.78 (t, J = 7.4
Hz, 2H) 47 ##STR00063## 7.16-7.06 (m, 2H), 6.84-6.67 (m, 2H), 3.79
(t, J = 5.5 Hz, 2H), 3.75 (t, J = 3.4 Hz, 3H), 3.50-3.41 (m, 2H),
2.55 (t, J = 7.7 Hz, 3H), 2.43 (s, 1H), 1.87 (s, 2H), 1.84-1.77 (m,
2H) 48 ##STR00064## 7.19-7.10 (m, 1H), 6.71 (d, J = 10.8 Hz, 4H),
3.75 (s, 5H), 3.49-3.40 (m, 2H), 2.55 (t, J = 7.7 Hz, 4H), 2.43 (s,
2H), 1.88-1.84 (m, 2H)
Example 49
Preparation of
N-hydroxy-3-(1-naphthalene-2-ylmethyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)--
propionamide (1e')
[0286] N-hydroxy-3-(1-naphth
alene-2-ylmethyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide
(1e') was prepared by the similar procedure described in above
Example 1 (See Table 8).
TABLE-US-00008 TABLE 8 NMR spectrum or Example Chemical structure
LC-MS data 49 ##STR00065## RT: 3.93-5.93 (Mass: 311.2)
Example 50
Preparation of
N-hydroxy-3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide
(2h')
##STR00066##
[0287] Step 1. Preparation of
3-(2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester
(2f)
[0288] 0.1 ml of triethylsilane (0.63 mM) was added to the reaction
solution containing 200 mg of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic
acid methyl ester (0.63 mM) dissolved in 0.7 ml of trifluoroacetic
acid solution at 0.degree. C. After the reaction mixture was heated
for 1 hr, the mixture was filtered and concentrated in vacuo to
remove solvent. Then the resulting mixture was dissolved in 20 ml
of chloroform solution to separate into an organic layer and water
layer. The organic layer was washed with 5 ml of saturated
NaHCO.sub.3 solution and 5 ml of saturated NaCl solution, dried
over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
resultant was purified by Silica gel column chromatography with a
solvent mixture mixed with EtOAc and hexanes (19:1) as an eluant to
give 50 mg of 3-(2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid
methyl ester (20 (yield: 47%).
[0289] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 6.76 (br t, 1H),
3.89 (d, J=1.3 Hz, 2H), 3.63 (t, J=1.9 Hz, 3H), 2.58 (s, 4H)
Step 2. Preparation of
3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl
ester (2g)
[0290] 0.33 ml of NaHMDS solution (1.0 M in THF, 0.33 mM) was added
to 0.6 ml of THF solution containing 50 mg of
3-(2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester
(2f) (0.295 mM) prepared by the Step 1 in a dropwise manner at
-79.degree. C. and stirred for 30 mins. After 0.3 ml of dimethyl
sulfate 0.359 mM) was added thereto, the reaction mixture was
stirred for 4 hrs at 0.degree. C. Then the resulting mixture was
dissolved in 2 ml of saturated NH.sub.4Cl solution and extracted
with 7 ml of ethyl acetate to separate into an organic layer and
water layer. The organic layer was washed with 2 ml of saturated
NaHCO.sub.3 solution and 2 ml of saturated NaCl solution, dried
over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
resultant was purified by Silica gel column chromatography with
EtOAc as an eluant to give 18 mg of
3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl
ester (2g) (yield: 33%).
[0291] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 6.65 (br t, 1H),
3.81 (s, 1H), 3.64 (s, 3H), 3.01 (s, 3H), 2.60 (t, 4H).
Step 3. Preparation of
N-hydroxy-3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide
h)
[0292] 18 mg of
3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl
ester (2g) prepared by the above Step 2 was dissolved in methanol
solution (0.1 mM) and then 1.7 M methanolic suspension solution
containing NH.sub.2OK (0.09 ml, 0.15 mM) was added thereto at
0.degree. C. and the resulting mixture was stirred for 1 hr at room
temperature. The resulting mixture was neutralized with 0.03 ml of
acetic acid, diluted with 10% methanol/chloroform solution,
filtered and concentrated in vacuo. The resulting compound was
purified by Silica gel column chromatography with a solvent mixture
mixed with EtOAc and methanol (5:2) as an eluant to give 11 mg of
N-hydroxy-3-(1-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionamide
(2h) (yield: 59%).
[0293] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 6.76 (br t, 1H),
3.84 (s, 2H), 3.00 (s, 3H), 2.59 (t, J=7.2 Hz, 2H), 2.42 (t, J=7.2
Hz, 2H)
Example 51
Preparation of
3-(1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-propionamide
(3h')
3-(1-allyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-hydroxy-propionamide
(3h') was prepared by the similar procedure described in above
Example 50 (See Table 9)
TABLE-US-00009 [0294] TABLE 9 Example Chemical structure NMR
spectrum data 51 ##STR00067## 6.89 (br t, 1H), 5.98-5.67 (m, 2H),
5.10-5.08 (m, 1H), 3.36 (t, J = 1.8 Hz, 2H), 2.61 (s, 2H), 2.06 (s,
2H), 1.87 (s, 2H)
Example 52
Preparation of
N-hydroxy-3-[1-(2-naphthalene-1-yl-ethyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l]-propionamide (4n')
[0295]
N-hydroxy-3-[1-(2-naphthalene-1-yl-ethyl)-2-oxo-2,5-dihydro-1H-pyrr-
ol-3-yl]-propionamide (4n') was prepared by the similar procedure
described in above Example 28 (See Table 10).
Example 53
Preparation of
N-hydroxy-3-[1-(2-naphthalene-2-yl-ethyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-y-
l]-propionamide (5n')
[0296]
N-hydroxy-3-[1-(2-naphthalene-2-yl-ethyl)-2-oxo-2,5-dihydro-1H-pyrr-
ol-3-yl]-propionamide (5n') was prepared by the similar procedure
described in above Example 28 (See Table 10).
Example 54
Preparation of
N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-2,5-dihydro-1H-pyrrol-3-yl]--
propionamide (6n')
[0297]
N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-2,5-dihydro-1H-pyrrol--
3-yl]-propionamide (6n') was prepared by the similar procedure
described in above Example 28 (See Table 10).
TABLE-US-00010 TABLE 10 Example Chemical structure NMR spectrum
data 52 ##STR00068## 8.01 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.7 Hz,
1H), 7.66 (d, J = 8.1 Hz, 1H), 7.48-7.20 (m, 4H), 6.62 (br t, 1H),
3.56 (s, 2H), 3.30-3.25 (m, 2H), 2.51 (t, J = 7.3 Hz, 2H), 2.25 (t,
J = 7.3 Hz, 2H) 53 ##STR00069## 7.73-7.66 (m, 3H), 7.53 (s, 1H),
7.40-7.32 (m, 2H), 7.22 (s, 1H), 6.61 (br t, 1H), 3.69 (t, J = 7.3
Hz, 2H), 3.60 (s, 2H), 2.97 (t, J = 7.0 Hz, 2H), 2.49 (t, J = 7.2
Hz, 2H), 2.24 (t, J = 7.3 Hz, 2H) 54 ##STR00070## 7.08 (br t, 1H),
6.85 (t, J = 4.0 Hz, 1H), 6.74 (s, 1H), 6.68 (br t, 1H), 3.65 (s,
4H), 3.27-3.29 (m, 1H), 3.05 (t, J = 6.1 Hz, 2H), 2.51 (d, J = 4.8
Hz, 2H), 2.28 (s, 1H)
Example 55
Preparation of
3-[1-(3-biphenyl-4-yl-propyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-hydroxy-
-propionamide (7w')
[0298]
3-[1-(3-biphenyl-4-yl-propyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N-h-
ydroxy-propionamide (7w') was prepared by the similar procedure
described in above Example 40 (See Table 11).
Example 56
Preparation of
N-hydroxy-3-[1-(3-naphthalene-2-yl-propyl)-2-oxo-2,5-dihydro-1H-pyrrol-3--
yl]-propionamide (8w')
[0299]
N-hydroxy-3-[1-(3-naphthalene-2-yl-propyl)-2-oxo-2,5-dihydro-1H-pyr-
rol-3-yl]-propionamide (8w') was prepared by the similar procedure
described in above Example 40 (See Table 11).
TABLE-US-00011 TABLE 11 Example Chemical structure NMR spectrum
data 55 ##STR00071## 7.51 (dd, J = 8.0 Hz, 4H), 7.37 (t, J = 7.4
Hz, 2H), 7.26 (q, J = 7.2 Hz, 2H), 6.81 (s, 1H), 4.79 (s, 2H), 3.89
(s, 2H), 3.48 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H), 2.56
(t, J = 5.1 Hz, 2H), 2.32 (t, J = 6.9 Hz, 1H) 56 ##STR00072## 10.54
(s, 1H), 7.71 (dd, J = 7.9 Hz, 3H), 7.54 (s, 1H), 7.41-7.33 (m,
2H), 7.24 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 3.67 (s, 2H), 3.40 (s,
2H), 2.69 (t, J = 6.7 Hz, 2H), 2.57 (s, 2H), 2.41 (s, 2H), 1.86 (s,
2H)
Example 57
Preparation of
3-[1-(2,4-Dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]N-hydroxy-
propionamide (e1)
Step 1. Preparation of But-3-enyl-(2,4-dimethoxybenzyl)amine
(b)
[0300] 0.5 ml of 1-Bromo-3-butene (4.926 mM) and 0.94 ml of
diisopropyl ethylamine (5.396 mM) were added to the reaction
solution containing 0.74 ml of 2,4-dimethoxybenzylamine(a) (4.926
mM) dissolved in methylene chloride with stirring and the solution
was left alone at room temperature for overnight. The reaction
mixture was washed with saturated NaCl solution, dried over
MgSO.sub.4, filtered and concentrated in vacuo. The resulting
compound was purified with Silica gel column chromatography with
EtOAc solvent as an eluant to give 436 mg of the pure title
compound (b) (yield: 40%).
[0301] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.10 (d, J=8.1 Hz,
1H), 6.41 (m, 2H), 5.75 (m, 1H), 5.01 (m, 2H), 3.78 (s, 3H), 3.77
(s, 3H), 3.70 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.24 (m, 2H)
Step 2. Preparation of
4-[But-3-enyl-(2,4-dimethoxybenzyl)-carbamoyl]-pent-4-enoic acid
methyl ester (c)
[0302] 714 mg of 2-methylene-pentane dionate-5-methyl ester (4.519
mM), 953 mg of EDC (4.971 mM) and 110 mg of DMAP (0.9 mM) were
added to 0.5 M of reaction solution dissolving the compound (b)
prepared by above step 1 in methylene chloride and the mixture was
stirred for 5 hrs at room temperature. The resulting mixture was
diluted with ethyl acetate and washed with 5% HCl solution (10 ml)
and 10 ml of sat. NaHCO.sub.3 solution to separate into an organic
layer and water layer. The organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with a solvent mixture
mixed with EtOAc and hexanes (1:2) as an eluant to give 1.39 g of
4-[but-3-enyl-(2,4-dimethoxybenzyl)-carbamoyl]-pent-4-enoic acid
methyl ester (c) (yield: 40%).
Step 3. Preparation of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propion-
ic acid methyl ester (d) 130 mg of the compound (c) (0.360 mM)
prepared by the above Step 2 was added to the catalyst solution
containing 20 mg of ruthenium (0.024 mM) dissolved in
CH.sub.2Cl.sub.2. Then the mixture was stirred for 24 hrs at room
temperature, filtered and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with
methanol/chloroform (1:10) solvent mixture as an eluant to give 108
mg of the title compound (d) (yield: 90%).
[0303] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.17 (d, J=8.9 Hz,
1H), 6.41 (m, 2H), 6.26 (t, J=4.3 Hz, 1H), 4.53 (s, 2H), 3.77 (s,
3H), 3.76 (s, 3H), 3.62 (s, 3H), 3.28 (t, J=7.1 Hz, 2H), 2.61-2.47
(m, 4H), 2.22 (m, 2H)
[0304] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta. 173.6, 164.8,
160.2, 158.5, 134.2, 133.9, 130.4, 118.0, 104.1, 98.3, 55.2, 51.3,
45.0, 44.3, 33.3, 26.6, 23.9
Step 4. Preparation of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydro-
xy-propionamide (e1) 46 mg of compound (d) prepared by the above
Step 3 was dissolved in methanol solution (0.138 mM) and then 1.7 M
methanolic suspension solution containing NH.sub.2OK (0.122 ml,
0.207 mM) was added thereto at 0.degree. C. and the resulting
mixture was stirred for 3 hrs at room temperature. The resulting
mixture was neutralized with 0.02 ml of acetic acid, diluted with
10 ml of ethyl acetate solution, filtered and concentrated in
vacuo. The resulting compound was purified by column chromatography
on Silica gel with methanol/chloroform (1:10) solvent mixture as an
eluant to give 32 mg of the title compound (e1) (yield: 73%).
[0305] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.122 (d, J=9.0
Hz, 1H), 6.415-6.331 (m, 3H), 4.505 (s, 2H), 3.750 (s, 3H), 3.744
(s, 3H), 3.271 (t, J=6.9 Hz, 2H), 2.552 (m, 2H), 2.381 (m, 2H),
2.220 (m, 2H)
[0306] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta. 170.1, 165.4,
160.2, 158.5, 135.8, 133.5, 130.4, 117.5, 104.2, 98.3, 55.3, 44.9,
44.6, 32.8, 27.1, 23.8
Example 58
Preparation of
N-hydroxy-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid (e2)
[0307]
N-hydroxy-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propio-
nic acid (e2) was prepared by the similar procedure described in
above Example 57 (See Table 12).
Example 59
Preparation of
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pr-
opionamide (e3)
[0308]
N-hydroxy-3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3--
yl)-propionamide (e3) was prepared by the similar procedure
described in above Example 57 (See Table 12).
Example 60
Preparation of
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy
propionamide (e4)
[0309] 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy
propionamide (e4) was prepared by the similar procedure described
in above Example 57 (See Table 12).
Example 61
Preparation of
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pr-
opionamide (e5)
[0310]
N-hydroxy-3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3--
yl]-propionamide (e5) was prepared by the similar procedure
described in above Example 57 (See Table 12).
Example 62
Preparation of
N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionam-
ide (e6)
[0311]
N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pro-
pionamide (e6) was prepared by the similar procedure described in
above Example 57 (See Table 12).
TABLE-US-00012 TABLE 12 Example Chemical structure NMR spectrum
data 58 ##STR00073## 7.38 (m, 5H), 6.44 (t, J = 4.3 Hz, 1H), 4.61
(s, 2H), 3.33 (m, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.28 (m, 4H) 59
##STR00074## 8.14 (d J = 8.4 Hz 2H), 7.40 (t J = 7.2 Hz 2H), 6.42
(br t 1H), 4.67 (s 2H), 3.32 (t J = 6.3 Hz 2H), 2.67-2.32 (m 6H) 60
##STR00075## 7.29-7.18 (m 5H) 6.40 (br t 1H), 3.62 (t J = 7.2 Hz
2H), 3.19 (t J = 7.1 Hz 2H), 2.85 (t J = 7.1 Hz 2H), 2.54-2.44 (m
2H), 2.18-2.15 (m 4H) 61 ##STR00076## 7.24-7.11 (m, 5H), 6.31 (br
t, 1H), 3.35 (br t, 2H), 3.23 (br t, 2H), 2.55 (d, J = 6.6 Hz, 4H),
2.33 (s, 2H), 2.18 (s, 2H), 1.80 (br t, 2H) 62 ##STR00077##
7.28-7.13 (m, 5H), 6.36 (t, J = 3.9, 1H), 3.39 (t, J = 6.75, 2H),
3.29 (t, J = 7.05, 2H), 2.62 (t, J = 7.05, 2H), 2.54 (t, J = 6.75,
2H) 2.40 (t, J = 6.75, 2H), 2.27 (ab, J = 6.0, 5.4, 2H), 1.58 (t, J
= 2.7, 4H)
Example 63
Preparation of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propion-
ic acid (f1)
##STR00078##
[0313] 11 mg of LiOH.H.sub.2O solution (0.262 mM) was added to 0.75
ml of THF solution containing 58 mg of 3-[1-(2,4-dimethoxy
benzyl)-2-oxo-1,2,5,6-tetrahydro pyridine-3-yl]-propionic acid
methyl ester (d) (0.174 mM) in a dropwise manner at 0.degree. C.
After the reaction mixture was stirred for 2 hrs at 0.degree. C.
and for 1 hr at room temperature, 5% HCl was added to the mixture
to pH 2. Then the mixture was extracted three times with 10 ml of
ethyl acetate, the organic layer was washed with saturated NaCl
solution, dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resulting compound was purified with
Silica gel column chromatography with methanol/chloroform (1:10)
solvent mixture as an eluant to give 44 mg of the title compound
(f1) (yield: 80%).
[0314] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.16 (d, J=8.9 Hz,
1H), 6.42 (m, 2H), 6.29 (t, J=4.3 Hz, 1H), 4.54 (s, 2H), 3.76 (s,
3H), 3.76 (s, 3H), 3.29 (t, J=7.2 Hz, 2H), 2.56 (m, 4H), 2.22 (m,
2H)
[0315] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta. 177.7, 165.1,
160.1, 158.5, 134.6, 133.9, 130.5, 117.7, 104.1, 98.3, 55.2, 44.9,
44.5, 33.5, 26.3, 23.8
Example 64
Preparation of
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid
([2)
[0316] 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid ([2) was prepared by the similar procedure described in above
Example 63 (See Table 13).
Example 65
Preparation of
3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid ([3)
[0317]
3-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propio-
nic acid ([3) was prepared by the similar procedure described in
above Example 63 (See Table 13).
Example 66
Preparation of
3-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid ([4)
[0318]
3-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propi-
onic acid ([4) was prepared by the similar procedure described in
above Example 63 (See Table 13).
Example 67
Preparation of
3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid ([5)
[0319]
3-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-propio-
nic acid ([5) was prepared by the similar procedure described in
above Example 63 (See Table 13).
Example 68
Preparation of
3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid ([6)
[0320]
3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid ([6) was prepared by the similar procedure described in above
Example 63 (See Table 13).
TABLE-US-00013 TABLE 13 Example Chemical structure NMR spectrum
data 64 ##STR00079## 7.25 (m, 5H), 6.34 (t, J = 4.2 Hz, 1H), 4.60
(s, 2H), 3.26 (t, J = 7.1 Hz, 2H), 2.59 (m, 4H), 2.25 (m, 2H) 65
##STR00080## 8.16 (d J = 8.7 Hz 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.39
(t J = 4.3 Hz, 1H) 4.69 (s, 2H) 3.32 (t, J = 7.2 Hz, 2H) 2.64-2.53
(m, 4H), 2.33 (dd J = 6.9 Hz, 5.7 Hz, 2H) 66 ##STR00081## 9.92 (br
s 1H), 7.28-7.15 (m, 5H), 6.28 (t, J = 4.4, 1H), 3.60 (t J = 7.4,
2H) 3.16 (t, J = 7.2, 2H), 2.84 (t, J = 7.4, 2H) 2.58-2.48 (m, 4H)
2.15 (AB, J = 11.4, 6.8, 2H) 67 ##STR00082## 7.28-7.10 (m, 5H),
6.48 (br, t, 1H), 5.75-5.60 (m, 1H), 5.01 (d, J = 16.5 Hz, 2H),
3.41-3.26 (m, 3H) 2.63-2.26 (m, 7H), 1.84 (t, J = 8.6 Hz, 2H) 68
##STR00083## 7.256-7.138 (m, 5H), 6.33 (br, t, 1H), 3.42 (t, J =
6.9 , 2H), 3.32 (t, J = 7.35, 2H), 2.63 (t, J = 7.05, 2H), 2.547
(d, J = 2.4, 4H), 2.30 (d, J = 4.5, 2H), 1.61 (q, J = 1.5, 4H)
Example 69
Preparation of
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-pyridin-2-yl-propion-
amide (g1)
##STR00084##
[0322] Pyridyl amine was added to organic solvent dissolving 30 mg
of 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid (0.12 mM) in EDC. The resulting compound was purified by
Silica gel column chromatography with methanol/chloroform (1:20)
solvent mixture as an eluant to give 16 mg of the title compound
(g1) (yield: 39%).
Example 70
Preparation of
N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pro-
pionamide (g2)
##STR00085##
[0324] 40 mg of 1,2-phenylenediamine (0.37 M), 77 mg of EDC (0.4 M)
and 1 mg of DMAP (3 M %) were added to reaction solution dissolving
3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid
prepared by above Example 8 in 1 ml of methylene chloride under
Argon atmosphere. After the mixture was stirred for 13 hrs at room
temperature, the resulting mixture was diluted with ethyl acetate
and washed with 10% NaOH solution (10 ml). Then the residue was
extracted with 50 ml of chloroform, dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The resultant was
purified by Silica gel column chromatography with a solvent mixture
mixed with methanol and chloroform (1:20) as an eluant to give 96
mg of
N-(2-amino-phenyl)-3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-pro-
pionamide (g2) (yield: 91%).
[0325] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.8.29 (s, 1H),
7.29-7.19 (m, 5H), 7.13 (d, 1H, J=7.8 Hz), 6.99-6.94 (m, 1H), 6.68
(t, 2H, J=7.9 Hz), 6.37 (t, 1H, J=8.4 Hz), 4.57 (t, 2H, J=7.4 Hz),
3.88 (s, 2H), 3.29-3.21 (m, 2H), 2.68 (t, 2H, J=6.5 Hz), 2.59 (t,
2H, 6.5 Hz), 2.26-2.217 (m, 2H)
Example 71
Preparation of
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridi-
n-3-yl)-propionamide (g3)
[0326]
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro--
pyridin-3-yl)-propionamide (g3) was prepared by the similar
procedure described in above Example 69 and 70 (See Table 14).
Example 72
Preparation of
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridi-
n-3-yl)-propionamide (g4)
[0327]
N-(2-amino-phenyl)-3-[1-(2-methyl-benzyl)-2-oxo-1,2,5,6-tetrahydro--
pyridin-3-yl)-propionamide (g4) was prepared by the similar
procedure described in above Example 69 and 70 (See Table 14).
TABLE-US-00014 TABLE 14 Example Chemical structure NMR spectrum
data 71 ##STR00086## 8.23 (s, 1H), 7.12 (dd, 5H, J = 6.6 Hz), 6.979
(t, 1H, J = 7.5 Hz), 6.697 (t, 2H, J = 8.9), 6.408 (t, 1H, J = 7.4
Hz), 4.602 (s, 2H), 3.874 (s, 2H), 3.239 (t, 2H, J = 7.1 Hz,),
2.702 (t, 2H, J = 6.8 Hz), 2.604 (t, 2H, J = 6.3 Hz), 2.260 (t, 5H,
J = 6.3 Hz) 72 ##STR00087## 8.305 (s, 1H), 7.189-7.091 (m, 2H),
6.969-6.914 (m, 2H), 6.794-6.741 (m, 2H), 6.691-6.631 (m, 2H),
6.355 (t, 1H, J = 4.1 Hz), 4.539 (s, 2H), 3.965 (s, 2H), 3.707 (s,
3H), 3.253 (t, 2H, J = 7.0 Hz), 2.661-2.539 (m, 4H), 2.22 (dd, 2H,
J = 7.1 Hz)
Example 73
Preparation of
N-benzyloxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-propion-
amide (g5)
##STR00088##
[0329] Benzyloxyamine was added to organic solvent dissolving 30 mg
of 3-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid (0.15 mM) prepared by above Example 12 in EDC. The resulting
compound was purified by Silica gel column chromatography with
ethylacetate/chloroform (1:1) solvent mixture as an eluant to give
41 mg of the title compound (g5) (yield: 75%).
[0330] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.41-7.15 (m, 1H),
6.34 (br t, 1H), 4.88 (s, 2H), 3.58 (t, J=7.4 Hz, 2H), 3.16 (t,
J=7.2 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.53 (t, J=6.8 Hz, 2H), 2.26
(br s, 1H), 2.19 (dd, J=11.4, 7.1 Hz, 2H)
Example 18
Preparation of
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydr-
oxy-propionamide (j1)
Step 1. Preparation of
3-[1-(4-amino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic
acid methyl ester (h) 50 mg of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propion-
ic acid methyl ester (d) (0.16 mM) prepared by the Step 3 of above
Example 1 was dissolved in methanol solution at room temperature.
Then 154 mg of Zn (2.36 mM) and 0.01 ml of acetic acid (0.16 mM)
were added thereto and the mixture was stirred for 20 hrs at
80.degree. C. The resulting compound was purified by Silica gel
column chromatography with a solvent mixture mixed with
ethylacetate and hexane (1:1) as an eluant to give 43 mg of
3-[1-(4-amino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propio-
nic acid methyl ester (h) (yield: 92%).
[0331] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.22 (d, 1H, J=8.5
Hz), 8.11 (d, 1H, J=8.4 Hz), 7.37 (t, 2H, J=8.3 Hz), 6.33 (t, 1H,
J=4.3 Hz), 4.66 (d, 2H, J=7.5 Hz), 3.63 (s, 3H), 3.29 (t, 2H, J=6.6
Hz), 2.63 (t, 2H, J=6.9 Hz), 2.54 (t, 2H, J=6.6 Hz), 2.28 (t, 2H,
J=4.2 Hz)
Step 2. Preparation of
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propio-
nic acid methyl ester (i) 17.5 mg of
3-[1-(4-amino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic
acid methyl ester (h) prepared by above Step 1 was dissolved in
methylene chloride solution (0.06 mM). And then 6 .mu.l of
(AcO).sub.2O(0.07 mM), 0.01 ml of triethylamine (0.08 mM) and 1.0
mg of DMAP (0.008 mM) were added thereto and the mixture was
stirred for 3 hrs at 0.degree. C. The reaction was stopped by
adding methanol and the mixture was extracted three times with 10
ml of ethyl acetate. The organic layer was washed with saturated
NaCl solution, dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resulting compound was purified with
Silica gel column chromatography with ethylacetate as an eluant to
give 46 mg of
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-y-
l)-propionic acid methyl ester (i) (yield: 44%).
[0332] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.8.34 (s, 1H), 7.40
(d, 2H, J=8.4 Hz), 7.10 (d, 2H, J=8.4 Hz), 6.29 (t, 1H, J=4.2 Hz),
4.50 (s, 2H), 3.61 (s, 3H), 3.22 (t, 2H, J=7.1 Hz), 2.59 (t, 2H,
J=7.1 Hz), 2.51 (d, 2H, J=6.6 Hz), 2.22 (dd, 2H, J=6.9 Hz), 2.09
(s, 3H)
Step 3. Preparation of
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydr-
oxy-propionamide (j1)
##STR00089##
[0334]
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)--
propionic acid methyl ester (i) prepared by above Step 2 dissolved
in organic solvent such as methanol was reacted with amine salt to
give
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydr-
oxy-propionamide (j1).
[0335] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.50 (d J=8.0 Hz
2H), 7.23 (d J=8.0 Hz 2H), 6.44 (br t 1H), 4.57 (S 2H), 3.33 (t,
J=6.5 Hz, 6H) 2.57 (br t, 2H) 2.30-2.26 (m, 4H) 2.10 (s, 2H)
Example 75
Preparation of
N-4-5-(2-hydroxycarbamoyl-ethyl)-6-oxo-3,6-dihydro-2-pyridin-1-yl-methyl]-
-phenyl-benzamide (j2)
[0336]
N-4-[5-(2-hydroxycarbamoyl-ethyl)-6-oxo-3,6-dihydro-2-pyridin-1-yl--
methyl]-phenyl-benzamide (j2) was prepared by the similar procedure
described in above Example 74 (See Table 15).
Example 76
Preparation of
N-hydroxy-3-[1-(4-dimethylsulfonylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro--
pyridin-3-yl]-propionamide (j3)
[0337]
N-hydroxy-3-[1-(4-dimethylsulfonylamino-benzyl)-2-oxo-1,2,5,6-tetra-
hydro-pyridin-3-yl]-propionamide (j3) was prepared by the similar
procedure described in above Example 74 (See Table 15).
Example 77
Preparation of
N-hydroxy-3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl-1,2,5,6-tetrahydr-
o-pyridin-3-A-propionamide (j4)
[0338]
N-hydroxy-3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl-1,2,5,6-tet-
rahydro-pyridin-3-yl]-propionamide (j4) was prepared by the similar
procedure described in above Example 74 (See Table 15).
TABLE-US-00015 TABLE 15 Example Chemical structure NMR spectrum
data 75 ##STR00090## 7.90 (t J = 7.05 Hz 2H), 7.67 (d, J = 8.10 Hz,
2H) 7.59-7.47 (m, 3H) 7.30 (d J = 8.10 Hz 2H), 6.45 (br t, 2H) 4.61
(s, 2H) 3.36 (t, J = 7.2, 2H) 3.30 (q, J = 1.5 Hz, 4H) 2.58 (br t,
2H) 76 ##STR00091## 7.24 (q, J = 8.6 Hz, 4H) 6.45 (br t, 1H) 4.58
(s, 2 H) 3.38-3.29 (m, 7H) 2.93 (s, 3H) 2.57 (t, 2H, J = 7.1)
2.34-2.24 (m, 4H) 77 ##STR00092## 7.78 (d, J = 8.0 Hz, 2H), 7.31
(d, J = 7.5 Hz, 2H) 7.27-7.21 (m, 4H) 6.97 (t, J = 7.2 Hz, 1H) 4.61
(d, J = 3.5 Hz, 1H) 3.47 (s, 4H) 3.36-3.30 (m, 1H) 2.71-2.64 (m,
1H) 2.51-2.44 (m, 3H), 2.32 (d, J = 4.5 Hz, 1H)
Example 78
Preparation of
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propio-
nic acid (k)
##STR00093##
[0340]
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]--
propionic acid methyl ester (i) prepared by above Step 2 of Example
18 dissolved in organic solvent such as tetrahydrofurane was
reacted with LiOH to give
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propio-
nic acid (k).
[0341] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.50 (d J=8.0 Hz
2H), 7.23 (d J=8.6 Hz 2H), 6.45 (t J=4.5 Hz 1H), 4.58 (S 2H), 3.32
(t, J=7.5 Hz, 3H) 2.57 (t, J=7.5 Hz, 2H) 2.46 (t, J=7.5 Hz, 2H)
Example 79
Preparation of
3-[1-(4-benzoylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propi-
onic acid (k2)
[0342]
3-[1-(4-benzoylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-
-propionic acid (k2) was prepared by the similar procedure
described in above Example 78 (See Table 16).
Example 80
Preparation of
3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2-oxo-1,2,5,6-tetrahydro-p-
yridin-3-yl]-propionic acid (k3)
3-2-oxo-1-[4-(toluene-4-sulfonylamino)-benzyl]-2-oxo-1,2,5,6-tetrahydro-p-
yridin-3-yl]-propionic acid (k3) was prepared by the similar
procedure described in above Example 78 (See Table 16).
TABLE-US-00016 [0343] TABLE 16 Example Chemical structure NMR
spectrum data 79 ##STR00094## 7.83 (d, J = 6.9 Hz, 2H), 7.59 (d, J
= 8.4 Hz, 2H), 7.49-7.37 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 6.33
(q, J = 4.5 Hz, 1H) 3.26 (t, J = 7.2 Hz, 3H) 2.54-2.40 (m, 4H) 2.24
(ab, J = 11.6 Hz, 3.5 Hz. 2H) 80 ##STR00095## 7.74 (d, J = 8.1 Hz,
4H), 7.18 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 8.1, 2H), 4.53 (s, 2H),
3.20 (br t, 2H), 2.40 (s, 9H)
Example 81
Preparation of
N-hydroxy-3-(2-oxo-1-phenethyl-piperidine-3-yl)-propionamide
(m)
Step 1. Preparation of
[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-acetic acid methyl
ester (l)
[0344]
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-p-
ropionic acid methyl ester was dissolved in alcohol solvent under
nitrogen atmosphere. Then Pd--C was added thereto, and the mixture
was hydrogenated under a hydrogen balloon for 1 to 2 hrs at room
temperature.
[0345] The reaction mixture was filtered and concentrated in vacuo.
The resulting compound was purified with Silica gel column
chromatography with a solvent mixture mixed with EtOAc/hexane (1:1)
as an eluant to give
[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-acetic acid methyl
ester (1) (yield: 74%).
[0346] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.13 (d, 1H, J=8.4
Hz), 6.42 (d, 2H, J=7.2 Hz), 4.51 (ab, 2H, J=32.9, 7.4 Hz), 3.76
(s, 6H), 3.66 (s, 3H), 3.24-3.18 (m, 2H), 2.93-2.72 (m, 2H),
2.56-2.43 (m, 1H), 1.98-1.55 (m, 4H)
Step 2. Preparation of
N-hydroxy-3-(2-oxo-1-phenethyl-piperidine-3-yl)-propionamide
(m)
##STR00096##
[0348] [1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]acetic acid
methyl ester (1) prepared by above Step 1 was reacted with amine
salt to give
N-hydroxy-3-(2-oxo-1-phenethyl-piperidine-3-yl)-propionamide
(m).
[0349] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.26-7.17 (m 5H),
3.61-3.44 (m 2H) 3.08-2.83 (m 4H), 2.56-2.16 (m 4H)
Example 82
Preparation of
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydr-
oxy-acetamide (p1)
Step 1. Preparation of 3-(benzyl-but-3-enyl-carbamoyl)-but-3-enoic
acid methyl ester (n)
[0350] 2-Methylene-pentane dionate-5-methyl ester, EDC and DMAP
were added to reaction solution dissolving the
but-3-enyl-(2,4-dimethoxybenzyl)amine (b) prepared by above Step 1
of Example 1 in methylene chloride and the mixture was stirred for
5 hrs at room temperature to give
3-(benzyl-but-3-enyl-carbamoyl)-but-3-enoic acid methyl ester
(n).
[0351] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.30-7.19 (m, 5H),
5.69 (br t, 1H), 5.23 (s, 2H), 5.00 (t, 2H, J=12.6 Hz), 4.74 (s,
2H), 3.61 (s, 3H), 3.42 (s, 4H), 2.30 (q, 2H, J=7.2 Hz)
Step 2. Preparation of
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid methyl ester (o)
[0352] 3-(benzyl-but-3-enyl-carbamoyl)-but-3-enoic acid methyl
ester (n) prepared by above Step 1 was added to the catalyst
solution containing Grubb's (I) catalysis such as ruthenium
dissolved in organic solvent such as CH.sub.2Cl.sub.2 to give
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid methyl ester (o).
[0353] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.17 (d, 1H, J=6.2
Hz), 6.42-6.36 (m, 3H), 4.54 (s, 2H), 3.76 (d, 6H, J=3.0 Hz), 3.66
(s, 3H), 3.35 (t, 2H, J=6.9), 3.28 (s, 2H), 2.29 (ab, 2H, J=11.3,
3.4 Hz)
Step 3. Preparation of
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydr-
oxy-acetamide (p1)
##STR00097##
[0355]
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-ac-
etic acid methyl ester (o) prepared by above Step 2 dissolved in
alcohol solvent was reacted with amine salt to give
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydr-
oxy-acetamide (p1).
[0356] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.14 (d, J=8.7 Hz,
1H), 6.54 (br t, 1H) 6.44 (d, J=6.0 Hz, 2H), 4.55 (s, 2H), 3.78 (s,
6H), 3.41-3.32 (m, 2H), 3.20 (s, 2H), 2.0 (d, J=4.5 Hz, 2H)
Example 83
Preparation of
2-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-acetamide
(p2)
[0357]
2-(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-acetam-
ide (p2) was prepared by the similar procedure described in above
Example 82 (See Table 17).
Example 84
Preparation of
N-hydroxy-2-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N--
hydroxy-acetamide (p3)
[0358]
N-hydroxy-2-[1-(4-nitro-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3--
yl)-N-hydroxy-acetamide (p3) was prepared by the similar procedure
described in above Example 82 (See Table 17).
Example 85
Preparation of
N-hydroxy-2-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N-
-hydroxy-acetamide (p4)
[0359]
N-hydroxy-2-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-
-yl]-N-hydroxy-acetamide (p4) was prepared by the similar procedure
described in above Example 82 (See Table 17).
Example 86
Preparation of
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-N--
hydroxy-acetamide (p5)
[0360]
N-hydroxy-2-[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3--
yl]-N-hydroxy-acetamide (p5) was prepared by the similar procedure
described in above Example 82 (See Table 17).
TABLE-US-00017 TABLE 17 Example Chemical structure NMR spectrum
data 83 ##STR00098## 7.34-7.22 (m, 5H), 6.58 (t, J = 4.5 Hz, 1H)
4.60 (s, 2H) 3.39-3.30 (m, 3H) 3.20 (s, 2H) 2.39-2.30 (m, 2H) 84
##STR00099## 8.21 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H)
6.63 (t, J = 4.3 Hz, 1H), 4.75 (s, 2H), 3.41 (ab, J = 6.5 Hz, 4H),
2.43 (ab, J = 6.2 Hz, 2H) 85 ##STR00100## 7.22 (d, J = 6.5 Hz, 2H)
7.14 (s, 3H) 6.51 (br t, 1H) 3.43-3.32 (m, 5H) 3.11 (s, 1H) 2.59
(s, 2H) 2.29 (s, 2H) 1.84 (s, 2H) 86 ##STR00101## 7.28-7.13 (m,
5H), 6.54 (br t, 1H), 3.44-3.31 (m, 5H), 3.14 (s, 1H) 2.62 (t, J =
7.1 Hz, 2H), 2.34 (s, 2H), 1.58 (t, J = 3.4 Hz, 4H)
Example 87
Preparation of
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid (q1)
##STR00102##
[0362]
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-ac-
etic acid methyl ester (o) prepared by the Step 2 of Example 26
dissolved in TFA was reacted with LiOH to give
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid (q1).
[0363] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.7.18 (d, J=8.7 Hz,
1H), 6.54 (t, J=4.3 Hz, 1H), 6.45 (d, J=6.6 Hz, 2H), 4.60 (s, 2H),
3.79 (s, 6H) 3.39 (t, J=7.3 Hz, 2H), 3.34 (s, 2H), 2.32 (ab, J=11.7
Hz, 3.6 Hz, 2H)
Example 88
Preparation of
(1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid
(q2)
[0364] (1-benzyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid
(q2) was prepared by the similar procedure described in above
Example 87 (See Table 18).
Example 89
Preparation of
(2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic acid
(q3)
[0365] (2-oxo-1-phenethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid (q3) was prepared by the similar procedure described in above
Example 87 (See Table 18).
Example 90
Preparation of
[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid (q4)
[0366]
[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid (q4) was prepared by the similar procedure described in above
Example 87 (See Table 18).
Example 91
Preparation of
[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid (q5)
[0367]
[2-oxo-1-(4-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl)-acetic
acid (q5) was prepared by the similar procedure described in above
Example 87 (See Table 18).
TABLE-US-00018 TABLE 18 Example Chemical structure NMR spectrum
data 88 ##STR00103## 7.29-7.18 (m 5H) 6.50 (t, J = 4.5 Hz, 1H),
4.58 (s, 2H), 3.31 (d J = 7.2 Hz 4H), 2.29 (ab, J = 11.0 Hz, 3.5
Hz, 2H) 89 ##STR00104## 7.31-7.18 (m, 5H), 6.53 (t, J = 4.5 Hz,
1H), 3.67 (t, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.23 (t, J = 7.2 Hz,
2H) 2.90 (t, J = 7.2 Hz 2.23 (ab, J = 11.7 Hz, 3.6 Hz, 2H) 90
##STR00105## 7.32-7.12 (m, 5H) 6.47 (br t, 1H) 3.56 (t, J = 10.8
Hz, 2H), 3.11 (s, 4H) 2.78 (d, J = 6.0 Hz, 2H) 2.14 (d, J = 10.8
Hz, 2H) 91 ##STR00106## 7.29-7.14 (m, 5H), 6.55 (t, J = 4.2 Hz,
1H), 3.46 (t, J = 6.7 Hz, 2H), 3.38 (t, J = 7.3 Hz, 2H), 3.31 (s,
2H) 2.64 (t, J = 7.1 Hz, 2H) 2.37 (ab, J = 6.3 Hz, 1H) 1.67-1.58
(m, 4H)
Example 92
Preparation of
2-[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-N-hydroxy-acetamide
(s1)
Step 1. Preparation of
[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-acetic acid methyl
ester
[0368] Lr)
[0369] 26 mg of
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic
acid methyl ester(o) (0.08 mM) was dissolved in methanol solution
under Ar atmosphere. 1.7 mg of 10% Pd--C was added thereto and the
mixture was hydrogenated under a hydrogen balloon. The reaction
mixture was stirred for 5 hrs at room temperature, filtered and
concentrated in vacuo. The resulting compound was purified with
Silica gel column chromatography to give 25 mg of
[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-acetic acid methyl
ester (r) (yield: 99%).
[0370] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.13 (d, J=8.4 Hz,
2H), 6.41 (dd, J=8.4 Hz, 2H), 6.41 (s, 1H), 4.51 (dd, J=32.7, 14.9
Hz, 2H), 3.76 (s, 6H), 3.66 (s, 3H), 3.22 (dd, J=7.5, 4.6 Hz, 2H),
2.90 (dd, J=15.9, 5.1 Hz, 1H), 2.76 (m, 1H), 2.52 (dd, J=16.2, 7.5
Hz, 2H), 1.98-1.55 (m, 4H)
Step 2. Preparation of
[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-N-hydroxy-acetamide
(s1)
##STR00107##
[0372] [1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]acetic acid
methyl ester (r) prepared by the Step 1 was reacted with amine salt
to give
[1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]-N-hydroxy-acetamide
(s1).
[0373] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.15 (d, J=9.0 Hz,
1H), 6.46 (t, J=4.65, 2H), 4.56 (q, J=7.2 Hz, 23.7 Hz, 2H), 3.79
(s, 6H), 3.31-3.19 (m, 2H), 2.86-2.69 (m, 2H), 2.41 (d, J=14.1 Hz,
1H), 1.89-1.79 (m, 2H)
Example 93
Preparation of
(2-oxo-1-phenethyl-piperidine-3-yl)-N-hydroxy-acetamide (s2)
[0374] (2-oxo-1-phenethyl-piperidine-3-yl)-acetic acid (s2) was
prepared by the similar procedure described in above Example 92
(See Table 19).
Example 94
Preparation of
[2-oxo-1-(3-phenyl-propyl)-piperidine-3-yl]-N-hydroxy-acetamide
(s3)
[0375] [2-oxo-1-(3-phenyl-propyl)-piperidine-3-yl]-acetic acid (s3)
was prepared by the similar procedure described in above Example 92
(See Table 19).
TABLE-US-00019 TABLE 19 Example Chemical structure NMR spectrum
data 93 ##STR00108## 7.315-7.169 (m, 5H), 3.60 (t, J = 7.35, 1H),
3.15 (dd, J = 4.8, 11.1, 1H), 2.917-2.856 (m, 1H), 2.728-2.659 (m,
1H), 1.698-1.426 (m, 4H), 1.23 (d, J = 7.05, 5H) 94 ##STR00109##
7.29-7.12 (m, 5H) 3.47-3.35 (m. 2H), 3.29-3.23 (m, 2H) 2.63-2.45
(m. 4H) 2.03-1.80 (m. 4H) 1.59-1.47 (m, 2H), 1.33-1.19 (m, 3H)
Example 95
Preparation of
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy--
butylamide (v1)
Step 1. Preparation of
5-[(4-methoxy-benzyl)-but-3-enyl-carbamoyl]-hex-5-enoic acid methyl
ester (t)
[0376] 2-Methylene-pentane dionate-5-methyl ester, EDC and DMAP
were added to reaction solution dissolving the
but-3-enyl-(2,4-dimethoxybenzyl)amine (b) prepared by above Step 1
of Example 1 in methylene chloride solution and the mixture was
stirred for 5 hrs at room temperature to give
5-[(4-methoxy-benzyl)-but-3-enyl-carbamoyl]-hex-5-enoic acid methyl
ester (t).
Step 2. Preparation of
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-butyric
acid methyl ester (u)
[0377] 5-[(4-methoxy-benzyl)-but-3-enyl-carbamoyl]-hex-5-enoic acid
methyl ester (t) prepared by above Step 1 was added to the catalyst
solution containing Grubb's (I) catalysis such as ruthenium
dissolved in organic solvent such as CH.sub.2Cl.sub.2 to give
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-butyric
acid methyl ester (u).
[0378] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.19 (d, J=8.4 Hz,
2H), 6.83 (d, J=8.4 Hz, 2H), 6.25 (t, J=4.2 Hz, 1H), 4.54 (s, 2H),
3.77 (s, 3H), 3.65 (s, 3H), 3.25 (t, J=6.9 Hz, 2H) 2.33 (t, J=7.3
Hz, 4H), 2.24 (q, J=4.5 Hz, 2H), 1.80 (t, J=7.2 Hz, 2H) 1.56 (s,
2H)
Step 3. Preparation of
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy--
butylamide (v1)
##STR00110##
[0380]
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-buty-
ric acid methyl ester (u) prepared by Step 2 dissolved in alcohol
solvent was reacted with amine salt to give
4-[1-(4-methoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-N-hydroxy--
butylamide (v1).
[0381] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.19-7.15 (m, 2H),
6.83 (d, J=7.8 Hz, 2H), 6.28 (br t, 1H), 4.53 (s, 2H), 3.76 (s,
3H), 3.25 (dt, JA=7.5 Hz, JB=1.8 Hz, 2H), 2.38-2.23 (m, 6H),
1.85-1.76 (m, 2H)
Example 96
Preparation of
4-(1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-butylamid-
e (v2)
[0382]
4-(1-phenethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-but-
ylamide (v2) was prepared by the similar procedure described in
above Example 95 (See Table 20).
Example 97
Preparation of
N-hydroxy-4-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-b-
utylamide (v3)
[0383]
N-hydroxy-4-[2-oxo-1-(3-phenyl-propyl)-1,2,5,6-tetrahydro-pyridin-3-
-yl]-butylamide (v3) was prepared by the similar procedure
described in above Example 95 (See Table 20).
Example 98
Preparation of
N-hydroxy-4-[2-oxo-1-(3-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-bu-
tylamide (v4)
[0384]
N-hydroxy-4-[2-oxo-1-(3-phenyl-butyl)-1,2,5,6-tetrahydro-pyridin-3--
yl]-butylamide (v4) was prepared by the similar procedure described
in above Example 95 (See Table 20).
TABLE-US-00020 TABLE 20 Example Chemical structure NMR spectrum
data 96 ##STR00111## 7.29-7.13 (m, 5H), 6.24 (br t, 1H), 3.56 (t, J
= 7.56 Hz 2H), 3.31-3.29 (m, 1H), 3.16 (t, J = 6.9 Hz, 2H), 2.80
(t, J = 7.2 Hz, 2H), 2.14-2.03 (m, 5H), 1.66-1.61 (m, 2H) 97
##STR00112## 7.29-7.17 (m, 5H), 6.32 (br t, 1H), 3.46 (t, J = 7.3
Hz, 2H), 3.35 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H),
2.37-2.28 (m, 5H), 1.99-1.73 (m, 5H) 98 ##STR00113## 7.29-7.15 (m,
5H), 6.31 (br t, 1H), 3.45 (t, J = 6.5 Hz 2H), 3.32 (t, J = 7.1 Hz,
2H), 2.64 (t, J = 7.0 Hz, 2H), 2.27 (d, J = 7.2 Hz, 6H), 1.60 (s,
6H)
Example 99
Preparation of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid (g)
##STR00114##
[0386] 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid (g)
was dissolved in 0.5 ml of DMF solution. Then BnONH.sub.2.HCl (30
mg, 0.188 mmol), diisopropyl methylamine (0.033 ml, 0.189 mmol),
EDC (43 mg, 0.224 mmol) and DMAP (5 mg, 0.041 mmol) were added
thereto and the mixture was stirred for overnight at room
temperature. The mixture was diluted with 7 ml of ethyl acetate and
washed with 5% HCl (1 ml) and sat. NaHCO.sub.3 solutions (1 ml).
The organic layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resulting compound was purified by
column chromatography on Silica gel with methanol/chloroform (1:20)
solvent mixture as an eluant to give 126 mg (yield: 55%) of the
title compound (h).
[0387] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 9.28 (s, br, 1H),
7.35 (m, 5H), 6.45 (s, br, 1H), 5.70 (s, br, 1H), 4.87 (s, 2H),
3.47 (s, br, 2H), 2.53 (m, 2H), 2.27 (m, 4H)
[0388] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta. 170.1, 166.9,
137.8, 135.6, 133.0, 129.1, 128.5, 78.0, 39.7, 32.8, 26.9, 24.1
Example 100
Preparation of
N-Benzyloxy-3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide
(h)
##STR00115##
[0390] 29 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic
acid (g) was dissolved in 0.5 ml of DMF solution (0.171 mM). 30 mg
of BnONH.sub.2.HCl (0.188 mM), 0.033 ml of diisopropyl methylamine
(0.189 mM), 43 mg of EDC (0.224 mM) and 5 mg of DMAP (0.041 mM)
were added thereto and the mixture was stirred for overnight at
room temperature. The mixture was diluted with 7 ml of ethyl
acetate and washed with 5% HCl (1 ml) and 1 ml of sat. NaHCO.sub.3
solution. The organic layer was dried over anhydrous MgSO.sub.4,
filtered and concentrated in vacuo. The resulting compound was
purified by column chromatography on Silica gel with
methanol/chloroform (1:20) solvent mixture as an eluant to give 126
mg (yield: 55%) of the title compound (h).
[0391] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 9.28 (s, br, 1H),
7.35 (m, 5H), 6.45 (s, br, 1H), 5.70 (s, br, 1H), 4.87 (s, 2H),
3.47 (s, br, 2H), 2.53 (m, 2H), 2.27 (m, 4H)
[0392] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta. 170.1, 166.9,
137.8, 135.6, 133.0, 129.1, 128.5, 78.0, 39.7, 32.8, 26.9, 24.1
Example 101
Preparation of
3-(1-Allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-propionamide
(j1)
Step 1. Preparation of
3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl
ester (f)
[0393] 310 mg of
3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propion-
ic acid methyl ester (d) (0.93 mM) was dissolved in 3 ml of
trifluoroacetic acid solution. Then 0.222 ml of triethyl silane
(1.395 mmol) was added thereto and the mixture was heated for 20
min at 80.degree. C. The solvent was removed in vacuo and the
remaining residue was diluted in 20 ml of chloroform. The organic
layer was washed with 5 ml of sat. NaHCO.sub.3 solution and 5 ml of
sat. NaCl solution. Then the organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The resulting
compound was purified by column chromatography on Silica gel with
EtOAc solvent as an eluant to give 126 mg (yield: 55%) of the title
compound (f).
[0394] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.6.64 (s, br, 1H),
6.35 (t, J=3.0 Hz, 1H), 3.59 (s, 3H), 3.31 (m, 2H), 2.48 (m, 4H),
2.26 (m, 2H)
[0395] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.173.4, 166.8,
136.1, 133.5, 51.4, 39.5, 33.1, 26.0, 24.0
Step 2. Preparation of
3-(1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid
methyl ester (i1)
[0396] 0.220 ml of NaHMDS solution (1.0 M in THF, 0.22 mM) was
added to 0.5 ml of the THF solution containing 40 mg of
3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl
ester (0.218 mM) prepared by the Step 1 in a dropwise manner at
-79.degree. C. and stirred at -79.degree. C. for 30 mins. After
0.028 ml of allyl bromide (0.327 mM) was added to the reaction
mixture, the mixture was stirred at 0.degree. C. for 3 hrs. The
reaction mixture was quenched by 2 ml of sat. NH.sub.4Cl solution
and then the organic layer was extracted with 7 ml of ethyl
acetate. The combined organic layer was washed with 2 ml of sat.
NH.sub.4Cl solution and 2 ml of sat. NaCl solution. Then the
organic layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resulting compound was purified by
column chromatography on Silica gel with EtOAc/hexane (1:2) solvent
mixture as an eluant to give 36 mg (yield: 74%) of the title
compound (i1).
[0397] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 6.28 (m, 1H), 5.74
(m, 1H), 5.14 (m, 2H), 3.99 (d, J=5.7 Hz 2H), 3.61 (s, 3H), 3.27
(t, J=6.9 Hz, 2H), 2.51 (m, 4H), 2.27 (m, 2H)
[0398] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta. 173.6, 164.6,
134.3, 134.1, 133.3, 117.1, 51.4, 49.0, 44.6, 33.3, 26.6, 23.8
Step 3. Preparation of
3-(1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-N-hydroxy-propionamide
(j1)
##STR00116##
[0400] 24 mg of
3-(1-allyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid
methyl ester (i1) prepared from the above Step 2 was dissolved in
methanol solution (0.11 mM) and then 0.122 ml of 1.7M NH.sub.2OK
suspension solution (0.207 mM) was added thereto at 0.degree. C.
and stirred for 3 hrs at room temperature. The resulting mixture
was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of
ethyl acetate solution, filtered and concentrated in vacuo. The
resulting compound was purified by column chromatography on Silica
gel with methanol/chloroform (1:10) solvent mixture as an eluant to
give 11 mg (yield: 48%) of the title compound (j1).
[0401] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.6.39 (br t, 1H),
5.78-5.67 (m, 1H), 5.17 (d, J=5.4 Hz, 1H), 5.12 (s, 1H), 3.98 (d,
J=5.4 Hz, 2H), 3.30 (t, J=7.0 Hz, 2H), 2.54-2.28 (m, 6H)
Example 102
Preparation of
N-hydroxy-3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide
(j2)
Step 1. Preparation of
3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid
methyl ester (i2)
[0402] 0.22 ml of 1.0M NaHMDS solution in THF (0.22 mM) was added
to 0.5 ml of THF solution containing 80 mg
3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl
ester (f) prepared from the step 1 in Example 3 (0.44 mM) in a
dropwise manner at -79.degree. C. and then stirred for 30 min.
After 0.48 ml of methyl bromide (0.48 mM) was added to the reaction
mixture, the solution was stirred at 0.degree. C. for 3 hrs. The
reaction mixture was quenched by 2 ml of sat. NH.sub.4Cl solution
and then the organic layer was extracted with ethyl acetate (7 ml).
The combined organic layer was washed with 2 ml of sat. NH.sub.4Cl
solution (2 ml) and 2 ml of sat. NaCl solution subsequently. Then
the organic layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The resulting compound was purified by
column chromatography on Silica gel with EtOAc solvent as an eluant
to give 62 mg (yield: 72%) of the title compound (i2).
Step 2
Preparation of
N-hydroxy-3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionamide
(j2)
##STR00117##
[0404] 50 mg of
3-(1-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid
methyl ester prepared from the above Step 1 was dissolved in
methanol (0.25 mM) and then 0.122 ml of 1.7M NH.sub.2OK suspension
solution in methanol (0.207 mM) was added thereto at 0.degree. C.
and the resulting mixture was stirred for 3 hrs at room
temperature. The resulting mixture was neutralized with 0.02 ml of
acetic acid, diluted with 10 ml of ethyl acetate, filtered and
concentrated in vacuo. The resulting compound was purified by
column chromatography on Silica gel with methanol/chloroform (1:20)
solvent mixture as an eluant to give 19 mg (yield: 35%) of the
title compound (j2).
[0405] .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta. 6.15 (t, J=4.3 Hz,
1H), 3.41 (t, J=7.2 Hz, 2H), 2.97 (s, 3H), 2.51 (t, J=7.5 Hz, 2H),
2.35 (m, 2H), 2.22 (t, J=7.5 Hz, 2H)
Example 103
Preparation of
N-hydroxy-3-(1-(naphthalene-2-yl-methyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-
-3-yl)-propionamide
[0406] 70 mg of
3-[1-(Naphthyl-2-yl)methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propion-
ic acid methyl ester was dissolved in methanol solution (0.22 mM)
and then 0.64 ml of 1.7M NH.sub.2OK suspension in methanol (1.08
mM) was added thereto at 0.degree. C. and the resulting mixture was
stirred for 5 hrs at room temperature. The resulting mixture was
neutralized with 0.02 ml of acetic acid and concentrated in vacuo.
The resulting solid was filtered with 10% methanol/chloroform
solvent mixture and concentrated in vacuo. The resulting compound
was purified by column chromatography on Silica gel with
methanol/chloroform (1:9) solvent mixture as an eluant to give 61
mg (yield: 95%) of the title compound (See Table 21).
Example 104
Preparation of
N-hydroxy-3-[2-oxo-1-(2-thiophen-2-yl-ethyl)-1,2,5,6-tetrahydro-pyridin-3-
-yl]-propionamide
[0407] 60 mg of
3-[2-oxo-1-(2-thiophen-2-yl)ethyl-1,2,5,6-tetrahydro-pyridin-3-yl]-propio-
nic acid methyl ester was dissolved in methanol to be 0.20 mM
solution and then 0.6 ml of 1.7M NH.sub.2OK suspension solution in
methanol (1.02 mM) was added thereto at 0.degree. C. and the
resulting mixture was stirred for 5 hrs at room temperature. The
resulting mixture was neutralized with 0.02 ml of acetic acid and
concentrated in vacuo. The resulting solid was filtered with 10%
methanol/chloroform solvent mixture and concentrated in vacuo. The
resulting compound was purified by column chromatography on Silica
gel with methanol/chloroform (1:9) solvent mixture as an eluant to
give 44 mg (yield: 73%) of the title compound (See Table 21).
TABLE-US-00021 TABLE 21 Example Chemical structure NMR spectrum
data 103 ##STR00118## 8.07-7.99 (m, 1H), 7.83-7.74 (m, 2H),
7.50-7.29 (m, 4H), 6.32 (br t, 1H), 5.01 (s, 2H), 3.44 (s, 2H),
3.15 (q, J = 6.9 Hz, 2H), 2.71-2.54 (m, 2H), 2.42 (s, 2H), 2.09 (s,
2H) 104 ##STR00119## 7.11 (d, J = 4.8 Hz, 1H), 6.89 (t, J = 3.9 Hz,
1H), 6.82 (s, 1H), 6.35 (br t, 1H), 3.64-3.59 (m, 2H), 3.22 (t, J =
3.22 Hz, 2H), 3.09-3.04 (m, 2H), 2.54-2.50 (m, 2H), 2.35 (s, 2H),
2.20 (s, 2H)
Experimental Example 1
Effect of the Compound of the Present Invention on NO
Production
[0408] To test the inhibiting activity of the compounds prepared
from above Examples 1 to 6 on the production of nitric oxide (NO)
caused by activated macrophage by lipopolysaccharide(LPS), the
amount of accumulated NO.sup.2- in the cells was determined as an
indicator of NO production in the medium.
[0409] Each 200 .mu.l of RAW 264.7 cells (ATCC, USA), a mouse
macrophage cell line was seeded onto each well of 96-well
microtiter plate (Nunc, Sweden) to the concentration ranging from
1.times.10.sup.6 cells/ml to 5.times.10.sup.6 cells/ml, and
incubated in DMEM (Dulbeco's modified eagles medium) media
containing 5% FBS (fetal bovine serum) at 37.degree. C. in 5%
CO.sub.2 incubator.
[0410] Various concentrations of the compounds of the present
invention ranging from 0.10.1 to 10 .mu.M and LPS (Sigma, USA) in
the final concentration of 0.3 .mu.g/ml to activate the cell were
treated to activate the cell simultaneously. The treated cells were
cultured at 37.degree. C. for 24 hours in 5% CO.sub.2 incubator and
the cultured cells were collected after the cultivation.
[0411] And then, to the collected cell culture, an equal volume of
Griess reagent (1% sulfanilamide, 0.1% naphthylethylenediamine
dihydrochloride, and 2% phosphoric acid) was added and the culture
was incubated at room temperature for 10 mins. The amount of
nitrite production was determined by measuring the absorbance at
540 nm versus a NaNO.sub.2 standard curve. The result was shown in
Table 22.
[0412] As shown in Table 3, it is confirmed that compounds of the
present invention showed effective NO inhibition activity.
Experimental Example 2
Effect of the Compound of the Present Invention on TNF-alpha
[0413] To test the inhibiting activity of the compounds prepared
from above Examples on the production of TNF-alpha, the
concentration of TNF-alpha in the cell supernatant was
measured.
[0414] Each 200 .mu.l of RAW 264.7 cells (ATCC, USA), a mouse
macrophage cell line was seeded onto each well of 96-well
microtiter plate (Nunc, Sweden) to the concentration ranging from
1.times.10.sup.6 cells/ml to 5.times.10.sup.6 cells/ml, and
incubated in DMEM (Dulbeco's modified eagles medium) media
containing 5% FBS (fetal bovine serum) at 37.degree. C. in 5%
CO.sub.2 incubator.
[0415] Various concentrations of the compounds of the present
invention ranging from 0.10.1 to 10 .mu.M and LPS (Sigma, USA) in
the final concentration of 0.3 .mu.g/ml were treated to activated
cell simultaneously. The treated cells were cultured at 37.degree.
C. for 24 hours in 5% CO.sub.2 incubator and the cultured cells
were collected after the cultivation
[0416] And then the concentration of TNF-alpha secreted from the
culture supernatant of RAW 264.7 cells was determined by ELISA
according to the manufacture's instruction (R&D Systems,
Minneapolis, Minn.).
[0417] The result was shown in Table 22 and 23.
[0418] As shown in Table 22 and 23, it was confirmed that compounds
of the present invention showed effective TNF-alpha inhibition
activity.
TABLE-US-00022 TABLE 22 Example NO inhibition 1 B 2 A 3 A 4 AAA 5 A
6 B 7 A 8 A 9 C 10 A 11 AA 12 AA 13 A 14 C 15 B 16 C 17 C 18 B 19 B
20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 B 29 A 30 B 31 B 32 B 33
B 34 A 35 A 36 -- 37 -- 38 -- 39 A 40 A 41 -- 42 -- 43 A 44 A 45 A
46 A 47 -- 48 -- 49 AA 50 C 51 C 52 A 53 A 54 A 55 A 56 AAA 57 A 58
A 59 A 60 AA 61 AA 62 AAA 63 C 64 C 65 C 66 C 67 C 74 C 75 C 76 C
77 B 78 A 79 A 80 AAA 81 A 82 B 83 A 84 A 85 C 86 A 87 AA 88 AA 89
A 90 C 91 B 92 A 93 A 94 AAA 95 A 96 B 97 A 98 A 99 C 100 A 101 AA
102 AA 103 A 104 C
TABLE-US-00023 TABLE 23 TNF-alpha Example inhibition 1 B 2 A 3 A 4
AA 5 A 6 A 7 A 8 A 9 B 10 A 11 AA 12 AA 13 A 14 C 15 B 16 C 17 C 18
C 19 B 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 A 29 A 30 A 31 C
32 C 33 B 34 A 35 A 36 -- 37 -- 38 -- 39 AAA 40 AA 41 -- 42 -- 43 A
44 A 45 A 46 B 47 -- 48 -- 49 AA 50 C 51 C 52 A 53 AA 54 A 55 A 56
AAA 57 B 58 A 59 A 60 A 61 A 62 AA 63 C 64 C 65 C 66 C 67 C 74 C 75
C 76 C 77 B 78 A 79 A 80 AA 81 A 82 A 83 A 84 A 85 B 86 A 87 AA 88
AA 89 A 90 C 91 B 92 A 93 A 94 AA 95 A 96 A 97 A 98 A 99 B 100 A
101 AA 102 AA 103 A 104 C AA: IC.sub.50's < 1, A: IC.sub.50's
< 5, B: IC.sub.50's < 10, C: IC.sub.50's > 10,
Experimental Example 3
Toxicity test
Methods
[0419] The acute toxicity tests on ICR mice (mean body weight
25.+-.5 g) and Sprague-Dawley rats (235.+-.10 g, Jung-Ang Lab
Animal Inc.) were performed using the compounds of example 80.
[0420] Four group consisting of 10 mice or rats was administrated
orally with 4 mg/kg, 40 mg/kg, 400 mg/kg and 4,000 mg/kg of test
sample or solvents (0.2 ml, i.p.) respectively and observed for 2
weeks.
Results
[0421] There were no treatment-related effects on mortality,
clinical signs, body weight changes and gross findings in any group
or either gender. These results suggested that the extract prepared
in the present invention were potent and safe.
[0422] Hereinafter, the formulating methods and kinds of excipients
will be described, but the present invention is not limited to
them. The representative preparation examples were described as
follows.
TABLE-US-00024 Preparation of powder the compounds of example 80 50
mg Lactose 100 mg Talc 10 mg
[0423] Powder preparation was prepared by mixing above components
and filling sealed package.
TABLE-US-00025 Preparation of tablet the compounds of example 80 50
mg Corn Starch 100 mg Lactose 100 mg Magnesium Stearate 2 mg
[0424] Tablet preparation was prepared by mixing above components
and entabletting.
TABLE-US-00026 Preparation of capsule the compounds of example 80
50 mg Corn starch 100 mg Lactose 100 mg Magnesium Stearate 2 mg
[0425] Tablet preparation was prepared by mixing above components
and filling gelatin capsule by conventional gelatin preparation
method.
TABLE-US-00027 Preparation of injection the compounds of example 80
50 mg Distilled water for injection optimum amount PH controller
optimum amount
[0426] Injection preparation was prepared by dissolving active
component, controlling pH to about 7.5 and then filling all the
components in 2 ml ample and sterilizing by conventional injection
preparation method.
TABLE-US-00028 Preparation of liquid the compounds of example 80
0.1~80 g Sugar 5~10 g Citric acid 0.05~0.3% Caramel 0.005~0.02%
Vitamin C 0.1~1% Distilled water 79~94% CO.sub.2 gas 0.5~0.82%
[0427] Liquid preparation was prepared by dissolving active
component, filling all the components and sterilizing by
conventional liquid preparation method.
[0428] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the present
invention, and all such modifications as would be obvious to one
skilled in the art are intended to be included within the scope of
the following claims.
INDUSTRIAL APPLICABILITY
[0429] As described in the present invention, the 2-oxo-cyclic
compound of the present invention have potent anti-inflammatory
activity, therefore, it can be used as the therapeutics for
treating and preventing the inflammatory disease comprising the
pain or inflammation caused by rheumatic disease, for example,
rheumatoid arthritis, spondyloarthopathies, gout, osteoarthritis,
systemic lupus erythematosus and juvenile arthritis, and
inflammatory syndrome for example, from myositis, gingivitis,
synovitis, ankylosing spondylitis, burstitis, burns and scar,
inflammatory Crohn's disease, Types I diabetes.
* * * * *