Note: Descriptions are shown in the official language in which they were submitted.
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BIPHENYL BUTYRTC ACID DERIVATIVE AS A MATRIX
METALLOPROTEINASE INHIBITOR
BACKGROUND OF THE TNVENTION
Field of the Invention
The present invention relates to biphenyl butyric
to acid derivatives, more specifically, to novel biphenyl
butyric acid derivatives represented as the following
general formula (I), useful as matrix metalloproteinase
inhibitor and pharmaceutically acceptable salts thereof and
a process for preparing the compounds.
O,
OH
R 1 n~ ~ (~J
~3
DPSCr~ption of t~h Prior Art
Matrix metalloproteinase("MMP") is a Ca2+-dependent
proteinase containing zinc ion(Zn2+) at its active site. To
the present, at least 18 matrix metalloproteinases
including stromelycin, collagenase and a family of
gelatinise have been identified in the art. MMP degrades
various extracellular matrix components of collagen,
laminin, proteoglycan, fibronectin, elastin and gelatin
under biological conditions, which, in turn, leads to
growth of articulation tissue, bone tissue and connective
tissue, and remodeling of the tissues. MMP is secreted as
an inactive form of proenzyme, which is subsequently
3o activated in extracellular side, together with a naturally
occuring inhibitor, TIMP(tissue inhibitor of
metalloproteinase).
Meanwhile, MMP inhibitor is useful to prevention and
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treatment of all sorts of diseases caused by overexpression
or overactivation of MMP. Such diseases are, for example,
rheumatoid, arthrosteitis, unusual bone resorption,
osteoporosis, periodontitis, interstitial nephritis,
arteriosclerosis, pulmonary emphysema, cirrhosis, cornea
injury, metastasis, invasion or growth of tumor cell,
autoimmune disease, disease caused by Vascular emigration
or infiltration of leukocytes, arterialization(see: Beeley
et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994). For
1o instance, it was reported that synthetic MMP inhibitor has
an anti-cancer activity in vivo along with inhibition of
basement membrane remodeling in the mouse model bearing
ovarian cancer(see: Cancer Res., 53:2087, 1993).
Particularly, considering the fact that MMP-2 and MMP-9
among the above MMP enzymes play an essential role in
angiogenesis required for the growth of cancer cells (see:
Biochim. Biophys. Acta, 695, 1983), and that MMP-1 and MMP-
3 among MMP enzymes play an important role in the progress
of arthritis as observed in much higher concentration than
2o normal in the synovium and cartilage of a patient of
rheumatoid arthritis(see: Arthritis Rheum., 35:35-42, 1992),
the selectivity to MMP-1/MMP-2 is considered to play a
crucial role in reducing side effects such as arthralgia.
Therefore, researches have been made while focusing on the
development of selective inhibitors, and many MMP
inhibitors have been designed and synthesized in many
aspects(,~ee J. Enzyme Inhibitor, 2:1-22, 1987; Current
Medicinal Chemistry, 2:743-762, 1995; Progress in Medicinal
Chemistry, 29:271-334, 1992; Exp. Opin. Ther. Patents,
5:1287-1296, 1995; Drug Discovery Today, 1:16-26, 1996;
Chem. Rev., 99:2735-2776, 1999; Drugs of the Future 2000,
25(6), 551-557; Exp. Opin. Invest. Drugs, 2000, 2167-2177).
Some compounds possessing inhibitory activity against
MMP are known. In general, they have a zinc binding
group("ZBG"), which is coordinated to the zinc ion of MMP
enzymes at the active site of them. Such ZBGs include
hydroxamic acid, carboxylic acid, phosphoric acid,
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phosphinic acid, thiol and so forth(see: WO 92/09564; WO
95/04033; WO 00/04030; WO 00/43404; WO 95/13289; WO
96/11209; WO 95/09834; WO 95/09620; WO 00/40577; WO
00/40600; WO 98/03166; Chem. Rev. 99:2735-2776, 1999).
Especially, several kinds of succinic acid derivatives
based on substrate backbone have been designed and
synthesized as a peptide-mimic inhibitor. (see WO
99/25693; WO 90/05719; WO 94/02446; WO 95/09841; WO
95/19956; WO 95/19957; WO 95/19961; WO 96/06074; WO
96/16931; WO 98/43959; WO 98124759; WO 98/30551; WO
98/30541; WO 97/32846; WO 99/01428; EP 897908; WO 98/38179;
JP 95002797; WO 99/18074; WO 99/19296; EP 641323). The
peptide-mimic inhibitors are known to contain a hydroxamic
acid as a ZBG and display a broad spectrum for MMP enzymes.
However, some of the above peptide-mimic inhibitors
induce the side effect of arthralgia in clinical trial(see:
Current Pharmaceutical Design, 5:787-819, 1999; Current
Opinion in Drug Discovery & Development, 3:353-361, 2000).
They are also often poorly absorbed, exhibiting low oral
bioavailability and furthermore, possess lower selectivity
to MMP-1/MMP-2(see:Drugs of the Future, 21(12):1215-1220,
1996) .
In 1994, non-peptide inhibitors were developed to
solve the said problems which are substantially
distinguished in terms of chemical structure from the above
peptide-mimic inhibitors having simple sulfonyl amino acid
derivative represented as a chemical formula below(s_ee: USP
5,506,242; J. Med. Chem., 40:2525-2532, 1997).
~~~"~~.~~~~
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Under a consideration that the small molecule of
sulfonamide-derived MMP inhibitors have activities in vitro
against MMP enzymes, and have advantages over the said
peptide-mimic inhibitors, a variety of sulfonamide
inhibitors have been synthesized and reported in the
literature(see: WO 98/50348; WO 97/20824; WO 00/09485; WO
99/58531; WO 99/51572; WO 99/52889; WO 99/52910; WO
99/37625; WO 98/32748; WO 99/18076; WO 99/06410; WO
99/07675; WO 98/27069; WO 97/22587; EP 979816; EP895988; EP
878467; EP 1041072). To improve in vitro enzymatic
activity, selectivity, and pharmacokinetic profiles, new
sulfonamide derivatives have been designed and synthesized,
by changing P1' of the above sulfonamide inhibitor which
binds to S1' sub-site of the enzymes.
While the above sulfonamide inhibitors have
relatively high inhibitory activity against MMP, they do
not have a higher selectivity to MMP-1/MMP-2 as compared
with previous peptide-mimic inhibitors. Some of them have
also side effect of arthralgia in clinical trials(see:
2o Current Pharmaceutical Design, 5:787-819, 1999; Current
Opinion in Drug Discovery & Development, 3:353-361, 2000;
Exp. Opin. Invest. Drugs, 9:2159-2165, 2000; SCRIP, 2467:19,
1999; Drugs of the Future, 24(1):16-21, 1999). Although
the sulfonamide inhibitors containing a hydroxamic acid as
a ZBG typically showed a very strong in vitro inhibitory
activity as compared with those containing a carboxylic
acid as a ZBG, they also have revealed a limitation in oral
administration due to their lower bioavailability and lower
metabolic stability in vivo(see: J. Med. Chem., 41:640-649,
1988; Investigational New Drugs 16:303-313, 1999; Exp. Opin.
Ther. Patents, 10:111-115, 2000: WO 00/63194; WO 00/27808;
WO 99/18079; USP 6,117,869).
Other non-peptide inhibitors, 3-oxo-3-biphenylbutyric
acid derivatives, were found to solve the said problems and
increase the selectivity which contain a butyric acid group
represented as a chemical formula below(see WO 96/15096).
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~H
~I ~''~--~
While the above inhibitors have a very low in vitro
inhibitory activity against MMP as compared with peptide-
s mimic succinic acid derivatives or sulfonyl amino acid
derivatives, they have a far higher selectivity to MMP-
1/MMP-2 and also little side effect of arthralgia in
clinical trials(see: Drugs of the Future, 24(1):16-21,
1999). To improve the problem of said inhibitors, a
1o variety of biphenyl butyric acid derivatives as MMP
inhibitors have been designed and reported(see: USP
5,789,434; USP 5,854,277; USP 5,859,047; USP 5,861,427; USP
5,861,428; USP 5,874,473; USP 5,886,022; USP 5,886,024; USP
5, 886, 043) .
Another butyric acid derivatives represented as the
following formula have been reported, however, they also
have still the drawback of a low inhibitory activity
against MMP(see: WO 98/09940; WO 98/06711).
~H
~H
I ~ ~'-~
H0F
Under the circumstance, there are strong reasons for
developing alternative compounds whose inhibitory action on
MMP and selectivity to MMP-1/MMP-2 are increased to reduce
side effects.
SUMMARY OF THE INVENTION
The present inventors have made an effort to develop
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novel compounds whose inhibitory action on MMP and
selectivity to MMP-1/MMP-2 are increased to reduce side
effects, and finally found that novel synthetic inhibitors
of biphenyl butyric acid derivatives selectively inhibit
MMP activity in vitro.
A primary object of the present invention is,
therefore, to provide biphenyl butyric acid derivatives
inhibiting MMP activity.
to
The other object of the invention is to provide a
process for preparing the said compounds.
DETAILED DESCRIPTION OF THE INENTION
The present invention provides biphenyl butyric acid
derivatives which inhibit the activity of MMP, represented
as the following general formula(I), the isomers and the
pharmaceutically acceptable salts thereof, and a process
2o for preparing the said compounds.
p
~H
n~ ~--~~J
O ~-Ra
~3
wherein,
R1 is hydrogen, alkyl, cycloalkyl, halogen,
vitro, cyano, -OCF3, -OCHZF,
-I~-R.4
~~4
-ORS, -SR4,
-S (0) RQ or -S (O) 2 where RQ and RQa, which may be the same or
different, are alkyl, aryl, arylalkyl, heteroaryl or
cycloalkyl;
3o R2 and R3, which may be the same or different,
are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or
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cycloalkyl; and,
n is 1 or 2.
In the above formula, RZ and R3 are taken together
with carbon, nitrogen, oxygen or sulfur to form CS-6 ring,
which includes the followings:
t~ t~ I~ I~ J-R ~
wherein,
Rg is hydrogen, alkyl, aryl, arylalkyl,
1o heteroaryl or cycloalkyl; and,
X is 0 or S.
Also, in case that R3 is hydrogen, R~ may further
include a substituent represented as the following
25 structural formula:
R~
wherein,
R5 is hydrogen, alkyl, aryl, arylalkyl,
heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl,
2o arylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,
arylsulfinylalkyl, arylsulfonylalkyl or cycloalkyl; and,
R6 and R7, which may be the same or different,
are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or
cycloalkyl.
o In case that R3 is not hydrogen, R3 and R5 of the
above formula(I) are taken together with carbon, nitrogen,
oxygen or sulfur to form C5-6 ring in which
-N-R2
R3
3o moiety includes the followings:
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~I~ '10
X11
~1~
~ ~~
wherein,
R6 and R, are the same as above;
R9 is hydrogen, hydroxy, alkoxy, aryloxy, thiol
or alkylthio;
Rlo is oxo, hydroxyamine or hydrazone;
R11 and Rl~ are hydrogen or C1_6 lower alkyl; and,
Y is CHz, 0 or S.
Also, R6 and R~ are taken together with carbon,
nitrogen, oxygen or sulfur to form CS_6 ring, which
includes the followings:
hJ f~ ~I f~ !-F~,~
wherein,
Re and X are the same as above.
Otherwise mentioned, all kinds of isomers of the
biphenyl butyric acid derivatives are fallen within the
2o scope of the invention.
The pharmaceutically acceptable salts of the
invention include acid-added salts and hydrates. In
general formula(I), the compound of the invention can be
converted to the salts corresponding to them, preferably
alkali metal salts(sodium, potassium, etc.), alkaline earth
metal salts(calcium, magnesium, etc.), ammonium salts, non-
toxic salts of pharmaceutical organic amine and water-
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soluble salts. The compound of the general formula(I) can
be converted to inorganic acid salts(hydrochloride,
hydrogen bromide, hydrogen iodide, sulfate, phosphate,
nitrate, etc.) and organic acid salts(acetate, lactate,
tartarate, oxalate, fumarate, glucuronate, etc.),
preferably non-toxic salts and water-soluble salts. The
compound of the general formula(I) and its salts can be
also converted to the hydrates corresponding to them by the
conventionally known method in the art.
Two processes for preparing the compounds of the
general formula(I) are illustrated by the following steps.
First, the above compounds may be prepared by the following
Process 1.
Proces3s l:
~ 0~ OEt
Br ~ Et feet
---~. I ~,.i
-~t-Bu0 OEt OBu-t
~~
R ~ (a7 (n~ R 1 ~I'~
~ O OEt ~ 0 OEt
~Et
d epratectia n O Et
H~~s ~ I ~ O
r
I ~H I R ~'R
R~ f~ R~ (~I) 3
hydrolysis
decarba~tvlati~ a
R
L~J
2o wherein,
R1, R~ and R3 are the same as above .
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t~~l: Synthesis of t-butylester compound(IV)
A compound(II) is reacted with a compound(III) to
5 give t-butylester compound(IV): the compound(II) may be
commercially available or prepared by the conventionally
known methods and the compound(III) may be prepared by
partial modification of the conventionally known
methods(see: B.S. Furniss, et al., VOGEL's Textbook of
so Practical Organic Chemistry, 5th ed., pp942-943, 1988; WO
96/15096). '
Step 2: Synthesis of a compound(V)
The t-butylester compound(IV) is deprotected to give
a butylester group-free compound(V): the deprotection is
preferably accomplished by using TFA or anhydrous HCl.
_~p 3: Synthesis of a compound(VI)
The compound(V) is condensed with an amine compound
to give a compound(VI) containing diethylester group: the
amine compound comprises R~ and R3 defined in the above and
condensation with the amine compound can be carried out by
a variety of methods such as acid chloride method, active
ester method, mixed anhydride method, etc.
Ste~4: Synthesis of a compound(I)
Diethylester groups of the compound(VI) are
hydrolyzed to carboxylic groups and then the compound is
decarboxylated to give a compound(I).
The compounds of the general formula(I) may also be
prepared by the following Process 2.
Process 2:
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0
gr Et
+t-goo oEt
00
(B~
a ~,.~Et ~ o
h~rdralysis ~~~~,,.f",. dePratectian
decarbouylatian ~. ~ O~W-t
OBu~t
~ 1 Cl'q5 ~ 1 f ~~
HN
~H ~3 '~~
3
~1'R
l~J
0~
h~dral~sis ~ '1
~1
wherein,
R1, RZ and R3 are the same as above .
S~_ep l: Synthesis of t-butylester compound(IV)
A compound(II) is reacted with a compound(III) to
give t-butylester compound(IV): the compound(II) may be
l0 commercially available or prepared by the conventionally
known methods and the compound(III) may be prepared by
partial modification of the conventionally known
methods(see: B.S. Furniss, et al., VOGEL's Textbook of
Practical Organic Chemistry, 5t'' ed., pp942-943, 1988; WO
i5 96/15096) .
Step 2: Synthesis of a compound(VII)
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One of ethylester groups of t-butylester compound(IV)
is hydrolyzed to a carboxylic group and then
decarboxylating the compound to give a compound(VII): the
hydrolysis is carried out in the presence of a base and
decarboxylation in the presence of an organic solvent; and,
the base includes, but not limited to, preferably 1 equi.
of KOH/EtOH and the organic solvent includes preferably
1,4-dioxane.
Ste~~ 3 Synthesis of a compound(VIII)
The compound(VII) is deprotected to give a butylester
group-free compound(VIII): the deprotection is preferably
carried out by using TFA or anhydrous HCl.
Step 4: Synthesis of a compound(TX)
The compound(VIII) is condensed with an amine
2o compound to give a compound(IX) containing ethylester
group: the amine compound comprises RZ and R3 defined in
the above and condensation with the amine compound can be
carried. out by a variety of methods such as acid chloride
method, active ester method, mixed anhydride method, etc.,
most preferably, active ester method.
Step 5: Synthesis of a compound(I)
Ethylester group of the compound(IX) is hydrolyzed to
a carboxylic group to prepare a compound ( I ) ( see : V~10
96/15096).
The present invention is further illustrated in the
following examples, which should not be taken to limit the
scope of the invention.
Exampl~l_: Preparation of 5-(Biphenyl-4-yl)-5-oxo-3,3-
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diethoxycarbonylvaleric acid t-butyl ester(IV,
R1=H )
To 100m1 flask were added NaH(95o, 505mg, 20.0mmo1)
and high-purity THF(l5mL), and cooled to a temperature of
-10'C. Then, diethyl t-butoxycarbonylmethylmalonate(III,
4.9g, 18.17mmo1) dissolved in THF(lOmL) was added slowly,
and stirred for 30min at room temperature. And then, 4-
phenyl-a -bromoacetophenone(II, R1=H, 5g, 18.17mmol)
1o dissolved in THF(l5mL) was added slowly, and stirred for
1hr and 30min at room temperature, and extracted with 1N
HCl(30mL) and ethylacetate(30mL). The organic phase was
washed with water(lOmL), and added anhydrous MgS04, stirred
for 5 min, filtered and distilled under reduced pressure to
give the titled compound(8.65g, 950).
1H NMR(300MHz, CDC13) : S 1.24 (t, 6H) , 1.38 (s, 9H) ,
3. 39 (s, 2H) , 3. 97 {s, 2H) , 4.24 (q, 4H) , 7 . 45 (m, 3H) , 7. 61 (d,
2H) , 7 . 69 (d, 2H) , 8 . 04 (d, 2H)
2o
Example 2: Preparation of 5-(4'-methoxybiphenyl-4-yl)-5-
oxo-3,3-diethoxycarbonylvaleric acid t-butyl
ester (IV, R1=OMe)
The titled compound was prepared in a similar manner
as in Example 1, except for employing 4-(4'-methoxyphenyl)-
a -bromoacetophenone(II, R1=OMe).
1H NMR(300MHz, CDC13) : 8 1.24 (t, 6H) , 1.38 (s, 9H) ,
3.21 (s, 2H) , 3. 86 (s, 3H) , 3. 94 (s, 2H) , 4.24 (q, 4H) , 7 . 0 (d,
2H) , 7 . 58 (d, 2H) , 7 . 65 (d, 2H) , 8 . 02 (d, 2H)
Example 3: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo-
3,3-diethoxycarbonylvaleric acid t-butyl ester
( IV, R1=Br )
The titled compound was prepared in a similar manner
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as in Example 1, except for employing 4-(4'-bromophenyl)-a
-bromoacetophenone (II, R1=Br)
1H NMR(300MHz, CDC13) : S 1.24 (t, 6H) , 1.39 (s, 9H) ,
3.21(s, 2H), 3.95(s, 2H), 4.24(q, 4H), 7.48(d, 2H), 7.60(d,
2H), 7.65(d, 2H), 8.04(d, 2H)
Example 4: Preparation of 5-(4'-chlorobiphenyl-4-yl)-5-oxo-
3,3-diethoxycarbonylvaleric acid t-butyl ester
(IV, R1=Cl)
The titled compound was prepared in a similar manner
as in Example 1, except for employing 4- ( 4' -chlorophenyl ) -
a -bromoacetophenone(II, Rl=Cl).
1H NMR(300MHz, CDC13) : 8 1.25 (t, 6H) , 1.39 (s, 9H) ,
3.21(s, 2H), 3.95(s, 2H), 4.24(q, 4H), 7.44(d, 2H), 7.56(d,
2H) , 7 . 65 (d, 2H) , 8. 06 (d, 2H)
Example 5: Preparation of 5-(Biphenyl-4-yl)-5-oxo-3,3-
diethoxycarbonylvaleric acid(V, R1=H)
To 5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonyl-
valeric acid t-butyl ester(IV, R1=H, 1.5g, 3.2mmo1)
dispersed in methylene chloride(MC)(20mL) was added
TFA(2mL) and stirred for 24hr at room temperature. After
MC was removed under reduced pressure, ethylacetate(20mL)
and 1N NaOH were added slowly, and the separated organic
layer was extracted with water. And then, the aqueous
solution was collected, treated with 1N HCl(30mL) and
extracted with ethylacetate. The separated organic layer
was dried over anhydrous MgS04,filtered and distilled under
reduced pressure to give the titled compound(1.2g, 910).
1H NMR (300MHz, CDC13) : s 1. 24 (t, 6H) , 3. 39 (s, 2H) ,
3.97(s, 2H), 4.24(q, 4H), 7.45(m, 3H), 7.61(d, 2H), 7.69(d,
2H) , 8. 04 (d, 2H)
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Example 6: Preparation of 5-(4'-methoxybiphenyl-4-yl)-5-
oxo-3,3-diethoxycarbonylvaleric acid(V, R1=OMe)
5 The titled compound was prepared in a similar manner
as in Example 5, except for employing 5-(4'-
methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric
acid t-butyl ester(IV, R1=OMe).
10 1H NMR (300MHz, CDC13) : s 1. 24 (t, 6H) , 3.21 (s, 2H) ,
3. 86 (s, 3H) , 3. 94 (s, 2H) , 4.24 (q, 4H) , 7. 0 (d, 2H) , 7. 58 (d,
2H), 7.65(d, 2H), 8.02(d, 2H)
Example 7: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo-
15 3, 3-diethoxycarbonylvaleric acid (V, R1=Br)
The titled compound was prepared in a similar manner
as in Example 5, except for employing 5-(4'-bromobiphenyl
4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl
ester (IV, R1=Br) .
1H NMR (300MHz, CDC13) : S 1. 24 (t, 6H) , 3.21 (s, 2H) ,
3.95(s, 2H), 4.24(q, 4H), 7.48(d, 2H), 7.60(d, 2H), 7.65(d,
2H) , 8. 04 (d, 2H)
Example 8: Preparation of N-phenyl-5-(biphenyl-4-yl)-5-oxo-
3,3-diethoxycarbonylvaleramide(VI, R1=H)
5-(Biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric
3o acid(V, Rl=H, 0.5g, l.2mmol), EDC(0.23g, l.2mmol) and
HOBt(0.16g, l,2mmol) were dissolved in MC(5mL) and cooled
to a temperature of 0'C. And, TEA(170mL, l.2mmo1) was
added and stirred for l0min, followed by addition of
aniline(122mL, l.3mmol) and stirring for 2hr and 30min at
room temperature. And then, 1N HCl was added and extracted
by employing MC, and dried over anhydrous MgS04, filtered,
and distilled under reduced pressure, and subjected to a
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column chromatography(Hx/EA=411, v/v) to give the titled
compound ( 0 . 365g, 62 0 ) .
1H NMR (300MHz, CDC13) : s 1. 24 (t, 6H) , 3. 32 (s, 2H) ,
4. 05 (s, 2H) , 4.24 (q, 4H) , 7. 07 (t, 1H) , 7.26 (m, 1H) , 7.45 (m,
5H), 7.65(m, 5H), 8.04(d, 2H)
Example 9: Preparation of N-cyclopropyl-5-(biphenyl-4-yl)-
5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=H)
The titled compound was prepared in a similar manner
as in Example 8, except for employing 5-(biphenyl-4-yl)-5-
oxo-3,3-diethoxycarbonylvaleric acid(V, R1=H) and
cyclopropylamine.
1H NMR (300MHz, CDC13) : s 0. 41 (m, 2H) , 0. 69 (m, 2H) ,
2.62(m, 1H), 3.08(x, 2H), 4.00(s, 2H),, 4.24(q, 4H), 5.9(s,
1H), 7.45(m, 3H), 7.61(d, 2H), 7.69(d, 2H), 8.04(d, 2H)
2o Example 10: Preparation of N-(a -methylbenzyl)-5-(biphenyl-
4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI,
Ri=H ) ( VI )
The titled compound was prepared in a similar manner
as in Example 8, except for employing 5-(biphenyl-4-yl)-5-
oxo-3,3-diethoxycarbonylvaleric acid(V, R1=H) and a -
methylbenzylamine.
1H NMR(300MHz, CDC13) : ~ 1.24 (t, 6H) , 1.41 (d, 3H) ,
3. 17 (d, 2H) , 3. 97 (d, 2H) , 4 . 21 (q, 4H) , 5. 0 (m, 1H) , 5. 95 (d,
1H) , 7 .19 (m, 5H) , 7 . 46 (m, 3H) , 7. 61 (d, 2H) , 7 . 67 (d, 2H) ,
8.04(d, 2H)
Example 11: Preparation of N-phenyl-5-(4'-methoxybiphenyl
4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI,
R1=OMe )
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The titled compound was prepared in a similar manner
as in Example 8, except for employing 5-(4'-
methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric
acid(V, R1=OMe) and aniline.
1H NMR (300MHz, CDC13) : s 1.24 (t, 6H) , 3. 34 (s, 2H) ,
3.86(s, 3H), 4.04(s, 2H), 4.24(q, 4H), 7.0(d, 2H), 7.05(t,
1H), 7.26(t, 2H), 7.44(d, 2H), 7.54(d, 2H), 7.62(d, 2H),
8.02 (d, 2H)
Example 12: Preparation of N-[1,5-dioxo-5-(4'-
methoxybiphenyl-4-yl)-3,3-
diethoxycarbonylpentane-1-yl]-4-
methylpiperazine (VI, R1=OMe) (VI)
The titled compound was prepared in a similar manner
as in Example 8, except for employing 5-(4'-
methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric
acid(V, R1=OMe) and N-methylpiperazine.
1H NMR(300MHz, CDC13) : s 1.24 (t, 6H) , 2.30 (s, 3H) ,
2. 34 (br, 4H) , 3. 35 (s, 2H) , 3. 55 (br, 4H) , 3. 86 (s, 3H) ,
4. 10 (s, 2H) , 4.24 (q, 4H) , 7. 0 (d, 2H) , 7. 58 (d, 2H) , 7. 65 (d,
2H) , 8 . 02 (d, 2H)
Example 13: Preparation of N-[1,5-dioxo-5-(4'-
bromobiphenyl-4-yl)-3,3-
diethoxycarbonylpentane-1-yl]piperidine(VI,
R1=Br )
The titled compound was prepared in a similar manner
as in Example 8, except for employing 5-(4'-bromobiphenyl-
4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=Br) and
piperidine.
1H NMR (300MHz, CDC13) : s 1. 24 (t, 6H) , 2. 85 (Br, 4H) ,
3. 37 (s, 2H) , 3. 64 (br, 4H) , 4 . 00 (s, 2H) , 4 . 26 (q, 4H) , 7. 48 (d,
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2H) , 7. 59 (d, 2H) , 7. 66 (d, 2H) , 8. 04 (d, 2H)
Example 14: Preparation of N-[1,5-dioxo-5-(4'-
bromobiphenyl-4-yl)-3,3-
diethoxycarbonylpentane-1-yl]-4-
benzoylpiperazine (VI, R1=Br)
The titled compound was prepared in a similar manner
as in Example 8, except for employing N-
L0 benzoylpiperazine(s~e ,: Kondo, K. et al, J. Chem. Soc,
Perkin Trans 1, 1998, 2973-2974) and 5-(4'-bromobiphenyl-4-
yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=Br).
1H NMR(300MHz, CDC13) : S 1.24 (t, 6H) , 3.18 (s, 2H) ,
3. 54 (br, 4H) , 3. 75 (br, 4H) , 4. 00 (s, 2H) , 4.24 (q, 4H) ,
7.40(m, 4H), 7.42(d, 2H), 7.62(m, 4H), 7.86(d, 1H), 8.02(d,
2H)
Example 15: Preparation of 1,5-dioxo-1-(1-phenylcarbamoyl-
1-ethylamino)-5-(4'-bromobiphenyl-4-yl)-3,3-
diethoxycarbonylpentane(VI, R1=Br)
5-(4'-bromobiphenyl-4-yl)-5-oxo-3,3-
diethoxycarbonylvaleric acid(V, R1=Br, 140mg, 0.285mmol),
EDC(60mg, 0.313mmol) and HOBt(42.4mg, 0.313mmol) were
dissolved in MC(5mL) and cooled to a temperature of 0'C.
And, TEA(44.3mL, 0.313mmol) was added and stirred for l0min,
followed by addition of L-Ala-CONH-Ph(56mg, 0.342mmol) and
stirring for l2hrs at room temperature. And then, 1N HC1
3o was added and extracted with MC, and dried over anhydrous
MgS04, filtered, and distilled under reduced pressure, and
subjected to a column chromatography(CHC13/MeOH=19/1, v/v)
to give the titled compound(120mg, 69%).
1H NMR (300MHz, CDC13) : S 1. 24 (t, 6H) , 1. 43 (d, 3H) ,
3. 06 (d, 1H) , 3. 17 (d, 1H) , 3. 94 (s, 2H) , 4.23 (q, 4H) , 4. 60 (m,
1H), 6.15(d, 1H), 7.07(t, 1H), 7.27(m, 1H), 7.45(d, 2H),
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7.58(m, 6H), 7.97(d, 2H), 8.60(s, 1H)
example 16: Preparation of N-phenyl-5-(biphenyl-4-yl)-5-
oxo-3-carboxylvaleramide(I, R1=H)
To N-phenyl-5-(biphenyl-4-yl)-5-oxo-3,3-
diethoxycarbonylvaleramide(VI, R1=H,0.36g, 0.74mmol)
dissolved in ethanol (lOmL) was added 1N NaOH(1.55mL,
1.55mmo1) and stirred for 2hr at room temperature. Ethanol
to was removed under reduced pressure, added water and washed
with ethylacetate, and then, acidified by adding 1N HCl,
extracted with ethylacetate, and dried over anhydrous MgS04,
filtered and distilled under reduced pressure. The
resultant was dissolved in 1,4-dioxane(lOmL), refluxed for
3hr and solvent was evaporated under reduced pressure. The
residue was recrystallized with MC/MeOH(19/1, v/v) and
hexane to give the titled compound(0.17g, 600).
zH NMR (300MHz, CDC13) : 6 2. 76 (dd, 1H) , 2. 90 (dd, 1H) ,
3. 42 (dd, 1H) , 3. 49 (m, 1H) , 3. 58 (dd, 1H) , 7. 10 (t, 1H) ,
7.26(m, 1H), 7.45(m, 5H), 7.65(m, 5H), 8.07(d, 2H)
Example 17: Preparation of N-cyclopropyl-5-(biphenyl-4-yI)
5-oxo-3-carboxylvaleramide(I, R1=H)
The titled compound was prepared in a similar manner
as in Example 16, except for employing N-cyclopropyl-5-
(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI,
R1=H ) .
1H NMR(300MHz, CDC13) : S 0.47 (m, 2H) , 0.73 (m, 2H) ,
2 . 48 (dd, 1H) , 2 . 68 (m, 2H) , 3. 39 (m, 2H) , 3. 54 (dd, 1H) ,
7.40(m, 3H), 7.62(d, 2H), 7.69(d, 2H), 8.02(d, 2H)
example 18: Preparation of N-(a -methylbenzyl)-5-(biphenyl-
4-yl)-5-oxo-3-carboxylvaleramide(I, R1=H)
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The titled compound was prepared in a similar manner
as in Example 16, except for employing N-(a -methylbenzyl)-
5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI,
R1-H ) .
5
1H NMR(300MHz, CDC13) : s 1.44 (d, 3H) , 2.48 (dd, 1H) ,
2.68(m, 2H), 3.39(m, 2H), 3.54(dd, 1H), 4.98(m, 1H), 7.40(m,
3H), 7.61(d, 2H), 7.69(d, 2H), 8.02(d, 2H)
1o Exanl~le 19: Preparation of N-phenyl-5-(4'-methoxybiphenyl-
4-yl ) -5-oxo-3-carboxylvaleramide ( I, R1=OMe )
The titled compound was prepared in a similar manner
as i.n Example 16, except for employing N-phenyl-5
15 (biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI,
R1=OMe ) .
1H NMR (300MHz, CDC13) : 8 2. 70 (dd, 1H) , 2. 91 (dd, 1H) ,
3.40(dd, 1H), 3.49(m, 1H), 3.55(dd, 1H), 3.84(s, 3H),
20 6.98(d, 2H), 7.06(t, 1H), 7.30(m, 2H), 7.50(m, 4H), 7.62(d,
2H), 8.01(d, 2H)
Example 20: Preparation of N-[1,5-dioxo-5-(4'-
methoxybiphenyl-4-yl)-3-carboxylpentane-1-yl]-
4-methylpiperazine(I, R1=OMe)(VI)
The titled compound was prepared in a similar manner
as in Example 16, except for employing N-[1,5-dioxo-5-(4'-
methoxybiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]-4-
3o methylpiperazine (VI, R1=OMe) .
1H NMR(300MHz, CDC13) : S 1.20 (s,' 3H) , 2.45 (s, 1H) ,
2.65(m, 4H), 2.82(dd, 1H), 3.28(dd, 1H), 3.39(br, 4H),
3. 65 (dd, 1H) , 3. 84 (s, 3H) , 4 . 23 (m, 1H) , 6. 98 (d, 2H) , 7. 54 (d,
2H) , 7 . 62 (d, 2H) , 8 . 00 (d, 2H)
Example 2 Preparation of N-phenyl-5-(4'-bromobiphenyl-4-
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y1 ) -5-oxo-3-carboxylvaleramide ( I, R1=OMe ) ( I )
The titled compound was prepared in a similar manner
as in Example 16, except for employing N-phenyl-5-(4'-
bromobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI,
R1=Br ) .
1H NMR (300MHz, CDC13+DMSO) : s 2. 73 (dd, 1H) , 2. 89 (dd,
1H), 3.33(dd, 2H), 3.55(m, 1H), 7.05(t, 1H), 7.28(t, 2H),
7 . 52 (m, 6H) , 7. 65 (d, 2H) , 8. 04 (d, 2H)
Example 22: Preparation of N-[1,5-dioxo-5-(4'-
bromobiphenyl-4-yl)-3-carboxylpentane-1-yl]
piperidine (I, R1=Br)
The titled compound was prepared in a similar manner
as in Example 16, except for employing N-[1,5-dioxo-5-(4'-
bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]
piperidine (VI, R1=Br) .
1H NMR(300MHz, CDC13) : S 2.85 (Br, 4H) , 3.37 (m, 2H) ,
3.64(br, 4H), 4.00(m, 2H), 4.13(m, 1H), 7.48(d, 2H), 7.59(d,
2H), 7.66(d, 2H), 8.04(d, 2H)
Example23: Preparation of N-[1,5-dioxo-5-(4'-
bromobiphenyl-4-yl)-3-carboxylpentane-1-yl]-4-
benzoylpiperazine(I, R1=Br)
The titled compound was prepared in a similar manner
as in Example 16, except for employing N-[1,5-dioxo-5-(4'-
bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]-4-
benzoylpiperazine (VI, R1=Br) .
1H NMR (300MHz, CDC13) : s 2. 59 (dd, 1H) , 2. 86 (br, 4H) ,
3.10(dd, 1H), 3.42(dd, 2H), 3.62(Br, 4H), 3.80(m, 1H),
7 . 40 (m, 4H) , 7 . 42 (d, 2H) , 7. 62 (m, 4H) , 7. 86 (d, IH) , 8 . 02 (d,
2H)
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Example 24: Preparation of 1,5-dioxo-1-(1-phenylcarbamoyl-
1-ethylamino)-5-(4'-bromobiphenyl-4-yl)-3-
carboxylpentane(I, Rz=Br)
To 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-
(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane(VI,
R1=Br, 120mg, 0.197mmol) dissolved in ethanol(5mL) was
added 1N NaOH(lmL, lmmol) and stirred for 5hr at room
1o temperature. Ethanol was removed under reduced pressure,
added water and washed with ethylacetate, and then,
acidified by adding 1N HCl, extracted with ethylacetate,
and dried over anhydrous MgS04, filtered and distilled
under reduced pressure. The resultant was dissolved in 1,4-
dioxane(lOmL), refluxed for 2hr and solvent was evaporated
under reduced pressure. The residue was recrystallized
with MC/MeOH(19/1, v/v) and hexane to give the titled
compound(64mg, 60%).
1H NMR (300MHz, CDC13) : s 1. 43 (d, 3H) , 3. 06 (d, 1H) ,
3.17(d, 1H), 3.40(dd, 1H), 3.53(m, 3H), 4.56(m, 1H), 6.15(d,
1H), 7.07(t, 1H), 7.27(m, 1H), 7.45(d, 2H), 7.58(m, 6H),
7. 97 (d, 2H) , 8. 60 (s, 1H)
Example 25: Preparation of 5-(4'-chlorobiphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid t-butyl
ester(VII, R1=Cl)
KOH(85%, 0.72g, ll.Ommol) dissolved in ethanol(30mL)
was added slowly to 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3,3-
diethoxycarbonylvaleric acid t-butyl ester(IV, R1=Cl, 5.26g,
10.46mmol) dissolved in ethanol(30mL). The reaction
mixture was stirred for 6hr at room temperature, and
acidified by adding 1N HCl, extracted with ethylacetate,
and dried over anhydrous MgSOa, filtered and distilled
under reduced pressure. The resultant was dissolved in
1,4-dioxane(lOmZ), refluxed for 3hr and solvent was
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evaporated under reduced pressure to give the titled
compound(3.51g, 780).
1H NMR (300MHz, CDC13) : 6 1. 24 (t, 3H) , 1. 45 (s, 9H) ,
2.66(ddd, 2H), 3.24(dd, 1H), 3.45(m, 1H), 3.53(dd, 1H),
4. 16 (q, 2H) , 7. 42 (d, 2H) , 7.55 (d, 2H) , 7. 65 (m, 2H) , 8. 03 (d,
2H)
Examz~le 26: Preparation of 5-(biphenyl-4-yl)-5-oxo-3-
1o ethoxycarbonylvaleric acid t-butyl ester(VII,
Ri-H )
The titled compound was prepared in a similar manner
as in Example 25, except for employing 5-(biphenyl-4-yl)-5-
oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester(IV,
R1=H ) .
1H NMR(300MHz, CDC13) : S 1.24 (t, 3H) , 1. 45 (s, 9H) ,
2.66(ddd, 2H), 3.24(dd, 1H), 3.45(m, 1H), 3.53(dd, 1H),
4 . 16 (q, 2H) , 7 . 45 (m, 3H) , 7 . 61 (d, 2H) , 7 . 69 (d, 2H) , 8 . 04 (d,
2H)
Example 27: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo
3-ethoxycarbonylvaleric acid t-butyl ester(VII,
R1=Br )
The titled compound was prepared in a similar manner
as in Example 25, except for employing 5-(4'-bromobiphenyl
4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester
(IV, R1=Br) .
1H NMR(300MHz, CDC13) : 8 1.24 (t, 3H) , 1.45 (s, 9H) ,
2.66(ddd, 2H), 3.24(dd, 1H), 3.45(m, 1H), 3.53(dd, 1H),
4 . 16 (q, 2H) , 7 . 48 (d, 2H) , 7. 60 (d, 2H) , 7 . 65 (d, 2H) , 8 . 04 (d,
2H)
example 28: Preparation of 5-(4'-chlorobiphenyl-4-yl)-5-
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oxo-3-ethoxycarbonylvaleric acid(VIII, R1=C1)
To 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-
ethoxycarbonylvaleric acid t-butyl ester(VII, R1=Cl, 3.518,
8.14mmo1) dispersed in MC(50mL) was,added TFA(7.4mL) and
stirred for 24hr at room temperature. MC was removed under
reduced pressure, and added ethylacetate(20mL). Then, 1N
NaOH was added slowly and stirred for l0min, and the
separated organic layer was extracted with water. And then,
to the aqueous solution was collected, treated with 1N
HCl(30mL) and extracted with ethylacetate. The separated
organic layer was dried over anhydrous MgS04, filtered and
distilled under reduced pressure. The residue was
recrystallized with CHC13 and hexane to give the titled
compound(2.7g, 88%).
1H NMR (300MHz, CDC13) : S 1.24 (t, 3H) , 2. 84 (ddd, 2H) ,
3.30(dd, 1H), 3.48(m, 1H), 3.57(dd, 1H), 4.18(q, 2H),
7.42(d, 2H), 7.55(d, 2H), 7.65(m, 2H), 8.03(d, 2H)
2o
Example 29: Preparation of 5-(biphenyl-4-yl)-5-oxo-3-
ethoxycarbonylvaleric acid(VIII, R1=H)
The titled compound was prepared in a similar manner
as in Example 28, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid t-butyl ester((VII, R1=H).
1H NMR (300MHz, C.DC13) : S 1. 24 (t, 3H) , 2. 84 (ddd, 2H) , 3. 30 (dd,
1H) , 3. 48 (m, 1H) , 3. 57 (dd, 1H) , 4. 18 (q, 2H) , 7 . 45 (m, 3H) ,
7 . 61 (d, 2H) , 7 . 69 (d, 2H) , 8 . 04 (d, 2H)
Example30: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo-
3-ethoxycarbonylvaleric acid(VIII, R1=Br)
The titled compound was prepared in a similar manner
as in Example 28, except for employing 5-(4'-bromobiphenyl-
4-yl)-5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester((VII,
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R1=Br ) .
1H NMR(300MHz, CDC13) : S 1.24 (t, 3H) , 2. 84 (ddd, 2H) ,
3.30(dd, 1H), 3.48(m, 1H), 3.57(dd, 1H), 4.18(q, 2H),
5 7.48(d, 2H), 7.60(d, 2H), 7.65(d, 2H), 8.04(d, 2H)
Examx~le 31: Preparation of N-(3-cyanophenyl)-5-(biphenyl-4-
yl)-5-oxo-3-ethoxycarbonylvaleramide~(IX, R1=H)
10 5-(Biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid
(VIII, R1=H, 50mg, 0.147mmo1) was dissolved in THF(3mL) and
cooled to a temperature of OC. And, N-
methylmorpholine(35mL, 0.323mmo1) and ethylchloroformate
(l6mL, 0.162mmo1) were added slowly, and stirred for 30 min
15 at room temperature. And then, 3-aminbbenznitrile
dissolved in THF(1mL) was added, stirred for 3hr and 30min,
filtered and distilled under reduced pressure. After
diluting with chloroform, washing with 1N HCl, 10o NaHC03
and water in a sequential order, the resultant was dried
20 over anhydrous MgS04, filtered and distilled under reduced
pressure to give the titled compound(55.5mg, 860).
1H NMR (300MHz, CDC13) : s 1. 22 (t, 3H) , 2 . 74 (dd, 1H) ,
3.01(dd, 1H), 3.54(m, 3H), 4.22(q, 2H), 7.42(m, 4H), 7.65(m,
25 5H) ., 8. 01 (m, 3H) , 8.20 (s, 1H)
Example 32: Preparation of N-(3-acetylphenyl)-5-[(biphenyl-
4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX,
R1=H ) ( IX )
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid((VIII, R1=H) and 3-
aminoacetophenone.
1H NMR (300MHz, CDC13) : S 1. 23 (t, 3H) , 2. 59 (s, 3H) ,
2.80(dd, 1H), 3.00(dd, 1H), 3.56(m, 3H), 4.20(q, 2H),
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7.40(m, 4H), 7.60(m, 5H), 8.03(m, 3H), 8.20(s, 1H)
xample 3333: Preparation of N-(3-acetylphenyl)-5-[(4'
chlorobiphenyl-4-yl)]-5-oxo-3
ethoxycarbonylvaleramide(IX, R1=C1)
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-[(4'
chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvalerio acid
(VIII, R1=Cl) and 3-aminoacetophenone.
1H NMR(300MHz, CDC13) : S 1.24 (t, 3H) , 2. 60 (s, 3H) ,
2.80(dd, 1H), 2.94(dd, 1H), 3.56(m, 3H), 4.20(q, 2H),
7.44(m, 3H), 7.54(d, 2H), 7.66(m, 3H), 7.82(s, 1H), 8.04(m,
3H)
Example 34: Preparation of N-(2-chlorophenyl)-5-[(biphenyl-
4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX,
R1=H )
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-(-[(biphenyl-4-
yl)]-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and 2-
chloroaniline.
1H NMR (300MHz, CDC13) : 8 1.24 (t, 3H) , 2. 88 (dd, 1H) ,
3.03(dd, 1H), 3.48~3.66(m, 3H), 4.24(q, 2H), 7.05(t, 1H),
7.43(m, 4H), 7.62(d, 2H), 7.70(d, 2H), 7.90(s, 1H), 8.06(d,
2H) , 8. 30 (s, 1H)
Example 35: Preparation of N-(3-chlorophenyl)-5-[(biphenyl-
4-yl)]- 5-oxo-3-ethoxycarbonylvaleramide(IX,
R1=H )
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-[(biphenyl-4-yl)]-
5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and 3-
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chloroaniline.
1H NMR(300MHz, MeOH-d4) : s 1.24 (t, 3H) , 2.88 (dd, 1H) ,
3.03(dd, 1H), 3.48~3.66(m, 3H), 4.24(q, 2H), 7.23(d, 2H),
7 . 42 (m, 3H) , 7 . 48 (d, 2H) , 7 . 62 (d, 2H) , 7 . 69 (d, 2H) , 8 . 04 (d,
2H)
Example 36: Preparation of N-(4-chlorophenyl)-5-[(biphenyl-
4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX,
R1=H)(IX)
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-[(biphenyl-4-yl)]
5-oxo-3-ethoxycarbonylvaleric acid(VIII, Rl=H) and 4
chloroaniline.
1H NMR(300MHz, DMSO-d6) : s 1.24 (t, 3H) , 2.76 (dd, 1H) ,
2.90(dd, 1H), 3.53(m, 3H), 4.20(q, 2H), 7.06(d, 2H), 7.21(t,
1H) , 7 . 44 (m, 4H) , 7 . 62 (d, 2H) , 7 . 68 (d, 2H) , 8 . 04 (d, 2H)
ao
Example 37: Preparation of N-[3-(N,N-
diethylcarbamoyl)phenyl]-5-[(4'-
chlorobiphenyl-4-yl)]-5-oxo-3-
ethoxycarbonylvaleramide(IX, R1=C1)(IX)
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-[(4'-
chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid
(VIII, R1=Cl) and 3-(N,N-diethylcarbamoyl)aniline.
1H NMR ( 300MHz, CDC13) : 8 1. 11 (t, 3H) , 1. 23 (t, 6H) ,
2.73(dd, 1H), 2.90(dd, 1H), 3.26(br, 2H), 3.52(m, 5H),
4.22(q, 2H), 7.08(d, 1H), 7.32(t, 1H), 7.44(d, 2H), 7.54(m,
3H), 7.65(d, 2H), 7.80(s, 1H), 8.03(d, 2H)
Examble 38: Preparation of N-[3-(N-phenylcarbamoyl)phenyl]-
5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-
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thoxycarbonylvaleramide(IX, R1=C1)
The titled compound was prepared in a similar manner
as in Example 31, except for employing 5-[(4'-
chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid
(VIII, R1=Cl) and 3-(N-phenylcarbamoyl)aniline.
1H NMR(300MHz, CDC13) : s 1.17 (t, 3H) , 2. 85 (dd, 1H) ,
3.10(dd, 1H), 3.56(d, 2H), 3.65(m, 1H), 4.15(q, 2H), 7.15(t,
1H) , 7 . 34 (m, 4H) , 7 . 50 (d, 3H) , 7 . 61 (d, 3H) , 7 . 75 (d, 3H) ,
8 . 00 (d, 2H) , 8. 35 (s, 1H) , 8. 50 (s, 1H)
Example 39: Preparation of (L)-1,5-dioxo-1-(1-
phenylcarbamoyl-1-ethylamino)-5-(biphenyl-4-
yl)-3-ethoxycarbonylpentane(IX, R1=H)
5-(Biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric
acid(VIII, R1=H, 100mg, 0.29mmo1) was dissolved in THF(5mL)
and cooled to a temperature of 0°C. And, N-
2o methylmorpholine(70mL, 0.65mmol) and ethyl
chloroformate(3lmL, 0.32mmo1) were added and stirred for 30
min. And then, L-Ala-CONH-Ph(see: Kruse, C. H, et al, J.
Org. Chem., 50:2792, 1985; Fink, C. A, et al, Bioorg. Med.
Chem. Lett., 9:195-200, 1999) dissolved in THF(1mL) was
added, stirred for 3hr and 30min, filtered and distilled
under reduced pressure. After diluting with chloroform,
washing with 1N HCl, 10% NaHC03 and water in a sequential
order, the resultant was dried over anhydrous MgS09,
filtered and distilled under reduced pressure to give the
3o titled compound(105mg, 73%).
1H NMR (300MHz, CDC13) : s 1. 20 (dt, 3H) , 1. 47 (dd, 3H) ,
2.55(ddd, 1H), 2.75(ddd, 1H), 3.48(m, 3H), 4.14(m, 2H),
4.63(m, 1H), 6.15(dd, 1H), 7.07(t, 1H), 7.27(m, 1H), 7.45(m,
3H), 7.58(m, 6H), 7.97(t, 2H), 8.40~8.60(d, 1H)
Example 40: Preparation of (D)-1,5-dioxo-1-(1-
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phenylcarbamoyl-1-ethylamino)-5-(biphenyl-4-
yl)-3-ethoxycarbonylpentane(IX, R1=H)
The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid and D-Ala-CONH-Ph(105mg,
730) .
1H NMR (300MHz, CDC13) : 8 1. 20 (dt, 3H) , 1. 47 (dd, 3H) ,
2.55(ddd, 1H), 2.75(ddd, 1H), 3.48(m, 3H), 4.14(m, 2H),
4.63(m, 1H), 6.15(dd, 1H), 7.07(t, 1H), 7.27(m, 1H), 7.45(m,
3H), 7.58(m, 6H), 7.97(t, 2H), 8.40~8.60(d, 1H)
Examp a 41: Preparation of 1,5-dioxo-1-[1-(0-
chlorophenyl)carbamoyl-1-ethylamino]-5-
(biphenyl-4-yl)-3-ethoxycarbonylpentane (IX,
R1=H ) ( IX )
The titled compound was prepared in a similar manner
2o as in Example 39, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Ala-
CONH-o-ClPh.
1H NMR (300MHz, CDC13) : s 1. 20 (dt, 3H) , 1. 47 (dd, 3H) ,
2.55(ddd, 1H), 2.75(ddd, 1H), 3.48(m, 3H), 4.14(m, 2H),
4.63(m, 1H), 6.15(dd, 1H), 7.08(t, 1H), 7.29(t, 2H), 7.45(m,
3H) , 7 . 58 (m, 4H) , 7 . 70 (d, 2H) , 7 . 97 (t, 2H) , 8 . 60 (d, 1H)
Example 42: Preparation of 1,5-dioxo-1-[1-(m-
3o chlorophenyl)carbamoyl-1-ethylamino]-5-
(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX,
R1=H ) ( IX )
The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Ala-
~CONH-m-ClPh.
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1H NMR (300MHz, CDC13) : 8 1.20 (dt, 3H) , 1. 47 (dd, 3H) ,
2.55(ddd, 1H), 2.75(ddd, 1H), 3.48(m, 3H), 4.14(m, 2H),
4 . 63 (m, 1H) , 6. 15 (dd, 1H) , 7. 07 (t, 1H) , 7. 30 (t, 2H) , 7. 45 (m,
5 3H), 7.58(m, 4H), 7.68(d, 2H), 7.97(t, 2H), 8.60(d, 1H)
Example 43: Preparation of 1,5-dioxo-1-[1-(p-
chlorophenyl)carbamoyl-1-ethylamino]-5-
(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX,
10 R1=H ) ( IX )
The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(biphenyl-4-yl)-5
oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Ala
15 CONH-p-ClPh.
1H NMR (300MHz, CDC13) : s 1. 20 (dt, 3H) , 1. 47 (dd, 3H) ,
2.55(ddd, 1H), 2.75(ddd, 1H), 3.48(m, 3H), 4.14(m, 2H),
4.63(m, 1H), 6.15(dd, 1H), 7.08(t, 1H), 7.29(t, 2H), 7.45(m,
20 3H) , 7 . 58 (m, 4H) , 7. 70 (d, 2H) , 7. 97 (t, 2H) , 8 . 60 (d, 1H)
Example 44: Preparation of N-X1,5-dioxo-5-[(biphenyl-4-
yl)]-3-ethoxylcarbonylpentane-1-yl}-2-(N-
phenylcarbamoyl)pyrrolidine(IX, R1=H)
The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Pro-
CONH-Ph.
1H NMR (300MHz, CDC13) : S 1. 17 (t, 3H) , 1. 90 (m, 1H) ,
2.06(m, 1H), 2.58(br, 2H), 2.70~3.00(m, 2H), 3.50(m, 2H),
3.57(m, 2H), 3.70(m, 1H), 4.15(m, 2H), 4.78(m, 1H), 7.05(t,
1H), 7.27(m, 2H), 7.45(m, 3H), 7.58(m, 5H), 8.03(d, 2H),
9. 2~9. 4 (d, 1H)
~xamx~le 45: Preparation of 1,5-dioxo-1-[1-phenylcarbamoyl-
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2-phenyl-1-ethylamino]-5-(biphenyl-4-yl)-3-
ethoxycarbonylpentane(TX, R1=H)
The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(biphenyl-4-yl)-5-
oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and Z-Phe-
CONH-Ph.
1H NMR (300MHz, CDC13) : S 1. 17 (dt, 3H) , 2. 382. 55 (ddd,
1H), 2.70(ddd, 1H), 3.20(m, 2H), 3.45(m, 3H), 4.13(dq, 2H),
4.75~4.90(dq, 1H), 6.10~6.30(dd, 1H), 7.08(t, 1H), 7.24(m,
6H) , 7 . 42 (m, 4H) , 7 . 63 (m, 5H) , 8 . 00 (d, 2H) , 7 . 90 & 8 . 30 (d,
1H)
Examble 46: Preparation of N-X1,5-dioxo-5-[(4'-
chlorobiphenyl-4-yl)]-3-
ethoxylcarbonylpentane-1-yl}-2-(N-
phenylcarbamoyl)pyrrolidine(IX, R1=H)
2o The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(4'-
chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid
(VIII, R1=C1) and Z-Pro-CONH-Ph.
1H NMR (300MHz, CDCl3) : 8 1. 20 (t, 3H) , 1. 90 (m, 1H) ;
2 . 06 (m, 1H) , 2 . 58 (br, 2H) , 2. 703. 00 (m, 2H) , 3. 50 (m, 2H) ,
3.57(m, 2H), 3.70(m, 1H), 4.15(m, 2H), 4.78(m, 1H), 7.05(t,
1H), 7.27(m, 2H), 7.45(m, 2H), 7.58(m, 5H), 8.03(d, 2H),
9.29.4 (d, 1H)
Example 47: Preparation of 1,5-dioxo-1-[1-phenylcarbamoyl-
2-phenyl-1-ethylamino]-5-(4'-chlorobiphenyl-4-
yl)-3-ethoxycarbonylpentane(IX, R1=Cl)
The titled compound was prepared in a similar manner
as in Example 39, except for employing 5-(4'-
chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid
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(VIII, R1=C1) and L-Phe-CONH-Ph.
1H NMR(300MHz, CDC13).: 8 1.17 (dt, 3H) , 2.382.55 (ddd,
1H), 2.70(ddd, 1H), 3.20(m, 2H), 3.45(m, 3H), 4.13(dq, 2H),
4.75~4.90(dq, 1H), 6.10~6.30(dd, 1H), 7.07(t, 1H), 7.26(m,
6H), 7.45(m, 3H), 7.56(m, 5H), 7.99(d, 2H), 7.90 & 8.30(d,
1H)
Example 48: Preparation of N-(3-cyanophenyl)-5-[(biphenyl-
4-yl)]-5-oxo-3-carboxylvaleramide(I, R1=H)
To N-(3-cyanophenyl)-5-(biphenyl-4-yl)-5-oxo-3-
ethoxycarbonylvaleramide(IX, R1=H, 11.8mg, 0.0268mmo1)
dissolved in ethanol(2mL) was added 1N NaOH(0.5 mL) and
stirred for lhr and 30min at room temperature, added water
and washed with ethylacetate. And, the resultant was
acidified by adding 1N HCl, and extracted by employing MC,
and dried over anhydrous MgS04. And then, the resultant
was filtered and distilled under reduced pressure, and,
2o recrystallized with CHC13/MeOH(19/l, v/v) and hexane to
give the titled compound(10.4mg, 940).
1H NMR (300MHz, CDC13) : S 2. 74 (dd, 1H) , 3. O1 (dd, 1H) ,
3.54(m, 3H), 7.42(m, 4H), 7.65(m, 5H), 8.01(m, 3H), 8.20(s,
lH)
Example 49: Preparation of N-(3-acetylphenyl)-5-[(biphenyl-
4-yl)]-5-oxo-3-carboxylvaleramide(I, R1=H)
3o The titled compound was prepared in a similar manner
as in Example 48, except for employing N-(3-acetylphenyl)-
5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide(IX,R1=H).
1H NMR(300MHz, CDC13) : 8 2.59 (s, 3H) , 2.80 (dd, 1H) ,
3.00(dd, 1H), 3.56(m, 3H), 7.40(m, 4H), 7.60(m, 5H), 8.03(m,
3H) , 8.20 (s, 1H)
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example 50: Preparation of N-(3-acetylphenyl)-5-[(4'-
chlorobiphenyl-4-yl)]-5-oxo-3-
carboxylvaleramide(I, R1=H)
The titled compound was prepared in a similar manner
as in Example 48, except for employing N-(3-acetylphenyl)-
5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide
(IX, R1=H) .
l0 1H NMR(300MHz, CDC13) : 8 2. 60 (s, 3H) , 2. 80 (dd, 1H) ,
2.94(dd, 1H), 3.56(m, 3H), 7.44(m, 3H), 7.54(d, 2H), 7.66(m,
3H), 7.82(s, 1H), 8.04(m, 3H)
Example 51: Preparation of N-(3-chlorophenyl)-5-[(biphenyl-
4-yl) ] -5-oxo-3-carboxylvaleramide (I, R1=H)
The titled compound was prepared in a similar manner
as in Example 48, except for employing N-(3-chlorophenyl)-
5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide(IX,R1=H).
1H NMR (300MHz, MeOH-d4) : s 2. 88 (dd, 1H) , 3. 03 (dd, 1H) ,
3.48~3.66(m, 3H), 7.23(d, 2H), 7.42(m, 3H), 7.48(d,
2H) , 7 . 62 (d, 2H) , 7 . 69 (d, 2H) , 8 . 04 (d, 2H)
Example 52: Preparation of 1,5-dioxo-1-(1-phenylcarbamoyl-
1-ethylamino) -5- (biphenyl-4-yl) -3-
carboxylpentane (I, Rl=H)
To 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-
(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX, R1=H, 105mg,
0.215mmol) dissolved in ethanol(5mL) was added 1N NaOH(lmL,
lmmol) and stirred for 90min at room temperature, added
water and washed with ethylacetate. And then, the
resultant was acidified by adding 1N HCl, and extracted
with MC, and dried over anhydrous MgS04, filtered and
distilled under reduced pressure. The residue was
recrystallized with CHC13/MeOH(19/1, v/v) and hexane to
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give the titled compound(88mg, 890).
1H NMR(300MHz, CDC13) : s 1.47 (dd, 3H) , 2.55 (ddd, 1H) ,
2.75(ddd, 1H), 3.48(m, 3H), 4.63(m, 1H), 6.15(dd, 1H),
7 . 07 (t, 1H) , 7 . 27 (m, 1H) , 7. 45 (m, 3H) , 7 . 58 (m, 6H) , 7. 97 (t,
2H) , 8. 408. 60 (d, 1H)
Examx~le 53: Preparation of N-{1,5-dioxo-5-[(4'-
chlorobiphenyl-4-yl)]-3-carboxylpentane-1-yl}-
Lo 3-(N-phenylcarbamoyl)-1,2,3,4-
tetrahydroisoquinoline(I, R1=Cl)
The titled compound was prepared in a similar manner
as in Example 52, except for employing N-{1,5-dioxo-.5-[(4'-
chlorobiphenyl-4-yl)]-3-ethoxycarbonylpentane-1-yl}-3-(N-
phenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline(IX, R~=C1).
1H NMR (300MHz, CDC13) : 6 2. 703.20 (m, 2H) , 3. 383. 57 (m,
4H), 4.11(m, 1H), 4.66(m, 2H), 5.33(d, 1H), 6.92(t, 1H),
7. 15 (m, 4H) , 7 . 45 (m, 7H) , 7. 93 (d, 2H) , 8. 66 (m, 1H)
Examx~le 54: In vitro inhibition on gelatinase A(MMP-2)
The present test was accomplished by measuring the
fluorescence intensity of a fluorescent material(7-
methoxycoumarin-4-acetyl-Pro-Leu-Gly) produced from the
cleavage of a fluorescent synthetic peptide substrate((7-
methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu-j3 -(2,4-
dinitrophenylamino)Ala-Ala-Arg-NHz(Sigma Chem. Co.,
3o U.S.A.)) by gelatinase A(Boehringer Manneheim cat# 1782916,
from human fibrosarcoma cells).
Enzymatic reaction employing a fluorescent synthetic
substrate was accomplished by leaving test compounds, TNBC
buffer solution(25mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.010
Brij-35, 5mM CaCl2), gelatinase A(final concentration in
well: 4.17nM) activated with 1 mM of
APMA(aminophenylmercuric acetate) for 30 minutes at 37°C
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just before the enzymatic reaction, and the substrate,
fluorescent synthetic peptide(final concentration in well:
9.25uM) in 96 well plate and then reacting for 30 minutes
at 37°C, and the fluorescence intensity was measured at
5 excitation 328nm and emission 393nm by
spectrofluorimeter(Fmax(molecular device)). The inhibition
rate(o) was calculated from the following equation:
~11~1~1t3~1. .~,~~~~,~o~ _
1o wherein,
A represents fluorescence intensity before the
reaction with an inhibitor;
B represents fluorescence intensity after the
reaction with an inhibitor
15 C represents fluorescence intensity before the
reaction without an inhibitor; and,
D represents fluorescence intensity after the
reaction without an inhibitor.
2o Example 55: In vitro inhibition on gelatinase B(MMP-9)
In vitro inhibition rate on gelatinase B(MMP-9) was
measured in a similar manner as in Example 54, except for
employing gelatinase B(Boehringer Manneheim cat# 1758896,
25 from human blood) with a different concentration(final
concentration in well: 2.715nM) and a different
concentration of the substrate, fluorescent synthetic
peptide(final concentration in well: 4.575uM).
3o Example 5~: In vitro inhibition on collagenase(MMP-1)
In vitro inhibition rate on collagenase(MMP-1) was
measured in a similar manner as in Example 54, except for
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employing collagenase(AngioLab. Co., Ltd) with a final
concentration in well of 7.25nM.
ht
O
i
Hhf
-w~1
No R1 R~ R3 ICSO (u ICso (~1
. M) M)
MMP-2 MMP-9
1 Br (L)-Me Ph 0.018 0.3
2 H (D) -Me Ph 2. 79 27 . 22
3 H (L)-Me Ph 0.08 3.21
4 H (L)-Me o-Cl-Ph 0.17 6.13
H (L) -Me m-C1-Ph 0 .13 3. 65
6 H (L)-Me p-C1-Ph 0.27 7.18
7 C1 (L) -Me Ph 0. 015 0 . 22
8 H (L)-Ph Ph 0.037 0.28
9 Cl (L)-Ph Ph 0.007 0.099
Cl Ph 0.008 0.027
No. R1 Rz ICSO (u ICSO (~L
M) M)
MMP-2 MMP-9
1 H ~~~ 0 . 018 0 . 7 7
2 C1 ~ ~ 0.004 0.085
.~t~
3 H a N~ 0.0062 0.11
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H
D hi~R~
R
No. R1 RZ R3 ICso (~i ICso (1~ ICso (u
M) M) M)
MMP-2 MMP-9 MMP-1
1 H Ph H 2.68
2 H Cyclopropyl H 3.22
3 H (+) -a -MeanH 1.16
4 Me0 Ph H 0.29
Me0 1.30
lil~rf.~
6 Br Ph H 0.17 6.2
7 Br 0.98 16.5
8 Br ~' 0 . 7 9 . 6
3
9 Cl Ph H 0.11 3.39
H o-Cl-Ph H 1.25 2.16
11 H m-Cl-Ph H 0.57 10.46
12 H p-Cl-Ph H 1.03 12.10
13 H m-CN-Ph H 2.82 76.61
14 H m-acetyl-Ph H 0.99 36.25
C1 m-acetyl-Ph H 0.14 1.61
16 Cl ~~ H 0.0081 0.09 137.97
5 As clearly illustrated and demonstrated as above, the
present invention provides novel biphenylbutyric acid
derivatives which inhibit MMP activity, their isomers and
the pharmaceutically acceptable salts thereof, and a
process for preparing the compounds. Since the
to biphenylbutyric acid derivatives of the present invention
selectively inhibit MMP activity in vitro, the MMP
inhibitors comprising the biphenylbutyric acid derivatives
as an active ingredient can be practically applied for the
prevention and treatment of diseases caused by
15 overexpression and overactivation of MMP.
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.Although the preferred embodiments of the present
invention have been disclosed for illustrative purpose,
those who are skilled in the art will appreciate that
various modifications, additions and substitutions are
possible, without departing from the scope and spirit of
the invention as described in the accompanying claims.
15
25
35
