U.S. patent application number 10/262841 was filed with the patent office on 2003-03-27 for piperazine compounds as inhibitors of mmp or tnf.
This patent application is currently assigned to FUJISAWA PHARMACEUTICAL CO., LTD.. Invention is credited to Kayakiri, Natsuko, Neya, Masahiro, Oku, Teruo, Sato, Kentaro, Yamazaki, Hitoshi.
Application Number | 20030060473 10/262841 |
Document ID | / |
Family ID | 27157970 |
Filed Date | 2003-03-27 |
United States Patent
Application |
20030060473 |
Kind Code |
A1 |
Neya, Masahiro ; et
al. |
March 27, 2003 |
Piperazine compounds as inhibitors of MMP or TNF
Abstract
A compound of formula (I) wherein A is a sulfonyl or a carbonyl;
R.sup.1 is an optionally substituted aryl, an optionally
substituted heterocyclic group, an optionally substituted lower
alkyl or an optionally substituted lower alkenyl; R.sup.2 is a
hydrogen, an optionally substituted lower alkyl, an optionally
substituted aryl or an optionally substituted heterocyclic group;
R.sup.3 is an optionally substituted lower alkyl, an optionally
substituted lower alkoxy, an optionally substituted aryloxy, an
optionally substituted lower alkenyl, an optionally substituted
aryl, an optionally substituted heterocyclic group or an optionally
substituted amino; R.sup.4 is a hydrogen, an optionally substituted
lower alkyl, an optionally substituted aryl or an optionally
substituted heterocyclic group; R5 is a hydrogen, an optionally
substituted lower alkyl, an optionally substituted aryl or an
optionally substituted heterocyclic group; and R.sup.10 is a
hydroxy or a protected hydroxy, and a pharmaceutically acceptable
salt thereof. The compound of the present invention is useful as a
medicament for prophylactic and therapeutic treatment of MMP-or
TNF.alpha.-medicated diseases.
Inventors: |
Neya, Masahiro; (Ibaraki,
JP) ; Yamazaki, Hitoshi; (Ibaraki, JP) ;
Kayakiri, Natsuko; (Osaka, JP) ; Sato, Kentaro;
(Ibaraki, JP) ; Oku, Teruo; (Osaka, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
FUJISAWA PHARMACEUTICAL CO.,
LTD.
4-7, Doshomachi 3-chome, Chuo-ku
Osaka
JP
541-8514
|
Family ID: |
27157970 |
Appl. No.: |
10/262841 |
Filed: |
October 3, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10262841 |
Oct 3, 2002 |
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09982869 |
Oct 22, 2001 |
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6489324 |
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10262841 |
Oct 3, 2002 |
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09319928 |
Jul 26, 1999 |
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6333324 |
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09319928 |
Jul 26, 1999 |
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PCT/JP97/04613 |
Dec 15, 1997 |
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Current U.S.
Class: |
514/252.13 ;
514/255.01; 544/359; 544/384; 544/386 |
Current CPC
Class: |
A61P 17/06 20180101;
A61P 43/00 20180101; A61P 17/02 20180101; C07D 241/04 20130101;
C07D 409/12 20130101; C07D 413/14 20130101; C07D 417/14 20130101;
C07D 405/12 20130101; C07D 417/12 20130101; C07D 405/14 20130101;
A61P 19/02 20180101; C07D 409/14 20130101 |
Class at
Publication: |
514/252.13 ;
514/255.01; 544/359; 544/384; 544/386 |
International
Class: |
A61K 031/496; A61K
031/495; C07D 43/02; C07D 241/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 17, 1996 |
AU |
PO 4249 |
Jun 3, 1997 |
AU |
PO 7156 |
Aug 14, 1997 |
AU |
PO 8568 |
Claims
1. A compound of the formula (I): 5wherein A is a sulfonyl or a
carbonyl; R.sup.1 is an optionally substituted aryl, an optionally
substituted heterocyclic group, an optionally substituted lower
alkyl or an optionally substituted lower alkenyl; R.sup.2 is a
hydrogen, an optionally substituted lower alkyl, an optionally
substituted aryl or an optionally substituted heterocyclic group;
R.sup.3 is an optionally substituted lower alkyl, an optionally
substituted lower alkoxy, an optionally substituted aryloxy, an
optionally substituted lower alkenyl, an optionally substituted
aryl, an optionally substituted heterocyclic group or an optionally
substituted amino: R.sup.4 is a hydrogen, an optionally substituted
lower alkyl, an optionally substituted aryl or an optionally
substituted heterocyclic group; R.sup.5 is a hydrogen, an
optionally substituted lower alkyl, an optionally substituted aryl
or an optionally substituted heterocyclic group; and R.sup.1 0 is a
hydroxy or a protected hydroxy, provided that when A-R.sup.3 is
methylsulfonyl, then R.sup.1 is an aryl substituted by a
substituent selected from the group consisting of halogen, cyano,
nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy,
lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group, an
optionally substituted heterocyclic group, an optionally
substituted alkyl or an optionally substituted lower alkenyl, and
the above-mentioned heterocyclic group is each selected from the
group consisting of unsaturated 3- to 8-membered heteromonocyclic
group containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 to 5 nitrogen atoms, unsaturated 3- to 8-membered
heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms, saturated 3- to 8-membered heteromonocyclic group
containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or
2 sulfur atoms and 1 to 3 nitrogen atoms, saturated 3- to
8-membered heteromonocyclic group containing 1 or 2 sulfur atoms
and 1 to 3 nitrogen atoms, unsaturated 3- to 8-membered
heteromonocyclic group containing a sulfur atom, unsaturated 3- to
8-membered heteromonocyclic group containing an oxygen atom,
saturated 3- to 8-membered heteromonocyclic group containing an
oxygen atom, unsaturated condensed 7- to 13-membered heterocyclic
group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and
unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 or 2 oxygen atoms, or a pharmaceutically acceptable
salt thereof.
2. The compound of claim 1, wherein R.sup.2 is a hydrogen or an
optionally substituted lower alkyl, and R.sup.4 is a hydrogen or an
optionally substituted lower alkyl, or a pharmaceutically
acceptable salt thereof.
3. The compound of claim 2, wherein R.sup.1 is an aryl optionally
substituted by a substituent selected from the group consisting of
halogen, cyano, nitro, amino, acylamino, lower alkylamino,
carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and
heterocyclic group; a heterocyclic group optionally substituted by
a substituent selected from the group consisting of halogen, cyano,
nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy,
lower alkoxy, aryloxy, lower alkyl, aryl, heterocyclic group,
haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl,
nitroaryl, biphenylyl, aryloxyaryl, trihaloalkylaryl,
cyano(lower)alkoxyaryl, cyanoaryl, cyano(lower)alkylaryl, lower
alkanoyloxyaryl, lower alkanoyloxy(lower)alkylaryl,
di(lower)alkylaminosulfonylaryl, hydroxy(lower)alkylaryl, lower
alkoxycarbonylaryl, lower alkoxycarbonyl(lower)alkoxyaryl, lower
alkylsulfonyloxyaryl, aryl substituted by halogen and hydroxy, aryl
substituted by halogen and alkanoyloxy, aryl substituted by halogen
and lower alkoxy, lower alkyl-heterocyclic group and
aryl-heterocyclic group; a lower alkyl optionally substituted by
halogen; or a lower alkenyl optionally substituted by aryl; the
said heterocyclic group each being selected from the group
consisting of unsaturated 5- or 6-membered heteromonocyclic group
containing 1 to 4 nitrogen atoms, unsaturated 5- or 6membered
heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group
containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
unsaturated 5- or 6-membered heteromonocyclic group containing a
sulfur atom, and unsaturated 9- to 10-membered heterobicyclic group
containing 1 or 2 oxygen atoms, R.sup.3 is a lower alkyl optionally
substituted by a substituent selected from the group consisting of
halogen, heterocyclic group, carbamoyl, lower alkylcarbamoyl,
carboxy, protected carboxy, heterocyclic-carbonyl,
di(lower)alkylamino, protected amino, arylcarbonylamino,
heterocyclic-carbonylamino, lower alkanoylamino, lower
alkylsulfonylamino, di(lower)alkylaminosulfonylamino,
heterocyclic-sulfonylamino, heterocyclic-thio, lower
alkylheterocyclic-thio and heterocyclic-thio; a lower alkoxy; an
aryloxy; an aryl(lower)alkoxy; an optionally substituted lower
alkenyl; an optionally substituted heterocyclic group; or a group
of the formula: 6wherein R.sup.8 and R.sup.9 are the same or
different and each is hydrogen, lower alkyl, carboxy(lower)alkyl,
lower alkoxycarbonyl(lower)al- kyl, carbamoyl(lower)alkyl,
hydroxy(lower)akyl, aryl, cyclo(lower)alkyl,
heterocyclic-(lower)alkyl; the said heterocyclic group each being
selected from the group consisting of unsaturated 5- or 6-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated
5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen
atoms, unsaturated 5- or 6-membered heteromonocyclic group
containing 1 or 2 oxygen atom and 1 to 3 nitrogen atoms, saturated
5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen
atom and 1 to 3 nitrogen atoms, unsaturated 5- or 6-membered
heteromonocyclic group containing 1 or 2 sulfur atom and 1 to 3
nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group
containing a sulfur atom, and unsaturated 9- or 10-membered
heterobicyclic group containing 1 or 2 oxygen atoms, or a
pharmaceutically acceptable salt thereof.
4. The compound of claim 3, wherein R.sup.1 is a heterocyclic group
selected from the group consisting of unsaturated 5- or 6-membered
heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3
nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic
group containing a sulfur atom, each of which is optionally
substituted by a substituent selected from the group consisting of
halogen; phenyl; halophenyl; hydroxyphenyl; lower alkoxyphenyl;
lower alkylphenyl; nitrophenyl; biphenylyl; phenoxyphenyl;
trihalo(lower) alkyphenyl; cyano(lower)alkoxyphenyl; cyanophenyl;
cyano(lower)alkylphenyl; lower alkanoyloxyphenyl; lower
alkanoyloxy(lower)alkylphenyl; di(lower)alkylaminosulfonylphenyl;
hydroxy(lower)alkylphenyl; lower alkoxycarbonylphenyl; lower
alkoxycarbonyl(lower)alkoxyphenyl; lower alkylsulfonyloxyphenyl;
phenyl substituted by halogen and hydroxy; phenyl substituted by
halogen and lower alkanoyloxy; phenyl substituted by halogen and
lower alkoxy; heterocyclic group selected from the group consisting
of unsaturated 9- or 10 membered heterobicyclic group containing 1
or 2 oxygen atoms, unsaturated 5- or 6membered heteromonocyclic
group containing 1 to 4 nitrogen atoms, unsaturated 5- or
6-membered heteromonocyclic group containing 1 or 2 oxygen atoms
and 1 to 3 nitrogen atoms and unsaturated 5- or 6membered
heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3
nitrogen atoms; and a lower alkyl- or (phenyl-)heterocyclic group,
said heterocyclic group being unsaturated 5- or 6-membered
heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms; R.sup.2 is a hydrogen, R.sup.3 is a lower alkyl; a
halo(lower)alkyl; a heterocyclic(lower)alkyl, said heterocyclic
group being selected from the group consisting of unsaturated 5- or
6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
saturated 5- or 6-membered heteromonocyclic group containing 1 to 4
nitrogen atoms and saturated 5- or 6-membered heteromonocyclic
group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; a
carbamoyl(lower)alkyl; a lower alkylcarbamoyl(lower)alkyl; a
carboxy(lower)alkyl; a phenyl(lower)alkoxycarbonyl(lower)alkyl; a
heterocyclic-carbonyl(lower)alkyl, said heterocyclic group being
saturated 5- or 6-membered heteromonocyclic group containing 1 or 2
oxygen atoms and 1 to 3 nitrogen atoms; a
di(lower)alkylamino(lower)alkyl- ; a
phenyl(lower)alkoxycarbonylamino(lower)alkyl; a lower
alkoxycarbonylamino(lower)alkyl; a benzoylamino(lower)alkyl; a
heterocyclic carbonylamino(lower)alkyl, said heterocyclic group
being unsaturated 5- or 6-membered heteromonocyclic group
containing 1 to 4 nitrogen atoms; a lower
alkanoylamino(lower)alkyl; a lower alkylsulfonylamino(lower)alkyl;
a di(lower)alkylaminosulfonylamino(lower)- alkyl; a
heterocyclic-sulfonylamino(lower)alkyl, said heterocyclic group
being unsaturated 5- or 6-membered heteromonocyclic group
containing 1 to 4 nitrogen atoms; a heterocyclic-thio(lower)alkyl,
said heterocyclic group being selected from the group consisting of
unsaturated 5- or 6-membered heteromonocyclic group containing 1 to
4 nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group
containing 1 to 4 nitrogen atoms, unsaturated 9- or 10-membered
heterobicyclic group containing 1 to 5 nitrogen atoms and
unsaturated 5- or 6-membered heteromonocyclic group containing 1 to
2 sulfur atoms and 1 to 3 nitrogen atoms; a lower
alkylheterocyclic-thio(lower)alkyl, said heterocyclic group being
unsaturated 5- or 6-membered heteromonocyclic group containing 1 to
4 nitrogen atoms; a heterocyclic-thio(lower)alkyl, said
heterocyclic group being unsaturated 9- or 10-membered
heterobicyclic group containing 1 to 5 nitrogen atoms; a lower
alkoxy; a phenyloxy; a fluorenyl(lower)alkoxy; a
heterocyclic(lower)alkenyl, said heterocyclic group being
unsaturated 5- or 6-membered heteromonocyclic group containing 1 to
4 nitrogen atoms; a heterocyclic group, said heterocyclic group
being selected from the group consisting of unsaturated 5- or
6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
saturated 5- or 6-membered heteromonocyclic group containing 1 to 4
nitrogen atoms and unsaturated 5- or 6-membered heteromonocyclic
group containing a sulfur atom, which is optionally substituted by
heterocyclic group, said heterocyclic group being unsaturated 5- or
6-membered heteromonocyclic group containing 1 or 2 oxygen atoms
and 1 to 3 nitrogen atoms; a mono- or di(lower)alkylamino; a
carboxy(lower)alkylamino; a lower alkoxycarbonyl(lower)alkylamino;
an N-(lower)alkyl-N-(lower)alkoxyc- arbonylamino; a
carbamoyl(lower)alkylamino; a hydroxyamino(lower)alkyl; a
phenylamino; or a cyclo(lower)alkylamino; R.sup.4 is a hydrogen,
R.sup.5 is a hydrogen, and R.sup.1 0 is a hydroxy, a lower alkoxy,
a phenyl(lower)alkoxy, a fluorenyl(lower)alkoxy or a
tetrahydropyranyloxy, or a pharmaceutically acceptable salt
thereof.
5. The compound of claim 4, wherein R.sup.1 is a thienyl
substituted by a substituent selected from the group consisting of
halogen, phenyl, halophenyl, hydroxyphenyl, lower alkoxyphenyl,
lower alkylphenyl, nitrophenyl, biphenylyl, phenoxyphenyl,
trihalo(lower)alkylphenyl, cyano(lower)alkoxyphenyl, cyanophenyl,
cyano(lower)alkylphenyl, lower alkanoyloxyphenyl, lower alkanoyloxy
(lower) alkylphenyl, di(lower) alkylaminosulfonylphenyl, hydroxy
(lower) alkylphenyl, lower alkoxycarbonylphenyl, lower
alkoxycarbonyl (lower) alkoxyphenyl, lower alkylsulfonyloxyphenyl,
phenyl substituted by halogen and hydroxy, phenyl substituted by
halogen and lower alkanoyloxy, phenyl substituted by halogen and
lower alkoxy, thiazolyl, oxazolyl, pyridyl, benzodihydrofuranyl,
benzodioxolenyl, lower alkyloxadiazolyl and phenyloxadiazolyl; a
thiazolyl substituted by phenyl or a thiadiazolyl substituted by
phenyl; R.sup.3 is a lower alkyl, a halo(lower)alkyl, a
morpholinyl(lower)alkyl, a piperidinyl( lower)alkyl, a
pyridyl(lower)alkyl, a carbamoyl(lower)alkyl, a lower
alkylcarbamoyl(lower)alkyl, a carboxy(lower)alkyl, a
phenyl(lower)alkoxycarbonyl(lower)alkyl, a
morpholinylcarbonyl(lower)alky- l, a
di(lower)alkylamimno(lower)alkyl, a
phenyl(lower)alkoxycarbonylamino(- lower)alkyl, a lower
alkoxycarbonylamino(lower)alkyl, a benzoylamino(lower)alkyl, a
pyridyl-carbonylamino(lower)alkyl, a lower
alkanoylamino(lower)alkyl, a lower alkylsulfonylamino(lower)alkyl,
a di(lower)alkylaminosulfonylamino(lower)alkyl, a
pyridyl-sulfonylamino(low- er)alkyl, a triazolylthio(lower)alkyl,
an imidazolylthio(lower)alkyl, a thiazolylthio(lower)alkyl, a
benzimidazolylthio(lower)alkyl, a lower
alkyltriazolylthio(lower)alkyl, a lower alkoxy, a
fluorenyl(lower)alkoxy, a phenoxy, a pyridyl(lower)alkenyl, a
pyridyl, a piperidinyl, a thienyl substituted by oxazolyl, a mono-
(or di-) (lower)alkylamino, a carboxy(lower)alkylamino, a lower
alkoxycarbonyl(lower)alkylamino, an
N-(lower)alkyl-N-(lower)alkoxycarbonyl(lower)alkylamino, a
carbamoyl(lower)alkylamino, a hydroxy(lower)alkylamino, a
phenylamino or a cyclo(lower)alkylamino, and R.sup.1 0 is a
hydroxy, or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5, wherein R.sup.1 is a thienyl, a
halothienyl, a phenylthienyl, a halophenylthienyl, a
hydroxyphenylthienyl, a lower alkoxyphenylthienyl, a lower
alkylphenylthienyl, a nitrophenylthienyl, a biphenylylthienyl, a
phenoxyphenylthienyl, a trihalo(lower)alkylphenylthi- enyl, a
cyano(lower)alkoxyphenylthienyl, a cyanophenylthienyl, a
cyano(lower)alkylphenylthienyl, a lower alkanoyloxyphenylthienyl, a
lower alkanoyloxy(lower)alkylphenylthienyl, a
di(lower)alkylaminosulfonylphenyl- thienyl, a
hydroxy(lower)alkylphenylthienyl, a lower
alkoxycarbonylphenylthienyl, a lower
alkoxycarbonyl(lower)alkoxyphenylthi- enyl, a lower
alkylsulfonyloxyphenylthienyl, a phenylthienyl wherein the phenyl
group being substituted by halogen and hydroxy, a phenylthienyl
wherein the phenyl group being substituted by halogen and lower
alkanoyloxy, or a phenylthienyl wherein the phenyl group being
substituted by halogen and lower alkoxy, or a pharmaceutically
acceptable salt thereof.
7. A process for the preparation of the piperazine compound of
claim 1 or a salt thereof, which comprises, (1) reacting a compound
of the formula (II): 7wherein A, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 are each as defined in claim 1 and R.sup.1 0 a is a
protected hydroxy, or a salt thereof, with a compound of the
formula (III):R.sup.1--SO.sub.2-X (III) wherein R.sup.1 is as
defined in claim 1 and X is a leaving group, to give a compound of
the formula (IV): 8wherein A, R.sup.1, R.sup.2, R.sup.3, R.sub.4,
R.sup.5 and R.sup.1 0 a are each as defined above, or a salt
thereof, (2) subjecting a compound of the formula (IV): 9wherein A,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.1 0 a are
each as defined above, or a salt thereof, to elimination reaction
of the hydroxy protective group, to give a compound of the formula
(V): 10wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
are each as defined above, or a salt thereof, (3) reacting a
compound of the formula (VI): 11wherein A, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are each as defined above, or a salt
thereof, with a compound of the formula (VII):H.sub.2N--R.sup.1 0 a
(VII) wherein R.sup.1 0 a is as defined above, or a salt thereof,
to give a compound of the formula (IV): 12wherein A, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.1 0 a are each as
defined above, or a salt thereof, (4) reacting a compound of the
formula (VIII): 13wherein A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
R.sup.1 0 a are each as defined above and R.sup.3 a is an alkyl
substituted by halogen, or a salt thereof, with a compound of the
formula (IX):H--R.sup.1 1 (IX) wherein R.sup.1 1 is a
di(lower)alkylamino, an N-containing heterocyclic group or an
optionally substituted heterocyclic-thio, or a salt thereof, to
give a compound of the formula (X): 14wherein A, R.sup.1, R.sup.2,
R.sup.4, R.sup.5 and R.sup.1 0 a are each as defined above and
R.sup.3 b is a di(lower) alkylamino (lower)alkyl, an N-containing
heterocyclic(lower)alkyl or an optionally substituted
heterocyclic-thio(lower)alkyl, or a salt thereof, (5) subjecting a
compound of the formula (XI): 15wherein A, R.sup.1, R.sup.2,
R.sup.4, R.sub.5 and R.sup.1 0 a are each as defined above and
R.sup.3 c is a protected carboxy(lower)alkyl or a protected
carboxy(lower)alkylamimno, or a salt thereof, to elimination
reaction of the hydroxy protective group, to give a compound of the
formula (XII): 16wherein A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and
R.sup.1 0 a are each as defined above, and R.sup.3 d is a
carboxy(lower)alkyl or a carboxy(lower)alkylamino, or a salt
thereof, (6) subjecting a compound of the formula (XII): 17wherein
A, R.sup.1, R.sup.2, R.sup.3 d , R.sup.4, R.sup.5 and R.sup.1 0 a
are each as defined above, or a salt thereof, to amidation
reaction, to give a compound of the formula (XIII): 18wherein A,
R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.1 0 a are each as
defined above, and R.sup.3 e is an N-containing
heterocyclic-carbonyl(lower)alkyl- , an optionally substituted
amino-carbonyl(lower)alkyl or an optionally substituted
amino-carbonyl(lower)alkylamino, or a salt thereof, (7) reacting a
compound of the formula (XIV): 19wherein R.sup.1, R.sup.2, R.sup.4,
R.sup.5 and R.sup.1 0 a are each as defined above, or a salt
thereof, with a compound of the formula (XV):R.sup.3-A-X (XV)
wherein R.sup.3, A and X are each as defined above, or a salt
thereof, to give a compound of formula (IV): 20wherein A, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.1 0 a are each as
defined above, or a salt thereof, (8) reacting a compound of the
formula (XVI): 21wherein A, R.sup.1, R.sup.2, R.sup.4, R.sup.5,
R.sup.1 0 a and X are each as defined above, or a salt thereof,
with a compound of the formula (XVII):H.sub.2N--R.sup.3 f (XVII)
wherein R.sup.3 f is a hydroxy(lower)alkyl, or a salt thereof, to
give a compound of the formula (XVIII): 22wherein A, R.sup.1,
R.sup.2, R.sup.3 f, R.sup.4, R.sup.5 and R.sup.1 0 a are each as
defined above, or a salt thereof, (9) subjecting a compound of the
formula (XIX): 23wherein A, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.1 0 a are each as defined above, and R.sup.1 a is a
heterocyclic group having a substituent which is aryl substituted
by acyloxy, or a salt thereof, to elimination reaction of the
hydroxy protective group, to give a compound of the formula (XX):
24wherein A, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each as
defined above, and R.sup.1 b is a heterocyclic group having a
substituent which is aryl substituted by hydroxy, or a salt
thereof, or (10) subjecting a compound of the formula (XXI):
25wherein A, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.1 0 a are
each as defined above, and R.sup.1 c is a heterocyclic group having
a substituent which is aryl substituted by cyanoalkyloxy, or a salt
thereof, to solvolysis, to give a compound of the formula (XXII):
26wherein A, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each as
defined above, and R.sup.1 d is a heterocyclic group having a
substituent which is aryl substituted by alkoxycarbonylalkyloxy, or
a salt thereof.
8. A pharmaceutical composition which comprises the compound of
claim 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier or excipient.
9. A process for preparing a pharmaceutical composition which
comprises admixing the compound of claim 1 or a pharmaceutically
acceptable salt thereof with a pharmaceutically acceptable carrier
or excipient.
10. Use of the compound of claim 1 or a pharmaceutically acceptable
salt thereof as a medicament.
11. Use of the compound of claim 1 or a pharmaceutically acceptable
salt thereof as an inhibitor of matrix metalloproteinases (MMP) or
tumor necrosis factor .alpha. (TNF.alpha.).
12. Use of the compound of claim 1 or a pharmaceutically acceptable
salt thereof for manufacturing a medicament for treating and/or
preventing MMP- or TNF.alpha.-mediated diseases.
13. A method for treating and/or preventing MMP- or
TNF.alpha.-mediated diseases which comprises administering the
compound of claim 1 or a pharmaceutically acceptable salt thereof
to a human being or an animal.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new compounds and
pharmaceutically acceptable salts thereof.
[0002] More particularly, it relates to new compounds and
pharmaceutically acceptable salts thereof which are useful as
inhibitors of matrix metalloproteinases (hereinafter to be referred
to as MMP) or the production of tumor necrosis factor .alpha.
(hereinafter to be referred to as TNF.alpha.), to pharmaceutical
compositions comprising the same, to use of the same as
medicaments, and to methods for using the same therapeutically in
the treatment and/or the prevention of MMP- or TNF.alpha.-mediated
diseases.
BACKGROUND ART
[0003] Some piperazine compounds to be useful as metalloproteinase
inhibitors, or the like are known (WO 97/20824, etc.).
DISCLOSURE OF THE INVENTION
[0004] One object of the present invention is to provide new and
useful compounds and pharmaceutically acceptable salts thereof, and
to provide a process for preparing said new compound and salts
thereof, which have pharmacological activities such as MMP- or
TNF.alpha.-inhibitory activity and the like.
[0005] Another object of the present invention is to provide a
pharmaceutical composition comprising, as an active ingredient,
said compound or a pharmaceutically acceptable salt thereof.
[0006] A further object of the present invention is to provide use
of said compounds and pharmaceutically acceptable salts thereof as
medicaments for prophylactic and therapeutic treatment of MMP- or
TNF.alpha.-mediated diseases.
[0007] A still further object of the present invention is to
provide a method for using the same for the treatment and/or the
prevention of MMP- or TNF.alpha.-mediated diseases in mammals,
especially humans.
[0008] The compounds of the present invention have inhibitory
activity on MMP or the production of TNF.alpha., and are useful for
the treatment and/or prevention of diseases such as stroke,
arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis,
periodontal disease, epidermolysis bullosa, scleritis, psoriasis
and other diseases characterized by matrix metalloproteinase
activity, as well as AIDS, sepsis, septic shock and other diseases
caused by the production of TNF.alpha..
[0009] There are a number of structurally related metalloproteases
which effect the breakdown of structural proteins. Matrix-degrading
metalloproteases, such as gelatinase (MMP-2, MMP-9), stromelysin
(MMP-3) and collagenase (MMP-1, MMP-8, MMP-13), are involved in
tissue matrix degradation and have been implicated in many
pathological conditions involving abnormal connective tissue and
basement membrane matrix metabolism, such as arthritis (e.g.,
osteoarthritis and rheumatoid arthritis), cerebral disease (e.g.,
stroke, etc.), tissue ulceration (e.g., corneal, epidermal and
gastric ulcerations), abnormal wound healing, periodontal disease,
bone disease (e.g., Paget's disease and osteoporosis), tumor
metastasis or invasion and HIV-infection.
[0010] A tumor necrosis factor is recognized to be involved in many
infections and autoimmune diseases. Furthermore, it has been shown
that TNF is the prime mediator of the inflammatory response seen in
sepsis and septic shock.
[0011] The object compounds of the present invention are novel and
can be represented by the following formula (I): 1
[0012] wherein
[0013] A is a sulfonyl or a carbonyl;
[0014] R.sup.1 is an optionally substituted aryl, an optionally
substituted heterocyclic group, an optionally substituted lower
alkyl or an optionally substituted lower alkenyl;
[0015] R.sup.2 is a hydrogen, an optionally substituted lower
alkyl, an optionally substituted aryl or an optionally substituted
heterocyclic group;
[0016] R.sup.3 is an optionally substituted lower alkyl, an
optionally substituted lower alkoxy, an optionally substituted
aryloxy, an optionally substituted lower alkenyl, an optionally
substituted aryl, an optionally substituted heterocyclic group or
an optionally substituted amino:
[0017] R.sup.4 is a hydrogen, an optionally substituted lower
alkyl, an optionally substituted aryl or an optionally substituted
heterocyclic group;
[0018] R.sup.5 is a hydrogen, an optionally substituted lower
alkyl, an optionally substituted aryl or an optionally substituted
heterocyclic group; and
[0019] R.sup.1 0 is a hydroxy or a protected hydroxy, provided that
when A-R.sup.3 is methylsulfonyl, then R.sup.1 is an aryl
substituted by a substituent selected from the group consisting of
halogen, cyano, nitro, amino, acylamino, lower alkylamino,
carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and
heterocyclic group, an optionally substituted heterocyclic group,
an optionally substituted lower alkyl or an optionally substituted
lower alkenyl, and the above-mentioned heterocyclic group is each
selected from the group consisting of
[0020] unsaturated 3- to 8-membered heteromonocyclic group
containing 1 to 4 nitrogen atoms,
[0021] saturated 3- to 8-membered heteromonocyclic group containing
1 to 4 nitrogen atoms,
[0022] unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 to 5 nitrogen atoms,
[0023] unsaturated 3- to 8-membered heteromonocyclic group
containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
[0024] saturated 3- to 8membered heteromonocyclic group containing
1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
[0025] unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
[0026] unsaturated 3- to 8membered heteromonocyclic group
containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
[0027] saturated 3- to 8-membered heteromonocyclic group containing
1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
[0028] unsaturated 3- to 8-membered heteromonocyclic group
containing sulfur atom,
[0029] unsaturated 3- to 8-membered heteromonocyclic group
containing oxygen atom,
[0030] saturated 3- to 8-membered heteromonocyclic group containing
oxygen atom,
[0031] unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and
[0032] unsaturated condensed 7- to 13-membered heterocyclic group
containing 1 or 2 oxygen atoms,
[0033] and a pharmaceutically acceptable salt thereof.
[0034] The object compounds of the present invention can be
prepared by the following processes. 2
[0035] In the above formulas (II), (III), (IV), (V), (VI), (VII),
(VIII), (X), (XI), (XII), (XIII), (XIV) (XV), (XVI), (XVIII),
(XIX), (XX), (XXI) and (XXII), A, R.sup.1, R.sup.2, R.sup.3 ,
R.sup.4 and R.sup.5 are as defined above, R.sup.1 0 a is a
protected hydroxy, X is a leaving group, R.sup.1 ais a heterocyclic
group having a substituent which is aryl substituted by acyloxy,
R.sup.1 b is a heterocyclic group having a substituent which is
aryl substituted by hydroxy, R.sup.1 c is a heterocyclic group
having a substituent which is aryl substituted by cyanoalkyloxy,
R.sup.1 d is a heterocyclic group having a substituent which is
aryl substituted by alkoxycarbonylalkyloxy, R.sup.3 a is an alkyl
substituted by halogen, R.sup.3 b is a
di(lower)alkylamino(lower)al- kyl, an N-containing
heterocyclic-(lower)alkyl or an optionally substituted
heterocyclic-thio(lower)alkyl, R.sup.3 c is a protected
carboxy(lower)alkyl or a protected carboxy(lower)alkylamino,
R.sup.3 d is a carboxy(lower)alkyl or a carboxy(lower)alkylamino,
R.sup.3 c is an N-containing heterocycliccarbonyl(lower)alkyl, an
optionally substituted amino-carbonyl(lower)alkyl or an optionally
substituted amino-carbonyl(lower)alkylamino, R.sup.3 f is a
hydroxy(lower)alkyl, and R.sup.1 1 is a di(lower)alkylamino, an
N-containing heterocyclic group or an optionally substituted
heterocyclic-thiol. Heterocyclic group, aryl, acyl, alkyl, alkoxy,
protected carboxy and halogen in the R.sup.1 a, R.sup.1 b, R.sup.1
c, R.sup.1 d, R.sup.3 a, R.sup.3 b, R.sup.3 c, R.sup.3 d, R.sup.3
e, R.sup.3 f, and R.sup.1 1 are as defined below.
[0036] The starting compounds (II), (VI), (XIV) and (XVI) can be
prepared according to the following Preparations or by a
conventional method.
[0037] Suitable pharmaceutically acceptable salts of the object
compounds may be conventional non-toxic salts and include an acid
addition salt such as an organic acid salt (e.g., acetate,
trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate,
benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic
acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate,
nitrate, phosphate, etc.), or a salt with a base such as an amino
acid (e.g., arginine, aspartic acid, glutamric acid, etc.), an
alkali metal salt (e.g., sodium salt, potassium salt, etc.), an
alkaline earth metal salt (e.g., calcium salt, magnesium salt,
etc.), an ammonium salt, an organic base salt (e.g., trimethylamine
salt, triethylamine salt, pyridine salt, picoline salt,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.),
or the like.
[0038] The object compounds and pharmaceutically acceptable salts
thereof may include solvates such as enclosure compounds (e.g.,
hydrate, etc.).
[0039] Suitable examples and illustrations of the various
definitions, which the present invention includes within its scope
and which are shown in the above and subsequent descriptions of the
present specification, are as follows.
[0040] Suitable "aryl" in the term "optionally substituted aryl"
and "optionally substituted aryloxy" includes an aryl having 6 to
10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesityl,
naphthyl and the like, preferably phenyl, and may have one or more
substituents. Examples of the substituents for substituted aryl are
halogen, cyano, nitro, amino, acylamino, lower alkylamino,
carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, optionally
substituted aryl, optionally substituted heterocyclic group and the
like, preferably halogen, nitro and lower alkoxy (e.g., methoxy,
etc.).
[0041] Suitable "heterocyclic group" in the term "optionally
substituted heterocyclic group" means saturated or unsaturated, 3-
to 8-membered monocyclic or polycyclic heterocyclic group
containing at least one hetero atom such as oxygen atom, sulfur
atom, nitrogen atom and the like.
[0042] More preferable heterocyclic groups are:
[0043] unsaturated 3- to 8-membered, preferably 5- or 6-membered,
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and
its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),
tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.),
dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl,
2,5-dihydro-1,2,4-triazinyl, etc.), and the like;
[0044] saturated 3- to 8-membered, preferably 5- or 6membered,
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
piperidino, pyrazolidinyl, piperazinyl, and the like;
[0045] unsaturated condensed 7- to 13-membered, preferably 9- or
10-membered, heterocyclic group containing 1 to 5 nitrogen atoms,
for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,
quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl,
tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.),
dihydrotriazolopyridazinyl, and the like;
[0046] unsaturated 3- to 8membered, preferably 5- or 6-membered,
heteromonocyclic group containing 1 or 2 oxygen atoms and I to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.), and the like;
[0047] saturated 3- to 8-membered, preferably 5- or 6-membered,
heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, morpholinyl, morpholino, and the
like;
[0048] unsaturated condensed 7- to 13membered, preferably 9- or
10-membered, heterocyclic group containing 1 or 2 oxygen atoms and
1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl,
and the like;
[0049] unsaturated 3- to 8-membered, preferably 5- or 6-membered,
heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, 1, 2-thiazolyl,
thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.),
and the like;
[0050] saturated 3- to 8-membered, preferably 5- or 6membered,
heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolidinyl, and the like;
[0051] unsaturated 3- to 8-membered, preferably 5- or 6-membered,
heteromonocyclic group containing sulfur atom, for example,
thienyl, and the like;
[0052] unsaturated 3- to 8-membered, preferably 5- or 6-membered,
heteromonocyclic group containing oxygen atom, for example, furyl,
and the like;
[0053] saturated 3- to 8-membered, preferably 5- or 6membered,
heteromonocyclic group containing oxygen atom, for example,
oxolanyl, and the like;
[0054] unsaturated condensed 7- to 13membered, preferably 9- or
10-membered, heterocyclic group containing 1 or 2 sulfur atoms and
1 to 3 nitrogen atoms, for example, benzothiazolyl,
benzothiadiazolyl, and the like;
[0055] unsaturated condensed 7- to 13-membered, preferably 9- or
10-membered, heterocyclic group containing 1 or 2 oxygen atoms, for
example, benzodihydrofuranyl, benzodioxolenyl, and the like;
[0056] The most preferable heterocyclic groups may be unsaturated
5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen
atoms, saturated 5- or 6-membered, heteromonocyclic group
containing 1 to 4 nitrogen atoms, unsaturated 5- or 6membered
heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group
containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated 5- or 6-membered heteromonocyclic group containing 1 or
2 sulfur atoms and 1 to 3 nitrogen atoms, unsaturated 5- or
6-membered heteromonocyclic group containing a sulfur atom, and
unsaturated 9- or 10-membered heterobicyclic group containing 1 or
2 oxygen atoms.
[0057] These heterocyclic groups may have one or more substituents.
Examples of the substituents for substituted heterocyclic group are
halogen, cyano, nitro, amino, acylamino, lower alkylamino,
carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl,
optionally substituted heterocyclic group, haloaryl, hydroxyaryl,
lower alkoxyaryl, lower alkylaryl, nitroaryl, biphenylyl,
aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl, cyanoaryl,
cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower
alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl,
hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower
alkoxycarbonyl(lower)alkoxyaryl, lower alkoxysulfonyloxyaryl, aryl
substituted by halogen and hydroxy, aryl substituted by halogen and
alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower
alkyl-heterocyclic group and aryl-heterocyclic group and the like,
preferably halogen; phenyl; halophenyl; hydroxyphenyl; lower
alkoxyphenyl; lower alkylphenyl; nitrophenyl; biphenylyl;
phenoxyphenyl; trihalo(lower)alkylphenyl; cyano(lower)alkoxyphenyl;
cyanophenyl; cyano(lower)alkylphenyl; lower alkanoyloxyphenyl;
lower alkanoyloxy(lower)alkylphenyl;
di(lower)alkylaminosulfonylphenyl; hydroxy(lower)alkylphenyl; lower
alkoxycarbonylphenyl; lower alkoxycarbonyl(lower)alkoxyphenyl;
lower alkoxysulfonyloxyphenyl; phenyl substituted by halogen and
hydroxy, phenyl substituted by halogen and lower alkanoyloxy;
phenyl substituted by halogen and lower alkoxy; heterocyclic group
selected from the group consisting of unsaturated 9- or 10-membered
heterobicyclic group containing 1 or 2 oxygen atoms,
[0058] unsaturated 5- or 6 membered heteromonocyclic group
containing 1 to 4 nitrogen atoms,
[0059] unsaturated 5- or 6-membered heteromonocyclic group
containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms and
[0060] unsaturated 5- or 6-membered heteromonocyclic group
containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms;
[0061] and a lower alkyl- or (phenyl-)heterocyclic group, said
heterocyclic group being unsaturated 5- or 6-membered
heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms.
[0062] Suitable "lower alkyl" in the term "optionally substituted
lower alkyl" is a straight or branched alkyl having 1 to 6 carbon
atoms, and exemplified by methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl, hexyl and the like, preferably methyl
and propyl, which may have one or more substituents. Examples of
the substituents for substituted alkyl are halogen, cyano, nitro,
acylamino, carbamoyl, hydroxy, lower alkoxy, optionally substituted
aryloxy, optionally substituted aryl, heterocyclic group,
heterocyclic-carbonyl, lower alkylcarbamoyl, carboxy, protected
carboxy, di(lower)alkylamino, lower alkylamino, protected amino,
arylcarbonylamino, heterocyclic-carbonylamin- o, lower
alkanoylamino, lower alkylsulfonylamino, di(lower)alkylaminosulfo-
nylamino, heterocyclic-sulfonylamino, heterocyclic-thio, lower
alkylheterocyclic-thio and the like, preferably halogen for
R.sup.1, and halogen, carbamoyl, heterocyclic group,
heterocyclic-carbonyl, lower alkylcarbamoyl, carboxy, protected
carboxy, di(lower)alkylamino, lower alkylamino, protected amino,
arylcarbonylamino, heterocyclic-carbonylamin- o, lower
alkanoylamino, lower alkylsulfonylamino, di(lower)alkylaminosulfo-
nylamino, heterocyclic-sulfonylamino, heterocyclic-thio and lower
alkylheterocyclic-thio for R.sup.3.
[0063] Suitable "lower alkenyl" in the term "optionally substituted
lower alkenyl" is a straight or branched alkenyl having 2 to 6
carbon atoms, and exemplified by ethenyl, 1-propenyl, 2-propenyl,
1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl and the like,
preferably ethenyl, which may have one or more substituents.
Examples of the substituents for substituted alkyl are halogen,
cyano, nitro, acylamino, lower alkylamino, carbamoyl, hydroxy,
lower alkoxy, optionally substituted aryloxy, optionally
substituted aryl, heterocyclic group, heterocyclic-carbonyl and the
like, preferably aryl (e.g., phenyl, etc.) for R.sup.1, and
heterocyclic group (e.g., pyridyl, etc.) for R.sup.3.
[0064] Suitable "lower alkoxy" in the term "optionally substituted
alkoxy" is a straight or branched alkenyl having 1 to 6 carbon
atoms, and exemplified by methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy
and the like, preferably methoxy, which may have one or more
substituents. Examples of the substituents for substituted alkoxy
are halogen, cyano, nitro, acylamino, lower alkylamino, carbamoyl,
hydroxy, lower alkoxy, optionally substituted aryloxy, optionally
substituted aryl, heterocyclic group, heterocyclic-carbonyl and the
like, preferably aryl (e.g., fluorenyl, etc.).
[0065] Suitable "optionally substituted amino" includes a group of
the formula: 3
[0066] wherein R.sup.8 and R.sup.9 are the same or different and
each is hydrogen, lower alkyl, carboxy(lower)alkyl, lower
alkoxycarbonyl(lower)al- kyl, carbamoyl(lower)alkyl,
hydroxy(lower)alkyl, aryl or cyclo(lower)alkyl.
[0067] Suitable "protected hydroxy" includes hydroxy protected by a
conventional protective group, for example, substituted lower
alkoxy such as lower alkoxy(lower)alkoxy (e.g., methoxymethoxy),
lower alkoxy(lower)alkoxy(lower)alkoxy (e.g., methoxyethoxymethoxy)
and substituted or unsubstituted aryl(lower)alkoxy (e.g.,
benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy
(e.g., acetoxy, propionyloxy, pivaloyloxy), aroyloxy (e.g.,
benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy,
tert-butoxycabbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy),
substituted or unsubstituted aryl(lower)alkoxycarbonyloxy (e.g.,
benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy), arenesulfonyloxy
(e.g., benzenesulfonyloxy, tosyloxy) and alkanesulfonyloxy (e.g.,
methanesulfonyloxy, ethanesulfonyloxy); tri(lower)alkylsilyloxy
(e.g., trimethylsilyloxy); tetrahydropyranyloxy; and the like.
[0068] The term "lower" is intended to mean 1 to 6 carbon atoms,
preferably 1 to 4 carbon atoms, unless otherwise indicated.
[0069] Suitable "halogen" includes fluorine, bromine, chlorine and
iodine.
[0070] Suitable acyl moiety of "acylamino" includes acyl such as
aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl
substituted by aromatic or heterocyclic group(s) derived from
carboxylic, carbonic, sulfonic and carbamic acids.
[0071] The aliphatic acyl includes saturated or unsaturated,
acyclic or cyclic ones, for example, alkanoyl such as lower
alkanoyl (e.g., formyl, acetyl, propionyl, butylyl, isobutylyl,
valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such
as lower alkylsulfonyl (e.g., mesyl, ethylsulfonyl, propylsulfonyl,
isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl,
hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g.,
methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as
lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, tert-butoxycabbonyl, etc.),
alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.,
vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower
alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.),
cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g.,
cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,
etc.), and the like.
[0072] The aromatic acyl may include C.sub.6-C.sub.1 0 aroyl (e.g.,
benzoyl, toluoyl, xyloyl, etc.), N-(C.sub.6-C.sub.1 0)arylcamoyl
(e.g., N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl,
etc.), C.sub.6-C 1 0 arenesulfonyl (e.g., benzenesulfonyl, tosyl,
etc.), and the like.
[0073] The heterocyclic acyl may include heterocyclic-carbonyl
(e.g., furoyl, thenoyl, nicotinoyl, isonicotinoyl,
thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.),
and the like.
[0074] The aliphatic acyl substituted by aromatic group(s) may
include aralkanoyl such as phenyl(lower)alkanoyl (e.g.,
phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.),
aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g.,
benzyloxycarbonyl, phenethyloxycarbonyl, etc.), aryloxyalkanoyl
such as phenoxy(lower)alkanoyl (e.g., phenoxyacetyl,
phenoxypropionyl, etc.), and the like.
[0075] The aliphatic acyl substituted by heterocyclic group(s) may
include heterocyclic-alkanoyl such as heterocyclic-(lower) alkanoyl
(e.g., thienylacetyl, imidazolylacetyl, furylacetyl,
tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl,
thienylpropionyl, thiadiazolylpropionyl, etc.), and the like.
[0076] These acyl groups may be further substituted by one or more
suitable substituents such as nitro and the like, and preferable
acyl having such substituent(s) may be nitroaralkoxycarbonyl (e.g.,
nitrobenzyloxycarbonyl, etc.) and the like.
[0077] Suitable "lower alkyl" and lower alkyl moiety of "lower
alkylamino", "lower alkylaryl", "trihaloalkylaryl",
"cyano(lower)alkylaryl", "lower alkanoyloxy(lower)alkylaryl",
"lower alkylsulfonyloxyaryl", "di(lower)alkylaminosulfonylaryl",
"hydroxy(lower)alkylaryl", "lower alkyl-heterocyclic group", "lower
alkylcarbamoyl", "di(lower)alkylamino", "lower alkylsulfonylamino",
"di(lower)alkylaminosulfonylamino", "lower alkylheterocyclic-thio",
"carboxy(lower)alkyl", "lower alkoxycarbonyl(lower)alkyl",
"carbamoyl(lower)alkyl" and "hydroxy(lower)alkyl" are the same as
lower alkyl defined above with regard to "optionally substituted
lower alkyl".
[0078] Suitable "lower alkoxy" and lower alkoxy moiety of "lower
alkoxyaryl", "cyano(lower)alkoxyaryl", "lower alkoxycarbonylaryl",
"lower alkoxycarbonyl(lower)alkoxyaryl" and "lower
alkoxycarbonyl(lower)alkyl" are the same as alkoxy defined above
with regard to "optionally substituted alkoxy".
[0079] Suitable "aryl" and aryl moiety of "aryloxy", "haloaryl",
"hydroxyaryl", "lower alkoxyaryl", "lower alkylaryl", "nitrooryl",
"aryloxyaryl", "trihaloalkylaryl", "cyano(lower)aikoxyaryl",
"cyanoaryl", "cyano(lower)alkylaryl", "lower alkanoyloxyaryl",
"lower alkanoyloxy(lower)alkylaryl",
"di(lower)alkylaminosulfonylaryl", "hydroxy(lower)alkylaryl",
"loweralkoxycarbonylaryl", "lower alkoxycarbonyl(lower)alkoxyaryl",
"lower alkylsulfonyloxyaryl", "aryl substituted by halogen and
hydroxy", "aryl substituted by halogen and alkanoyloxy", "aryl
substituted by halogen and lower alkoxy", "aryl-heterocyclic group"
and "arylcarbonylamino" are the same as aryl defined above with
regard to "optionally substituted aryl".
[0080] Suitable "heterocyclic group" of the substituent and
heterocyclic group moiety of "heterocyclic-carbonyl", "lower
alkyl-heterocyclic group", "aryl-heterocyclic group",
"heterocyclic-carbonylamino", "heterocyclic-sulfonylamino",
"heterocyclic-thio", "lower alkyl-heterocyclic-thio",
"heterocyclic-(lower)alkyl" and "heterocyclic-thio" are the same as
heterocyclic group defined above with regard to "optionally
substituted heterocyclic group".
[0081] Suitable halo moiety of "haloaryl" and "trihaloalkylaryl" is
halogen defined above.
[0082] Suitable alkanoyl moiety of "lower alkanoyloxyaryl", "lower
alkanoyloxy(lower)alkyl", "alkanoyloxy" and "lower alkanoylamino"
is a straight or branched alkanoyl having 1 to 10, preferably 1 to
6, carbon atoms. Such group includes, for example, formyl, acetyl,
propionyl, isopropionyl, butyryl, isobutyryl, valeryl, pivaloyl,
hexanoyl and the like, preferably acetyl.
[0083] Suitable "protected carboxy" includes esterified carboxy
wherein "esterified carboxy" is as defined below.
[0084] Suitable examples of the ester moiety of the esterified
carboxy are lower alkyl ester (e.g., methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester,
tert-butyl ester, pentyl ester, hexyl ester, etc.) and the like,
which may have at least one suitable substituent. Examples of the
substituted lower alkyl ester are lower alkanoyloxy(lower)alkyl
ester [e.g., acetoxymethyl ester, propionyloxymethyl ester,
butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl
ester, hexanoyloxymethyl ester, 1-(or 2-)-acetoxyethyl ester, 1-(or
2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl
ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or
3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or
2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or
2-)hexanoyloxyethyl ester, isobutyryloxymethylester,
2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethylester,
1- (or 2-) pentanoyloxyethyl ester, etc.], lower
alkanesulfonyl(lower)alkyl ester (e.g., 2-mesylethyl ester, etc.),
mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester,
2,2,2-trichloroethyl ester, etc.); lower
alkoxycarbonyloxy(lower)alkyl ester [e.g., methoxycarbonyloxymethyl
ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl
ester, tert-butoxycarbonyloxymethyl ester, 1-(or
2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl
ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.],
phthalidylidene(lower)a- lkyl ester, (5-lower
alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxol-4- -yl)methyl ester,
(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl
ester (e.g., vinyl ester, allyl ester, etc.; lower alkynyl ester
(e.g., ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester
which may have at least one suitable substituent (e.g., benzyl
ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester,
trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester,
3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester,
etc.); aryl ester which may have at least one suitable substituent
(e.g., phenyl ester, 4-chlorophenyl ester, tolyl ester,
tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,
etc.); phthalidyl ester; and the like.
[0085] More preferable examples of the protected carboxy thus
defined may be C.sub.2-C.sub.4 alkenyloxycarbonyl and phenyl(or
nitrophenyl)(C.sub.1-C.sub.4)-alkoxycarbonyl, and the most
preferable one may be ethoxycarbonyl.
[0086] Suitable "amino-protective group" includes "acyl" mentioned
above.
[0087] More preferable examples of "amino-protective group" are
C.sub.2-C.sub.4 alkoxycarbonyl and phenyl(or
nitrophenyl)(C.sub.1-C.sub.4- )alkoxycarbonyl, and the most
preferable one is tert-butoxycarbonyl.
[0088] Suitable "cyclo(lower)alkyl" is, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0089] Suitable "leaving group" includes halogen as mentioned
above, acyloxy such as sulfonyloxy (e.g., mesyloxy, tosyloxy,
etc.), alkoxy (e.g., tert-butoxy, etc.), aralkoxy (e.g., benzyloxy,
etc.), and the like.
[0090] Of the object compounds (I),
[0091] (1) the preferred one may be the compound of the formula (I)
wherein
[0092] R.sup.2 is a hydrogen or an optionally substituted lower
alkyl, and
[0093] R.sup.4 is a hydrogen or an optionally substituted lower
alkyl,
[0094] (2) the more preferred one may be the compound of the
formula (I) wherein
[0095] A is a sulfonyl or a carbonyl;
[0096] R.sup.1 is an aryl optionally substituted by a substituent
selected from the group consisting of halogen, cyano, nitro, amino,
acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy,
phenoxy, lower alkyl, aryl and heterocyclic group;
[0097] a heterocyclic group optionally substituted by a substituent
selected from the group consisting of halogen, cyano, nitro, amino,
acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy,
aryloxy, lower alkyl, aryl, heterocyclic group, haloaryl,
hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroaryl,
biphenylyl, aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl,
cyanoaryl, cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower
alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl,
hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower
alkoxycarbonyl(lower)alkoxyaryl, lower alkylsulfonyloxyaryl, aryl
substituted by halogen and hydroxy, aryl substituted by halogen and
alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower
alkyl-heteromonocyclic group and aryl-heterocyclic group; a lower
alkyl optionally substituted by halogen; or a lower alkenyl
optionally substituted by aryl;
[0098] R.sup.2 is a hydrogen or an optionally substituted lower
alkyl;
[0099] R.sup.3 is a lower alkyl optionally substituted by a
substituent selected from the group consisting of halogen,
heterocyclic group, carbamoyl, lower alkylcarbamoyl, carboxy,
protected carboxy, heterocyclic-carbonyl, di(lower)alkylamino,
protected amino, arylcarbonylamino, heterocyclic-carbonylamino,
lower alkanoylamino, lower alkylsulfonylamino,
di(lower)alkylaminosulfonylamino, heterocyclic-sulfonyl amino,
heterocyclic-thio, lower alkylheterocyclic-thio and
heterocyclic-thio; a lower alkoxy; an aryloxy; an aryl (lower)
alkoxy; an optionally substituted lower alkenyl; an optionally
substituted heterocyclic group; or a group of the formula: 4
[0100] wherein R.sup.8 and R.sup.9 are the same or different and
each is hydrogen, lower alkyl, carboxy(lower)alkyl, lower
alkoxycarbonyl(lower)al- kyl, carbamoyl(lower)alkyl,
hydroxy(lower)alkyl, aryl, cyclo(lower)alkyl or
heterocyclic-(lower)alkyl;
[0101] R.sup.4 is a hydrogen or an optionally substituted lower
alkyl;
[0102] R.sup.5 is a hydrogen, an optionally substituted lower
alkyl, an optionally substituted aryl or an optionally substituted
heterocyclic group and
[0103] R.sup.1 0 is a hydroxy or a protected hydroxy; and
[0104] (3) the most preferred one may be the compound of the
formula (I) wherein
[0105] A is a sulfonyl or a carbonyl;
[0106] R.sup.1 is a thienyl substituted by a substituent selected
from the group consisting of halogen, phenyl, halophenyl,
hydroxyphenyl, lower alkoxyphenyl, lower alkylphenyl, nitrophenyl,
biphenylyl, phenoxyphenyl, trihalo(lower)alkylphenyl,
cyano(lower)alkoxyphenyl, cyanophenyl, cyano(lower)alkylphenyl,
lower alkanoyloxyphenyl, lower alkanoyloxy(lower)alkylphenyl,
di(lower)alkylaminosulfonylphenyl, hydroxy(lower)alkylphenyl, lower
alkoxycarbonylphenyl, lower alkoxycarbonyl(lower)alkoxyphenyl,
lower alkylsulfonyloxyphenyl, phenyl substituted by halogen and
hydroxy, phenyl substituted by halogen and lower alkanoyloxy,
phenyl substituted by halogen and lower alkoxy, thiazolyl,
oxazolyl, pyridyl, benzodihydrofuranyl, benzodioxolenyl, lower
alkyloxadiazolyl and phenyloxadiazolyl, a thiazolyl substituted by
phenyl or a thiadiazolyl substituted by phenyl;
[0107] R.sup.2 is a hydrogen;
[0108] R.sup.3 is a lower alkyl, a halo(lower)alkyl, a
morpholinyl(lower)alkyl, a piperidinyl(lower)alkyl, a
pyridyl(lower)alkyl, a carbamoyl(lower)alkyl, a lower
alkylcarbamoyl(lower)alkyl, a carboxy(lower)alkyl, a
phenyl(lower)alkoxycarbonyl(lower)alkyl, a
morpholinylcarbonyl(lower)alky- l, a
di(lower)alkylamino(lower)alkyl, a
phenyl(lower)alkoxycarbonylamino(l- ower)alkyl, a lower
alkoxycarbonylamino(lower)alkyl, a benzoylamino(lower)alkyl, a
pyridyl-carbonylamino(lower)alkyl, a lower
alkanoylamino(lower)alkyl, a lower alkylsulfonylamino(lower)alkyl,
a di(lower)alkylaminosulfonylamino(lower)alkyl, a
pyridyl-sulfonylamino(low- er)alkyl, a triazolylthio(lower)alkyl,
an imidazolylthio(lower)alkyl, a thiazolylthio(lower)alkyl, a
benmimidazolylthio(lower)alkyl, a lower
alkyltriazolylthio(lower)alkyl, a lower alkoxy, a
fluorenyl(lower)alkoxy, a phenoxy, a pyridyl(lower)alkenyl, a
pyridyl, a piperidinyl, a thienyl substituted by oxazolyl, a mono-
(or di-)(lower)alkylamino, a carboxy(lower)alkylamino, a lower
alkoxycarbonyl(lower)alkylamino, an
N-(lower)alkyl-N-(lower)alkoxycarbonyl(lower)alkylamino, a
carbamoyl(lower)alkylamino, a hydroxy(lower)alkyiamino, a
phenylamino or a cyclo(lower)alkylamino;
[0109] R.sup.4 is a hydrogen;
[0110] R.sup.5 is a hydrogen and
[0111] R.sup.1 0 is a hydroxy.
[0112] The processes for preparing the object compounds are
explained in detail in the following.
[0113] Process 1
[0114] The compound (IV) or a salt thereof can be prepared by
reacting the compound (II) or a salt thereof with the compound
(III) or a salt thereof.
[0115] Suitable salts of the compounds (II), (III) and (IV) may be
the same as those exemplified with respect to the compound (I).
[0116] The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, acetonitrile, chloroform,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylformamide, pyridine and dichloromethane, a
mixture thereof, or any other organic solvents which do not
adversely affect the reaction.
[0117] This reaction can be carried out in the presence of an
organic or inorganic base such as alkali metal (e.g., lithium,
sodium, potassium, etc.), alkaline earth metal (e.g., calcium,
etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline
earth metal hydride (e.g., calcium hydride, etc.), alkali metal
hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkali metal bicarbonate (e.g., sodium
bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide
(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide,
etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.),
trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g.,
pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.),
quinoline, lithium diisopropylamide, and the like.
[0118] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to heating.
[0119] Process 2
[0120] The compound (V) and a salt thereof can be prepared by
eliminating the hydroxy protective group of the compound (IV) or a
salt thereof.
[0121] Suitable salts of the compounds (IV) and (V) may be the same
as those exemplified above with regard to the compound (I).
[0122] Suitable method of this elimination reaction includes
conventional ones such as hydrolysis, reduction and the like.
[0123] The hydrolysis is preferably carried out in the presence of
a base or an acid including Lewis acid.
[0124] Suitable base includes an inorganic base and an organic base
such as an alkali metal (e.g., sodium, potassium, etc.), an
alkaline earth metal (e.g., magnesium, calcium, etc.), the
hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine
(e.g., trimethylamine, triethylamine, etc.), picoline,
1,5-diazabicyclo[4.3.0]non-5-one, and the like.
[0125] Suitable acid includes an organic acid (e.g., formic acid,
acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic
acid, etc.), and an inorganic acid (e.g., hydrochloric acid,
hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen
bromide, etc.).
[0126] The elimination using Lewis acid such as trihaloacetic acid
(e.g., trichloroacetic acid, trifluoroacetic acid, etc.) and the
like is preferably carried out in the presence of cation trapping
agent (e.g., anisole, phenol, etc.). This reaction is usually
carried out without solvent.
[0127] Alternatively, the reaction may be carried out in a
conventional solvent such as water, alcohol (e.g., methanol,
ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane,
toluene, methylene chloride, ethylene dichloride, chloroform,
N,N-dimethylformamide and N,N-dimethylacetamide, a mixture thereof,
or any other organic solvents which do not adversely affect the
reaction.
[0128] The reaction temperature is not critical and the reaction is
usually carried out under cooling to warming.
[0129] The reduction is carried out in a conventional manner,
including chemical reduction and catalytic reduction.
[0130] Suitable reducing reagents to be used in chemical reduction
are a hydride (e.g., hydrogen iodide, hydrogen sulfide, lithium
aluminum hydride, sodium borohydride, sodium cyanoborohydride,
etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or
a metallic compound (e.g., chromium chloride, chromium acetate,
etc.) and an organic acid or an inorganic acid (e.g., formic acid,
acetic acid, propionic acid, trifluoroacetic acid,
p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid,
etc.).
[0131] Suitable catalyst to be used in catalytic reduction is
conventional one such as platinum catalyst (e.g., platinum plate,
spongy platinum, platinum black, colloidal platinum, platinum
oxide, platinum wire, etc.), palladium catalyst (e.g., spongy
palladium, palladium black, palladium oxide, palladium on carbon,
colloidal palladium, palladium on barium sulfate, palladium on
barium carbonate, etc.), nickel catalyst (e.g., reduced nickel,
nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g., reduced
cobalt, Raney cobalt, etc.), iron catalyst (e.g., reduced iron,
Raney iron, Ullman iron, etc.), and the like.
[0132] The reduction is usually carried out in a conventional
solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl
alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene
chloride, ethylene dichloride, chloroform, N,N-dimethylformamide,
N,N-dimethylacetamide and cyclohexane, a mixture thereof, or any
other organic solvents which do not adversely affect the
reaction.
[0133] When the above-mentioned acids to be used in chemical
reduction are liquid, they can also be used as a solvent.
[0134] The reaction temperature of this reduction is not critical
and the reaction is usually carried out under cooling to
warming.
[0135] Process 3
[0136] The compound (IV) or a salt thereof can be prepared by
reacting the compound (VI) or its reactive derivative at the
carboxy group, or a salt thereof, with the compound (VII) or its
reactive derivative at the amino group, or a salt thereof.
[0137] Suitable salts of the compounds (VI) and (VII) may be the
same as those exemplified for the compound (I).
[0138] The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, acetonitrile, chloroform,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylformamide, pyridine and dichloromethane, a
mixture thereof, or any other organic solvents which do not
adversely affect the reaction.
[0139] This reaction can be carried out in the presence of an
organic or inorganic base such as alkali metal (e.g., lithium,
sodium, potassium, etc.), alkaline earth metal (e.g., calcium,
etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline
earth metal hydride (e.g., calcium hydride, etc.), alkali metal
hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkali metal bicarbonate (e.g., sodium
bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide
(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide,
etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.),
trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g.,
pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.),
quinoline, lithium diisopropylamide, and the like.
[0140] Suitable reactive derivative at the amino group of the
compound (VII) may include Schiff's base type imino or its
tautomeric enamine type isomer formed by the reaction of the
compound (VII) with a carbonyl compound such as aldehyde, ketone or
the like; a silyl derivative formed by the reaction of the compound
(VII) with a silyl compound such as bis(trimethylsilyl)acetamide,
mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like;
a derivative formed by the reaction of the compound (VII) with
phosphorus trichloride or phosgene, and the like.
[0141] Suitable reactive derivative at the carboxy group of the
compound (VI) may include an acid halide, an acid anhydride, an
activated amide, an activated ester, and the like. Suitable
examples of the reactive derivative may be an acid chloride; an
acid azide; a mixed acid anhydride with acid such as substituted
phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric
acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated
phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid,
thiosulfuric acid, sulfuric acid, sulfonic acid (e.g.,
methanesulfonic acid, etc.), aliphatic carboxylic acid (e.g.,
acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic
acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid,
trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.,
benzoic acid, etc.); a symmetrical acid anhydride; an activated
amide with imidazole, 4-substituted imidazole, dimethylpyrazole,
triazole or tetrazole; or an activated ester (e.g., cyanomethyl
ester, methoxymethyl ester, dimethyliminomethyl
[(CH.sub.3).sub.2N+.dbd.CH--] ester, vinyl ester, propargyl ester,
p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl
ester, pentachlorophenyl ester, mesylphenyl ester, phenyl azophenyl
ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl
thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester,
piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a
N-hydroxy compound (e.g., N,N-dimethylhydroxylamine,
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.), and the
like. These reactive derivative can be optionally be selected from
them according to the kind of the compound (VI) to be used.
[0142] The reaction is preferably carried out in the presence of a
conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-mrpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethyiami- nocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiim- ide;
N,N'-carbonylbis-(2-methylimidazole);
pentamethyleneketene-N-cyclohex- ylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; diphenyl phosphorylazide;
thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g.,
ethyl chloroformate, isopropyl chloroformate); triphenylphosphine;
2-ethyl-7-hydroxybenzisoxaz- olium salt;
2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;
1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by
the reaction of N,N-dimethylforamide with thionyl chloride,
phosgene, trichloromethyl chloroformate, phosphorus oxychloride or
oxalyl chloride.
[0143] The reaction temperature is not critical, and the reaction
is usually carried out under cooling.
[0144] Process 4
[0145] The compound (X) or a salt thereof can be prepared by
reacting the compound (VIII) or a salt thereof with the compound
(IX) or a salt thereof.
[0146] Suitable salts of the compounds (VIII), (IX) and (X) may be
the same as those exemplified for the compound (I).
[0147] The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, acetonitrile, chloroform,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylformamide, pyridine and dichloromethane, a
mixture thereof, or any other organic solvents which do not
adversely affect the reaction.
[0148] This reaction can be carried out in the presence of an
organic or inorganic base such as alkali metal (e.g., lithium,
sodium, potassium, etc.), alkaline earth metal (e.g., calcium,
etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline
earth metal hydride (e.g., calcium hydride, etc.), alkali metal
hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkali metal bicarbonate (e.g., sodium
bicarbonate, potassium bicarbonate, etc.), alkai metal alkoxide
(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide,
etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.),
triakkylamine (e.g., triethylamine, etc.), pyridine compound (e.g.,
pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.),
quinoline, lithium diisopropylamide, and the like.
[0149] The reaction is carried out in the presence of alkali metal
halide (e.g., sodium iodide, potassium iodide, etc.), alkali metal
thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate,
etc.), di(lower)alkyl azodicarboxylate (e.g., diethyl
azodicarboxylate, diisopropyl azodicarboxylate, etc.), and the
like.
[0150] The reaction is preferably carried out in the presence of a
conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylam- inocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiim- ide;
N,N'-carbonylbis-(2-methylimidazole);
pentamethyleneketene-N-cyclohex- ylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
1-alkoxy1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; diphenyl phosphorylazide;
thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g.,
ethyl chloroformate, isopropyl chloroformate); triphenylphosphine;
2-ethyl-7-hydroxybenzisoxaz- olium salt;
2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
1-(phlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;
1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by
the reaction of N,N-dimethylforamide with thionyl chloride,
phosgene, trichloromethyl chloroformate, phosphorus oxychloride or
oxalyl chloride.
[0151] The reaction temperature is not critical, and the reaction
is usually carried out under cooling.
[0152] Process 5
[0153] The compound (XII) or a salt thereof can be prepared by
eliminating the hydroxy protective group of the compound (XI) or a
salt thereof.
[0154] Suitable salts of the compounds (XI) and (XII) may be the
same as those exemplified for the compound (I).
[0155] The reaction of this process can be carried out in a manner
similar to that in Process 2.
[0156] Process 6
[0157] The compound (XIII) or a salt thereof can be prepared by
subjecting the compound (XII) or a salt thereof to amidation
reaction.
[0158] Suitable salts of the compounds (XII) and (XIII) may be the
same as those exemplified for the compound (I).
[0159] The reaction of this process can be carried out in a manner
similar to that in Process 4.
[0160] Process 7
[0161] The compound (IV) or a salt thereof can be prepared by
reacting the compound (XIV) or a salt thereof with the compound
(XV) or a salt thereof.
[0162] Suitable salts of the compounds (XIV) and (XV) may be the
same as those exemplified for the compound (I).
[0163] The reaction of this process can be carried out in a manner
similar to that in Process 1.
[0164] Process 8
[0165] The compound (XVIII) or a salt thereof can be prepared by
reacting the compound (XVI) or a salt thereof with the compound
(XVII) or its reactive derivative at the carboxy group, or a molt
thereof.
[0166] Suitable salts of the compounds (XVI), (XVII) and (XVIII)
may be the same as those exemplified for the compound (I).
[0167] Suitable reactive derivative at the amino group of the
compound (XVII) may include Schiff's base type imino or its
tautomeric enamine type isomer formed by the reaction of the
compound (XVII) with a carbonyl compound such as aldehyde, ketone
or the like; a silyl derivative formed by the reaction of the
compound (XVII) with a silyl compound such as
bis(trimethylsilyl)aacetamide, mono(trimethylsilyl)acetamide,
bis(trimethylsilyl)urea or the like; a derivative formed by the
reaction of the compound (XVII) with phosphorus trichloride or
phosgene, and the like.
[0168] The reaction is usually carried out in a conventional
solvent such as water, acetone, dioxane, acetonitrile, chloroform,
methylene chloride, ethylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylformide, pyridine and dichloromethane, a
mixture thereof, or any other organic solvents which do not
adversely affect the reaction.
[0169] This reaction can be carried out in the presence of an
organic or inorganic base such as alkali metal (e.g., lithium,
sodium, potassium, etc.), alkaline earth metal (e.g., calcium,
etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline
earth metal hydride (e.g., calcium hydride, etc.), alkali metal
hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
alkali metal carbonate (e.g., sodium carbonate, potassium
carbonate, etc.), alkali metal bicarbonate (e.g., sodium
bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide
(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide,
etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.),
trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g.,
pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.),
quinoline, lithium diisopropylamide, and the like.
[0170] The reaction is carried out in the presence of alkali metal
halide (e.g., sodium iodide, potassium iodide, etc.), alkali metal
thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate,
etc.), di(lower)alkyl azodicarboxylate (e.g., diethyl
azodicarboxylate, diisopropyl azodicarboxylate, etc.), and the
like.
[0171] The reaction is preferably carried out in the presence of a
conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylam- inocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiim- ide;
N,N'-carbonylbis-(2-methylimidazole);
pentamethyleneketene-N-cyclohex- ylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
chloride); phosphorus trichloride; diphenyl phosphorylazide;
thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g.,
ethyl chloroformate, isopropyl chloroformate); triphenylphosphine;
2-ethyl-7-hydroxybenzisoxaz- olium salt;
2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;
1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by
the reaction of N,N-dimethylforamide with thionyl chloride,
phosgene, trichloromethyl chloroformate, phosphorus oxychloride or
oxalyl chloride.
[0172] The reaction temperature is not critical, and the reaction
is usually carried out under cooling.
[0173] Process 9
[0174] The compound (XX) or a salt thereof can be prepared by
eliminating the hydroxy protective group of the compound (XIX) or a
salt thereof.
[0175] Suitable salts of the compounds (XIX) and (XX) may be the
same as those exemplified for the compound (I).
[0176] The reaction of this process can be carried out in a manner
similar to that in Process 2.
[0177] Process 10
[0178] The compound (XXII) or a salt thereof can be prepared by
subjecting the compound (XXI) or a salt thereof to solvolysis.
[0179] Suitable salts of the compounds (XXII) and (XXI) may be the
same as those exemplified for the compound (I).
[0180] The solvolysis is carried out in a conventional solvent such
as water, alcohol (e.g., methanol, ethanol, etc.), a mixture
thereof, or any other organic solvents which do not adversely
affect the reaction.
[0181] The reaction temperature is not critical, and the reaction
is usually carried out under cooling to heating.
[0182] The compounds obtained can be isolated and purified by a
conventional method such as pulverization, recrystallization,
column chromatography, reprecipitation and the like.
[0183] The object compounds can be transformed into their salts in
a conventional manner.
[0184] It is to be noted that the object compounds may include one
or more stereoisomers due to asymmetric carbon atoms, and all of
such isomers and mixtures thereof are included within the scope of
this invention.
[0185] Collagenases initiate the degradation of collagen in
vertebrates and, in addition to their normal function in the
metabolism of connective tissue and wound healing, they have been
implicated to be involved in a number of pathological conditions
such as joint destruction in rheumatoid arthritis, periodontal
disease, corneal ulceration, tumor metastasis, osteoarthritis,
decubitus restenosis after percutaneous transluminal coronary
angiopsty, osteoporosis, proriasis, chronic active heatitis,
autoimmune keratitis, and the like, and therefore the compounds of
the present invention are useful for treating and/or preventing
such pathological conditions.
[0186] For therapeutic purposes, the compounds and pharmaceutically
acceptable salts thereof of the present invention can be used in
the form of a pharmaceutical preparation containing, as an active
ingredient, one of said compounds in admixture with a
pharmaceutically acceptable carrier such as an organic or inorganic
solid or liquid excipient suitable for oral, parenteral or external
administration. The pharmaceutical preparations may be capsules,
tablets, dragees, granules, solutions, suspensions, emulsions,
sublingual tablets, suppositories, ointments, and the like. If
desired, there may be included, in these preparations, auxiliary
substances, stabilizing agents, wetting agents, emulsifying agents,
buffers and other commonly used additives.
[0187] While the dose of the compound will vary depending upon the
age and condition of patient and the like, in the case of
intravenous administration, a daily dose of 0.01-100 mg of the
active ingredient per kg weight of a human being, and in the case
of intramuscular administration, a daily dose of 0.05-100 mg of the
same per kg weight of a human being, or in the case of oral
administration, a daily dose of 0.1-100 mg of the same per kg
weight of a human being, is generally given for the treatment of
MMP or TNF.alpha. mediated diseases.
[0188] In order to illustrate the usefulness of the object
compound, the pharmacological test data of a representative
compound of the compound are shown in the following.
[0189] Inhibitory activity of collagenase
[0190] 1. Test method
[0191] Human collagenase was prepared from the culture medium of
human skin fibroblast stimulated with interleukin-1.beta. (1
ng/ml). Latent collagenase was activated by incubation with trypsin
(200 .mu.g/ml) at 37.degree. C. for 60 minutes and the reaction was
stopped by adding soybean trypsin inhibitor (800 .mu.g/ml).
Collagenase activity was determined using FTTC-labeled calf skin
type I collagen. FTTC-collagen (2.5 mg/ml) was incubated at
37.degree. C. for 120 minutes with the activated collagenase and
test compound in 50 mM Tris buffer (containing 5 mM CaCl.sub.2, 200
mM NaCl and 0.02% NaN.sub.3, pH 7.5). After stopping the enzyme
reaction by adding the equal volume of 70% ethanol-200 mM Tris
buffer (pH 9.5), the reaction mixture was centrifuged, and
collagenase activity was estimated by measuring the fluorescence
intensity of supernatant at 495 nm (excitation) and 520 nm
(emission).
[0192] 2. Test Compound
[0193] Compound of Example 5
[0194] 3. Test Result
1 Test Compound Inhibitory activity Example 5 95.3% at 1 .times.
10.sup.-6 M
[0195] The following examples are given for the purpose of
illustrating the present invention in detail.
[0196] Preparation 1
[0197] To a solution of pyrazine-2-carboxylic acid (100 g) in
ethanol (EtOH, 1000 ml) was added conc. sulfuric acid (45 ml) at
room temperature. After refluxing for 8 hours, the reaction mixture
was concentrated in vacuo. The residue was dissolved in ethyl
acetate (AcOEt, 1500 ml) and water (H.sub.2O, 1000 ml), and sodium
hydrogencarbonate (NaHCO.sub.3) was added to adjust the pH of the
mixture to 8. The aqueous layer was extracted with AcOEt (1000 ml),
and the combined organic layer was washed with brine and dried over
magnesium sulfate (MgSO.sub.4). The solution was concentrated in
vacuo, and the residue was crystallized from hexane (1000 ml) to
give 111.2 g of ethyl pyrazine-2-carboxylate.
[0198] m.p.: 48-49.degree. C.
[0199] Preparation 2
[0200] A solution of ethyl pyrazine-2-carboxylate (60 g) in EtOH
(500 ml) was subjected to catalytic reduction using palladium
hydroxide on carbon (5.0 g), in hydrogen at 3 atm for 4 hours. The
catalyst was removed by filtration and the filtrate was
concentrated in vacuo to give 62.8 g of ethyl
1,4,5,6-tetrahydropyrazine-2-carboxylate as an oil.
[0201] Preparation 3
[0202] To a solution of ethyl
1,4,5,6-tetrahydropyrazine-2-carboxylate (61.5 g) in acetonitrile
(MeCN, 500 ml) was added a solution of di-tert-butyl dicarbonate
(85.9 g) in MeCN (100 ml) under cooling on an ice bath. After
stirring for 5 hours at room temperature, the solution was
concentrated in vacuo. The residue was dissolved in AcOEt (1500
ml). The solution was washed with 5% hydrogen chloride (HCl)
solution, 1M NaHCO.sub.3 solution and brine, dried over MgSO.sub.4
and concentrated in vacuo. The residue was crystallized from AcOEt
(100 ml) and diethyl ether (Et.sub.2O, 600 ml) to give 77.7 g of
ethyl 1-tert-butoxycarbonyl-1,4,5,6-
-tetrahydropyrazine-2-carboxylate.
[0203] m.p.: 127-129.degree. C.
[0204] Mass (ESI+) : 257 (M+H)
[0205] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.):
[0206] 1.28(3H, t, J=7.5 Hz), 1.49(9H, s), 3.28-3.34(2H, m),
3.46-3.58(2H, m), 4.19(2H, q, J=7.5 Hz), 4.40-4.52(1H, m), 7.06(1H,
d, J=7.0 Hz)
[0207] Preparation 4
[0208] A solution of ethyl
1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazin- e-2-carboxylate
(69.0 g) in acetic acid (AcOH, 500 ml) was subjected to catalytic
reduction using platinum dioxide (4.0 g) at 40.degree. C. in
hydrogen at 3 atm for 4 hours. The catalyst was removed by
filtration, and the filtrate was concentrated in vacuo. The residue
was dissolved in H.sub.2O (800 ml) and the solution was washed with
Et.sub.2O (500 ml.times.2). To the aqueous layer was added
NaHCO.sub.3 to adjust the pH of the solution to 8 and the solution
was extracted with AcOEt (800 ml.times.2). The combined organic
layer was washed with saturated aqueous NaHCO.sub.3 solution and
brine, dried over MgSO.sub.4 and concentrated in vacuo to give 62.8
g of ethyl 1-tert-butoxycarbonyl-piperazine-2carboxyla- te as an
oil.
[0209] Mass (ESI+): 259 (M+H)
[0210] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(3H1, t,
J=7.5 Hz), 1.45(4.5H, s), 1.48(4.5H, s), 2.63-2.68(1H, m),
2.83-3.22(3H, m), 3.43-3.59(1H, m), 3.70-3.91(1H, m), 4.14-4.30(2H,
m), 4.42-4.70(1H,m)
[0211] Preparation 5
[0212] To a solution of ethyl
1-tert-butoxycarbonylpiperazine-2-carboxylat- e (117.5 g, 455 mmol)
in EtOH (1.53 l) was added powdered (L)-tartaric acid (37.5 g, 250
mmol, 0.55 eq) at 65.degree. C. After complete dissolution (15
minutes), seed crystals were added. The mixture was stirred at
70-75.degree. C. for 30 minutes to allow precipitation of crystals.
After cooling to ambient temperature over 2 hours, the mixture was
further stirred for 3 hours. The resulting solid was recovered,
washed with EtOH (100 ml, 50 ml.times.2) and dried for one day to
give 71.1 g (174 mmol) of
(2R)-1-tert-butoxycarbonyl-2-ethoxycarbonylpiperazin- e
(2R,3R)-(+)-tartrate.
[0213] [.alpha.].sub.D.sup.2 0=+62.1.degree.(c=1.17, H.sub.2O)
[0214] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.) : 1.20(3H, t,
J=7.5 Hz), 1.35(5H, s), 1.40(4H, s), 2.48-2.62(1H, m),
2.78-3.09(3H, m), 3.30-3.40(1H, m), 3.61-3.71(1H, m), 4.05-4.20(2H,
m), 4.19(2H, s), 4.44-2.57(1H, m)
[0215] Preparation 6
[0216] A suspension of
(2R)-1-tert-butoxycarbonyl-2-ethoxycarbonylpiperazi- ne
(2R,3R)-(+)-tartrate (18 g) in AcOEt (400 ml) was washed with 1M
aqueous NaHCO.sub.3 solution (500 ml) and brine. The organic layer
was dried over MgSO.sub.4 and concentrated in vacuo to give
(2R)-1-tert-butoxycarbonyl-2-ethoxycarbonylpiperazine as
crystals.
[0217] m.p.: 47-48.degree. C. po [.alpha.].sub.D.sup.2
0=+66.3.degree.[c=1.0, methanol(MeOH)]
[0218] Mass (ESI+): 259.2 (M+H)
[0219] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.29(3H, t,
J=7.5 Hz), 1.45(4.5H, s), 1.48(4.5H, s), 2.63-2.68(1H, m),
2.83-3.22(3H, m), 3.43-3.59(1H, m), 3.70-3.91(1H, m), 4.14-4.30(2H,
m), 4.42-4.70(1H, m)
[0220] Preparation 7
[0221] A mixture of
(2R)-1-tert-butoxycarbonyl-2-ethoxycarbonylpiperazine (1.67 g) and
1N aqueous sodium hydroxide (9.53 ml) in dioxane (16 ml) was
stirred for 2 hours at ambient temperature. The mixture was
adjusted to pH 5 with 1N HCl on an ice bath. To the mixture was
added sodium carbonate (1.35 g), and then methanesulfonyl chloride
(873 mg) dropwise on an ice bath. After stirring at the same
temperature for 2 hours, the resulting mixture was acidified with
4N HCl, and extracted with AcOEt. The extract was dried over sodium
sulfate and concentrated in vacuo to give 1.95 g of
(2R)-1-tert-butoxycarbonyl-4-methanesulfonylpiperazine-2-c-
arboxylic acid as an amorphous powder.
[0222] Mass (ESI): 307 (M-1)
[0223] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.39(5H, s),
1.42(4H, s), 2.67-2.78(1H, m), 2.78-2.90(4H, m), 2.90-3.20(2H, m),
3.34-3.57(1H, m), 3.79-4.00(1H, m), 4.60-4.72(1H, m)
[0224] Preparation 8
[0225] To a mixture of
(2R)-1-tert-butoxycarbonyl-4-methanesulfonylpiperaz-
ine-2-carboxylic acid (1.95 g), O-benzylhydroxylamine hydrochloride
(1.51 g) and 1-hydroxybenzotriazole (HOBT, 1.03 g) in
N,N-dimethylformamide (DMF, 20 ml) was added triethylamine (191 mg)
on an ice bath. To the mixture was added dropwise
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSCD, 1.18 g) at a
temperature below 6.degree. C. After stirring at the same
temperature for 4 hours, the mixture was concentrated in vacuo. The
residue was partitioned by dissolving same in AcOEt and H.sub.2O.
The organic layer was washed with 2.5% aqueous citric acid,
saturated aqueous NaHCO.sub.3 solution and brine, dried over sodium
sulfate and concentrated in vacuo. The obtained oil was purified by
chromatography on silica gel (SiO.sub.2O) [eluent: from 0.5 to 1.5%
MeOH-chloroform (CHCl.sub.3)] to give 1.35 g of
(2R)-1-tert-butoxycarbonyl-4-methanesulfo-
nylpiperazine-2-(N-benzyloxy)carboxamide as an amorphous
powder.
[0226] Mass (ESI): 412 (M-1)
[0227] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.43(9H, s),
2.78-3.02(7H, m), 3.60-3.70(1H, m), 4.16-4.23(1H, m), 4.62-4.70(1H,
m), 4.89(1H, d, J=10.5 Hz), 4.98(1H, d, J=10.5 Hz), 7.35-7.41(5H,
m)
[0228] Preparation 9
[0229] To a solution of
(2R)-1-tert-butoxycarbonyl-4-methanesulfonylpipera-
zine-2-(N-benzyloxy)carboxamide (1.34 g) in AcOEt (6.5 ml) was
added 4N HCl-AcOEt (6.5 ml) at ambient temperature. The suspension
was stirred at the same temperature for 2 hours and concentrated in
vacuo to give 1.20 g of
(2R)-4-methanesulfonylpiperazine-2-(N-benzyloxy)carboxamide
hydrochloride as a solid.
[0230] Mass (ESI): 248 (M-1)
[0231] .sup.1H-NMR (300 MHz, DMSO-d.sub.6.delta.): 3.00-3.07(4H,
m), 3.07-3.16(2H, m), 3.27-3.40(1H, m), 3.58-3.67(1H, m),
3.74-3.83(1H, m), 3.93(1H, dd, J=4, 9 Hz), 4.85(2H, s),
7.38-7.45(5H, m)
EXAMPLE 1
[0232] To a mixture of
(2R)-4-methanesulfonylpiperazine-2-(N-benzyloxy)car- boxamide
hydrochloride (1.34 g) and pyridine (13.5 ml) was added
4-methoxybenzenesulfonyl chloride (910 mg) at ambient temperature.
After stirring for 2 hours, the mixture was concentrated. The
residue was partitioned by dissolving same in AcOEt and H.sub.2O.
The organic layer was washed with 5% aqueous citric acid, saturated
aqueous NaHCO.sub.3 solution and brine, dried over sodium sulfate
and concentrated in vacuo. The residue was purified by
chromatography on SiO.sub.2 (eluent: from 0.5 to 1%
MeOH-CHCl.sub.3) to give 1.46 g of
(2R)-4-methanesulfonyl-1-(4-meth-
oxybenzenesulfonyl)piperazine-2-(N-benzyloxy)carboxamide as an
amorphous powder.
[0233] Mass (ESI): 482 (M-1)
[0234] .sup.1H-NMR (300 MHz, CDCl.sub.3.delta.): 2.48-2.61(2H, m),
2.88(3H, s), 2.95-3.09(1H, m), 3.45-3.55(1H, m), 3.73-3.82(1H, m),
3.90(3H, s), 4.12-4.20(1H, m), 4.44-4.51(1H, m), 4.89(1H, d, J=10
Hz), 4.99(1H, d, J=10 Hz), 7.00(2H, d, J=8 Hz), 7.36-7.44(5H, m),
7.71(2H, d, J=8 Hz), 9.00(1H, brs)
EXAMPLE 2
[0235] A mixture of
(2R)-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)pip-
erazine-2-(N-benzyloxy)carboxamide (1.00 g), 10% palladium on
barium sulfate (200 mg) and cyclohexene (3 ml) in EtOH (9 ml) was
refluxed for 8 hours. The mixture was filtered and the obtained
filtrate was concentrated in vacuo. The residue was purified by
chromatography on SiO.sub.2 (eluent: from 1 to 6% MeOH-CHCl.sub.3)
to give 735 mg of
(2R)-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)piperazine-2-(N-hydrox-
y)carboxamide as an amorphous powder.
[0236] Mass (ESI): 392 (M-1)
[0237] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.54-2.67(1H,
m), 2.80-2.89(4H, m), 3.40-3.49(1H, m), 3.52-3.71(2H, m),
3.72-3.81(1H, m), 3.85(3H, s), 4.38-4.42(1H, m), 7.10(2H, d, J=8
Hz), 7.74(2H, d, J=8 Hz), 8.91(1H, brs)
EXAMPLE 3
[0238] To a solution of
(2R)-4methanesulfonyl-1-(4methoxybenzenesulfonyl)p-
iperazine-2-(N-hydroxy)carboxamide (1.00 g) in a mixture of EtOH (3
ml) and H.sub.2O (3 ml) was added 1N aqueous sodium hydroxide
solution (2.18 ml) at ambient temperature. After the mixture was
freeze-dried, the resulting powder was collected with AcOEt to give
825 mg of
(2R)-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)piperazine-2-(N-hydrox-
y)carboxamide sodium salt as a powder.
[0239] Mass (ESI): 392 (M-1)
[0240] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.60(1H, dt,
J=4, 10 Hz), 2.74(1H, dd, J=4, 10 Hz), 2.80(3H, s), 3.38-3.48(2H,
m), 3.69(1H, dt, J=4, 10 Hz), 3.99(1H, d, J=10 Hz), 4.22(1H, d, J=2
Hz), 7.05(2H, d, J=8 Hz), 7.83(2H, d, J=8 Hz)
[0241] Preparation 10
[0242] A solution of
(2R)-1-tert-butoxycarbonyl-4-methanesulfonyl-piperazi-
ne-2-carboxylic acid (2.90 g) in 4N HCl-AcOEt solution (40 ml) was
stirred at room temperature for 30 minutes. The solution was
concentrated in vacuo and the residue was solidified with Et.sub.2O
to give 2.15 g of (2R)-4-methanesulfonylpiperazine-2-carboxylic
acid hydrochloride as a powder.
[0243] Mass (ESI): 207.1 (M-1)
[0244] .sup.1H-NMR (300 MHz, D.sub.2O, .delta.): 3.02-3.14(2H, m),
3.08(3H, s), 3.42-3.51(1H, m), 3.52-3.78(3H, m), 3.95-4.05(1H, m),
4.09-4.18(1H, m)
[0245] Preparation 11
[0246] To a solution of
(2R)-4-methanesulfonylpiperazine-2-carboxylic acid hydrochloride
(2.10 g) in H.sub.2O (20 ml) and dioxane (20 ml) were added
NaHCO.sub.3 (2.38 g) and a solution of benzyloxycarbonyl chloride
(1.76 g) in Et.sub.2O (10 ml) at room temperature. After stirring
for 2 hours, Et.sub.2O and dioxane were evaporated in vacuo. The
solution was acidified with 1N HCl and extracted with AcOEt (80
ml). The organic layer was washed with brine, dried over MgSO.sub.4
and concentrated in vacuo to give 3.0 g of
(2R)-1-benzyloxycarbonyl-4-methanesulfonylpiperazine-2-carb- oxylic
acid as an amorphous powder.
[0247] Mass (ESI-): 341.3 (M-H)
[0248] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.70-2.85(2H,
m), 2.81(3H, s), 2.90-3.01(1H, m), 3.20-3.42(1H, m), 3.62-3.80(1H,
m), 4.00-4.19(1H, m), 4.20-4.34(1H, m), 4.56-4.78(2H, m), 5.03(1H,
bs), 7.38(5H, bs)
[0249] Preparation 12
[0250] To a solution of
(2R)-1-benzyloxycarbonyl-4-methanesulfonylpiperazi- ne-2-carboxylic
acid (3.00 g), O-(2-tetrahydropyranyl)hydroxylamine (1.23 g) and
HOBT (1.42 g) in DMF (50 ml) was added WSCD.HCl (2.02 g) under
cooling on an ice bath. After stirring for 30 minutes, the solution
was concentrated in vacuo. The residue was dissolved in AcOEt (100
ml). The solution was washed with 5% aqueous citric acid solution,
1M NaHCO.sub.3 solution and brine, dried over MgSO.sub.4, and
concentrated in vacuo to give 3.58 g of
(2R)-1-benzyloxycarbonyl-4-methanesulfonylpiperazine-2-[N--
(2-tetrahydropyranyloxy)]carboxamide as an amorphous powder.
[0251] Mass (ESI-): 440.3 (M-H)
[0252] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.49-1.91(6H,
m), 2.80-3.32(2H, m), 2.92(3H, bs), 3.52-3.64(1H, m), 3.68-3.78(1H,
m), 3.83-3.95(1H, m), 4.00-4.15(1H, m), 4.20(1H, d, J=12 Hz),
4.76-4.86(1H, m), 4.90-4.98(1H, bs), 5.20(2H, s), 7.36(5H, bs)
[0253] Preparation 13
[0254] A solution of
(2R)-1-benzyloxycarbonyl-4-methanesulfonylpiperazine--
2-[N-(2-tetrahydropyranyloxy)]carboxamide (3.5 g) in EtOH (50 ml)
was subjected to catalytic reduction using palladium hydroxide on
carbon (700 mg), in hydrogen at 3 atm for 8 hours. The catalyst was
removed by filtration and the filtrate was concentrated in vacuo to
give 1.87 g of
(2R)-4-methanesulfonylpiperazine-2-[N-(2-tetrahydropyranyloxy)]carboxamid-
e.
[0255] Mass (ESI+): 308.2 (M+H)
[0256] .sup.1H-NMR (300 MHz, DMSO-d.sub.6.delta.): 1.45-1.78(6H,
m), 2.88-3.09(2H, m), 2.99(3H, s) 3.15-3.32(2H, m), 3.46-3.60(2H,
m), 3.68-3.82(2H, m), 3.86-4.00(1H, m), 4.88(1H, d, J=12 Hz)
EXAMPLE 4
[0257] To a solution of
(2R)-4-methanesulfonylpiperazine-2-[N-(2-tetrahydr-
opyranyloxy)]carboxamide (1.80 g) in pyridine (30 ml) was added
4-nitrobenzenesulfonyl chloride (1.56 g) in dichloromethane
(CH.sub.2Cl.sub.2, 10 ml) under cooling on an ice bath. After
stirring for 2 hours, the solution was concentrated in vacuo. The
residue was dissolved in AcOEt (50 ml). The solution was washed
with 5% aqueous citric acid solution, 1M NaHCO.sub.3 solution and
brine, dried over MgSO.sub.4 and concentrated in vacuo. The residue
was purified by SiO.sub.2 column chromatography (eluent:
CHCl.sub.3) to give 2.15 g of
(2R)-1-(4-nitrobenzenesulfonyl)-4-methanesulfonylpiperazine-2-[N-(2-tetra-
hydropyranyloxy)]carboxamide as an amorphous powder.
[0258] Mass (ESI-): 491.3 (M-H)
[0259] .sup.1H-NMR (300 MHz, CDCl.sub.3.delta.): 1. 50-1.90(6H, m),
2.84-3.09(2H1, m), 2.86(3H, s), 3.23-3.47(1H, m), 3.58-3.69(1H, m),
3.72-3.82(1H, m), 3.84-3.95(1H, m), 4.09-4.22(1H, m), 4.62-4.78(1H,
br), 4.90(1H, bs), 7.95-8.13(2H, m), 8.32-8.42(2H, m), 9.11(1H,
bs)
EXAMPLE 5
[0260] To a solution of
(2R)-1-(4-nitrobenzenesulfonyl)-4-methanesulfonylp-
iperazine-2-[N-(2-tetrahydropyranyloxy)]carboxamide (2.0 g) in MeOH
(10 ml) was added 10% HCl-MeOH (30 ml) at room temperature. After
stirring for 30 minutes, the solution was concentrated in vacuo.
The residue was purified by SiO.sub.2 column chromatography
(eluent: CHCl.sub.3) to give 1.33 g of
(2R)-1-(4-nitrobenzenesulfonyl)-4-methanesulfonylpiperazine-2-(-
N-hydroxy)-carboxamide as an amorphous powder.
[0261] Mass (ESI-): 407.2 (M-H)
[0262] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.63-2.78(1H,
m), 2.86(3H, s), 2.98(1H, dd, J=4.5, 12 Hz), 3.80(2H, d, J=12 Hz),
3.45-3.69(2H, m), 4.49(1H, bs), 8.05(2H, d, J=7.5 Hz), 8.40(2H, d,
J=7.5 Hz), 8.94(1H, s)
EXAMPLE 6
[0263]
(2R)-1-(4-Nitrobenzenesulfonyl)-4-methanesulfonylpiperazine-2-(N-hy-
droxy)carboxamide sodium salt (310 mg) was obtained in
substantially the same manner as in Example 3.
[0264] Mass (ESI-): 407.2 (M-H)
[0265] .sup.1H-NMR (300 MHz, CD.sub.3OD, .delta.): 2.62(3H, s),
2.64-2.73(1H, m), 2.80(1H, dd, J=3.5, 12 Hz), 3.44(1H, d, J=12 Hz),
3.50-3.59(2H, m), 3.83(1H, d, J=12 Hz), 4.22(1H, bs), 7.88(2H, d,
J=7.5 Hz), 8.17(2H, d, J=7.5 Hz)
EXAMPLE 7
[0266]
(2R)-1-(4-Bromobenzenesulfonyl)-4-methanesulfonylpiperazine-2-[N-(2-
-tetrahydropyranyloxy)]carboxamide (300 mg) was obtained in
substantially the same manner as in Example 4.
[0267] Mass (ESI-): 524.3 (M-H)
[0268] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.92(6H,
m), 2.69-2.87(2H, m), 2.89(1.5H, s), 2.91(1.5H, s), 3.27-3.44(1H,
m), 3.58-3.74(2H, m), 3.82-3.99(2H, m), 4.20(1H, d, J=13 Hz),
4.55-4.66(1H, br), 4.93(1H, bs), 7.70(4H, s), 9.12(1H, bs)
EXAMPLE 8
[0269]
(2R)-1-(5-Chloro-2-thienylsulfonyl)-4-methanesulfonylpiperazine-2-[-
N-(2-tetrahydropyranyloxy)]carboxamide was obtained in
substantially the same manner as in Example 4.
[0270] Mass (ESI): 486 (M-1)
[0271] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.56-1.70(2H,
m), 1.70-1.89(4H, m), 2.76-2.95(6H, m), 3.60-3.74(2H, m),
3.87-4.00(2H, m), 4.19-4.28(1H, m), 4.55-4.64(1H, m), 4.93-5.00(1H,
m), 6.99(1H, d, J=4 Hz), 7.43-7.51(1H, m), 9.09(1H, brs)
EXAMPLE 9
[0272] To a solution of
(2R)-4-methanesulfonylpiperazine-2-[N-(2-tetrahydr-
opyranyloxy)]carboxamide (300 mg) in pyridine-CH.sub.2Cl.sub.2
(1:1, 10 ml) was added 5-bromo-2-thienylsulfonyl chloride at
0.degree. C., and the mixture was stirred at room temperature.
After 3.5 hours, N,N-dimethyl-1,3-propanediamine was added and the
mixture was stirred for 10 minutes. This mixture was diluted with
CHCl.sub.3 (20 ml), washed with 5% aqueous citric acid solution,
saturated aqueous NaHCO.sub.3 solution and brine, and dried over
MgSO.sub.4. The solvent was evaporated to give 478 mg of
(2R)-1-(5-bromo-2-thienylsulfonyl)-4-methanesulfonyl-piperazine-
-2-[N-(2-tetrahydropyranyloxy)]carboxamide (containing two
diastereoisomers) as a colorless oil.
[0273] Mass (ESI): 530, 532
[0274] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.56-1.91(6H,
m), 2.74-2.95(2H, m), 2.90(1.5H, s), 2.92(1.5H, s), 3.36-3.51(1H,
m), 3.59-3.71(2H, m), 3.85-4.01(2H, m), 4.21(1H, d, J=13 Hz),
4.62(1H, br), 4.96(1H, br), 7.12(1H, d, J=4 Hz), 7.39-7.48(1H,
m)
EXAMPLE 10
[0275]
(2R)-1-(4-Bromobenzenesulfonyl)-4-methanesulfonylpiperazine-2-(N-hy-
droxy)carboxamide (155 mg) was obtained in substantially the same
manner as in Example 5.
[0276] Mass (ESI-): 440.2 (M-H)
[0277] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.62-2.67(1H,
m), 2.85(1.5H, s), 2.94(1H, dd, J=4.5, 12 Hz), 3.44-3.66(2H, m),
3.69-3.85(2H, m), 4.43(1H, bs), 7.71(2H, d, J=8.5 Hz), 7.81(2H, d,
J=8.5 Hz), 8.95(1H, s)
EXAMPLE 11
[0278] (2R)
-1-(5Chloro-2-thienylsulfonyl)-4-methanesulfonylpiperazine-2-(-
N-hydroxy)carboxamide was obtained in substantially the same manner
as in Example 5.
[0279] Mass (ESI): 402 (M-1)
[0280] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.82(1H,
m), 2.98(3H, s), 3.01(1H, dd, J=4, 10 Hz), 3.49-3.59(1H, m),
3.59-3.75(2H, m), 3.80(1H, d, J=10 Hz), 4.40-4.47(1H, m), 7.30(1H,
d, J=4 Hz), 7.59(1H, d, J=4 Hz), 9.00(1H, brs)
EXAMPLE 12
[0281]
(2R)-1-(5-Bromo-2-thienylsulfonyl)-4-methanesulfonylpiperazine-2-(N-
-hydroxy)carboxamide was obtained in substantially the same manner
as in Example 5.
[0282] Mass (ESI): 446, 448
[0283] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.70-2.82(1H,
m), 2.88(3H, s), 3.02(2H, dd, J=4, 13 Hz), 3.54(1H, d, J=15 Hz),
3.68-3.78(2H, m), 3.80(1H, d, J=14 Hz), 4.35(1H, t, J=6 Hz),
4.44(1H, bs), 7.38(1H, d, J=4 Hz), 7.51 (1H, d, J=4 Hz), 9.00(1H,
s)
[0284] Preparation 14
[0285] N-[N-(tert-Butoxycarbonyl)-O-benzyl-L-seryl]-D-leucine
methyl ester (545 mg) was dissolved in 4N HCl-AcOEt (5 ml), and the
solution was stirred at ambient temperature for 1.5 hours. The
solvent was evaporated in vacuo. The resulting oil was dissolved in
dry MeOH (5 ml). Benzaldehyde (205 mg) and sodium cyanoborohydride
(NaBH.sub.3CN, 97 mg) were added to this solution, and the reaction
mixture was stirred at ambient temperature for 3 hours.
Benzaldehyde (60 mg) and NaBH.sub.3CN (30 mg) were added to the
reaction mixture and the mixture was stirred at ambient temperature
for 1.5 hours. After evaporation of the solvent in vacuo, the
residue was partitioned by dissolving same in AcOEt and saturated
aqueous NaHCO .sub.3 solution. The organic layer was washed with
saturated sodium chloride (NaCl) solution, dried over MgSO.sub.4,
and concentrated in vacuo. The residue was purified by SiO.sub.2
column chromatography (eluent: CHCl.sub.3) to give 376 mg of
N-(N,O-dibenzyl-L-seryl)-D-leucine methyl ester as an oil.
[0286] Mass (ESI+): 413 (M+H)
[0287] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.43(6H, d, J=6
Hz), 1.50-1.70(3H, m), 3.43(1H, m), 3.60-3.80(4H1, m), 3.72(3H, s),
4.45(1H, d, J=12 Hz), 4.51(1H, d, J=12 Hz), 4.58(1H, m),
7.20-7.40(10H, m), 7.79(1H, d, J=10 Hz)
[0288] Preparation 15
[0289] N-(N,O-Dibenzyl-L-seryl)-D-leucine methyl ester (376 mg) was
dissolved in toluene. AcOH (0.06 ml) was added and the mixture was
stirred at 100.degree. C. for one hour and at 110.degree. C. for 5
hours. The reaction mixture was partitioned by dissolving same in
AcOEt and saturated aqueous NaHCO.sub.3 solution. The organic layer
was washed with saturated NaCl solution, dried over MgSO.sub.4, and
concentrated in vacuo. The residue was purified by SiO.sub.2 column
chromatography (eluent: n-hexane/AcCEt=3/2, then 1/1). After
evaporation of the solvent, the crystals were collected using
isopropyl ether to give 312 mg of
(2S,5R)-1-benzyl-2-benzyloxymethyl-5- (2ethylpropyl)
-3,5-dioxopiperazine as a slightly yellowish powder.
[0290] m.p.: 95-97.degree. C.
[0291] Mass (ESI-): 379 (M-H)
[0292] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.86(3H, d, J=7
Hz), 0.95(3H, d, J=7 Hz), 1.50-1.75(2H, m), 2.02(1H, m), 3.66(1H,
d, J=10 Hz), 3.86(1H, d, J=10 Hz), 3.89(1H, s), 4.10(1H, d, J=15
Hz), 4.23(1H, dd, J=5, 10 Hz), 4.35(1H, d, J=12 Hz), 4.47(1H, d,
J=12 Hz), 5.13(1H, d, J=15 Hz), 5.84(1H, s), 7.15-7.40(10H, m)
[0293] Preparation 16
[0294] A solution of
(2S,5R)-1-benzyl-2-benzyloxymethyl-5-(2-methyl-propyl-
)-3,5-dioxopiperazine (12.5 g) in dry tetrahydrofuran (THF, 100 ml)
was dropwise added to a suspension of lithium aluminum hydride
(4.99 g) in dry THF (90 ml) at 55.degree. C. over 1 hour. The
reaction mixture was further stirred at 55.degree. C. for 2 hours,
and then cooled on an ice bath. The reaction was quenched by
careful dropwise addition of 10% H.sub.2O-THF (100 ml). AcOEt (700
ml) and MgSO.sub.4 (20 g) were added, and the mixture was stirred
at ambient temperature for one hour and at 55.degree. C. for 30
minutes. Insoluble matter was filtered off through a celite pad and
the cake was washed several times with AcOEt. The filtrate and
combined washings were concentrated in vacuo to give 11.0 g of
(2R,5R)-1-benzyl-2-benzyloxymethyl-5-(2-methylpropyl)-piperazine as
an oil.
[0295] Mass (ESI+): 353 (M+H)
[0296] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(3H, d, J=7
Hz), 1.33(3H, d, J=7 Hz), 1.00-1.65(3H, m), 1.37(1H, t, J=12 Hz),
2.45(1H, m), 2.65-2.85(2H, m), 3.10(1H, dd, J=4, 12 Hz), 3.18(1H,
d, J=15 Hz), 3.49(1H, dd, J=5, 10 Hz), 3.63(1H, dd, J=2, 10 Hz),
4.15(1H, d, J=15 Hz), 4.51(2H, s), 7.20-7.40(10H, m)
[0297] Preparation 17
[0298] A solution of (2R,5R)
-1-benzyl-2-benzyloxymethyl-5-(2-methyl-propy- l)piperazine (7.0 g)
and di-tert-butyl dicarbonate (5.2 g) in CH.sub.2Cl.sub.2 (50 ml)
was stirred at ambient temperature for 3 hours. The solvent was
evaporated in vacuo and the residue was purified by SiO.sub.2
column chromatography (eluent: CHCl.sub.3/n-hexane=1/1, then
CHCl.sub.3) to give 8.1 g of
(2R,5R)-1-benzyl-2-benzyloxymethyl-4-(tert-b-
utoxycarbonyl)-5-(2-methylpropyl)piperazine as an oil.
[0299] Mass (ESI+): 453 (M+H)
[0300] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.85(3H, d, J=7
Hz), 0.86(3H, d, J=7 Hz), 1.28(1H, m), 1.40-1.70(2H, m), 1.47(9H,
s), 2.28(1H, d, J=12 Hz), 2.62(1H, dd, J=5, 12 Hz), 3.00(1H, br),
3.20(1H, brd, J=13 Hz), 3.55(1H, t, J=10 Hz), 3.60(1H, d, J=13 Hz),
3.77(1H, dd, J=5, 10 Hz), 3.85(1H, d, J=13 Hz), 4.00-4.15(1H, br),
4.10(1H, d, J=13 Hz), 4.49(1H, d, J=12 Hz), 4.57(1H, d, J=12 Hz),
7.20-7.40(10H, m)
[0301] Preparation 18
[0302] 10% Palladium on carbon (0.8 g) was added to a solution of
(2R,5R)
-1-benzyl-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-(2-methylpropyl)piper-
azine (8.1 g) in AcOH (80 ml), and the mixture was hydrogenated in
hydrogen at 3 atm for 4 hours at ambient temperature. The catalyst
was removed by filtration through a celite pad and the filtrate was
washed with AcOH. The filtrate and combined washings were
concentrated in vacuo, and the residue was partitioned by
dissolving same in saturated aqueous NaHCO.sub.3 solution and
AcOEt. The organic layer was washed with NaCl solution, dried over
MgSO.sub.4, and concentrated in vacuo to give 5.8 g of
(2,5R)-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-5-(2-methylpropyl)pip-
erazine as an oil.
[0303] Mass (ESI+): 363 (M+H)
[0304] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.82(3H, d, J=7
Hz), 0.85(3H, d, J=7 Hz), 1.44(9H, s), 1.40-1.80(3H, m), 2.50(1H,
d, J=12 Hz), 3.03(1H, dd, J=5, 12 Hz), 3.10(1H, m), 3.20(1H, dd,
J=5, 13 Hz), 3.39(1H, dd, J=5, 10 Hz), 3.68(1H, t, J=10 Hz),
3.79(1H, d, J=13 Hz), 4.10(1H, m), 4.51(1H, d, J=12 Hz), 4.58(1H,
d, J=12 Hz), 7.25-7.40(5H, m)
[0305] Preparation 19
[0306]
(2R,5R)-2-Benzyloxymethyl-4-(tert-butoxycarbonyl)-1-(4-methoxybenze-
nesulfonyl)-5-(2-methylpropyl)piperazine (6.4 g) was obtained in
substantially the same manner as in Example 1.
[0307] m.p.: 119-120.degree. C.
[0308] Mass (ESI+): 555 (M+Na), 578 (M+2Na)
[0309] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.83-0.90(6H,
br), 1.20-1.50(3H, m), 1.41, 1.43(9H, s), 2.97-3.14(2H, m),
3.20-3.50(3H, m), 3.83(3H, s), 4.00-4.50(5H, m), 6.86(2H, d, J=8
Hz), 7.20-7.40(5H, m), 7.18, 7.22(2H, d, J=8 Hz)
[0310] Preparation 20
[0311] Palladium hydroxide on carbon (700 mg) was added to a
solution of
(2R,5R)-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-1-(4-methoxy-benzenesul-
fonyl)-5-(2-methylpropyl)piperazine (6.4 g) in MeOH (60 ml), and
the mixture was hydrogenated in hydrogen at 3.5 atm for 4 hours at
ambient temperature. The catalyst was removed by filtration through
a celite pad and the filtrate was washed with MeOH. The filtrate
and combined washings were concentrated in vacuo to give 5.3 g of
(2R,5R)-4-(tert-butoxycarbony-
l)-2-hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-5-(2-methylpropyl)piperaz-
ine as white crystals.
[0312] m.p.: 90-93.degree. C.
[0313] Mass (ESI-): 441 (M-H), (ESI+): 465 (M+Na)
[0314] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.):
[0315] 0.80-0.90(6H, br), 1.44(9H, s), 1.10-1.70(3H, m),
2.73-3.11(2H, m), 3.20(1H, dd, J=5, 13 Hz), 3.36-3.65(3H, m),
3.88(3H, s), 3.94(1H, m), 4.05-4.36(3H, m), 6.97(2H, d, J=8 Hz),
7.75(2H, d, J=8 Hz)
[0316] Preparation 21
[0317] Ruthenium (IV) oxide hydrate (238 mg) was added to a
solution of
(2R,5R)-4-(tert-butoxycarbonyl)-2-hydroxymethyl-1-(4-methoxybenzene-sulfo-
nyl)-5-(2-methylpropyl)piperazine (5.3 g) in acetone (50 ml) and
H.sub.2O (20 ml), followed by addition of sodium periodate (5.1 g)
with cooling on an ice bath. After stirring at the same temperature
for 40 minutes, the reaction was quenched with 2-propanol (50 ml).
Insoluble matter was removed by filtration through a celite pad,
and the filtrate was washed with acetone and AcOEt. The filtrate
and combined washings were concentrated in vacuo, and the residue
was partitioned by dissolving same in 5% aqueous sodium bisulfite
and AcOEt. The organic layer was washed with saturated NaCl
solution, dried over MgSO.sub.4, and concentrated in vacuo to give
5.6 g of (2R,5R)-4-(tert-butoxycarbonyl)-1-(4-methoxybenzen-
esulfonyl)-5-(2-methylpropyl)piperazine-2-carboxylic acid as an
amorphous powder.
[0318] Mass (ESI-): 455 (M-H), (ESI+): 479 (M+Na)
[0319] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.89(6H, d, =7
Hz), 1.30-1.65(3H,.m), 1.38(9H, s), 2.90-3.60(3H, m), 3.86(3H, s),
4.10-4.62(3H, m), 6.93(2H, d, J=8 Hz), 7.70(2H, d, J=8 Hz)
[0320] Preparation 22
[0321]
(2R,5R)-4-(tert-Butoxycarbonyl)-1-(4-methoxybenzenesulfonyl)-5-(2-m-
ethylpropyl)piperazine-2-(N-benzyloxy)carboxamide (5.3 g) was
obtained in substantially the same manner as in Preparation 8.
[0322] m.p.: 178-179.degree. C.
[0323] Mass (ESI+): 584 (M+Na)
[0324] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.75-0.96(6H,
br), 0.90-1.70(3H, m), 1.44(9H, s), 2.80-3.70(ca. 3H, br), 3.87(3H,
s), 4.00-4.70(ca. 3H, br), 4.88(2H, s), 6.97(2H, d, J=8 Hz),
7.39(5H, m), 7.63-7.83(2H, br), 8.77, 9.18(1H, br)
[0325] Preparation 23
[0326]
(2R,5R)-1-(4-Methoxybenzenesulfonyl)-5-(2-methylpropyl)-piperazine--
2-(N-benzyloxy)carboxamide hydrochloride (5.2 g) was obtained in
substantially the same manner as in Preparation 10.
[0327] m.p.: 168-173.degree. C.
[0328] Mass (ESI+): 462 (M+H)
[0329] .sup.H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.83(3H, d, J=7
Hz), 0.84(3H, d, J=7 Hz), 1.36(1H, m), 1.90-2.15(2H, m), 3.15(1H,
dd, J=4, 12 Hz), 3.25(1H, dd, J=4, 12 Hz), 3.30-3.50(2H, m),
3.75(1H, d, J=12 Hz), 3.83(3H, s), 4.18(1H, t, J=4 Hz), 4.77(2H,
s), 7.13(2H, d, J=8 Hz), 7.79(2H, d, J=8 Hz)
EXAMPLE 13
[0330]
(2R,5R)-4-Methanesulfonyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylp-
ropyl)piperazine-2-(N-benzyloxy)carboxamide (0.37 g) was obtained
in substantially the same manner as in Example 1.
[0331] m.p.: 165-166.degree. C.
[0332] Mass (ESI-): 538 (M-H)
[0333] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.77(3H, d, J=5
Hz), 0.83(3H, d, J=5 Hz), 1.11(1H, m), 1.18-1.40(2H, m), 2.91(3H,
s), 2.85-3.20(2H, m), 3.56(1H, d, J=13 Hz), 3.77(1H, m), 3.88(3H,
s), 4.12(1H, d, J=13 Hz), 4.36(1H, m), 4.86(1H, d, J=10 Hz),
4.95(1H, d, J=10 Hz), 6.98(2H, d, J=8 Hz), 7.40(5H, m), 7.71(2H, d,
J=8 Hz), 9.20(1H, brs)
EXAMPLE 14
[0334]
(2R,5R)-4-Methanesulfonyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylp-
ropyl)piperazine-2-(N-hydroxy)carboxamide (188 mg) was obtained in
substantially the same manner as in Example 2.
[0335] m.p.: 68-93.degree. C.
[0336] Mass (ESI-): 448 (M-H)
[0337] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.76(3H, d,
J=5 Hz), 0.80(3H, d, J=5 Hz), 1.17(1H, m), 1.20-1.44(2H, m),
2.87(3H, s), 3.20-3.44(2H, m), 3.71-3.89(3H, m), 3.83(3H, s),
4.31(1H, d, J=4 Hz), 7.08(2H, d, J=8 Hz), 7.72(2H, d, J=8 Hz),
8.92(1H, brs)
[0338] Preparation 24
[0339] Ethyl
1-(tert-butoxycarbonyl)-4-methanesulfonylpiperazine-2-carboxy- late
was obtained in substantially the same manner as in Example 4.
[0340] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.28(3H, t, J=8
Hz), 1.43(4H, s), 1.47(5H, s), 2.73(1H, t, J=14 Hz), 2.89(1H, d,
J=14 Hz), 3.08-3.34(1H, m), 3.61-3.78(1H, m), 3.86-4.09(1H, m),
4.12-4.29(2H, m), 4.22(2H, q, J=8 Hz), 4.67(0.5H, bs), 4.86(0.5H,
bs)
[0341] Preparation 25
[0342] Ethyl 4methanesulfonylpiperazine-2-carboxylate hydrochloride
was obtained in substantially the same manner as in Preparation
9.
[0343] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.26(3H, t,
J=8 Hz), 3.02(3H, s), 3.09-3.30(2H,m), 3.33-3.59(3H, m), 3.76(1H,
dd, J=4, 16 Hz), 4.26(2H, q, J=8 Hz), 4.50(1H, dd, J=4, 11 Hz)
[0344] Preparation 26
[0345] Ethyl
(2RS)-1-(3-chloropropylsulfonyl)-4-methanesulfonylpiperazine--
2-carboxylate (224 mg) was obtained in substantially the same
manner as in Example 4.
[0346] m.p.: 144-145.degree. C.
[0347] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.33(3H, t, J=7
Hz), 2.25-2.40(2H, m), 2.75-2.90(1H, overlapping), 2.80(3H, s),
3.00(1H, dd, J=4, 12 Hz), 3.20-3.40(2H, m), 3.48(1H, dt, J=4, 12
Hz), 3.68(2H, t, J=7 Hz), 3.76(1H, d, J=12 Hz), 3.83(1H, d, J=12
Hz), 4.15-4.40(3H, m), 4.75(1H, brs)
[0348] Preparation 27
[0349] A mixture of ethyl
(2RS)-1-(3-chloropropylsulfonyl)-4-methanesulfon-
ylpiperazine-2-carboxylate (203 mg) and 1N aqueous sodium hydroxide
(0.9 ml) in dioxane (2 ml) and EtOH (1 ml) was stirred for 2 hours
at ambient temperature. The mixture was acidified with 1N HCl (0.9
ml) and concentrated in vacuo. The resulting crystals were
collected with H.sub.2O, and washed with H.sub.2O and Et.sub.2O to
give 165 mg of
(2RS)-1-(3chloropropylsulfonyl)-4-methanesulfonylpiperazine-2-carboxylic
acid.
[0350] m.p.: 188-189.degree. C.
[0351] Mass (ESI-): 347 (M-H)
[0352] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.14(2H, m),
2.78(1H, dt, J=4, 12 Hz), 2.91(3H, s), 2.99(1H, dd, J=4, 12 Hz),
3.20-3.45(3H, overlapping with H.sub.2O), 3.53(1H, d, J=12 Hz),
3.68(1H, d, J=12 Hz), 3.76(2H, t, J=6 Hz), 4.00(1H, d, J=12 Hz),
4.62(1H, brs)
EXAMPLE 15
[0353]
(2RS)-1-(3-Chloropropylsulfonyl)-4methanesulfonylpiperazine-2-[(N-(-
2-tetrahydropyranyloxy)]carboxamide (172 mg) was obtained in
substantially the same manner as in Preparation 12.
[0354] Mass (ESI-): 446, 448 (M-H)
[0355] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-2.00(6H,
m), 2.33(2H, m), 2.90(3H, s), 2.83-3.00(1H, overlapping), 3.13(1H,
brd, J=12 Hz), 3.20-4.00(7H, br), 3.68(2H, t, J=5 Hz), 4.14(1H,
br), 4.65(1H, br), 5.01 (1H, br), 9.26(11H, br)
EXAMPLE 16
[0356]
(2RS)-1-(3-Chloropropylsulfonyl)-4-methanesulfonylpiperazine-2-(N-h-
ydroxy)carboxamide (95 mg) was obtained in substantially the same
manner as in Example 5.
[0357] Mass (ESI-): 362 (M-H)
[0358] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.15(2H, m),
2.78(1H, dt, J=4, 10 Hz), 2.90(3H, s), 3.06(1H, d, J=4, 10 Hz),
3.15-3.45(2H, overlapping with H.sub.2O), 3.53(1H, d, J=12 Hz),
3.73(2H, t, J=6 Hz), 3.57-3.80(2H, m), 3.88(1H, d, J=12 Hz),
4.39(1H, s), 9.06(1H, s)
[0359] Preparation 28
[0360] Ethyl
1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazinecarboxylate (60 g)
was dissolved in AcOH (400 ml), and the solution was subjected to
catalytic reduction using 10% palladium on carbon (12 g)-H.sub.2O
(30 ml), in hydrogen at 3 atm for 4 hours. The catalyst was removed
by filtration and the filtrate was concentrated under reduced
pressure. The residue was dissolved in AcOEt (1000 ml), and the
organic layer was washed with saturated aqueous NaHCO.sub.3
solution by stirring carefully to avoid foaming. The organic layer
was further washed with saturated brine, and dried over anhydrous
MgSO.sub.4. The solvent was evaporated under reduced pressure to
give 59.2 g of ethyl 1-tert-butoxycarbonyl-2-pi-
perazinecarboxylate as an oil (yield 97.9%).
[0361] TLC Rf 0.44 (CHCl.sub.3:MeOH, 9:1)
[0362] Mass (ESI+): 259 (M+H)
[0363] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(3H, t,
J=7.5 Hz), 1.45(4.5H, s), 1.48(4.5H, s), 2.63-2.68(1H, m),
2.83-3.22(3H, m), 3.43-3.59(1H, m), 3.70-3.91(1H, m), 4.14-4.30(2H,
m), 4.42-4.70(1H, m)
EXAMPLE 17
[0364]
(2R)-4Methanesulfonyl-1-(4-phenoxybenzenesulfonyl)piperazine-2-(N-b-
enzyloxy)carboxamide (39.5 g) was obtained in substantially the
same manner as in Example 1.
[0365] Mass (ESI+): 546 (M+H)
[0366] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.52-2.70(2H,
m), 2.98-3.15(1H, m), 2.89(3H, s), 3.52(1H, d, J=12 Hz), 3.78(1H,
d, J=13 Hz), 4.26(1H, d, J=13 Hz), 4.50(1H, br), 4.92(2H, dd, J=11
and 14 Hz), 7.01(2H, d, J=8 Hz), 7.10(2H, d, J=8 Hz), 7.26(1H, dd,
J=8, 8 Hz), 7.35-7.49(7H, m), 7.70(2H, d, J=8 Hz)
EXAMPLE 18
[0367] A solution of
(2R)-4-methanesulfonyl-1-(4-phenoxybenzenesulfonyl)-p-
iperazine-2-(N-benzyloxy)carboxamide (39.0 g) in dioxane (156 ml)
and EtOH (156 ml) was subjected to catalytic reduction using 10%
palladium on barium sulfate (3.9 g) in hydrogen at 3 atm for 4
hours. The catalyst was removed by filtration and the filtrate was
concentrated in vacuo. The residue was purified by chromatography
on SiO.sub.2 (eluent: from 0.5 to 2% MeOH-CHCl.sub.3) to give 31.5
g of (2R)-4-methanesulfonyl-1-(4-phenoxy-
benzenesulfonyl)piperazine-2-(N-hydroxy)carboxamide as an amorphous
powder.
[0368] Mass (ESI-): 454 (M-H)
[0369] m.p. 112-114.degree. C.
[0370] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.63(1H, td,
J=5, 13 Hz), 2.84(3H, s), 2.90(1H, dd, J=5, 14 Hz), 3.46(1H, d,
J=12 Hz), 3.53-3.72(3H, m), 4.40(1H, bs), 7.07-7.19(4H, m),
7.25(1H, dd, J=7, 7 Hz), 7.42-7.51(2H, m), 7.78(2H, d, J=8 Hz),
8.90(1H, s)
EXAMPLE 19
[0371]
(2R)-4-Methanesulfonyl-1-(4-phenoxybenzenesulfonyl)piperazine-2-(N--
hydroxy)carboxamide sodium salt (25.9 g) was obtained in
substantially the same manner as in Example 3.
[0372] Mass (ESI-): 454 (M-H)
[0373] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.65(1H, td,
J=4, 13 Hz), 2.78(1H, dd, J=5, 14 Hz), 2.80(3H, s), 3.45(2H, d,
J=11 Hz), 3.72(1H, td, J=4, 11 Hz), 3.99(1H, d, J=14 Hz), 4.21(1H,
s), 7.03(2H, d, J=8 Hz), 7.14(2H, d, J=8 Hz), 7.24(1H, dd, J=8, 8
Hz), 7.45(2H, dd, J=8, 8 Hz), 7.90(2H, d, J=8 Hz)
[0374] Preparation 29
[0375] N-(tert-Butoxycarbonyl)-O-benzyl-L-serine
N,O-dimethylhydroxylamine amide (2.5 g) was obtained in
substantially the same manner as in Preparation 8.
[0376] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.43(9H, s),
3.20(3H, s), 3.60-3.72(2H, m), 3.70(3H, s), 4.49(1H, d, J=10 Hz),
4.57(1H, d, J=10 Hz), 4.88(1H, m), 5.43(1H, d, J=7 Hz),
7.22-7.37(5H, m)
[0377] Preparation 30
[0378] 0.9M Methylmagnesium bromide (MeMgBr) in THF (100 ml) was
added dropwise to a solution of
N-(tert-butoxycarbonyl)-O-benzyl-L-serine N,O-dimethylhydroxylamine
amide (5.0 g) in dry THF (25 ml) with cooling on an ice bath. The
reaction mixture was stirred at the same temperature for 2 hours.
The reaction was quenched by adding saturated aqueous ammonium
chloride (NH.sub.4Cl) solution and the resulting mixture was
extracted with AcOEt. The organic layer was washed with saturated
aqueous NaHCO.sub.3 solution and saturated aqueous NaCl solution,
dried over MgSO.sub.4 and concentrated in vacuo to give 4.3 g of
(3S)-4-benzyloxy-3-tert-butoxycarbonylamino-2-butanone as an
oil.
[0379] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.43(9H, s),
2.20(3H, s), 3.68(1H, dd, J=3.8 Hz), 3.91(1H, dd, J=3.8 Hz),
4.34(1H, m), 4.47(1H, d, J=10 Hz), 4.57(1H, d, J=10 Hz),
7.20-7.40(5H, m)
[0380] Preparation 31
[0381] A solution of
(3S)-4-benzyloxy-3-tert-butoxycarbonylamino-2-butanon- e (4.3 g) in
dry MeOH (20 ml) was added to a solution of 2-aminoethanol (2.0 g)
and AcOH (1.8 g) in dry MeOH (20 ml). NaBH.sub.3CN (1.4 g) was
added and the mixture was stirred at ambient temperature overnight.
The mixture was concentrated in vacuo and the residue was
partitioned between AcOEt and aqueous NaHCO.sub.3 solution. The
organic layer was washed with saturated aqueous NaHCO.sub.3
solution and saturated aqueous NaCl solution. The organic layer was
mixed with 1N HCl (50 ml) and the mixture was stirred vigorously
for 1 hour. The organic layer was separated, washed with saturated
aqueous NaHCO.sub.3 solution and saturated aqueous NaCl solution,
dried over MgSO.sub.4 and concentrated in vacuo to give 4.1 g of
(2R,3RS)-O-benzyl-2-tert-butoxycarbonylamino-3-(2-hydroxyethylam-
ino)butanol as an oil.
[0382] Mass (ESI+): 339 (M+H)
[0383] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.11, 1.18,
1.23(3H, d, J=5 Hz), 1.45(9H, s), 2.60-3.00(3H, m), 3.45-3.95(5H,
m), 4.48(1H, d, J=10 Hz), 4.54(1H, d, J=10 Hz), 5.00-5.35(1H, m),
7.20-7.40(5H, m)
[0384] Preparation 32
[0385] A solution of triethylamine (7.6 g) in dioxane (20 ml) was
added to dropwise a solution of
(2R,3RS)-O-benzyl-2-tert-butoxycarbonylamino-3-(2--
hydroxyethylamino)butanol (8. 4 g) and methanesulfonyl chloride
(8.6 g) in dioxane (40 ml) with cooling on an ice bath. The
reaction mixture was stirred at ambient temperature for 2 hours and
the reaction was quenched by adding
3-(N,N-dimethylamino)propylamine (5 ml). The mixture was
concentrated in vacuo and the residue was partitioned between 0.6N
HCl and AcOEt. The organic layer was washed with saturated aqueous
NaHCO.sub.3 solution and saturated aqueous NaCl solution, dried
over MgSO.sub.4 and concentrated in vacuo. The residue was purified
by SiO.sub.2 column chromatography (eluent: AcOEt in n-hexane 40%,
50% and then 60%). The fraction containing the desired product was
concentrated in vacuo and was further purified by SiO.sub.2 column
chromatography (eluent: acetone in toluene 16%) to give 2.7 g of
(2R,
3R)-O-benzyl-2-tert-butoxycarbonylamino-3-[N-(2-methanesulfonyloxy-ethyl)-
-N-methanesulfonylaminolbutanol as an oil.
[0386] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.28(3H, d, J=5
Hz), 1.43(9H, s), 2.88(3H, s), 3.02(3H, s), 3.40-3.65(3H, m),
3.75-3.94(2H, m), 3.99(1H, m), 4.28-4.50(2H, m), 4.49(1H, d, J=10
Hz), 4.54(1H, d, J=10 Hz), 4.98(1H, d, J=8 Hz), 7.27-7.40(5H,
m)
[0387] Preparation 33
[0388]
(2R,3S)-O-Benzyl-2-tert-butoxycarbonylamino-3-[N-(2-methane-sulfony-
loxyethyl)-N-methanesulfonylamino]butanol (5.7 g) was obtained in
substantially the same manner as in Preparation 32.
[0389] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.23(3H, d, J=5
Hz), 1.43(9H, s), 2.92(3H, s), 3.05(3H, s), 3.37-3.60(4H, m),
3.69(1H, m), 4.05(1H, m), 4.25-4.50(2H, m), 4.45(1H, d, J=10 Hz),
4.56(1H, d, J=10 Hz), 5.24(1H, d, J=7 Hz), 7.25-7.40(5H, m)
[0390] Preparation 34
[0391] A solution of
(2R,3R)-O-benzyl-2-tert-butoxycarbonylamino-3-[N-(2-m-
ethanesulfonyloxyethyl)-N-methanesulfonylamino)butanol (2.6 g) in
dry DMF (15 ml) was added dropwise to a suspension of sodium
hydride (60% dispersion in mineral oil, 189 mg) in dry DMF (10 ml)
at 4.degree. C. over 20 minutes. The mixture was stirred at same
temperature for 45 minutes and then poured into a mixture of ice
and 1N HCl (8 ml). The mixture was extracted with AcOEt. The
organic layer was washed with saturated aqueous NaCl solution,
dried over MgSO.sub.2 and concentrated in vacuo. The residue was
purified by SiO.sub.2 column chromatography (eluent: AcOEt in
n-hexane 40% and 50%) to give 2.1 g of
(2R,3R)-2-benzyloxymethyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methy-
lpiperazine as an oil.
[0392] m.p.: 62-68.degree. C.
[0393] Mass (ESI+): 399 (M+H), 421 (M+Na)
[0394] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.36(3H, d, J=6
Hz), 1.43(9H, s), 2.84(3H, s), 3.11(1H, m), 3.43(1H, m),
3.52-3.68(2H, m), 3.70-3.85(3H, m), 4.09(1H, m), 4.50(1H, d, J=10
Hz), 4.57(1H, d, J=10 Hz), 7.27-7.38(5H, m)
[0395] Preparation 35
[0396] 10% Palladium on activated carbon (1.5 g) was suspended in
H.sub.2O (10 ml) and the suspension was added to a solution of
(2R,3R)-2-benzyloxymethyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methy-
l-piperazine (2.1 g) and ammonium formate (3.3 g) in MeOH (25 ml).
The mixture was refluxed for 1.5 hours. Ammonium formate (3.4 g) in
H.sub.20 (10 ml) and MeOH (10 ml) were added to the reaction
mixture, and the mixture was refluxed for 1.5 hours. 10% Palladium
on activated carbon (1.5 g) in H.sub.20 (10 ml) and ammonium
formate (3.4 g) were added to the reaction mixture and the mixture
was refluxed for 2.5 hours. The catalyst was removed by filtration
through a celite pad and the pad was washed with MeOH. The combined
filtrate and washings were concentrated in vacuo. The residue was
partitioned between AcOEt and brine. The organic layer was dried
over MgSO.sub.4 and concentrated in vacuo to give 1.5 g of
(2R,3R)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methane-sulfonyl-3-met-
hylpiperazine as a solid.
[0397] m.p.: 84-90.degree. C.
[0398] Mass (ESI+): 309 (M+H), 331 (M+Na)
[0399] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.32(3H, d, J=5
Hz), 1.47(9H, s), 2.87(3H, s), 3.25-3.48(3H, m), 3.70-3.90(4H, m),
4.07(1H, m)
[0400] Preparation 36
[0401]
(2R,3R)-1-tert-Butoxycarbonyl-4-methanesulfonyl-3-methyl-2-piperazi-
necarboxylic acid (1.0 g) was obtained in substantially the same
manner as in Preparation 21.
[0402] m.p.: 158.degree. C.
[0403] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.47(9H, s),
1.49(3H, d, J=6 Hz), 2.90(3H, s), 3.43(1H, m), 3.54(1H, m),
3.60-3.80(2H, m), 4.20(1H, m), 4.48(1H, d, J=3 Hz)
[0404] Preparation 37
[0405]
(2R,3R)-N-Benzyloxy-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methy-
l-2-piperazinecarboxamide (690 mg) was obtained in substantially
the same manner as in Preparation 8.
[0406] m.p.: 156-159.degree. C.
[0407] Mass (ESI+): 428 (M+H), 450 (M+Na)
[0408] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.21(3H, d, J=6
Hz), 1.37(9H, s), 2.94(3H, s), 3.25-3.55(3H, m), 3.84(1H, m),
3.98(1H, m), 4.25(1H, d, J=6 Hz), 4.81(2H, s), 7.30-7.50(5H, m)
[0409] Preparation 38
[0410]
(2R,3R)-N-Benzyloxy-4-methanesulfonyl-3-methyl-2-piperazine-carboxa-
mide hydrochloride (559 mg) was obtained in substantially the same
manner as in Preparation 10.
[0411] Mass (ESI+): 328 (M+H)
[0412] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.10(3H, d,
J=6 Hz), 3.00-3.30(3H, m), 3.13(3H, s), 3.69(3H, d, J=11 Hz),
4.00(1H, d, J=5 Hz), 4.32(1H, m), 4.86(2H, s), 7.35-7.50(5H, m)
EXAMPLE 20
[0413] A solution of 4-methoxybenzenesulfonyl chloride (284 mg) in
dioxane (2 ml) was added to a solution of
(2R,3R)-N-benzyloxy-4-methanesulfonyl-3-
-methyl-2-piperazinecarboxamide hydrochloride (200 mg) in pyridine
(2 ml) with cooling on an ice bath. The mixture was stirred at
ambient temperature for 3.5 hours. 4-Methoxybenzenesulfonyl
chloride (60 mg) in dioxane (1 ml) was added thereto, and the
mixture was stirred at ambient temperature for 2 hours.
4-Methoxybenzenesulfonyl chloride (60 mg) in dioxane (1 ml) was
added to the mixture. The reaction mixture was stirred at ambient
temperature for 2 hours, and the reaction was quenched by adding
3-(N,N-dimethyl-amino)propylamine (0.1 ml). The mixture was
partitioned between 0.6N HCl and AcOEt. The organic layer was
washed with 0.6N HCl, saturated aqueous NaHCO.sub.3 solution and
saturated aqueous NaCl solution, dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by SiO.sub.2 column
chromatography (eluent: AcOEt in n-hexane 60% to 80%) to give 273
mg of (2R,3R)-N-benzyloxy-4-methanesulfo-
nyl-1-(4-methoxy-benzenesulfonyl)-3-methyl-2-piperazinecarboxamide
as an amorphous powder.
[0414] Mass (ESI-): 496 (M-H)
[0415] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.38(3H, d, J=5
Hz), 2.77(3H, s), 3.17(1H, m), 3.40(1H, m), 3.55-3.75(2H, m),
3.86(3H, s), 3.93(1H, m), 4.26(1H, m), 4.85(1H, d, J=10 Hz),
4.92(1H, d, J=10 Hz), 6.99(2H, d, J=8 Hz), 7.40(5H, s), 7.76(2H, d,
J=8 Hz), 8.86(1H, brs)
EXAMPLE 21
[0416]
(2R,3R)-N-Hydroxy-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3--
methyl-2-piperazinecarboxamide (106 mg) was obtained in
substantially the same manner as in Example 18.
[0417] Mass (ESI-): 406 (M-H)
[0418] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.74(3H, d,
J=5 Hz), 2.78(3H, s), 3.07(1H, m), 3.55-3.75(4H, m), 3.84(3H, s),
4.19(1H, d, J=4 Hz), 7.09(2H, d, J=8 Hz), 7.72(2H, d, J=8 Hz),
8.97(1H, br)
[0419] Preparation 39
[0420] A solution of
(2R,3S)-O-benzyl-2-tert-butoxycarbonylamino-3-[N-(2-m-
ethanesulfonyloxyethyl)-N-methanesulfonylamino]butanol (1.1 g) in
dry THF (15 ml) was added dropwise to a suspension of sodium
hydride (60% dispersion in mineral oil, 80.1 mg) in dry THF (8 ml)
at 4.degree. C. over 15 minutes. The mixture was stirred at the
same temperature for 3.5 hours and then poured into saturated
aqueous NH.sub.4Cl solution, The mixture was extracted with AcOEt.
The organic layer was washed with saturated aqueous NaCl solution.
dried over MgSO.sub.4 and concentrated in vacuo. The residue was
purified by SiO.sub.2 column chromatography (eluent: AcOEt in
n-hexane 40% and 50%) to give 0.80 g of
(2R,3S)-2-benzyloxy-methyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-meth-
ylpiperazine as an oil.
[0421] Mass (ESI+): 399 (M+H), 421 (M+Na)
[0422] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(3H, d, J=5
Hz), 1.43(9H, s), 2.81(3H, s), 2.85-3.30(2H, m), 3.35-3.93(4H1, m),
4.08(1H, m), 4.27(1H, m), 4.50(1H, d, J=10 Hz), 4.59(1H, d, J=10
Hz), 7.25-7.40(5H, m)
[0423] Preparation 40
[0424] (2R,3S)-2-Benzyloxymethyl-4-methanesulfonyl-
1-(4-methoxybenzene-sulfonyl)-3-methylpiperazine (320 mg) was
obtained in substantially the same manner as in Preparation 10.
[0425] Mass (ESI+): 469 (M+H), 491 (M+Na)
[0426] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.31(3H, d, J=7
Hz), 2.81(3H, s), 2.97(1H, dt, J=2, 12 Hz), 3.19(1H, dt, J=2, 12
Hz), 3.38(1H, dd, J=5, 8 Hz), 3.50-3.70(3H, m), 3.83(3H, s),
4.01(1H, m), 4.26(1H, q, J=7 Hz), 4.37(1H, d, J=11 Hz), 4.49(1H, d,
J=11 Hz), 6.85(2H, d, J=8 Hz), 7.25-7.40(5H, m), 7.71 (2H, d, J=8
Hz)
[0427] Preparation 41
[0428] A mixture of
(2R,3S)-2-benzyloxymethyl-4-methanesulfonyl-1-(4-metho-
xybenzenesulfonyl)-3-methylpiperazine (330 mg) and palladium
hydroxide (40 mg) in dioxane (5 ml) and MeOH (5 ml) was
hydrogenated in hydrogen at 3.5 atm and ambient temperature for 1
day. The catalyst was removed by filtration through a celite pad
and the pad was washed with MeOH. The filtrate and combined
washings were concentrated in vacuo. The residue was purified by
SiO.sub.2 column chromatography (eluent: AcOEt/n-hexane 60%, then
MeOH/AcOEt 1%) to give 253 mg of (2R,3S)-2-hydroxymethyl-4-meth-
anesulfonyl-1-(4-methoxybenzene-sulfonyl)-3methylpiperazine.
[0429] Mass (ESI-): 377 (M-H)
[0430] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(3H, d, J=5
Hz), 2.08(1H, t, J=4 Hz), 2.88(3H, s), 3.08(1H, dt, J=2, 10 Hz),
3.20(1H, dt, J=2, 10 Hz), 3.48(1H, m), 3.62(1H, dd, J=2, 10 Hz),
3.69(1H, dd, J=2, 10 Hz), 3.70-3.90(2H, m), 3.87(3H, s), 4.26(1H,
q, J=5 Hz), 6.98(2H, d, J=8 Hz), 7.76(2H, d, J=8 Hz)
[0431] Preparation 42
[0432]
(2R,3S)-4-Methanesulfonyl-1-(4methoxybenzenesulfonyl)-3-methyl-2-pi-
perazinecarboxylic acid (231 mg) was obtained in substantially the
same manner as in Preparation 21.
[0433] m.p.: 150-152.degree. C.
[0434] Mass (ESI-): 391 (M-H)
[0435] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.42(3H, d, J=5
Hz), 2.83(3H, s), 3.24(1H, dt, J=2, 11 Hz), 3.36(1H, dt, J=2, 11
Hz), 3.56(1H, dd, J=2, 1 Hz), 3.70(1H, dd, J=2, 11 Hz), 3.88(3H,
s), 4.55(1H, brs), 4.66(1H, q, J=5 Hz), 6.97(2H, d, J=8 Hz),
7.73(2H, d, J=8 Hz)
EXAMPLE 22
[0436]
(2R,3S)-4-Methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methyl-N-(-
2-tetrahydropyranyloxy)-2-piperazinecarboxamide (235 mg) was
obtained in substantially the same manner as in Preparation 12.
[0437] Mass (ESI-): 490 (M-H)
[0438] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.17, 1.20(3H,
d, J=5 Hz), 1.45-1.70(6H, m), 2.86(3H, s), 3.10, 3.15(1H, m),
3.45-3.65(3H, m), 3.68, 3.73(1H, m), 3.83(3H, s), 3.86(1H, m),
4.09, 4.15(1H, s), 4.05-4.25(1H, m), 4.63, 4.71(1H, s), 7.07,
7.09(2H, d, J=8 Hz), 7.64, 7.67(2H, d, J=8 Hz)
EXAMPLE 23
[0439]
(2R,3S)-N-Hydroxy-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3--
methyl-2-piperazinecarboxamide (164 mg) was obtained in
substantially the same manner as in Example 5.
[0440] Mass (ESI-): 406 (M-H)
[0441] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.08(3H, d, J=5
Hz), 2.90(3H, s), 3.16(1H, dt, J=2, 10 Hz), 3.28(1H, dt, J=2, 10
Hz), 3.52 (1H, d, J=10 Hz), 3.67(1H, d, J=10 Hz), 3.89(3H, s),
4.32(1H, s), 4.68(1H, q, J=5 Hz), 7.03(2H, d, J=8 Hz), 7.80(2H, d,
J=8 Hz)
[0442] Preparation 43
[0443] A solution of sodium carbonate (1.63 g) in H.sub.2O (7.65
ml), 4-fluorobenzeneboronic acid (1.03 g) and
tetrakis(triphenylphosphine) palladium(0 ) (70.9 mg) were added
successively to a solution of 2-bromothiophene (1.00 g) in
dimethoxyethane (12.3 ml). The mixture was refluxed for 4 hours.
The mixture was cooled to ambient temperature and partitioned
between AcOEt and H.sub.2O. The organic layer was washed with 0.5N
aqueous NaOH solution and saturated aqueous NaCl solution, dried
over MgSO.sub.4 and concentrated in vacuo. The residue was purified
by SiO.sub.2 column chromatography (eluent: n-hexane and then AcOEt
in n-hexane 10%). The solvent was evaporated in vacuo to give 1.05
g of 2-(4-fluorophenyl)thiophene as a white solid.
[0444] m.p.: 51-52.degree. C.
[0445] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.01-7.14(3H,
m), 7.21-7.29(2H, m), 7.52-7.62(2H, m)
[0446] Preparation 44
[0447] 2-(4-Fluorophenyl)thiophene (538 mg) was added to a solution
of sulfur trioxide N,N-dimethylformamide complex in dichloroethane
(5 ml). The reaction mixture was stirred at 50.degree. C. for 3
hours and at 70.degree. C. for 2 hours. Sulfur trioxide
N,N-dimethylformamide complex (231 mg) was added to the reaction
mixture and the mixture was stirred at 80.degree. C. overnight. The
reaction mixture was cooled to ambient temperature. Thionyl
chloride (0.27 ml) was added to the reaction mixture and the
mixture was stirred at 70.degree. C. for 3 hours. The mixture was
concentrated in vacuo and the residue was partitioned between AcOEt
and ice water. The organic layer was washed with H.sub.2O,
saturated aqueous NaHCO.sub.3 solution and saturated aqueous NaCl
solution, dried over MgSO.sub.4 and concentrated in vacuo to give
694 mg of 5-(4-fluorophenyl)-2-thiophenesulfonyl chloride as a
blue-gray solid.
[0448] m.p.: 82-85.degree. C.
[0449] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.17(2H, t, J=8
Hz), 7.25(1H, d, J=1Hz), 7.61(2H, d, J=3.8 Hz), 7.83(1H, d, J=1
Hz)
[0450] Preparation 45
[0451] 2-(3-Fluorophenyl)thiophene (1.12 g) was obtained in
substantially the same manner as in Preparation 43.
[0452] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 6.96(1H, t, J=8
Hz), 7.09(1H, t, J=4 Hz), 7.22-7.40(5H, m)
[0453] Preparation 46
[0454] 2-(3-Fluorophenyl)thiophene-5-sulfonylchloride (1.54 g) was
obta ined in substantially the same manner as in Preparation
44.
[0455] m.p.: 75-84.degree. C.
[0456] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.20-7.30(1H,
m), 7.40-7.47(1H, m), 7.50(1H, d, J=4 Hz), 7.68(1H, t, J=8 Hz),
7.88(1H, d, J=4 Hz)
EXAMPLE 24
[0457]
(2R)-4-Methanesulfonyl-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrah-
ydropyranyloxy)-2-piperazinecarboxamide (273 mg) was obtained in
substantially the same manner as in Example 4.
[0458] Mass (ESI): 528 (M-1)
[0459] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.67(4H,
m), 1.70-1.90(2H, m), 2.78-2.95(5H, m), 3.32-3.49(1H, m),
3.55-3.72(2H, m), 3.86-4.03(2H, m), 4.20-4.30(1H, m), 4.60-4.69(1H,
m), 4.94-5.01(1H, m), 7.30(1H, d, J=3 Hz), 7.40-7.49(3H, m),
7.58-7.65(3H, m), 9.11-9.21(1H, m)
EXAMPLE 25
[0460]
(2R)-N-Hydroxy-4-methanesulfonyl-1-(5-phenylthiophene-2-sulfonyl)-2-
-piperazinecarboxamide (153 mg) was obtained in substantially the
same manner as in Example 5.
[0461] Mass (ESI): 444 (M-1)
[0462] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.69-2.80(1H,
m), 2.86(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.54(1H, d, J=14 Hz),
3.69-3.88(3H, m), 4.49(1H, d, J=2 Hz), 7.40-7.52(3H, m), 7.62(1H,
d, J=3 Hz), 7.70(1H, d, J=3 Hz), 7.76(2H, d, J=8 Hz), 9.00 (1H,
brs)
EXAMPLE 26
[0463] (2R)-1-{5-(3-Fluorophenyl)
thiophene-2-sulfonyl}-4-methanesulfonyl--
N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (370 mg) was
obtained in substantially the same manner as in Example 4.
[0464] Mass (ESI): 546 (M-1)
[0465] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.67(4H,
m), 1.71-1.90(2H, m), 2.78-2.95(5H, m), 3.30-3.50(1H, m),
3.57-3.73(2H, m), 3.87-4.03(2H, m), 4.20-4.29(1H, m), 4.59-4.69(1H,
m), 4.94-5.00(1H, m), 7.08-7.16(1H, m), 7.28-7.33(2H, m),
7.36-7.47(2H, m), 7.60-7.68(1H, m), 9.10-9.20(1H, m)
EXAMPLE 27
[0466]
(2R)-1-{5-(3-Fluorophenyl)thiophene-2-sulfonyl}-N-hydroxy-4-methane-
sulfonyl-2-piperazinecarboxamide (282 mg) was obtained in
substantially the same manner as in Example 5.
[0467] Mass (ESI): 462 (M-1)
[0468] .sup.1NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.69-2.80(1H,
m), 2.86(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.53(1H, d, J=14 Hz),
3.67-3.86(3H, m), 4.48(1H, d, J=2Hz), 7.28(1H, t, J=8 Hz),
7.49-7.61(2H, m), 7.61-7.72(3H, m), 9.00 (1H, brs)
EXAMPLE 28
[0469]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (224 mg) was
obtained in substantially the same manner as in Example 4.
[0470] Mass (ESI-): 546 (M-H)
[0471] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.90(6H,
m), 2.75-2.95(2H, m), 2.91, 2.94(3H, s), 3.32-3.50(1H, m),
3.55-3.75(2H, m), 3.85-4.05(2H, m), 4.23(1H, d, J=10 Hz),
4.55-4.68(1H, br), 4.97(1H, m), 7.15(2H, t, J=8 Hz), 7.23(1H, d,
J=1 Hz), 7.58(2H, d, J=3.8 Hz), 7.55-7.65(1H, m), 9.13, 9.16(1H,
brs)
EXAMPLE 29
[0472]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-methane-
sulfonyl-2-piperazinecarboxamide (103 mg) was obtained in
substantially the same manner as in Example 5.
[0473] Mass (ESI-): 462 (M-H)
[0474] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.65-2.90(2H,
m), 2.85(3H, s), 3.35-3.53(1H, m), 3.66(1H, d, J=12 Hz), 3.95(1H,
d, J=12Hz), 4.25(1H, d, J=12 Hz), 4.73(1H, s), 7.13(2H, t, J=8 Hz),
7.22(1H, d, J=1 Hz), 7.52-7.65(3H, m)
EXAMPLE 30
[0475] (2R)-1-[5-(4-Fluorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-4-methan-
esulfonyl-2-piperazinecarboxamide (0.90 g) and 1N NaOH (1.95 ml)
were used to give 0.94 g of
(2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-hydro-
xy-4-methanesulfonyl-2-piperazinecarboxamide sodium salt.
[0476] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.71 (1H, t,
J=10 Hz), 2.83(3H, s), 2.76-2.88(1H, m), 3.52(2H, d, J=10 Hz),
3.81(1H, t, J=10 Hz), 4.04(1H, d, J=10 Hz), 4.24(1H, s), 7.32(2H,
t, J=8 Hz), 7.52(1H, d, J=3 Hz), 7.73-7.87 (4H, m)
[0477] Preparation 47
[0478] 2-(4-Chlorophenyl)thiophene (1.52 g) was obtained in
substantially the same manner as in Preparation 43.
[0479] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.07(1H, dd,
J=4, 4 Hz), 7.25-7.37(4H, m), 7.53(2H, d, J=8 Hz)
[0480] Preparation 48
[0481] 5-(4Chlorophenyl)-2-thiophenesulfonyl chloride (1.55 g) was
obtained in substantially the same manner as in Preparation 44.
[0482] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.30(1H, d, J=4
Hz), 7.45(2H, d, J=9 Hz), 7.57(2H, d, J=9 Hz), 7.86(1H, d, J=4
Hz)
EXAMPLE 31
[0483]
(2R)-1-[5-(4Chlorophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N--
(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (424 mg) was
obtained in substantially the same manner as in Example 4.
[0484] Mass (ESI-): 562, 564 (M-H)
[0485] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.90(6H,
m), 2.77-2.95(5H, m), 3.38-3.49(1H, m), 3.57-3.75(2H, m),
3.86-4.00(2H, m), 4.24(1H, d, J=13 Hz), 4.58-4.65(1H, br),
4.92-4.98(1H, m), 7.07(1H, d, J=8 Hz), 7.41(2H, d, J=8 Hz),
7.52(2H, d, J=8 Hz), 7.60(1H, d, J=8 Hz), 9.17-9.27(1H, m)
[0486] Preparation 49
[0487] 5-(.sup.4-Methoxyphenyl)-2-thiophenesulfonyl chloride (1.64
g) was obtained in substantially the same manner as in Preparation
44.
[0488] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.85(3H, s),
6.98(2H, d, J=8 Hz), 7.20(1H, d, J=4 Hz), 7.57(1H, d, J=8 Hz),
7.81(1H, d, J=4 Hz)
EXAMPLE 32
[0489]
(2R)-1-[5-(4-Methoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl--
N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (454 mg) was
obtained in substantially the same manner as in Example 4.
[0490] Mass (ESI-): 558 (M-H)
[0491] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.55-1.91(6H,
m), 2.76-2.95(5H, m), 3.38-3.49(1H, m), 3.55-3.72(2H, m), 3.85(3H,
s), 3.90-4.05(2H, m), 4.23(1H, d, J=13 Hz), 4.60-4.67(1H, br),
4.96-5.01(1H, m), 6.93(2H, d, J=8 Hz), 7.19(1H, d, J=4 Hz),
7.52(2H, d, J=8 Hz), 7.60(1H, d, J=4 Hz), 9.25-9.39(1H, m)
[0492] Preparation 50
[0493] 5-(4-Tolyl)-2-thiophenesulfonyl chloride (782 mg) was
obtained in substantially the same manner as in Preparation 44.
[0494] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.44(3H, s),
7.26(2H, d, J=13 Hz), 7.27(1H, d, J=6 Hz), 7.50(2H, d, J=13 Hz),
7.81(1H, d, J=6 Hz)
EXAMPLE 33
[0495]
(2R)-1-[5-(4-Methylphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (372 mg) was
obtained in substantially the same manner as in Example 4.
[0496] Mass (ESI-): 542 (M-H)
[0497] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.75-3.00(5H, m), 3.35-3.51(1H, m), 3.56-3.75(2H, m), 3.85(3H,
s), 3.87-4.04(2H, m), 4.23(1H, d, J=13 Hz), 4.60-4.69(1H, br),
4.95-5.02(1H, m), 7.20-7.28(4H, m), 7.49(1H, d, J=11 Hz),
9.15-9.28(1H, m)
[0498] Preparation 51
[0499] 5-(4-Nitrophenyl)-2-thiophenesulfonyl chloride (915 mg) was
obtained in substantially the same manner as in Preparation 44.
[0500] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.48(2H, d, J=4
Hz), 7.84(1H, d, J=9 Hz), 7.91(1H, d, J=4 Hz), 8.47(1H, d, J=9
Hz)
EXAMPLE 34
[0501]
(2R)-1-[5-(4-Nitrophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N--
(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (242 mg) was
obtained in substantially the same manner as in Example 4.
[0502] Mass (ESI-): 573 (M-H)
[0503] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.54-1.84(6H,
m), 2.79-2.95(5H, m), 3.34-3.49(1H, m), 3.56-3.75(2H, m),
3.89-4.00(2H, m), 4.22(1H, d, J=13 Hz), 4.62-4.71(1H, br),
4.94-5.00(1H, m), 7.43(1H, d, J=14 Hz), 7.62-7.69(1H, br), 7.77(1H,
d, J=11 Hz), 8.29(1H, d, J=11 Hz), 9.17-9.30(1H, br)
[0504] Preparation 52
[0505] 2-(2-Fluorophenyl)thiophene (1.56 g) was obtained in
substantially the same manner as in Preparation 43.
[0506] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 6.96(1H, t, J=8
Hz), 7.09(1H, t, J=4 Hz), 7.22-7.40(5H, m)
[0507] Preparation 53
[0508] 2-(1-Fluorophenyl)thiophene-5-sulfonylchloride (1.10 g) was
obtained in substantially the same manner as in Preparation 44.
[0509] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.20-7.30(1H,
m), 7.40-7.47(1H, m), 7.50(1H, d, J=4 Hz), 7.68(1H, t, J=8 Hz)
7.88(1H, d, J=4 Hz)
EXAMPLE 35
[0510]
(2R)-1-[5-(3-Fluorophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (384 mg) was
obtained in substantially the same manner as in Example 4.
[0511] Mass (ESI): 546 (M-1)
[0512] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.68(4H,
m), 1.70-1.90(2H, m), 2.72-2.95(5H, m), 3.32-3.49(1H, m),
3.54-3.72(2H, m), 3.88-4.05(2H, m), 4.20-4.30(1H, m), 4.59-4.70(1H,
m), 4.95-5.00(1H, m), 7.15-7.28(2H, m), 7.33-7.41(1H, m), 7.46(1H,
d, J=4 Hz), 7.60-7.69(2H, m), 9.10-9.21(1H, m)
[0513] Preparation 54
[0514] Into a mixture of 2-mercapto-4-phenylthiazole (2.00 g) and
4N hydrochloric acid (20 ml) in 1,2-dichloroethane (10 ml) was
introduced Cl.sub.2 gas over 1 hour at below 15.degree. C. The
organic layer was separated, washed with H.sub.2O and brine and
dried over sodium sulfate. After concentration, the obtained
residue was crystallized from hexane to give 1.21 g of
4-phenylthiazole-2-sulfonylchloride.
[0515] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.41-7.53(3H,
m), 7.92(1H, s), 7.96(2H, d, J=8 Hz)
EXAMPLE 36
[0516]
(2R)-4-Methanesulfonyl-1-(4-phenylthiazole-2-sulfonyl)-N-(2-tetrahy-
dropyranyloxy)-2-piperazinecarboxamide (177 mg) was obtained in
substantially the same manner as in Example 4.
[0517] Mass (ESI): 529 (M-1)
[0518] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.40-1.80(6H,
m), 2.90-2.97(3H, m), 3.32-3.49(1H, m), 3.54-3.72(2H, m),
3.88-4.05(2H, m), 4.20-4.30(1H, m), 4.59-4.70(1H, m), 4.95-5.00(1H,
m), 7.15-7.28(2H, m), 7.33-7.41(1H, m), 7.46(1H, d, J=4 Hz),
7.60-7.69(2H, m), 9.10-9.21(1H, m)
EXAMPLE 37
[0519] (2R)-1-[5-(3-Isoxazolyl)
thiophene-2-sulfonyl]-4-methanesulfonyl-N--
(2-tetrahydropyranyloxy)-2-piperazineboxamide (348 mg) was obtained
in substantially the same manner as in Example 4.
[0520] Mass (ESI): 519 (M-1)
[0521] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.69(4H,
m), 1.70-1.90(2H, m), 2.78-2.95(5H, m) 3.35-3.52(1H, m),
3.58-3.79(2H, m), 3.86-4.01(2H, m), 4.19-4.29(1H, m), 4.58-4.72(1H,
m), 4.93-5.00(1H, m) 6.57(1H, s), 7.50(1H, d, J=3 Hz),
7.60-7.70(1H, m), 8.33(1H, s), 9.05-9.18(1H,m)
[0522] Preparation 55
[0523] 2-(4-Trifluoromethylphenyl)thiophene (1.57 g) was obtained
in substantially the same manner as in Preparation 43.
[0524] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.10-7.14(1H,
m), 7.34(1H, d, J=4 Hz), 7.40(1H, d, J=4 Hz), 7.62(2H, d, J=8 Hz),
7.71(2H, d, J=8 Hz)
[0525] Preparation 56
[0526] To a mixture of 2-(4-trifluoromethylphenyl)thiophene (1.56
g) and acetic anhydride (1.05 g) in AcOEt (7.8 ml) was added a
solution of sulfonic acid (637 mg) in AcOEt (1.5 ml) with
ice-cooling. After being allowed to ambient temperature, the
mixture was stirred for 2 hours and poured into cold water. The
resulting mixture was adjusted to have a pH of 7 with 3N aqueous
sodium hydroxide, then a pH of 2 with concentrated hydrochloric
acid. The separated solid was recoverd and washed with 4N aqueous
hydrochloric acid. The obtained solid was dried in vacuo to give
1.55 g of sodium 5-(4-trifluoromethylphenyl)-thiophene
sulfonate.
[0527] .sup.1H-NMR (300 MHz, D.sub.2O, .delta.): 7.40(1H, d, J=4
Hz), 7.47(1H, d, J=4 Hz), 7.72(2H, d, J=8 Hz), 7.78(2H, d, J=8
Hz)
[0528] Preparation 57
[0529] A mixture of sodium 5-(4-trifluoromethylphenyl)thiophene
sulfonate (1.50 g) and DMF (498 mg) in thionyl chloride (7.5 ml)
was stirred for 2 hours at 50.degree. C. The mixture was
concentrated and partitioned between AcOEt and 3% aqueous sodium
bicarbonate. The organic layer was separated, washed with 3%
aqueous NaHCO.sub.3 solution and brine, dried over sodium sulfate
and evaporated in vacuo after filtration to give 1.39 g of
5-(4-trifluoromethylphenyl)thiophene-2-sulfonylchloride as a
solid.
[0530] m.p.: 73-75.degree. C.
[0531] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.39(1H, d, J=3
Hz), 7.74(4H, s), 7.89(1H, d, J=3 Hz)
EXAMPLE 38
[0532] (2R)-4Methanesulfonyl-N-(2-tetrahydropyranyloxy) -1
-[5-(4-trifluoromethylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamid-
e was obtained in substantially the same manner as in Example
4.
[0533] Mass (ESI): 596 (M-1)
[0534] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.67(4H,
m), 1.70-1.90(2H, m), 2.77-2.95(5H, m), 3.33-3.50(1H, m),
3.56-3.73(2H, m), 3.86-4.03(2H, m), 4.20-4.28(1H, m), 4.60-4.70(1H,
m), 4.94-5.00(1H, m), 7.38(1H, d, J=3 Hz), 7.61-7.70(1H, m),
7.51(4H, s), 9.08-9.17(1H,m)
[0535] Preparation 58
[0536] 2-[3,4-(Methylenedioxy)phenyl]thiophene (1.53 g) was
obtained in substantially the same manner as in Preparation 43.
[0537] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 5.98(2H1, s),
6.81(1H, d, J=8 Hz), 7.03(1H, t, J=4 Hz), 7.07-7.12(2H, m),
7.18(1H, d, J=4 Hz), 7.21(1H, d, J=4 Hz)
[0538] Preparation 59
[0539] Sodium 2-[3,4-(methylenedioxy)phenyl]thiophene sulfonate
(1.89 g) was obtained in substantially the same manner as in
Preparation 56.
[0540] .sup.1H-NMR (300 MHz, D.sub.2O, .delta.): 5.99(2H, s),
6.88(1H, d, J=8 Hz), 7.11-7.19(3H, m), 7.40(1H, d, J=4 Hz)
[0541] Preparation 60
[0542] 2-[3,4-(Methylenedioxy)phenyl]thiophene-5-sulfonylehloride
(1.58 g) was obtained in substantially the same manner as in
Preparation 57.
[0543] m.p.: 117-119.degree. C.
[0544] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 6.05(2H,s),
6.89(1H, d, J=8 Hz), 7.08(1H, s) 7.14(1H, d, J=8 Hz), 7.17(1H, d,
J=4 Hz), 7.80(1H, d, J=4 Hz)
EXAMPLE 39
[0545]
(2R)-4-Methanesulfonyl-N-(2-tetrahydropyranyloxy)-1-{5-[3,4-(methyl-
enedioxy)phenyl]thiophene-2-sulfonyl)-2-piperazinecarboxamide (307
mg) was obtained in substantially the same manner as in Example
4.
[0546] Mass (ESI): 572 (M-1)
[0547] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.68(4H,
m), 1.71-1.90(2H, m), 2.75-2.95(5H, m), 3.31-3.49(1H, m),
3.56-3.71(2H, m), 3.85-4.03(2H, m), 4.20-4.30(1H, m), 4.56-4.67(1H,
m), 4.94-5.01(1H, m), 6.03(2H, s), 6.85(1H, d, J=8 Hz), 7.05(1H,s)
7.10(1H, d, J=8 Hz), 7.15(1H, d, J=3 Hz), 7.53-7.62(1H,m),
9.11-9.27(1H, m)
[0548] Preparation 61
[0549] To a mixture of 4-iodophenol (2 g) and potassium carbonate
(1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml)
at room temperature, and the mixture was stirred at 50.degree. C.
overnight. The resulting mixture was poured into water (50 ml), and
extracted with diethyl ether (25 ml.times.3). The combined organic
layer was washed with 0.5N hydrochloric acid, saturated aqueous
NaHCO.sub.3 solution and brine, and dried over MgSO.sub.4. The
solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as
a slightly brown solid. The product was used for the next reaction
without further purification.
[0550] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.40(3H, t, J=7
Hz), 3.97(2H, q, J=7 Hz), 6.66(2H, d, J=8 Hz), 7.54(2H, d, J=8
Hz)
[0551] Preparation 62
[0552] 2-(4-Ethoxyphenyl)thiophene (1.33 g) was obtained in
substantially the same manner as in Preparation 43.
[0553] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.40(3H, t, J7
Hz), 4.05(2H, q, J=7 Hz), 6.90(2H, d, J=8 Hz), 7.02-7.04 (1H, m),
7.16-7.21 (2H, m), 7.51(2H, d, J=8 Hz)
[0554] Preparation 63
[0555] 5-(4-Ethoxyphenyl)-2-thiophenesulfonyl chloride (766 mg) was
obtained in substantially the same manner as in Preparation 44.
[0556] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.42(3H, t, J=7
Hz), 4.09(2H, q, J=7 Hz), 6.94(2H, d, J=8 Hz), 7.19(1H, d, J=4 Hz),
7.55(2H, d, J=8 Hz), 7.80(1H, d, J=4 Hz)
EXAMPLE 40
[0557] (2R)-1-[5-(4-Ethoxyphenyl)
thiophene-2-sulfonyl]-4-methanesulfonyl--
N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (273 mg) was
obtained in substantially the same manner as in Example 4.
[0558] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45(3H, t, J=7
Hz), 1.52-1.89(6H, m), 2.73-2.96(2H, m), 2.88(1.5H, s), 2.94(1.5H,
s), 3.35-3.49(1H, m), 3.59-3.72(2H, m), 3.87-4.05(2H, m), 4.09(2H,
q, J=7 Hz), 4.27(1H, d, J=13 Hz), 4.59-4.68(1H, br), 5.02(1H, bs),
6.95(2H, d, J=8 Hz), 7.16(1H, d, J=4 Hz), 7.51(2H, d, J=8 Hz),
7.60(1H, d, J=4 Hz), 9.15-9.26(1H, m)
[0559] Preparation 64
[0560] 4-(2-Thienyl) benzonitrile (1.58 g) was obtained in
substantially the same manner as in Preparation 43.
[0561] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.13(1H, t, J=3
Hz), 7.40-7.48(2H, m), 7.51-7.82(4H, m)
[0562] Preparation 65
[0563] 2-(4Cyanophenyl)thiophene-5-sulfonylchloride (2.01 g) was
obtained in substantially the same manner as in Preparation 44.
[0564] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.42(1H, d, J=3
Hz), 7.74(2H, d, J=8 Hz), 7.79(2H, d, J=8 Hz) 7.90(1H, d, J=3
Hz)
EXAMPLE 41
[0565]
(2R)-1-[5-(4-Cyanophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N--
(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (296 mg) was
obtained in substantially the same manner as in Example 4.
[0566] Mass (ESI): 553 (M-1)
[0567] .sup.1H-NMR (300 MHz, CDCl.sub.3 , .delta.): 1.53-1.66(4H,
m), 1.72-1.87(2H, m), 2.78-2.95(5H, m), 3.34-3.50(1H, m),
3.58-3.75(2H, m), 3.88-4.02(2H, m), 4.18-4.25(1H, m), 4.60-4.70(1H,
m), 4.93-5.00(1H, m), 7.40(1H, d, J=3 Hz), 7.62-7.78(5H, m),
9.08-9.19(1H, m)
[0568] Preparation 66
[0569] 2-(4-Cyanomethylphenyl)thiophene (1.32 g) was obtained in
substantially the same manner as in Preparation 43.
[0570] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.) : 3.78(2H,s),
7.10(1H, t, J=3 Hz), 7.30-7.38(4H, m), 7.52(2H, d, J=8 Hz)
[0571] Preparation 67
[0572] 2-(4-Cyanomethylphenyl)thiophene-5-sulfonylchloride (2.21 g)
was obtained in substantially the same manner as in Preparation
44.
[0573] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.82(2H, s),
7.32(1H, d, J=3 Hz), 7.46(2H, d, J=8 Hz), 7.68(2H, d, J=8 Hz),
7.86(1H, d, J=3 Hz)
EXAMPLE 42
[0574]
(2R)-1-[5-(4-Cyanomethylphenyl)thiophene-2-sulfonyl]-4-methanesulfo-
nyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (293 mg) was
obtained in substantially the same manner as in Example 4.
[0575] Mass (ESI): 567 (M-1)
[0576] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.69(4H,
m), 1.71-1.90(2H, m), 2.77-2.98(5H, m), 3.33-3.50(1H, m),
3.58-3.73(2H, m), 3.82(2H, s), 3.88-4.06(2H, m), 4.20-4.29(1H, m),
4.60-4.70(1H, m) 4.94-5.01(1H, m), 7.31(1H, d, J=3 Hz), 7.42(2H, d,
J=8 Hz), 7.60-7.69(3H, m), 9.08-9.19(1H, m)
[0577] Preparation 68
[0578] 4-(2-Thienyl)phenol (10.2 g) was obtained in substantially
the same manner as in Preparation 43.
[0579] Mass (ESI): 175 (M-1)
[0580] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 6.80(2H, d,
J=8 Hz), 7.07(1H, t, J=3 Hz), 7.30(1H, d, J=3 Hz) 7.40(1H, d, J=3
Hz), 7.46(2H, d, J=8 Hz), 9.63(1H, brs)
[0581] Preparation 69
[0582] To a mixture of 4-(2-thienyl)phenol (1.00 g) and acetic
anhydride (869 mg) in tetrahydrofuran (10 ml) was added pyridine
(494 mg) with ice-cooling. The mixture was stirred for 1 hour at
said temperature and 1 hour at ambient temperature. After
concentration, the mixture was partitioned between AcOEt and
H.sub.2O. The separated organic layer was washed with 1% aqueous
citric acid, 3% aqueous NaHCO.sub.3 solution and brine, dried over
sodium sulfate and concentrated. The residue was triturated with
hexane to give 985 mg of 2-(4-acetoxyphenyl)thiophene as a
powder.
[0583] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.32(3H, s),
7.05-7.16(3H, m), 7.24-7.30(2H, m), 7.61(2H, d, J=8 Hz)
[0584] Preparation 70
[0585] 2-(4-Acetoxyphenyl)thiophene-5-sulfonylchloride (1.14 g) was
obtained in substantially the same manner as in Preparation 44.
[0586] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.33(3H, s),
7.21(2H, d, J=8 Hz), 7.29(1H, d, J=3 Hz), 7.63(2H, d, J=8 Hz),
7.84(1H, d, J=3 Hz)
EXAMPLE 43
[0587]
(2R)-1-5-(4-Acetoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (262 mg) was
obtained in substantially the same manner as in Example 44.
[0588] Mass (ESI): 586 (M-1)
[0589] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.69(4H,
m), 1.72-1.90(2H, m), 2.35(3H, s), 2.77-2.97(5H, m), 3.36-3.50(1H,
m), 3.58-3.72(2H, m), 3.87-4.04(2H, m), 4.20-4.29(1H, m),
4.59-4.69(1H, m), 4.94-5.01(1H, m), 7.20(2H, d, J=8 Hz),
7.24-7.30(1H, m), 7.59-7.67(3H, m), 9.08-9.19(1H, m)
[0590] Preparation 71
[0591] 2-(4-Hydroxymethylphenyl)thiophene (2.23 g) was obtained in
substantially the same manner as in Preparation 43.
[0592] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.70(1H, t, J=8
Hz), 4.71(2H, s), 7.06-7.10(1H, m), 7.18(1H, d, J=3 Hz), 7.31(1H,
d, J=3 Hz), 7.38(2H, d, J=8 Hz), 7.61(2H, d, J=8 Hz)
[0593] Preparation 72
[0594] 2-(4-Acetoxymethylphenyl)thiophene (2.55 g) was obtained in
substantially the same manner as in Preparation 69.
[0595] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.12(3H, s),
5.12(2H, s), 7.09(1H, t, J=3 Hz), 7.30(1H, d, J=3 Hz), 7.33(1H, d,
J=3 Hz), 7.48(2H, d, J=8 Hz), 7.61(2H, d, J=8 Hz)
[0596] Preparation 73
[0597] 2-(4-Acetoxymethylphenyl)thiophene-5-sulfonylchloride (3.00
g) was obtained in substantially the same manner as in Preparation
44. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.14(3H, s),
5.16(2H, s), 7.32(1H, d, J=3 Hz), 7.47(2H, d, J=8 Hz), 7.63(2H, d,
J=8 Hz), 7.87(1H, d, J=3 Hz)
EXAMPLE 44
[0598]
(2R)-1-[5-(4-Acetoxymethylphenyl)thiophene-2-sulfonyl]-4-methanesul-
fonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide was
obtained in substantially the same manner as in Example 4.
[0599] Mass (ESI): 600 (M-1)
[0600] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.89(6H,
m), 2.13(3H, s), 2.76-2.96(5H, m), 3.34-3.50(1H, m), 3.57-3.72(2H,
m), 3.87-4.04(2H, m), 4.20-4.28(1H, m), 4.59-4.68(1H, m),
4.94-5.00(1H, m), 5.13(2H, s), 7.30(1H, d, J=3 Hz), 7.42(2H, d, J=8
Hz), 7.58-7.65(3H, m), 9.08-9.19(1H, m)
[0601] Preparation 74
[0602] 2-(3-Fluoro-4-methoxyphenyl)thiophene (435 mg) was obtained
in substantially the same manner as in Preparation 43.
[0603] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.94(3H, s),
6.93-7.07(2H, m), 7.17-7.36(4H, m)
[0604] Preparation 75
[0605] 5-(3-Fluoro-4-methoxyphenyl)-2-thiophenesulfonyl chloride
(318 mg) was obtained in substantially the same manner as in
Preparation 44.
[0606] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.97(3H, s),
7.05(2H, t, J=7 Hz), 7.21(1H, d, J4 Hz), 7.36(1H, d, J=4 Hz),
7.39(1H, s), 7.83(2H, d, J=7 Hz)
EXAMPLE 45
[0607]
(2R)-1-[5-(3-Fluoro-4-methoxyphenyl)thiophene-2sulfonyl]-4-methanes-
ulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (396 mg)
was obtained in substantially the same manner as in Example 4.
[0608] Mass (ESI-): 576 (M-H)
[0609] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.57-1.93(6H,
m), 2.79-2.91(2H, m), 2.88(1.5H, s), 2.94(1.5H, s), 3,34-3.48(1H,
m), 3.57-3.69(2H, m), 3.84-4.03(2H, m), 3.93(3H, s), 4.22(1H, d,
J=13 Hz), 4.55-4.63(1H, br), 4.94-5.00(1H, m), 6.99(1H, dd, J=9, 9
Hz), 7.18(1H, d, J=4 Hz), 7.30(1H, s), 7.33(1H, d, J=4 Hz),
7.55-7.61(1H, m), 9.12-9.20(1H, br)
[0610] Preparation 76
[0611] 2-(3-Methoxyphenyl)thiophene (1.60 g) was obtained in
substantially the same manner as in Preparation 43. .sup.1H-NMR
(300 MHz, CDCl.sub.3, .delta.): 3.85(3H, s), 6.83(1H, dd, J=3, 8
Hz), 7.08(1H, t, J=3 Hz), 7.15(1H, d, J=3 Hz), 7.21(1H, d, J=8 Hz),
7.23-7.32(3H, m)
[0612] Preparation 77
[0613] Sodium 5-(3-methoxyphenyl)thiophene-2-sulfate (1.85 g) was
obtained in substantially the same manner as in Preparation 56.
[0614] Mass (ESI): 269 (M-1)
[0615] .sup.1H-NMR (300 MHz, D.sub.2O, .delta.): 3.87(3H, s),
6.99(1H, s), 7.20(1H, s), 7.29(1H, d, J=8 Hz), 7.33(1H, t, J=3 Hz),
7.39(1H, t, J=8 Hz), 7.46(1H, d, J=3 Hz)
[0616] Preparation 78
[0617] 2-(3-Methoxyphenyl)thiophene-5-sulfonylchloride (1.75 g) was
obtained in substantially the same manner as in Preparation 57.
[0618] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.88(3H, s),
6.99(1H, dd, J=3, 8 Hz), 7.13(1H, d, J=3 Hz), 7.21(1H, d, J=8 Hz),
7.30(1H, d, J=3 Hz), 7.39(1H, t, J=8 Hz), 7.83(1H, d, J=3 Hz)
EXAMPLE 46
[0619]
(2R)-4-Methanesulfonyl-1-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]--
N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (349 mg) was
obtained in substantially the same manner as in Example 4.
[0620] Mass (ESI): 558 (M-1)
[0621] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.65(4H,
m), 1.71-1.87(2H, m), 2.75-2.95(5H, m), 3.33-3.48(1H, m),
3.56-3.71(2H, m), 3.87(3H, s), 3.89-4.02(2H, m), 4.20-4.28(1H, m),
4.59-4.67(1H, m), 4.93-5.00(1H, m), 6.96(1H, d, J=8 Hz), 7.11(1H,
d, J=3 Hz), 7.19(1H, d, J=8 Hz), 7.29(1H, d, J=3 Hz), 7.35(1H, t,
J=8 Hz), 7.59-7.65(1H, m), 9.08-9.19(1H, m)
[0622] Preparation 79
[0623] N,N-Dimethyl-4-(2-thienyl)benzenesulfonamide (1.26 g) was
obtained in substantially the same manner as in Preparation 43.
[0624] .sup.1H-NMR (300 MHz, CDCl.sub.6, .delta.): 2.73(6H, s),
7.14(1H, t, J=3 Hz), 7.40(1H, d, J=3 Hz), 7.43(1H, d, J=3 Hz),
7.78(4H, s)
[0625] Preparation 80 2-(4-Dimethylaminosulfonylphenyl)
thiophene-5-sulfonylchloride (1.47 g) was obtained in substantially
the same manner as in Preparation 44.
[0626] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.78(6H, s),
7.42(1H, d, J=3 Hz), 7.79(2H, d, J=8 Hz), 7.86-7.91(2H, m)
EXAMPLE 47
[0627] (2R)-1-[5-(4-Dimethylaminosulfonylphenyl)
thiophene-2-sulfonyl-4-me-
thanesulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(426 mg) was obtained in substantially the same manner as in
Example 4.
[0628] Mass (ESI): 635 (M-1)
[0629] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.31-1.67(6H,
m), 2.64(6H, s), 2.77-2.91(4H, m), 3.02-3.17(1H, m), 3.23-3.37(1H,
m), 3.50-3.64(2H, m), 3.72-3.90(3H, m), 4.45-4.55(1H, m),
4.63-4.72(1H, m), 7.68(1H, d, J=3 Hz), 7.70(1H, d, J=3 Hz),
7.83(2H, d, J=8 Hz), 8.03(2H, d, J=8 Hz)
[0630] Preparation 81
[0631] To a mixture of 4-(2-thienyl)phenol (1.76 g) and
triethylamine (1.50 g) in MeCN (10 ml) was added dropwise
methanesulfonylchloride (1.26 g) with ice-cooling. The mixture was
stirred for 1 hour, then for 1 hour at ambient temperature. The
resulting mixture was concentrated and diluted with a mixture of
AcOEt and H.sub.2O to separate solid. The separated solid was
recovered and washed with H.sub.2Oand AcOEt to give 1.62 g of
.sup.2-(4-methanesulfonyloxyphenyl)thiophene.
[0632] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.17(3H, s),
7.08-7.14(1H, m), 7.28-7.38(4H, m), 7.65(2H, d, J=8 Hz)
[0633] Preparation 82
[0634]
2-(4-Methanesulfonyloxyphenyl)thiophene-5-sulfonylchloride(2.02 g)
was obtained in substantially the same manner as in Preparation
44.
[0635] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.22(3H, s),
7.31(1H, t, J=3 Hz), 7.40(2H, d, J=8 Hz), 7.70(2H, d, J=8 Hz),
7.87(1H, d, J=8 Hz)
EXAMPLE 48
[0636]
(2R)-1-[5-(4-Methanesulfonyloxyphenyl)thiophene-2-sulfonyl]-4-metha-
nesulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (392
mg) was obtained in substantially the same manner as in Example
4.
[0637] Mass (ESI): 622 (M-1)
[0638] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.70(4H,
m), 1.72-1.91(2H, m), 2.76-2.98(5H, m), 3.20(3H, s), 3.33-3.50(1H,
m), 3.58-3.74(2H, m), 3.85-4.05(2H, m), 4.19-4.29(1H, m),
4.58-4.70(1H, m), 4.94-5.02(1H, m), 7.26-7.34(1H, m), 7.40(2H, d,
J=8 Hz), 7.61-7.72(3H, m), 9.08-9.21(1H, m)
[0639] Preparation 83
[0640] 2-(2,4-Difluorophenyl)thiophene (863 mg) was obtained in
substantially the same manner as in Preparation 43.
[0641] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 6.85-6.96(2H,
m), 7.11(1H, t, J=3 Hz), 7.35(1H, d, J=3 Hz) 7.41(1H, d, J=3 Hz),
7.54-7.64(1H, m)
[0642] Preparation 84
[0643] 2-(2,4-Difluorophenyl)thiophene-5-sulfonylchloride (819 mg)
was obtained in substantially the same manner as in Preparation
44.
[0644] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 6.97-7.06(2H,
m), 7.42(1H, d, J=3 Hz), 7.60-7.70(2H, m), 7.88(1H, d, J=3 Hz)
EXAMPLE 49
[0645]
(2R)-1-[5-(2,4-Difluorophenyl)thiophene-2-sulfonyl]-4-methanesulfon-
yl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (309 mg) was
obtained in substantially the same manner as in Example 4.
[0646] Mass (ESI): 564 (M-1)
[0647] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.90(6H,
m), 2.74-2.95(5H, m), 3.34-3.51(1H, m), 3.54-3.71(2H, m),
3.87-4.03(2H, m), 4.19-4.29(1H, m), 4.58-4.69(1H, m), 4.94-5.01(1H,
m), 6.93-7.04(2H, m) 7.40(1H, d, J=3 Hz), 7.56-7.67(2H, m),
9.08-9.19(1H, m)
[0648] Preparation 85
[0649] A mixture of 4-(2-thienyl)phenol (1.30 g),
chloroacetonitrile (668 mg) and potassium carbonate (1.53 g) in DMF
(7 ml) was stirred for 5 hours at ambient temperature. The mixture
was diluted with H.sub.2O and the separated solid was recovered to
give 1.45 g of 2-(4-cyanomethoxyphenyl)thiophene.
[0650] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 4.80(2H, s),
7.00(2H, d, J=8 Hz), 7.08(1H, t, J=3 Hz), 7.22-7.30(2H, m),
7.60(2H, d, J=8 Hz)
[0651] Preparation 86
[0652] 2-(4Cyanomethoxyphenyl)thiophene-5-sulfonylchloride (1.92 g)
was obtained in substantially the same manner as in Preparation
44.
[0653] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 4.84(2H, s),
7.08(2H, d, J=8 Hz), 7.24(1H, d, J=3 Hz), 7.62(2H, d, J=8 Hz),
7.84(1H, d, J=3 Hz)
EXAMPLE 50
[0654]
(2R)-1-[5-(4Cyanomethoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfo-
nyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (266 mg) was
obtained in substantially the same manner as in Example 4.
[0655] Mass (ESI): 583 (M-1)
[0656] .sup.1-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.70(4H, m),
1.72-1.90(2H, m), 2.77-3.00(5H, m), 3.32-3.50(1H, m), 3.58-3.73(2H,
m), 3.86-4.05(2H, m), 4.20-4.30(1H, m), 4.58-4.69(1H, m), 4.83(2H,
s), 4.94-5.03(1H, m), 7.06(2H, d, J=8 Hz), 7.21(1H, d, J=3 Hz),
7.54-7.64(3H, m), 9.08-9.19(1H, m)
[0657] Preparation 87
[0658] Methyl 4-(2-thienyl)benzoate (2.07 g) was obtained in
substantially the same manner as in Preparation 43.
[0659] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.93(3H, s),
7.11(1H, t, J=3 Hz), 7.37(1H, d, J=3 Hz), 7.42(1H, d, J=3 Hz),
7.68(2H, d, J=8 Hz), 8.04(2H, d, J=8 Hz)
[0660] Preparation 88
[0661] 2-(4-Methoxycarbonylphenyl)thiophene-5-sulfonylchloride
(1.40 g) was obtained in substantially the same manner as in
Preparation 44.
[0662] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.96(3H, s),
7.41(1H, d, J=3 Hz), 7.71(2H, d, J=8 Hz), 7.89(1H, d, J=3 Hz),
8.14(2H, d, J=8 Hz)
EXAMPLE 51
[0663]
(2R)-4-Methanesulfonyl-1-[5-(4-methoxycarbonylphenyl)thiophene-2-su-
lfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (292 mg)
was obtained in substantially the same manner as in Example 4.
[0664] Mass (ESI): 586 (M-1)
[0665] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.69(4H,
m), 1.70-1.90(2H, m), 2.78-2.96(5H, m), 3.33-3.50(1H, m),
3.58-3.75(2H, m), 3.84-4.02(5H, m), 4.19-4.29(1H, m), 4.60-4.70(1H,
m),4.94-5.01(1H, m), 7.41(1H, d, J=3 Hz), 7.40(1H, d, J=3
Hz),7.61-7.70(3H, m), 8.11(2H, d, J=8 Hz), 9.08-9.9(1H, m)
[0666] Preparation 89
[0667] 4-Biphenylylthiophene (1.27 g) was obtained in substantially
the same manner as in Preparation 43.
[0668] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.10(2H, d, J=8
Hz), 7.28-7.50(5H, m), 7.59-7.70(5H, m)
[0669] Preparation 90
[0670] Sodium 5-(4-biphenylyl)-2-thiophenesulfonate (922 mg) was
obtained in substantially the same manner as in Preparation 56.
[0671] .sup.1H-NMR (300 MHz, DMSO-d.sub.6.delta.): 7.11(1H, d, J=14
Hz), 7.37(1H, d, J=4 Hz), 7.39(1H, d, J=8 Hz), 7.42-7.50(2H, m),
7.67-7.74(6H, m)
[0672] Preparation 91
[0673] 5-(4-Biphenylyl)-2-thiophenesulfonyl chloride (824 mg) was
obtained in substantially the same manner as in Preparation 57.
[0674] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 7.34(1H, d,
J=7 Hz), 7.39-7.51(3H, m), 7.56-7.65(2H1, m) 7.69(4H, s), 7.83(1H,
d, J=7 Hz)
EXAMPLE 52
[0675]
(2R)-1-[5-(4-Biphenylyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-(-
2-tetrahydropyranyloxy)-2-piperazinecarboxamide (339 mg) was
obtained in substantially the same manner as in Example 4.
[0676] Mass (ESI-): 604 (M-H)
[0677] .sup.1H-NMR (300 MHz, DMSO-d.sub.6.delta.): 1.38-1.70(6H,
m), 2.77-2.91(1, m), 2.88(3H, s), 3.02-3.19(1H, m), 3.45-3.64(2H,
m), 3.72-3.95(2H, m), 4.43-4.53(1H, m), 4.72(1H, bs), 7.40(1H, d,
J=8 Hz) 7.45-7.52(2H, m), 7.61-7.86(8H, m)
[0678] Preparation 92
[0679] 2-(4-Pyridyl)thiophene (2.53 g) was obtained in
substantially the same manner as in Preparation 43.
[0680] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.13(1H, d, J=5
Hz), 7.42(1H, d, J=4 Hz), 7.45-7.53(3H, m), 8.59(2H, d, J=5 Hz)
[0681] Preparation 93
[0682] Chlorosulfonic acid (1.4 ml) was added to
2-(4-pyridyl)thiophene (500 mg) at 0.degree. C. and the mixture was
stirred for 5 days at room temperature. Ice-water was carefully
added to this mixture at 0.degree. C. to decompose excess reagent.
This solution was poured into saturated aqueous NaHCO.sub.3
solution (ca. pH 7) and extracted with AcOEt (20 ml.times.3). The
combined organic layer was washed with brine, and dried over
MgSO.sub.4. After 4N HCl-AcOEt (10 ml) was added to the solution,
the solvent was removed in vacuo to give 300 mg of
5-(4-pyridyl)thiophenesulfonyl chloride as a white solid (yield
32.7%).
[0683] .sub.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 7.30(1H, d,
J=4 Hz), 8.05(1H, d, J=4 Hz), 8.27(2H, d, J=8 Hz), 8.81 (2H, d, J=8
Hz)
EXAMPLE 53
[0684]
(2R)-1-[5-(4-Pyridyl)thiophene-2-sulfonyl]-4methanesulfonyl-N-(2-te-
trahydropyranyloxy)-2-piperazinecarboxamide (335 mg) was obtained
in substantially the same manner as in Example 4.
[0685] Mass (ESI-): 529 (M-H)
[0686] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.55-1.91(6H,
m), 2.79-2.92(2H, m), 2.91(1.5H, s), 2.94(1.5H, s), 3.40-3.56(1H,
m), 3.58-3.77(2H, m), 3.86-4.03(2H, m), 4.21(1H, d, J=13 Hz),
4.53-4.59(1H, br), 4.92-5.00(1H, m), 7.49(2H, d, J=8 Hz), 7.49(1H,
d, J4 Hz), 7.62-7.70(1H, br), 7.69(2H, d, J=8 Hz), 9.18-9.28(1H,
br)
[0687] Preparation 94
[0688] To an ice-cooled dioxane (30 ml) was slowly added liquid
bromine (2.66 g) and this mixture was stirred for 30 minutes at
said temperature. To the mixture was added dropwise
2,3-dihydrobenzofuran (2 g), and the resulting mixture was stirred
for 3 hours at room temperature. The solvent was removed under
reduced pressure. The residue was dissolved in AcOEt (50 ml) and
the solution was washed with saturated aqueous NaHCO.sub.3 solution
and brine, and dried over MgSO.sub.4. The solvent was evaporated to
give an orange oil as a crude product. The crude product was
purified on an SiO.sub.2 column (hexane-AcOEt 20:1) to give 2.33 g
of 5-bromo-2,3 dihydrobenzofuran as white crystals (yield
70.3%).
[0689] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.11(2H, t, J=11
Hz), 4.57(2H, t, J=11 Hz), 6.66(1H, d, J=8 Hz), 7.20(1H, d, J=8
Hz), 7.30(1H, s)
[0690] Preparation 95
[0691] 2-(2,3-Dihydrobenzofuran-5-yl)thiophene (916 mg) was
obtained in substantially the same manner as in Preparation 43.
[0692] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.22(2H, t, J=11
Hz), 4.60(2H, t, J=11 Hz), 6.78(1H, d, J=8 Hz), 7.03(1H, dd, J=6,
12 Hz), 7.15(1H, d, J=4 Hz), 7.18(1H, d, J=6 Hz), 7.37(1H, d, J=8
Hz), 7.43(1H, s)
[0693] Preparation 96
[0694] Sodium 5-(2,3-dihydrobenzofuran-5-yl)-2-thiophenesulfonate
(1.14 g) was obtained in substantially the same manner as in
Preparation 56.
[0695] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.20(2H, t, J=9
Hz), 4.57(2H, t, J=9Hz), 6.77(1H, d, J=8Hz), 7.02(1H, d, J=4Hz),
7.09(1H, d, J=4 Hz), 7.31(1H, d, J=8 Hz), 7.48(1H, s)
[0696] Preparation 97
[0697] 5-(2,3-Dihydrobenzofuran-5-yl)-2-thiophenesulfonyl chloride
(770 mg) was obtained in substantially the same manner as in
Preparation 57.
[0698] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 3.30(2H, t, J=7
Hz), 4.66(2H, t, J=7 Hz), 6.83(1H, d, J=8 Hz), 7.17(1H, d, J=4 Hz),
7.41(1H, d, J=8 Hz), 7.45(1H, s), 7.79(1H, d, J=4 Hz)
EXAMPLE 54
[0699]
(2R)-1-[5-(2,3-Dihydrobenzofuran-5-yl)thiophene-2-sulfonyl]-4-metha-
nesulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (321
mg) was obtained in substantially the same manner as in Example
4.
[0700] Mass (ESI-): 570 (M-H)
[0701] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.54-1.92(6H,
m), 2.76-2.87(2H, m), 2.91(1.5H, s), 2.95(1.5H, s), 3.27(2H, t,
J=10 Hz), 3.31-3.47(1H, m), 3.58-3.71(2H, m), 3.86-4.04(1H, m),
4.20-4.30(1H, m), 4.65(2H, t, J=10 Hz), 4.91-5.00(1H, m), 6.82(1H,
d, J=8 Hz), 7.15(1H, d, J=4 Hz), 7.25(1H, d, J=4 Hz), 7.38(1H, d,
J=8 Hz), 7.42(1H, s), 7.52-7.59(1H, m), 9.10-9.25(1H, m)
[0702] Preparation 98
[0703] 2-(4-Phenoxyphenyl)thiophene (2.14 g) was obtained in
substantially the same manner as in Preparation 43.
[0704] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 6.99-7.09(5H,
m), 7.12(1H, dd, J=8, 8 Hz), 7.25(2H, d, J=5 Hz), 7.37(2H, dd, J=8
Hz), 7.58(2H, d, J=8 Hz)
[0705] Preparation 99
[0706] Sodium 5-(4-phenoxyphenyl)-2-thiophenesulfonate (717 mg) was
obtained in substantially the same manner as in Preparation 56.
[0707] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 7.01-7.10(4H,
m), 7.18(1H, dd, J=8, 8 Hz), 7.22(2H, d, J=4 Hz), 7.42(2H, dd, J=8
Hz), 7.65(2H, d, J=8 Hz)
[0708] Preparation 100
[0709] 5-(4-Phenoxyphenyl)-2-thiophenesulfonyl chloride (677 mg)
was obtained in substantially the same manner as in Preparation
57.
[0710] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.07(2H, d, J=8
Hz), 7.10(1H, d, J=8 Hz), 7.22(1H, dd, J=8, 8 Hz), 7.24(2H, d, J=4
Hz), 7.39(2H, dd, J=8 Hz), 7.60(2H, d, J=8 Hz), 7.85(1H, d, J=4
Hz)
EXAMPLE 55
[0711]
(2R)-1-[5-(4-Phenoxyphenyl)thiophene-2-sulfonyl)-4-methanesulfonyl--
N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (311 mg) was
obtained in substantially the same manner as in Example 4.
[0712] Mass (ESI-): 620 (M-H)
[0713] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.91(6H,
m), 2.75-2.89(2H, m), 2.90(1.5H, s), 2.94(1.5H, s), 3.35-3.48(1H,
m), 3.57-3.70(2H, m), 3.87-4.04(2H, m), 4.24(1H, d, J=13 Hz),
4.62(1H, bs), 4.98(1H, bs), 7.01-7.08(4H, m), 7.14-7.23(2H, m),
7.39(2H, dd, J=8, 8 Hz), 7.54(1H, d, J=8 Hz), 7.55-7.61(1H, m),
9.07(1H, bs)
[0714] Preparation 101
[0715] 2-(3-Fluoro-4-hydroxyphenyl)thiophene (3.80 g) was obtained
in substantially the same manner as in Preparation 43.
[0716] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.37(3H, s),
7.05-7.17(2H, m), 7.26-7.42(4H, m)
[0717] Preparation 102
[0718] 2-(3-Fluoro-4-acetoxyphenyl)thiophene (2.39 g) was obtained
in substantially the same manner as in Preparation 69.
[0719] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 5.18(1H, d, J=3
Hz), 6.96-7.07(2H, m), 7.18(1H, d, J=4 Hz), 7.22-7.35(3H, m)
[0720] Preparation 103
[0721] 2-(3-Fluoro-4-acetoxyphenyl)thiophene-5-sulfonyl chloride
(2.91 g) was obtained in substantially the same manner as in
Preparation 44.
[0722] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.47(3H,
s),,7.25-7.29(2H, m), 7.39-7.45(2H, m), 7.85(1H, d, J=4 Hz)
EXAMPLE 56
[0723]
(2R)-1-[5-(4-Acetoxy-3-fluorophenyl)thiophene-2-sulfonyl]-4-methane-
sulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (314
mg) was obtained in substantially the same manner as in Example
4.
[0724] Mass (ESI): 604 (M-1)
[0725] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.90(6H,
m), 2.36(3H, s), 2.76-2.96(5H, m), 3.32-3.49(1H, m), 3.57-3.73(2H,
m), 3.84-4.01(2H, m), 4.18-4.28(1H, m), 4.58-4.68(1H, m),
4.92-5.00(1H, m), 7.19-7.28(2H, m), 7.35-7.44(2H, m), 7.58-7.67(1H,
m), 9.05-9.15(1H, m)
[0726] Preparation 104
[0727] A mixture of N-(2-thienylcarbonylamino)ethanamide (5.37 g)
and phosphorus oxychloride (15 ml) was stirred for 8 hours at
90.degree. C. After cooling to ambient temperature, the mixture was
concentrated. The residue was partitioned between AcOEt and
saturated aqueous NaHCO.sub.3 solution. The organic layer was
separated and washed with saturated aqueous NaHCO.sub.3 solution
and brine. The resulting solution was dried over sodium sulfate and
concentrated to give 3.65 g of
2-methyl-5-(2-thienyl)-1,3,4-oxadiazole as a solid.
[0728] .sup.1H-NMR (300 MHz, CDCl.sub.3.delta.): 2.61(3H, s),
7.17(1H, t, J=3 Hz), 7.54(1H, d, J=3 Hz), 7.74(1H, d, J=3 Hz)
[0729] Preparation 105
[0730] 2-(5-Methyl-1,3,4-oxadiazol-2-yl)
thiophene-5-sulfonylchloride (1.06 g) was obtained in substantially
the same manner as in Preparation 44.
[0731] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.67(3H, s),
7.73(1H, d, J=3 Hz), 7.90(1H, d, J=3 Hz)
EXAMPLE 57
[0732]
(2R)-4-Methanesulfonyl-l-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-thiophe-
ne-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(327 mg) was obtained in substantially the same manner as in
Example 4.
[0733] Mass (ESI): 534 (M-1)
[0734] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.88(6H,
m), 2.63(3H, s), 2.79-2.98(5H, m), 3.38-3.53(1H, m), 3.60-3.80(2H,
m), 3.88-4.01(2H, m), 4.18-4.26(1H, m), 4.62-4.72(1H, m),
4.92-4.99(1H, m), 7.62-7.71(2H, m), 9.08-9.19(1H, m)
[0735] Preparation 106
[0736] To a mixture of acetic hydrazide (2.63 g) and NaHCO.sub.3
(3.44 g) in a solution of dioxane (40 ml) and H.sub.2O (4 ml) was
added dropwise 2-thiophenecarbonyl chloride (4.00 g) with
ice-cooling. After stirring for 2 hours at ambient temperature, the
mixture was diluted with AcOEt and filtered. After concentration of
the filtrate, the obtained residue was crystallized from a mixture
of AcOEt and hexane to give 5.38 g of
N-(2-thienylcarbonylamino)ethanamide.
[0737] Mass (ESI): 183 (M-1)
[0738] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.91(3H, s),
7.18(1H, t, J=3 Hz), 7.82(2H, d, J=3 Hz), 9.88(1H, brs), 10.33(1H,
brs)
[0739] Preparation 107
[0740] N-(2-Thienylcarbonylamino)benzamide (5.72 g) was obtained in
substantially the same manner as in Preparation 106.
[0741] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 3.57(2H, s),
7.22(1H, t, J=3 Hz), 7.49-7.64(3H, m), 7.86-7.95(4H, m)
[0742] Preparation 108
[0743] 2-Phenyl-5-(2-thienyl)-1,3,4-oxadiazole (4.08 g) was
obtained in substantially the same manner as in Preparation
104.
[0744] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.21(1H, t, J=3
Hz), 7.50-7.60(4H, m), 7.85(1H, d, J=3 Hz), 8.12(2H, d, J=8 Hz)
[0745] Preparation 109
[0746]
2-(5-Phenyl-1,3,4-oxadiazol-2-yl)thiophene-5-sulfonylchloride (3.21
g) was obtained in substantially the same manner as in Preparation
44.
[0747] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.):
[0748] 7.49-7.65(4H, m), 7.94(2H, d, J=3 Hz), 8.10-8.20(2H, m)
EXAMPLE 58
[0749]
(2R)-4-Methanesulfonyl-1-[5-(5-phenyl-1,3,4-oxadiazol-2-yl)-thiophe-
ne-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(198 mg) was obtained in substantially the same manner as in
Example 4.
[0750] Mass (ESI): 596 (M-1)
[0751] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48-1.89(6H,
m), 2.80-3.03(5H, m), 3.38-3.54(1H, m), 3.60-3.81(2H, m),
3.87-4.03(2H, m), 4.19-4.29(1H, m), 4.62-4.77(1H, m), 4.91-5.01(1H,
m), 7.50-7.76(4H, m), 7.72(1H, d, J=3 Hz), 8.13(2H, d, J=8 Hz),
9.08-9.19(1H, m)
[0752] Preparation 110
[0753] A mixture of phenyl 2-bromothiophene-5-sulfate (4.06 g),
hexamethylditin (5.00 g) and tetrakis(triphenylphosphine)palladium
(0) (735 mg) in toluene (245 ml) was stirred for 15 minutes at
ambient temperature and refluxed for 1 hour under nitrogen
atmosphere. The mixture was concentrated and purified by
chromatography on SiO.sub.2 (AcOEt/hexane 1:20, then 1:10) to give
2.34 g of phenyl 5-trimethylstannylthiophene-2-sulfate as an
oil.
[0754] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.48(9H, s),
7.02(2H, d, J=8 Hz), 7.13(1H, d, J=3 Hz), 7.20-7.41(3H, m),
7.63(1H, d, J=3 Hz)
[0755] Preparation 111
[0756] A mixture of 2-bromothiazole (200 mg), phenyl
5-trimethyl-stannylthiophene-2-sulfate (491 mg) and
tetrakis(triphenylphosphine)-palladium (0 ) (42.3 mg) in dioxane (4
ml) was stirred for 24 hours at 90.degree. C. The mixture was
concentrated and purified by chromatography on SiO.sub.2
(AcOEt/hexane 1:10, then 1:4). The obtained oil was crystallized
from hexane to give 231 mg of phenyl
5-(2-thiazolyl)thiophene-2-sulfate.
[0757] Mass (ESI): 324 (M+1)
[0758] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.12(2H, d, J=8
Hz), 7.27-7.38(3H, m), 7.40-7.44(2H, m), 7.51(1H, d, J=3 Hz),
7.87(1H, d, J=2 Hz)
[0759] Preparation 112
[0760] A mixture of phenyl 5-(2-thiazolyl)thiophene-2-sulfate (210
mg) and 1N aqueous sodium hydroxide (4 ml) in EtOH (6 ml) was
stirred for 4 hours at 80.degree. C. The mixture was adjusted to pH
3 with 4N aqueous hydrochloric acid and concentrated. The residue
was partitioned between AcOEt and H.sub.2O. The aqueous layer was
separated and washed with AcOEt. The obtained aqueous layer was
concentrated to give 290 mg of sodium
5-(2-thiazolyl)thiophene-2-sulfate as a solid.
[0761] Mass (ESI): 246 (M-1)
[0762] .sup.1H-NMR (300 MHz, D.sub.2O, .delta.): 7.48(1H, d, J=3
Hz), 7.58(1H, d, J=3 Hz), 7.69(1H, d, J=3 Hz) 7.84(1H, d, J=3
Hz)
[0763] Preparation 113
[0764] 2-(2-Thiazolyl)thiophene-5-sulfonylchloride (128 mg) was
obtained in substantially the same manner as in Preparation 44.
[0765] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.49(2H, d, J=3
Hz), 7.84(1H, d, J=3 Hz), 7.92(1H, d, J=3 Hz)
EXAMPLE 59
[0766]
(2R)-4-Methanesulfonyl-N-(2-tetrahydropyranyloxy)-1-[5-(2-thiazolyl-
)thiophene-2-sulfonyl]-2-piperazinecarboxamide (153 mg) was
obtained in substantially the same manner as in Example 4.
[0767] Mass (ESI): 535 (M-1)
[0768] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.74-3.00(5H, m), 3.32-3.51(1H, m), 3.58-3.76(2H, m),
3.86-4.05(2H, m), 4.19-4.30(1H, m), 4.58-4.70(1H, m), 4.93-5.01(1H,
m), 7.41(1H, d, J=3 Hz), 7.57(1H, d, J=3 Hz), 7.57-7.68(1H, m),
7.85(1H, d, J=3 Hz), 9.08-9.19(1H, m)
EXAMPLE 60
[0769]
(2R)-4-Methanesulfonyl-1-[5-phenyl-1,3,4-thiadiazol-2-sulfonyl]-N-(-
2-tetrahydropyranyloxy)-2-piperazinecarboxamide (117 mg) was
obtained in substantially the same manner as in Example 4.
[0770] Mass (ESI): 530 (M-1)
[0771] .sup.1H-NMR (300 MHz, CDCl.sub.3.delta.): 1.60-2.00(6H, m),
2.96-3.02(3H, m), 3.05-3.17(2H, m), 3.44-3.58(1H, m), 3.66-3.81(1H,
m), 3.81-3.90(1H, m), 3.92-4.02(1H, m), 4.11-4.27(1H, m),
4.50-4.60(1H, m), 4.90-4.99(1H, m), 5.06-5.12(1H, m), 7.51-7.65(3H,
m), 7.97(2H, d, J=8 Hz)
[0772] Preparation 114
[0773] To a mixture of 2-bromothiophene-5-sulfonylchloride (5.00 g)
and phenol (1.89 g) in MeCN (30 ml) was added dropwise
triethylamine (2.51 g) with ice-cooling. The mixture was stirred
for 1 hour at said temperature and 1 hour at ambient temperature.
The resulting mixture was concentrated and partitioned between
AcOEt and H.sub.2O. The organic layer was separated and washed with
1% aqueous citric acid and brine. The resulting solution was dried
over sodium sulfate and concentrated to give 6.34 g of phenyl
2-bromothiophene-5-sulfate (6.34 g) as a solid.
[0774] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.05-7.10(3H,
m), 7.28-7.40(4H, m)
[0775] Preparation 115
[0776] Phenyl 4-iodebenzenesulfate (1.6 g) was obtained as crystals
in substantially the same manner as in Preparation 114.
[0777] m.p.: 124-127.degree. C.
[0778] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.03(2H, d, J=6
Hz), 7.30-7.45(3H, m), 7.59(1H, d, J=8 Hz), 8.05(2H, d, J=8 Hz)
[0779] Preparation 116
[0780] Phenyl 4-(thiophene-2-yl)benzenesulfate (1.30 g) was
obtained as yellow crystals in substantially the same manner as in
Preparation 43.
[0781] m.p.: 122-124.degree. C.
[0782] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.01(2H, d, J=6
Hz), 7.15(1H, t, J=2 Hz), 7.20-7.35(3H, m), 7.43(1H, d, J=2 Hz),
7.46(1H, d, J=2 Hz), 7.73(2H, d, J=8 Hz), 7.81(2H, d, J=8 Hz)
[0783] Preparation 117
[0784] 4-(Thiophene-2-yl)benzenesulfonic acid sodium salt (0.33 g)
was obtained in substantially the same manner as in Preparation
112.
[0785] Mass (ESI-): 239(M-Na)
[0786] .sup.1H-NMR (300 MHz, D.sub.2O, .delta.): 7.18(1H, dd, J=1,
2 Hz), 7.51(1H, d, J=2 Hz), 7.55(1H, d, J=1 Hz), 7.82(4H, s)
[0787] Preparation 118
[0788] 4-(Thiophene-2-yl)benzenesulfonyl chloride (320 mg) was
obtained as crystals in substantially the same manner as in
Preparation 56.
[0789] m.p.: 103-104.degree. C.
[0790] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 7.17(1H, t, J=2
Hz), 7.46(1H, d, J=2 Hz), 7.50(1H, d, J=2 Hz), 7.81(1H, d, J=8 Hz),
8.03(1H, d, J=8 Hz)
EXAMPLE 61
[0791]
(2R)-4-Methanesulfonyl-1-[4-(thiophen-2-yl)benzenesulfonyl]-N-(2-te-
trahydropyranyloxy)-2-piperazinecarboxamide (169 mg) was obtained
as crystals in substantially the same manner as in Example 4.
[0792] m.p.: 194-195.degree. C.
[0793] Mass (ESI-): 528 (M-H)
[0794] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.93(6H,
m), 2.62-2.79(2H, m), 2.88, 2.91(3H, s), 3.35(1H, dt, J=2, 11 Hz),
3.57-3.72(2H, m), 3.84-4.04(2H, m), 4.21(1H, d, J=11 Hz), 4.60(1H,
m), 4.96(1H, m), 7.15(1H, t, J=2 Hz), 7.40(1H, d, J=2 Hz), 7.46(1H,
d, J=2 Hz), 7.73-7.89(4H, m), 9.13-9.28(1H, br)
[0795] Preparation 119
[0796] (2R)-
1-Benzyloxyoarbonyl-4-(9-fluorenylmethyloxycarbonyl)-2-pipera-
zinecarboxylic acid (7.5 g) was obtained as an amorphous powder in
substantially the same manner as in Preparation 11.
[0797] Mass (ESI-): 485 (M-H)
[0798] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.79-2.98(1H,
m), 3.06-3.34(2H, m), 3.82-4.08(2H, m), 4.30-4.92(5H, m),
5.08-5.24(2H, m), 7.23-7.40(9H, m), 7.47-7.62(2H, m), 7.75(2H, d,
J=8 Hz)
[0799] Preparation 120
[0800]
(2R)-1-Benzyloxycarbonyl-4-(9-fluorenylmethyloxycarbonyl)-N-(2-tetr-
ahydropyranyloxy)-2-piperazinecarboxamide (8.5 g) was obtained as
an amorphous powder in substantially the same manner as in
Preparation 12.
[0801] Mass (ESI-): 584 (M-H)
[0802] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.47-1.89(6H,
m), 2.97-3.15(1H, m), 3.17-3.40(1H, m), 3.48-3.67(1H, m),
3.74-4.06(4H, m); 4.18-4.75(5H, m), 4.83-5.02(1H, m), 5.19(2H, m),
7.27-7.45(9H, m), 7.49-7.69(2H, m), 7.78(2H, d, J=8 Hz)
[0803] Preparation 121
[0804]
(2R)-1-Benzyloxycarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecar-
boxamide (3.4 g) was obtained as an amorphous powder in
substantially the same manner as in Preparation 157 to be mentioned
later.
[0805] Mass (ESI+): 364 (M+H)
[0806] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48-1.93(6H,
m), 2.16-2.29(1H, m), 2.81-2.92(1H, m), 2.94-3.18(2H, m),
3.32-3.67(2H, m), 3.80-4.08(2H, m), 4.31-4.62(1H, m), 4.95(1H,
brs), 5.09-5.23(2H, m), 7.36(5H, s)
[0807] Preparation 122
[0808]
(2R)-i-Benzyloxycarbonyl-4-(N,N-dimethylaminosulfonyl)-N-(2-tetrahy-
dropyranyloxy)-2-piperazinecarboxamide (1.5 g) was obtained as an
amorphous powder in substantially the same manner as in Example 220
to be mentioned later.
[0809] Mass (ESI-): 469 (M-H)
[0810] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.88(6H,
m), 2.78-2.99(2H, m), 2.87, 2.88(6H, s), 3.09-3.30(1H, m),
3.48-3.64(2H, m), 3.80-4.25(3H, m), 4.75-4.86(1H, m), 4.92(1H,
brs), 5.18(2H, s), 7.38(5H, s)
[0811] Preparation 123
[0812]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-(2-tetrahydropyranyloxy)-2-pip-
erazinecarboxamide (920 mg) was obtained as an amorphous powder in
substantially the same manner as in Preparation 13.
[0813] Mass (ESI+): 337 (M+H)
[0814] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.92(6H,
m), 2.83(3H, s), 2.85(3H, s), 2.86-2.95(1H, m), 2.97-3.14(2H, m),
3.19-3.32(2H, m), 3.40-3.58(2H, m), 3.60-3.70(1H, m), 3.92-4.02(1H,
m), 4.93-4.98(1H, m)
EXAMPLE 62
[0815]
(2R)-1-[5-(4-Acetoxyphenyl)thiophene-2-sulfonyl]-4-(N,N-dimethylami-
nosulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (140
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 4.
[0816] Mass (ESI-): 615 (M-H)
[0817] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.92(6H,
m), 2.32(3H, s), 2.62-2.78(2H, m), 2.84(3H, s), 2.86(3H, s),
3.38-3.70(3H, m), 3.84-4.08(3H, m), 4.55-4.66(1H, m), 4.93-5.00(1H,
m), 7.09(2H, d, J=8 Hz), 7.23-7.28(2H, m), 7.58-7.65(2H, m),
9.17(1H, brs)
EXAMPLE 63
[0818]
(2R)-1-[5-(4Cyanophenyl)thiophene-2-sulfonyl]-4-(N,N-dimethylaminos-
ulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (110
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 4.
[0819] Mass (ESI-): 582 (M-H)
[0820] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.92(6H,
m), 2.61-2.78(2H, m), 2.82(3H, s), 2.84(3H, s), 3.38-3.70(3H, m),
3.85-4.09(3H, m), 4.55-4.68(1H, m), 4.92-5.01 (1H, m), 7.38(1H, d,
J=3 Hz), 7.59-7.78(5H, m), 9.18(1H, brs)
EXAMPLE 64
[0821]
(2R)-1-[5-(4Cyanomethylphenyl)thiophene-2-sulfonyl)-4-(N,N-dimethyl-
aminosulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazine-carboxamide
(115 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 4.
[0822] Mass (ESI-): 596 (M-H)
[0823] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.93(6H,
m), 2.62-2.77(2H, m), 2.82(3H, s), 2.85(3H, s), 3.38-3.70(3H, m),
3.81(2H, s), 3.86-4.09(3H, m), 4.55-4.68(1H, m), 4.92-5.02(1H, m),
7.31(1H, d, J=3 Hz), 7.42(2H, d, J=8 Hz), 7.58-7.66(3H, m),
9.17(1H, brs)
EXAMPLE 65
[0824]
(2R)-1-[5-(4-Acetoxymethylphenyl)thiophene-2-sulfonyl]-4-(N,N-dimet-
hylaminosulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazine-carboxamide(107
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 4.
[0825] Mass (ESI-): 629 (M-H)
[0826] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.93(6H,
m), 2.12(3H, s), 2.62-2.77(2H, m), 2.85(3H, s), 2.87(3H, s),
3.36-3.70(3H, m), 3.84-4.10(3H, m), 4.58-4.67(1H, m), 4.92-5.01(1H,
m), 5.13(2H, s), 7.29(1H, d, J=3 Hz), 7.43(2H, d, J=8 Hz),
7.57-7.65(3H, m), 9.17(1H, brs)
EXAMPLE 66
[0827]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-[5-(3-fluoro-4-methoxyphenyl)
thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)
-2-piperazinecarboxamide (424 mg) was obtained in substantially the
same manner as in Example 4.
[0828] Mass (ESI): 605 (M-1)
[0829] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.94(6H,
m), 2.60-2.77(2H, m), 2.80-2.92(6H, m), 3.37-3.71(3H, m),
3.86-4.10(6H, m), 4.56-4.68(1H, m), 4.94-5.02(1H, m), 7.01(1H, t,
J=8 Hz), 7.29(1H, d, J=3 Hz), 7.30-7.40(2H, m), 7.60(2H, d, J=3
Hz), 9.10-9.20(1H, m)
EXAMPLE 67
[0830] (2R)-4-(N,N-Dimethylaminosulfonyl)
-1-(4-methoxybenzenesulfonyl)-N--
(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (1 42 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 4.
[0831] Mass (ESI-): 505 (M-H)
[0832] .sup.1H-NMR (300 MHz, CDCl.sub.3,.delta.): 1.54-1.94(6H, m),
2.40-2.58(2H, m), 2.82(3H, s), 2.84(3H, s), 3.28-3.45(2H, m),
3.57-3.72(1H, m), 3.89(3H, s), 3.87-4.05(3H, m), 4.45-4.57(1H, m),
4.92-5.01(1H, m), 7.02(2H, d, J=8 Hz), 7.78(2H, d, J=8 Hz),
9.25(1H, brs)
EXAMPLE 68
[0833]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-(4-phenoxybenzenesulfonyl)-N-(-
2-tetrahydropyranyloxy)-2-piperazinecarboxamide (164 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 4.
[0834] Mass (ESI-): 567 (M-H)
[0835] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.95(6H,
m), 2.45-2.64(2H, m), 2.83(3H, s), 2.85(3H, s), 3.29-3.59(2H, m),
3.56-3.71(1H, m), 3.82-4.08(3H, m), 4.47-4.58(1H, m), 4.92-4.99(1H,
m), 7.06(2H, d, J=8 Hz), 7.10(2H, d, J=8 Hz), 7.26(1H, dd, J=8, 8
Hz), 7.38-7.49(2H, m), 7.78(2H, d, J=8 Hz), 9.22(1H, brs)
[0836] Preparation 124
[0837]
(2R)-1-Benzyloxycarbonyl-4-ethylaminocarbonyl-N-(2-tetrahydropyrany-
loxy)-2-piperazinecarboxamide (855 mg) was obtained in
substantially the same manner as in Example 225 to be mentioned
later.
[0838] Mass (ESI-): 433 (M-H)
[0839] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.14(3H, t, J=5
Hz), 1.50-1.90(6H, m), 2.75-3.17(3H, m), 3.23(2H, m), 3.59(1H, m),
3.84-4.15(2H, m), 4.25-4.40(1H, m), 4.70-5.00(3H, m), 5.20(2H, s),
5.20-5.40(1H, br), 7.37(5H, s)
[0840] Preparation 125
[0841]
(2R)-4-Ethylaminocarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazineca-
rboxamide (287 mg) was obtained in substantially the same manner as
in Preparation 13.
[0842] Mass (ESI+): 301 (M+H), 323 (M+Na)
[0843] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.14(3H, t, J=5
Hz), 1.50-1.94(6H, m), 2.73-2.90(2H, m), 3.15-3.30(3H, m), 3.35(1H,
dd, J=2, 12 Hz), 3.45-3.55(2H, m), 3.64(1H, m), 3.84(1H, m),
3.98(1H, m), 4.87(1H, brs), 4.94, 4.99(1H, brs)
EXAMPLE 69
[0844]
(2R)-1-t5-(4-Acetoxyphenyl)thiophene-2-sulfonyl]-4-ethylaminocarbon-
yl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (106 mg) was
obtained in substantially the same manner as in Example 4.
[0845] Mass (ESI-): 579 (M-H)
[0846] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.10(3H, t, J=4
Hz), 1.50-1.90(6H, m), 2.35(3H, s), 2.65(1H, dt, J=2, 12 Hz),
2.85(1H, dd, J=2, 12 Hz), 3.10-3.30(1H, m), 3.18(2H, m), 3.63(1H,
m), .3.85-4.10(3H, m), 4.28(1H, m), 4.59(1H, m), 4.92, 5.00(1H,
brs), 5.23(1H, m), 7.19(2H, d, J=8 Hz), 7.25(1H, m), 7.60(2H, d,
J=8 Hz), 7.62(1H, m), 9.32, 9.40(1H, s)
EXAMPLE 70
[0847]
(2R)-1-[5-(4-Cyanophenyl)thiophene-2-sulfonyl}-4-ethylamino-carbony-
l-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (95 mg) was
obtained in substantially the same manner as in Example 4.
[0848] Mass (ESI-): 546 (M-H)
[0849] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.10(3H, t, J=4
Hz), 1.50-1.90(6H, m), 2.60-2.75(1H, m), 2.86(1H, dd, J=2, 12 Hz),
3.10-3.32(3H, m), 3.63(1H, m), 3.85-4.07(3H, m), 4.31(1H, m),
4.60(1H, m), 4.93, 5.00(1H, brs), 5.16(1H, m), 7.40(1H, m),
7.67(1H, m), 7.69(2H, d, J=8 Hz), 7.74(2H, d, J=8 Hz), 9.36,
9.50(1H, s)
[0850] Preparation 126
[0851] Ethyl
(2R)-4-benzyloxycarbonyl-1-tert-butoxycarbonyl-2-piperazineca-
rboxylate (15.0 g) was obtained as an oil in substantially the same
manner as in Preparation 24.
[0852] Mass (ESI-): 391 (M-H)
[0853] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.08-1.30(3H,
m), 1.45, 1.48(9H, s), 2.80-3.31(3H, m), 3.74-4.22(4H, m),
4.50-4.78(2H, m), 5,09(1H, d, J=9 Hz), 5.16(1H, d, J=9 Hz),
7.28-7.42(5H, m)
[0854] Preparation 127
[0855] To a solution of ethyl
(2R)-4-benzyloxycarbonyl-1-tert-butoxycarbon-
yl-2-piperazinecarboxylate (15.0 g) in dioxane (100 ml) was added
1N NaOH (76.4 ml) at ambient temperature for 4 hours, the reaction
mixture was concentrated in vacuo to remove dioxane. The resulting
solution was acidified with 3N HCl to be pH2 and extracted with
AcOEt (300 ml). The organic layer was washed with saturated NaCl
solution, dried over MgSO.sub.4 and evaporated in vacuo to give
12.8 g of
(2R)-4-benzyloxycarbonyl-1-tert-butoxycarbonyl-2-piperazinecarboxylic
acid as an amorphous powder.
[0856] Mass (ESI-): 363 (M-H)
[0857] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45, 1.48(9H,
s), 2.82-3.02(1H, m), 3.09-3.30(2H, m), 3.76-4.18(2H, m),
4.59-4.85(2H, m), 5,04-5.24(2H, m), 7.34(5H, s)
[0858] Preparation 128
[0859]
(2R)-4-Benzyloxycarbonyl-N-tert-butoxy-1-tert-butoxycarbonyl-2-pipe-
razinecarboxamide (554 mg) was obtained as an amorphous powder in
substantially the same manner as in Preparation 8.
[0860] Mass (ESI-): 434 (M-H)
[0861] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.23(9H, s),
1.48(9H, s), 2.90-3.40(4H, m), 3.80-4.15(1H, br), 4.40-4.65 (2H,
m), 5.05-5.25 (2H, m), 7.27-7.45(5H, m)
[0862] Preparation 129
[0863]
(2R)-N-tert-Butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide
(249 mg) was obtained as crystals in substantially the same manner
as in Preparation 13.
[0864] m.p.: 113-114.degree. C.
[0865] Mass (ESI+): 302 (M+H)
[0866] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.27(9H, s),
1.48(9H, s), 2.65-3.04(4H, m), 3.43(1H, d, J=12 Hz), 3.72-3.90(1H,
br), 4.22-4.40(1H, br), 8.67(1H, brs)
[0867] Preparation 130
[0868] (2R)-4-[2-(Benzyloxycarbonylamino)
ethanesulfonyl]-N-tert-butoxy-1--
tert-butoxycarbonyl-2-piperazinecarboxamide (213 mg) was obtained
as amorphous powder in substantially the same manner as in Example
4.
[0869] Mass (ESI-): 541 (M-H)
[0870] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.23(9H, s),
1.49(9H, s), 2.84-3.10(3H, m), 3.25-3.75(5H, m), 3.75-4.20(2H, m),
4.64(1H, brs), 5.04(1H, d, J=10 Hz), 5.13(1H, d, J=10 Hz),
5.70-5.95(1H, br), 7.26-7.38(5H, m), 8.50-8.70(1H, br)
[0871] Preparation 131
[0872]
(2R)-4-(2-Aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl--
2-piperazinecarboxamide (150 mg) was obtained as crystals in
substantially the same manner as in Preparation 13.
[0873] m.p.: 171-172.degree. C.
[0874] Mass (ESI+): 409 (M+H)
[0875] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.15(9H, s),
1.37(9H, s), 2.79(1H, dt, J=1, 11 Hz), 2.88(2H, t, J=4 Hz),
3.07(2H, t, J=4 Hz), 3.15-3.55(2H, m), 2.72-3.93(2H, m),
4.38-4.55(1H, m)
[0876] Preparation 132
[0877] Acetic anhydride (36 mg) was added to a solution of
(2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-pipe-
razineboxamide (130 mg) in AcOH (2 ml). The reaction mixture was
stirred at ambient temperature for 3 hours. The mixture was
concentrated in vacuo, and the residue was partitioned between
AcOEt and saturated aqueous NaHCO.sub.3 solution. The organic layer
was washed with saturated aqueous NaCl solution, dried over
MgSO.sub.4, and concentrated in vacuo to give 142 mg of
(2R)-4-[2-(acetylamino)-ethanesulfonyl]-N-tert-butoxy-1-
-tert-butoxycarbonyl-2-piperazinecarboxamide.
[0878] Mass (ESI-): 449 (M-H)
[0879] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.26(9H, s),
1.50(9H, S), 1.98(3H, s), 2.75-3.17(3H, m), 3.17-3.45(2H, m),
3.54-3.75(3H, m), 3.93-4.24(2H, m), 4.68(1H, brs), 6.65-6.85(1H,
broad), 8.55-8.75(1H, broad)
[0880] Preparation 133
[0881]
(2R)-4-[2-(Acetylamino)ethanesulfonyl]-N-tert-butoxy-2-piperazineca-
rboxamide hydrochloride (112 mg) was obtained in substantially the
same manner as in Preparation 10.
[0882] Mass (ESI-): 349 (M-H)
[0883] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.20(9H, s),
1.82(3H, s), 3.00-4.10(11H, m), 8.18(1H, t, J=2 Hz)
EXAMPLE 71
[0884]
(2R)-4-[2-(Acetylamino)ethanesulfonyl]-N-tert-butoxy-1-[5-(4-fluoro-
phenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (134 mg) was
obtained as amorphous powder in substantially the same manner as in
Example 4.
[0885] Mass (ESI-): 589 (M-H)
[0886] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.29(9H, s),
1.97(3H, s), 2.82(1H, dt, J=2, 12 Hz), 3.21-3.44(3H, m),
3.52-3.67(3H, m), 4.05(1H, d, J=13 Hz), 4.21(1H, d, J=12 Hz),
4.62(1H, brs), 6.37(1H, br), 7.15(2H, t, J=8 Hz), 7.23(1H, d, J=2
Hz), 7.54-7.65(3H, m), 8.80(1H, s)
[0887] Preparation 134
[0888]
(2R)-N-tert-Butoxy-1-tert-butoxycarbonyl-4-[2-(methanesulfonyl-amin-
o)ethanesulfonyl)-2-piperazinecarboxamide (1.55 g) was obtained as
amorphous powder in substantially the same manner as in Example
4.
[0889] Mass (ESI-): 485 (M-H)
[0890] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.25(9H, s),
1.52(9H, s), 2.90-3.10(2H, m), 2.99(3H, s), 3.13-3.68(5H, m),
3.95-4.17(2H, m), 4.66(1H, brs), 6.09(1H, m), 8.76(11H, brs)
[0891] Preparation 135
[0892] (2R)-N-tert-Butoxy-4-[2-(methanesulfonylamino)
ethanesulfonyl]-2-piperazinecarboxamide hydrochloride (1 .22 g) was
obtained as crystals in substantially the same manner as in
Preparation 10.
[0893] m.p.: 146-158.degree. C.
[0894] Mass (ESI-): 385 (M-H)
[0895] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.20(9H, s),
2.97(3H, s), 3.03-3.52(8H, m), 3.68(1H, d, J=11 Hz), 3.90-4.05(2H,
m), 7.34(1H, t, J=4 Hz)
EXAMPLE 72
[0896] (2R)-N-tert-Butoxy-1-[5-(4-fluorophenyl)
thiophene-2-sulfonyl[-4-[2-
-(methanesulfonylamino)ethanesulfonyl]-2-piperazinecarboxamide (248
mg) was obtained in substantially the same manner as in Example
4.
[0897] Mass (ESI-): 625 (M-H)
[0898] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
1.59(9H, s), 2.75-2.90(2H, m), 2.98(3H, s), 3.25-3.65(6H, m),
4.03(1H, d, J=12 Hz), 4.19(1H, d, J=12 Hz), 4.62(1H, brs), 5.41(1H,
t, J=4 Hz), 7.15(2H, t, J=8 Hz), 7.24(1H, d, J=2 Hz), 7.54-7.63(3H,
m), 8.81(1H, s)
EXAMPLE 73
[0899]
(2R)-N-tert-Butoxy-4-[2-(methanesulfonylamino)ethanesulfonyl]-1-(5--
phenylthiophene-2-sulfonyl)-2-piperazinecarboxamide (249 mg) was
obtained in substantially the same manner as in Example 4.
[0900] Mass (ESI-): 607 (M-H)
[0901] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
1.59(9H, s), 2.75-2.90(2H, m), 2.98(3H, s), 3.25-3.65(6H, m),
4.04(1H, d, J=12 Hz), 4.20(1H, d, J=12 Hz), 4.63(1H, brs), 5.40(1H,
t, J=4 Hz), 7.3t(1H, d, J=2 Hz), 7.37-7.52(3H, m), 7.57-7.65(3H,
m), 8.83(1H, s)
EXAMPLE 74
[0902]
(2R)-N-tert-Butoxy-4-[2-(methanesulfonylamino)ethanesulfonyl]-1-[5--
(4-trifluoromethylphenyl)
thiophene-2-sulfonyl]-2-piperazinecarboxamide (269 mg) was obtained
in substantially the same manner as in Example 4.
[0903] Mass (ESI-): 675 (M-H)
[0904] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
1.60(9H, s), 2.77-2.90(2H, m), 2.98(3H, s), 3.20-3.65(6H, m),
4.03(1H, d, J=12 Hz), 4.20(1H, d, J=12 Hz), 4.63(1H, brs), 5.42(1H,
t, J=4 Hz), 7.38(1H, d, J=2 Hz), 7.65(1H, d, J=2 Hz), 7.72(4H, s),
8.80(1H, s)
EXAMPLE 75
[0905]
(2R)-N-tert-Butoxy-1-[5-(4-chlorophenyl)thiophene-2-sulfonyl]-4-[2--
(methanesulfonylamino)ethanesulfonyl)-2-piperazinecarboxamide (256
mg) was obtained in substantially the same manner as in Example
4.
[0906] Mass (ESI-): 641, 643 (M-H)
[0907] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
1.60(9H, s), 2.75-2.90(2H, m), 2.98(3H, s), 3.20-3.65(6H, m),
4.03(1H, d, J=12 Hz), 4.20(1H, d, J=12 Hz), 4.62(1H, brs), 5.42(1H,
t, J=4 Hz), 7.28(1H, d, J=2 Hz), 7.43(2H, d, J=8 Hz), 7.54(2H, d,
J=8 Hz), 7.62(1H, d, J=2 Hz), 8.82(1H, s)
EXAMPLE 76
[0908]
(2R)-N-tert-Butoxy-1-[5-(4-ethoxyphenyl)thiophene-2-sulfonyl]-4-[2--
(methanesulfonylamino)ethanesulfonyl]-2-piperazinecarboxamide (245
mg) was obtained in substantially the same manner as in Example
4.
[0909] Mass (ESI-): 651 (M-H)
[0910] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
1.45(3H, t, J=5 Hz), 2.75-2.90(2H, m), 2.98(3H, s), 3.25-3.63(6H,
m), 4.03(1H, d, J=12 Hz), 4.09(2H, q, J=5 Hz), 4.19(1H, d, J=12
Hz), 4.61(1H, br), 5.37(1H, t, J=4 Hz), 6.94(2H, d, J=8 Hz),
7.18(1H, d, J=2 Hz), 7.51(1H, d, J=8 Hz), 7.59(1H, d, J=2 Hz),
8.81(1H, s)
[0911] Preparation 136
[0912]
(2R)-N-tert-Butoxy-1-tert-butoxycarbonyl-4-{2-[(pyridine-3-sulfonyl-
)amino)ethanesulfonyl}-2-piperazinecarboxamide (544 mg) was
obtained in substantially the same manner as in Example 4.
[0913] Mass (ESI-): 548 (M-H)
[0914] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.28(9H, s),
1.51(9H, s), 2.88-3.11(2H, m), 3.15-3.60(5H, m), 3.61(1H, d, J=11
Hz), 3.95-4.10(2H, m), 4.65(1H, brs), 6.90(1H, br), 7.47(1H, dd,
J=4, 8 Hz), 8.24(1H, d, J=8 Hz), 8.81(1H, d, J=4 Hz), 8.84(1H,
brs), 9.13(1H, s)
[0915] Preparation 137
[0916]
(2R)-N-tert-Butoxy-4-{2-[(pyridine-3-sulfonyl)amino]-ethanesulfonyl-
}-2-piperazinecarboxamide dihydrochloride (613 mg) was obtained in
substantially the same manner as in Preparation 10.
[0917] Mass (ESI-): 448 (M-H)
[0918] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.20(9H, s),
3.00-3.27(5H, m), 3.28-3.53(4H, m), 3.66(1H, d, J=11 Hz), 3.93(1H,
d, J=11 Hz), 7.68(1H, dd, J=4, 8 Hz), 8.24(1H, dd, J=2, 8 Hz),
8.39(1H, t, J=4 Hz), 8.85(1H, d, J=4 Hz), 8.99(1H, d, J=2 Hz)
EXAMPLE 77
[0919]
(2R)-N-tert-Butoxy-1-{5-(4-chlorophenyl)thiophene-2-sulfonyl}-4-{2--
[(pyridine-3-sulfonyl)
amino]ethanesulfonyl}-2-piperazinecarboxamide (140 mg) was obtained
in substantially the same manner as in Example 4.
[0920] Mass (ESI-): 704, 706 (M-H)
[0921] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.31(9H, s),
2.75-2.90(2H, m), 3.25-3.53(5H, m), 3.57(1H, d, J=12 Hz), 4.04(1H,
d, J=12 Hz), 4.10(1H, d, J=12 Hz) 4.60(1H, brs), 5.42(1H, br),
7.28(1H, d, J=2 Hz), 7.43(2H, d, J=8 Hz), 7.40-7.50(1H, m),
7.54(1H, d, J=8 Hz), 7.62(1H, d, J=2 Hz), 8.18(1H, d, J=6 Hz),
8.81(1H, d, J=4 Hz), 8.83(1H, s), 9.10(1H, s)
[0922] Preparation 138
[0923]
(2R)-N-tert-Butoxy-1-tert-butoxycarbonyl-4-{2-[(N,N-dimethylaminosu-
lfonyl) amino]ethanesulfonyl}-2-piperazinecarboxamide (523 mg) was
obtained in substantially the same manner as in Example 220 to be
mentioned later.
[0924] Mass (ESI-): 514 (M-H)
[0925] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.25(9H, s),
1.51(9H, s), 2.81(6H, s), 2.89-3.57(7H, m), 3.67(1H, d, J=11 Hz),
3.95-4.15(2H, m), 4.65(1H, brs), 5.81(1H, br), 8.72(1H, br)
[0926] Preparation 139
[0927]
(2R)-N-tert-Butoxy-4-{2-[(N,N-dimethylaminosulfonyl)amino]-ethanesu-
lfonyl}-2-piperazinecarboxamide hydrochloride (395 mg) was obtained
in substantially the same manner as Preparation 10.
[0928] Mass (ESI-): 414 (M-H)
[0929] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.20(9H, s),
2.69(6H, s), 3.03-3.48(8H, m), 3.67(1H, d, J=11 Hz), 3.88-4.05(2H,
m), 7.49(1H, t, J=4 Hz)
EXAMPLE 78
[0930]
(2R)-N-tert-Butoxy-1-[5-(4-chlorophenyl)thiophene-2-sulfonyl]-4-{2--
[(N,N-dimethylaminosulfonyl)amino]ethanesulfonyl}-2-piperazinecarboxamide
(168 mg) was obtained in substantially the same manner as in
Example 4.
[0931] Mass (ESI-): 670, 672 (M-H)
[0932] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.28(9H, s),
2.75-2.90(2H, m), 2.78(6H, s), 3.28-3.50(5H, m), 3.62(1H, d, J=12
Hz), 4.04(1H, d, J=12 Hz), 4.18(1H, d, J=12 Hz), 4.61(1H, br),
5.19(1H, t, J=4 Hz), 7.28(1H, d, J=2 Hz), 7.44(2H, d, J=8 Hz),
7.54(1H, d, J=8 Hz), 7.62(1H, d, J=2 Hz), 8.74(1H, s)
[0933] Preparation 140
[0934] Methyl chloroformate (132 mg) in CHCl.sub.3 (3 ml) was added
dropwise to
(2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycar-
bonyl-2-piperazinecarboxamide (400 mg) in pyridine (2.5 ml) with
cooling on an ice bath. After stirring on the ice bath for 3 hours,
the reaction mixture was concentrated in vacuo. The residue was
partitioned between AcOEt and 3.6% HCl. The organic layer was
washed with saturated aqueous NaHCO.sub.3 solution and saturated
aqueous NaCl solution, dried over MgSO.sub.4, and concentrated in
vacuo to give 470 mg of
(2R)-N-tert-butoxy-1-tert-butoxycarbonyl-4-[2-(methoxycarbonylamino)-etha-
nesulfonyl]-2-piperazinecarboxamide.
[0935] Mass (ESI-): 465 (M-H)
[0936] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.27(9H, s),
1.51(9H, s), 2.81(6H,.s), 2.87-3.17(3H, m), 3.25-3.46(2H, m),
3.50-3.78(3H, m), 3.67(3H, s), 3.93-4.20(2H, m), 4.67(1H, brs),
5.72(1H, br), 8.63(1H, br)
[0937] Preparation 141
[0938] (2R)-N-tert-Butoxy-4-[2-(methoxycarbonylamino)
ethanesulfonyl]-2-piperazinecarboxamide hydrochloride (414 mg) was
obtaiend in substantially the same manner as in Preparation 10.
[0939] Mass (ESI-): 401 (M-H)
[0940] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.20(9H, s),
3.00-3.25(3H, m), 3.25-3.40(5H, m), 3.55(3H, s), 3.67(1H, d, J=11
Hz), 3.88-4.05(2H, m), 7.37(1H, m)
EXAMPLE 79
[0941] (2R)-N-tert-Butoxy-1-[5-(4-chlorophenyl)
thiophene-2-sulfonyl]-4-[2-
-(methoxycarbonylamino)ethanesulfonyl]-2-piperazinecarboxamide (253
mg) was obtained in substantially the same manner as in Example
4.
[0942] Mass (ESI-): 621, 623 (M-H)
[0943] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.28(9H, s),
2.75-2.90(2H, m), 3.24-3.44(3H, m), 3.50-3.65(3H, m), 3.65(3H, s),
4.04(1H, d, J=12 Hz), 4.18(1H, d, J=12 Hz), 4.59(1H, brs), 5.42(1H,
br), 7.28(1H, d, J=2 Hz), 7.43(2H, d, J=8 Hz), 7.54(1H, d, J=8 Hz),
7.62(1H, d, J=2 Hz), 8.72(1H, s)
[0944] Preparation 142
[0945]
(2R)-N-tert-Butoxy-1-tert-butoxycarbonyl-4-{2-[(pyridine-3-carbonyl-
)amino]ethanesulfonyl}-2-piperazinecarboxamide (896 mg) was
obtained in substantially the same manner as in Example 4.
[0946] Mass (ESI-): 512 (M-H)
[0947] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.25(9H, s),
1.50(9H, s), 2.88-3.12(3H, m), 3.39-3.70(3H, m), 3.76-4.05(3H, m),
4.17(1H, d, J=11 Hz), 4.70(1H, brs), 7.37(1H, dd, J=2, 6 Hz),
8.66(1H, d, J=6 Hz), 8.73(1H, d, J=2 Hz), 9.08(1H, s)
[0948] Preparation 143
[0949]
(2R)-N-tert-Butoxy-4-{2-[(pyridine-3-carbonyl)amino]ethane-sulfonyl-
}-2-piperazinecarboxamide dihydrochloride (869 mg) was obtained in
substantially the same manner as in Preparation 10.
[0950] Mass (ESI-): 412 (M-H)
[0951] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.20(9H, s),
1.82(3H, s), 3.00-4.10(11H, m), 7.75(1H, dd, J=2, 6 Hz), 8.47(1H,
d, J=6 Hz), 8.84(1H, d, J=2 Hz), 9.14(1H, s), 9.20-9.35(1H, br),
9.30(1H, t, J=4 Hz)
EXAMPLE 80
[0952]
(2R)-N-tert-Butoxy-1-{5-(4-fluorophenyl)thiophene-2-sulfonyl}-4-{2--
[(pyridine-3-carbonyl)amino]ethanesulfonyl}-2-piperazinecarboxamide
(99 mg) was obtained in substantially the same manner as in Example
220 to be mentioned later.
[0953] Mass (ESI-): 652 (M-H)
[0954] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
2.76-2.92(2H, m), 3.33(1H, d, J=12 Hz), 3.42(2H, t, J=4 Hz),
3.62(1H, d, J=12Hz), 3.65-3.80(1H, m), 3.85-4.00(1H, m), 4.05(1H,
d, J=12 Hz), 4.23(1H, d, J=12 Hz), 4.63(1H, brs), 7.15(2H, t, J=8
Hz), 7.24(1H, d, J=2 Hz), 7.36(1H, dd, J=2, 6 Hz), 7.55-7.65(3H,
m), 8.13(1H, d, J=6 Hz), 8.73(1H, d, J=2 Hz), 8.84(1H, s), 9.05(1H,
s)
EXAMPLE 81
[0955]
(2R)-1-[5-(4-Acetoxyphenyl)thiophene-2-sulfonyl]-N-tert-butoxy-4-{2-
-[(pyridine-3-carbonyl)amino]ethanesulfonyl}-2-piperazinecarboxamide
(78 mg) was obtained in substantially the same manner as in Example
220 to be mentioned later.
[0956] Mass (ESI-): 692 (M-H)
[0957] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.28(9H, s),
2.34(3H, s), 2.77-2.92(2H, m), 3.33(1H, d, J=12 Hz), 3.42(2H, t,
J=4 Hz), 3.62(1H, d, J=12 Hz), 3.67-3.82(1H, m), 3.84-4.00(1H, m),
4.05(1H, d, J=12 Hz), 4.24(1H, d, J=12 Hz), 4.63(1H, brs), 7.19(2H,
d, J=8 Hz), 7.27(1H, d, J=2 Hz), 7.37(1H, dd, J=2, 6 Hz), 7.61(2H,
d, J=8 Hz), 8.13(1H, d, J=6 Hz), 8.73(1H, d, J=2 Hz), 8.82(1H, s),
9.05(1H, s)
[0958] Preparation 144
[0959]
(2R)-4-[2-(Benzoylamino)ethanesulfonyl]-N-tert-1-tert-butoxycarbony-
l-2-piperazinecarboxamide (867 mg) was obtained in substantially
the same manner as in Example 4.
[0960] Mass (ESI-): 511 (M-H)
[0961] .sup.1H-NMR (300 MHz, CDCl.sub.3 , .delta.): 1.25(9H, s),
1.50(9H, s), 2.88-3.10(3H, m), 3.37-3.72(3H, m), 3.82-4.05(3H, m),
4.18(1H, d, J=11 Hz), 4.68(1H, brs), 7.43(2H, t, J=7 Hz), 7.50(1H,
t, J=7 Hz), 7.84(2H, d, J=7 Hz)
[0962] Preparation 145
[0963] (2R)-4-[2-(Benzoylamino)
ethanesulfonyl]-N-tert-butoxy-2-piperazine- carboxamide
hydrochloride (619 mg) was obtained in substantially the same
manner as in Preparation 10.
[0964] Mass (ESI-): 411 (M-H)
[0965] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.19(9H, s),
3.00-4.10(11H, m), 7.46(2H, t, J=7 Hz), 7.55(1H, t, J=7 Hz),
7.86(2H, d, J=7 Hz), 8.80(11H, t, J=4 Hz), 9.10-9.45(1H, br)
EXAMPLE 82
[0966] (2R)-4-[2-(Benzoylamino) ethanesulfonyl]-N-tert-butoxy-1
-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide
(187 mg) was obtained in substantially the same manner as in
Example 4.
[0967] Mass (ESI-): 651 (M-H)
[0968] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.30(9H, s),
2.77-2.90(2H, m), 3.31(1H, d, J=12 Hz), 3.40(2H, t, J=4 Hz),
3.61(1H, d, J=12 Hz), 3.70-4.00(2H, m), 4.03(1H, d, J=12 Hz),
4.24(1H, d, J=12 Hz), 4.62(1H, brs), 7.09(1H, m), 7.15(22H, t, J=8
Hz), 7.24(1H, d, J=2 Hz), 7.42(2H, t, J=7 Hz), 7.50(1H, t, J=7 Hz),
7.55-7.65(3H, m), 7.81(2H, d, J=7 Hz), 8.78(1H, s)
EXAMPLE 83
[0969] (2R)-1-[5-(4-Acetoxyphenyl) thiophene-2-sulfonyl)
-4-[2-(benzoylamino)ethanesulfonyl]-N-tert-butoxy-2-piperazinecarboxamide
(114 mg) was obtained in substantially the same manner as in
Example 44.
[0970] Mass (ESI-): 691 (M-H)
[0971] .sup.1H-NM (300 MHz, CDCl.sub.3, .delta.): 1.29(9H, s),
2.33(3H, s), 2.77-2.92(2H, m), 3.31(1H, d, J=12 Hz), 3.39(2H, m),
3.61(1H, d, J=12 Hz), 3.67-3.95(2H, m), 4.03(1H, d, J=12 Hz),
4.24(1H, d, J=12 Hz), 4.63(1H, brs), 7.11(1H, t, J=4 Hz), 7.19(2H,
d, J=8 Hz), 7.25(1H, d, J=2 Hz), 7.42(2H, t, J=7 Hz), 7.49(1H, t,
J=7 Hz), 7.61(2H, d, J=8 Hz), 7.81(2H, d, J=7 Hz), 8.78(1H, s)
EXAMPLE 84
[0972]
(2R)-4-Methanesulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarbo-
xamide (266 mg) and trans-.beta.-styrenesulfonyl chloride (210 mg)
were used to give 271 mg of
(2R)-4-methanesulfonyl-1-(2-phenyl-2-trans-ethenyl- sulfonyl) -N-
(2-tetrahydropyranyloxy) -2-piperazinecarboxamide as amorphous
powder in substantially the same manner as in Example 4.
[0973] Mass (ESI-): 472 (M-H)
[0974] .sup.1-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.95(6H, m),
2.92(3H, s), 2.95(1H, dt, J=2, 12 Hz), 3.11(1H, m), 3.62(1H, m),
3.71-3.85(3H, m), 3.93(1H, m), 4.22(1H, m), 4.62(1H, m), 4.98(1H,
m), 6.87(1H, d, J=14 Hz), 6.98(1H, d, J=14 Hz), 7.37-7.57(5H, m),
9.23(1H, brs)
EXAMPLE 85
[0975]
(2R)-N-Hydroxy-4-[3-(4-morpholino)propanesulfonyl]l-1(5-phenylthiop-
hene-2-sulfonyl)-2-piperazinecarboxamide hydrochloride (280 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[0976] Mass (ESI-): 557 (M-H)
[0977] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.95-2.13(3H,
m), 2.73-2.90(1H, m), 2.93-3.30(8H, m), 3.55-3.65(1H, m),
3.70-4.00(7H, m), 4.50(1H, brs), 7.38-7.52(3H, m), 7.62(1H, d, J=3
Hz), 7.68(1H, d, J=3 Hz), 7.76(2H, d, J=8 Hz)
EXAMPLE 86
[0978]
(2R)-N-Hydroxy-1-(5-phenylthiophene-2-sulfonyl)-4-[2-(4-pyridyl)-et-
hansulfonyl]-2-piperazinecarboxamide hydrochloride (78 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[0979] Mass (ESI-): 535 (M-H)
[0980] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.78-2.94(2H,
m), 3.01-3.10(2H, m), 3.12-3.37(3H, m), 3.70-4.11(3H, m), 4.52(1H,
brs), 7.38-7.52(3H, m), 7.60(1H, d, J=3 Hz), 7.68(1H, d, J=3 Hz),
7.72(2H, d, J=6 Hz), 8.00(2H, d, J=6 Hz), 8.82(2H, d, J=6 Hz)
EXAMPLE 87
[0981]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl)-N-hydroxy-4-[2-(4-p-
yridyl)ethansulfonyl]-2-piperazinecarboxamide hydrochloride (78 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 5.
[0982] Mass (ESI-): 553 (M-H)
[0983] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.78-2.96(1H,
m), 3.03-3.12(1H, m), 3.15-3.29(2H, m), 3.31-3.98(6H, m), 4.51(1H,
brs), 7.33(2H, t, J=8 Hz), 7.60(1H, d, J=3 Hz), 7.68(1H, d, J=3
Hz), 7.72-7.85(2H, m), 7.95-8.05(2H, m), 8.83(2H, d, J=6 Hz)
EXAMPLE 88
[0984]
(2R)-N-Hydroxy-1-(5-phenylthiophene-2-sulfonyl)-4-[3-(1-piperidino)-
propanesulfonyl]-2-piperazinecarboxamide hydrochloride (115 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[0985] Mass (ESI-): 555 (M-H)
[0986] .sup.1H-NMR (300 M, DMSO-d.sub.6, .delta.): 1.26-1.42(2H,
m), 1.60-1.82(5H, m), 1.98-2.12(3H, m), 2.72-2.91(3H, m),
2.98-3.10(3H, m), 3.12-3.26(3H, m), 3.53-3.64(3H, m), 3.78-3.80(2H,
m), 3.87(1H, d, J=12 Hz), 4.50(1H, brs), 7.38-7.52(3H, m),
7.58-7.64(1H, m), 7.67-7.72(1H, m), 7.72-7.79(2H, m), 9.03(1H,
brs)
EXAMPLE 89
[0987]
(2R)-4-(N-Ethylaminocarbonyl)-1-[5-(4-fluorophenyl)thiophene-2-sulf-
onyl]-N-hydroxy-2-piperazinecarboxamide (98 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[0988] Mass (ESI): 455 (M-H)
[0989] .sup.1H-NMR (300 MHz, DMSO-d.sub.6.delta.): 0.92(3H, t, J=7
Hz), 2.78-3.06(4H, m), 3.50-3.75(3H, m), 3.97-4.08(1H, m), 4.26(1H,
brs), 6.35-6.42(1H, m), 7.32(2H, t, J=8 Hz), 7.59(1H, d, J=3 Hz),
7.67(1H, d, J=3 Hz), 7.78(1H, d, J=3 Hz), 7.82(1H, d, J=3 Hz),
8.93(1H, s)
EXAMPLE 90
[0990]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(3-p-
yridyl)propionyl]-2-piperazinecarboxamide hydrochloride (136 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 5.
[0991] Mass (ESI): 517 (M-H)
[0992] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.58-3.08(4H,
m), 3.22-3.95(3H, m), 4.02-4.23(2H, m), 4.28-4.38(1H, m), 4.43(1H,
brs), 7.33(2H, t, J=8 Hz), 7.55-7.72(2H, m), 7.76-7.86(2H, m),
7.90-8.00(1H, m), 8.38-8.50(1H, m), 8.70(1H, d, J=7 Hz), 8.80(1H,
s)
EXAMPLE 91
[0993] (2R)-4-[3-(N,N-Diethylamino)propanesulfonyl]
-1(5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxam-
ide hydrochloride (40 mg) was obtained in substantially the same
manner as in Example 5.
[0994] Mass (ESI): 561 (M-H)
[0995] .sup.1H-NMR (30MHz, DMSO-d.sub.6, .delta.): 2.19(6H, t, J=7
Hz), 1.89-2.06(2H, m), 2.76-2.88(1H, m), 2.95-3.28(1H, m),
3.49-3.80(3H, m), 3.88(1H, d, J=12 Hz), 4.49(1H, brs), 7.33(2H, t,
J=8 Hz),.7.55-7.63(1H, m), 7.69(1H, d, J=3 Hz), 7.78-7.86(2H, m),
9.01(1H, s)
EXAMPLE 92
[0996]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(3-p-
yridyl)acrylyl]-2-piperazinecarboxamide hydrochloride (120 mg) was
obtaiend as an amorphous powder in substantially the same manner as
in Example 5.
[0997] Mass (ESI): 515 (M-H)
[0998] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.92-3.08(1H,
m), 3.22-3.90(4H, m), 4.08-4.20(1H, m), 4.33-4.52(2H, m),
7.19-7.36(2H, m), 7.44-7.85(6H, m), 8.18-8.30(2H, m), 8.88(2H,
s)
EXAMPLE 93
[0999] (2R)-1-(5-(4-Fluorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-4-(N-met-
hylaminocarbonyl)-2-piperazinecarboxamide (88 mg) was obtained as
an amorphous powder in substantially the same manner as in Example
5.
[1000] Mass (ESI): 441 (M-H)
[1001] .sup.1H-NMR (300 MHz, DMS0-d.sub.6, .delta.): 2.44(3H, d,
J=3 Hz), 2.77-2.90(1H, m), 2.94-3.07(1H, m), 3.50-3.75(3H, m),
4.02(1H, d, J=12 Hz), 4.25(1H, brs), 6.38(1H, d, J=3 Hz), 7.30(2H,
t, J=8 Hz), 7.57(1H, d, J=3 Hz), 7.65(1H, d, J=3 Hz), 7.72-7.85(1H,
m), 8.92(1H, s)
EXAMPLE 94
[1002]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-methoxy-
carbonyl-2-piperazinecarboxamide (85 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[1003] Mass (ESI): 442 (M-H)
[1004] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.80-3.06(1H,
m), 3.11-3.23(1H, m), 3.51(3H, m), 3.55-3.74(2H, m), 3.78-3.92(1H,
m), 4.05(1H, d, J=12 Hz), 4.28(1H, brs), 7.32(2H, t, J=8 Hz),
7.58(1H, d, J=3 Hz), 7.64(1H, d, J=3 Hz), 7.73-7.87(2H, m),
8.94(1H, s)
EXAMPLE 95
[1005]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-(N-prop-
ylaminocarbonyl)-2-piperazinecarboxamide (100 mg) was obtained as
an amorphous powder in substantially the same manner as in Example
5.
[1006] Mass (ESI): 469 (M-H)
[1007] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.77(3H, t,
J=8 Hz), 1.23-1.40(2H, m), 2.78-2.96(3H, m), 3.05(1H, dd, J=3, 8
Hz), 3.52-3.76(3H, m), 3.97-4.09(1H, m), 4.27(1H, brs),
6.35-6.46(1H, m), 7.34(2H, t, J=8 Hz), 7.60(1H, d, J=3 Hz),
7.69(1H, d, J=3 Hz), 7.75-7.88(2H, m), 8.94(1H, s)
EXAMPLE 96
[1008]
(2R)-4-Butyryl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-
-2-piperazinecarboxamide (102 mg) was obtained as an amorphous
powder in substantially the same manner as in Example 5.
[1009] Mass (ESI): 454 (M-H)
[1010] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.80, 0.84(3H,
t, J=8 Hz), 1.32-1.50(2H, m), 2.03-2.28(2H, m), 2.62-2.76(1H, m),
3.02-3.22(1H, m), 3.42-3.87(2H, m), 4.04(1H, d, J=12 Hz),
4.10-4.39(2H, m), 7.32(2H, t, J=8 Hz), 7.51-7.84(4H, m), 8.92,
8.99(1H, s)
EXAMPLE 97
[1011]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-[5-(4-fluorophenyl)-thiophene--
2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (155 mg) was obtained
as an amorphous powder in substantially the same manner as in
Example 5.
[1012] Mass (ESI): 491 (M-H)
[1013] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.60-2.78(2H,
m), 2.72(6H, m), 3.35-3.52(2H, m), 3.92-4.12(2H, m), 4.59(1H, brs),
7.14(2H, t J=8 Hz), 7.23(1H, d, J=3 Hz), 7.52-7.61(3H, m)
EXAMPLE 98
[1014]
(2R)-1-[5-(4Chlorophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N--
hydroxy-2-piperazinecarboxamide (296 mg) was obtained in
substantially the same manner as in Example 5.
[1015] Mass (ESI-): 478, 480 (M-H)
[1016] .sup.1H-NMR (3MHz, DMSO-d.sub.6, .delta.): 2.74-2.85(1H, m),
2.87(3H, s), 3.00(1H, dd, J=4, 10 Hz), 3.52(1H, d, J=8 Hz),
3.70-3.86(3H, m), 4.49(1H, s), 7.54(2H, d, J=8 Hz), 7.60-7.71(4H,
m), 7.77(2H, d, J=8 Hz), 9.00(1H, s)
EXAMPLE 99
[1017]
(2R)-1-[5-(4-Methoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl--
N-hydroxy-2-piperazinecarboxamide (252 mg) was obtained in
substantially the same manner as in Example 5.
[1018] Mass (ESI-): 474 (M-H)
[1019] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.70-2.81(1H,
m), 2.85(3H, s), 2.99(1H, dd, J=4, 13 Hz), 3.50-3.60(1H, m),
3.70-3.82(3H, m), 3.82(3H, s), 4.46(1H, s), 7.03(1H, d, J=9 Hz),
7.49(1H, d, J=4 Hz), 7.55(1H, d, J=4 Hz), 7.70(1H, d, J=9 Hz),
9.00(1H, s)
EXAMPLE 100
[1020]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-[3-(4-morpholinocarbonyl)-p-
ropane)sulfonyl-N-hydroxy-2-piperazinecarboxamide (110 mg) was
obtained in substantially the same manner as in Example 5.
[1021] Mass (ESI-): 585 (M-H)
[1022] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.75-1.88(2H,
m), 2.38(2H, t, J=10 Hz), 2.73-2.87(1H1, m), 2.99-3.19(2H, m),
3.35-3.45(4H, m), 3.48-3.60(6H, m), 3.62-3.90(3H, m), 4.46-4.51(1H,
m), 7.39-7.52(3H, m), 7.60-7.80(5H, m), 8.99(1H, s)
EXAMPLE 101
[1023]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-(3carbamoylpropane)-sulfony-
l-N-hydroxy-2-piperazinecarboxamide (25 mg) was obtained in
substantially the same manner as in Example 5.
[1024] Mass (ESI-): 530 (M-H)
[1025] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.72-1.86(2H,
m), 2.15(2H, t, J=9 Hz), 2.55(2H, d, J=7 Hz), 2.72-2.85(2H, m),
2.99-3.08(2H, m), 3.52-3.60(1H, m), 3.69-3.90(2H, m), 4.45-4.49(1H,
m), 7.39-7.49(3H, m), 7.60(1H, d, J=4 Hz), 7.59(1H, d, J=4HZ),
7.71-7.80(2H, m), 8.96(1H, br)
EXAMPLE 102
[1026]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-[3-(N-methylcarbamoyl)-prop-
ane]sulfonyl-N-hydroxy-2-piperazinecarboxamide (105 mg) was
obtained in substantially the same manner as in Example 5.
[1027] Mass (ESI-): 529 (M-H)
[1028] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.72-1.84(2H,
m), 2.14(2H, t, J=9 Hz), 2.52(3H, d, J=6 Hz), 2.73-2.85(2H, m),
2.97-3.05(2H, m), 3.57(1H, d, J=13 Hz), 3.65-3.88(3H, m), 4.46(1H,
bs), 7.38-7.49(3H, m), 7.59(1H, d, J=4HZ), 7.67(1H, d, J=4 Hz),
7.71-7.76(2H, m), 8.95(1H, bs)
EXAMPLE 103
[1029]
(2R)-1-[5-(4-Methylphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-hydroxy-2-piperazinecarboxamide (166 mg) was obtained in
substantially the same manner as in Example 5.
[1030] Mass (ESI-): 458 (M-H)
[1031] H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.34(3H, s),
2.69-2.81(1H, m), 2.86(3H, s), 2.98(1H, dd, J=4, 13 Hz),
3.50-3.60(1H, m), 3.71-3.85(3H1, m), 4.46(1H, s), 7.28(1H, d, J=11
Hz), 7.53(1H, d, J=4 Hz), 7.54(1H, d, J=4 Hz), 7.57(1H, d, J=9 Hz),
8.97(1H, s)
EXAMPLE 104
[1032] (2R)-
1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-(1-propanesulfon-
yl)-N-hydroxy-2-piperazinecarboxamide (72 mg) was obtained in
substantially the same manner as in Example 5.
[1033] Mass (ESI-): 490 (M-H)
[1034] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.91(3H, t,
J=7 Hz), 1.53-1.69(2H, m), 2.72-2.85(1H, m), 2.91-3.02(3H, m),
3.25-3.40(1H, m), 3.49-3.85(3H, m), 4.44(1H, s), 4.85-4.90(1H, m),
7.30(2H, dd, J=11, 11 Hz), 7.57(1H, d, J=4 Hz), 7.53-7.66(2H, m),
7.73-7.82(2H, m), 8.91-8.99(1H, m)
EXAMPLE 105
[1035]
(2R)-1-[5-(4-Nitrophenyl)thiophene-2-sulfonyl]-4-(1-propanesulfonyl-
)-N-hydroxy-2-piperazinecarboxamide (125 mg) was obtained in
substantially the same manner as in Example 5.
[1036] Mass (ESI-): 489 (M-H)
[1037] .sup.1 H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.53-1.69(2H,
m), 2.72-2.85(1H, m), 2.91-3.02(3H, m), 3.25-3.40(1H, m),
3.49-3.85(3H, m), 4.44(1H, s), 4.85-4.90(1H, m), 7.30(2H, dd, J=11,
11 Hz), 7.57(1H, d, J=4 Hz), 7.53-7.66(2H, m), 7.73-7.82(2H, m),
8.91-8.99(1H, m)
EXAMPLE 106
[1038]
(2R)-N-Hydroxy-1-(5-phenylthiophene-2-sulfonyl)-4-[2-(2-pyridyl)-et-
hanesulfonyl]-2-piperazinecarboxamide (89 mg) was obtaiend as
crystals in substantially the same manner as in Example 5.
[1039] Mass (ESI-): 535 (M-H)
[1040] m.p.: 170-174.degree. C.
[1041] .sup.1H-NMR (300 Mz DMSO-d.sub.6, .delta.); 2.70-2.95(1H,
m), 2.97-3.13(3H, m), 3.25-3.53(2H, m), 3.54-3.80(3H, m), 3.87(1H,
d, J=12 Hz), 4.47(1H, brs), 7.24(1H, dd, J4, 6 Hz), 7.34(1H, d, J=6
Hz), 7.37-7.52(3H, m), 7.61(1H, d, J=2 Hz), 7.68(1H, d, J=2 Hz),
7.71-7.78(3H, m), 8.46(1H, d, J=4 Hz)
EXAMPLE 107
[1042]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(1-p-
iperidino)propanesulfonyl]-2-piperazinecarboxamide hydrochloride
(135 mg) was obtained as amorphous powder in substantially the same
manner as in Example 5.
[1043] Mass (ESI-): 573 (M-H)
[1044] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.25-1.45(2H,
m), 1.60-1.85(4H, m), 1.95-2.10(2H, m), 2.73-2.93(3H, m),
2.97-3.10(3H, m), 3.10-3.30(3H, m), 3.59(1H, d, J=12 Hz),
3.65-3.80(2H, m), 3.86(1H, d, J=12 Hz), 4.49(1H, s), 7.33(2H, t,
J=8 Hz), 7.59(1H, d, J=2 Hz), 7.68(1H, d, J=2 Hz), 7.82(2H, dd,
J=4, 8 Hz)
EXAMPLE 108
[1045]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[(N-phe-
nyl)aminocarbonyl]-2-piperazinecarboxamide (118 mg) was obtained as
crystals in substantially the same manner as in Example 5.
[1046] Mass (ESI-): 503 (M-H)
[1047] m.p.: 187-188.degree. C.
[1048] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 3.05(1H, m),
3.17(1H, dd, J=3, 12 Hz), 3.60-3.80(2H, m), 3.94(1H, d, J=12 Hz),
4.69(1H, d, J=12 Hz), 4.33(1H, m), 6.91(1H, t, J=6 Hz), 7.18(2H, t,
J=8 Hz), 7.30(2H, t, J=6 Hz), 7.36(2H, d, J=6 Hz), 7.58(1H, d, J=2
Hz), 7.69(1H, d, J=2 Hz), 7.78(2H, dd, J=4, 8 Hz), 8.47(1H, s),
8.95(1H, s)
EXAMPLE 109
[1049]
(2R)-4-[(N-Cyclohexyl)aminocarbonyl]-1-[5-(4-fluorophenyl)-thiophen-
e-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (117 mg) was
obtained as crystals in substantially the same manner as in Example
5.
[1050] m.p.: 111-123.degree. C.
[1051] Mass (ESI-): 509 (M-H)
[1052] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.90-1.25(5H,
m), 1.43-1.74(5H, m), 2.84(1H, m), 3.04(1H, dd, J=2, 12 Hz),
3.17-3.35(1H, m), 3.50-3.74(3H, m), 3.98(1H, d, J=12 Hz), 4.24(1H,
s), 6.07(1H, d, J=6 Hz), 7.32(2H, t, J=8 Hz), 7.58(1H, d, J=2 Hz),
7.67(1H, d, J=2 Hz), 7.80(2H, dd, J=4, 8 Hz), 8.93(1H, s)
EXAMPLE 110
[1053]
(2R)-4-Ethoxycarbonyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N--
hydroxy-2-piperazinecarboxamide (85 mg) was obtained in
substantially the same manner as in Example 5.
[1054] Mass (ESI-): 456 (M-H)
[1055] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.13(3H, t,
J=6 Hz), 2.94(1H, m), 3.18(1H, dd, J=2, 12 Hz), 3.75(2H, m),
3.75-3.95(1H, m), 3.94(2H, q, J=6 Hz), 4.07(1H, d, J=12 Hz),
4.26(1H, s), 7.33(2H, t, J=8 Hz), 7.58(1H, d, J=2 Hz), 7.61(1H, d,
J=2 Hz), 7.81(2H, dd, J=4, 8 Hz), 8.93(1H, s)
EXAMPLE 111
[1056] (2R)-4-Dimethylcarbamoyl-1-[5-(4-fluorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (85 mg) was
obtained in substantially the same manner as in Example 5.
[1057] Mass (ESI-): 455 (M-H)
[1058] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.65(6H, s),
2.60-2.75(1H, m), 2.89(1H, dd, J=2, 12 Hz), 3.30-3.50(1H, m),
3.57-3.95(3H, m), 4.34(1H, brs), 7.33(2H, t, J=8 Hz), 7.58(1H, d,
J=2 Hz), 7.65(1H, d, J=2 Hz), 7.81 (2H, dd, J=4, 8 Hz), 8.91(1H,
brs)
EXAMPLE 112
[1059]
(2R)-1-[5-(2-2luorophenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-hydroxy-2-piperazinecarboxamide (291 mg) was obtained in
substantially the same manner as in Example 5.
[1060] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.73(1H, dt,
J=6, 14 Hz), 2.85(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.53(1H, d,
J=14 Hz), 3.67-3.86(3H, m), 4.46-4.51(1H, m), 7.34(1H, t, J=8 Hz),
7.43(1H, d, J=8 Hz), 7.49(1H, t, J=8 Hz), 7.65-7.74(2H, m),
7.92(1H, t, J=8 Hz), 9.00(1H, brs)
[1061] Mass (ESI): 462 (M-1)
EXAMPLE 113
[1062] (2R)-N-Hydroxy-4
methanesulfonyl-1-(4-phenylthiazole-2-sulfonyl)-2--
piperazinecarboxamide (88 mg) was obtained in substantially the
same manner as in Example 5.
[1063] Mass (ESI): 445 (M-1)
[1064] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.72-2.88(4H,
m), 2.85(3H, s), 3.05(1H, dd, J=6, 14 Hz), 3.58(1H, d, J=14 Hz),
3.71-3.40(3H, m), 4.55-4.61(1H, m), 7.39-7.53(3H, m), 8.00(1H, d,
J=8 Hz), 8.54(1H, s), 9.00(1H, brs)
EXAMPLE 114
[1065]
(2R)-4-(2-Benzyloxycarbonylaminoethanesulfonyl)-N-hydroxy-(5-phenyl-
thiophene-2-sulfonyl) -2-piperazinecarboxamide (38 mg) was obtained
in substantially the same manner as in Example 5.
[1066] Mass (ESI): 607 (M-1)
[1067] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.70-2.90(3H,
m), 3.05(1H, dd, J=6, 14 Hz), 3.12-3.20(2H, m), 3.57(1H, d, J=14
Hz), 3.64-3.78(2H, m), 3.83(1H, d, J=14 Hz), 4.42-4.50(1H, m),
4.90-4.98(1H, m), 5.02(2H, s), 7.28-7.51(8H, m), 7.60(1H, d, J=3
Hz), 7.68(1H, d, J=3 Hz), 7.74(2H, d, J=8 Hz), 8.98(1H, brs)
EXAMPLE 115
[1068]
(2R)-N-Hydroxy-1-(5-phenylthiophene-2-sulfonyl)-4-[3-(1,2,4-triazol-
yl-3-thio)propanesulfonyl]-2-piperazinecarboxamide hydrochloride
(78 mg) was obtained in substantially the same manner as in Example
5.
[1069] Mass (ESI): 571 (M-1)
[1070] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, (3) 1.92-2.05(2H1, m),
2.71-2.87(1H, m), 3.02(1H, dd, J=6, 14 Hz), 3.08-3.17(4H, m),
3.50-3.60(1H, m), 3.60-3.90(3H, m), 4.43-4.50(1H, m), 7.39-7.51(3H,
m), 7.61(1H, d, J=3 Hz), 7.70(1H, d, J=3 Hz), 7.76(2H, d, J=8 Hz),
8.43(1H, brs)
EXAMPLE 116
[1071]
(2R)-N-Hydroxy-1-[5-(3-isoxazolyl)thiophene-2-sulfonyl]-4-methanesu-
lfonyl-2-piperazinecarboxamide (259 mg) was obtained in
substantially the same manner as in Example 5.
[1072] Mass (ESI): 435 (M-1)
[1073] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.76(1H, dt,
J=6, 14 Hz), 2.87(3H, s), 3.01 (1H, dd, J=6, 14 Hz), 3.54(1H, d,
J=14 Hz), 3.65-3.85(3H, m), 4.46-4.51(1H, m), 7.12(1H, s), 7,75(1H,
d, J=3 Hz), 7.79(1H, d, J=3 Hz), 8.76(1H, s), 9.00(1H, brs)
EXAMPLE 117
[1074]
(2R)-N-Hydroxy-4-methanesulfonyl-1-[5-(4-trifluoromethylphenyl)-thi-
ophene-2-sulfonyl]-2-piperazinecarboxamide (164 mg) was obtained in
substantially the same manner as in Example 5.
[1075] Mass (ESI): 512 (M-1)
[1076] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.69-2.82(1H,
m), 2.86(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.53(1H, d, J=14 Hz),
3.66-3.85(3H, m), 4.45-4.51(1H, m), 7.73(1H, d, J=3 Hz), 7.78(1H,
d, J=3 Hz), 7.84(2H, d, J=8 Hz), 7.99(2H, d, J=8 Hz), 9.00(1H,
brs)
EXAMPLE 118
[1077]
(2R)-N-Hydroxy-4-methanesulfonyl-1-{5-[3,4-(methylenedioxy)-phenyl]-
thiophene-2sulfonyl}-2-piperazinecarboxamide (215 mg) was obtained
in substantially the same manner as in Example 5.
[1078] Mass (ESI): 488 (M-1)
[1079] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.67-2.79(1H,
m), 2.86(3H, s), 2.98(1H, dd, J=6, 14 Hz), 3.52(1H, d, J=14 Hz),
3.68-3.76(2H, m), 3.81(1H, d, J=14 Hz), 4.42-4.48(1H, m), 6.10(2H,
s), 7.00(1H, d, J=8 Hz), 7.23(1H, d, J=8 Hz), 7.48(1H, s), 7,50(1H,
d, J=3 Hz), 7.63(1H, d, J=3 Hz), 9.00(1H, brs)
EXAMPLE 119
[1080]
(2R)-1-[5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-
-hydroxy-2-piperazinecarboxamide (128 mg) was obtained in
substantially the same manner as in Example 5.
[1081] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.32(3H, t,
J=7 Hz), 2.68-2.80(1H, m), 2.86(3H, s), 2.96(1H, dd, J=4, 13 Hz),
3.51(1H, d, J=12 Hz), 3.69-3.76(2H, m), 3.80(1H, d, J=12 Hz),
4.07(2H, q, J=7 Hz), 4.43(1H, s), 7.00(2H, d, J=8 Hz), 7.44(1H, d,
J=4 Hz), 7.63(1H, d, J=4 Hz), 7.68(1H, d, J=8 Hz), 8.99(1H, bs)
EXAMPLE 120
[1082]
(2R)-1-[5-(4-Cyanophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-methanes-
ulfonyl-2-piperazinecarboxamide (203 mg) was obtained in
substantially the same manner as in Example 5.
[1083] Mass (ESI): 469 (M-1)
[1084] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.70-2.81(1H,
m), 2.87(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.55(1H, d, J=14 Hz),
3.70-3.86(3H, m)), 4.45-4.51(1H, m), 7.72(1H, d, J=3 Hz), 7.81(1H,
d, J=3 Hz), 7.97((4H, s), 9.00(1H, brs)
EXAMPLE 121
[1085] (2R)-1
-[5-(4-Cyanomethylphenyl)thiophene-2-sulfonyl]-N-hydroxy-
4-methanesulfonyl-2-piperazinecarboxamide (1I46 mg) was obtained in
substantially the same manner as in Example 5.
[1086] Mass (ESI): 483 (M-1)
[1087] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.80(1H,
m), 2.86(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.53(1H, d, J=14 Hz),
3.70-3.77(2H, m), 3.81(1H, d, J=14 Hz), 4.12(2H, s), 4.44-4.50(1H,
m), 7,46(2H, d, J=8 Hz), 7.63(1H, d, J=3 Hz), 7.68(1H, d, J=3 Hz),
7.79(2H, d, J=8 Hz), 9.00(1H, brs)
EXAMPLE 122
[1088]
(2R)-1-[5-(4-Acetoxymethylphenyl)thiophene-2-sulfonyl]-N-hydroxy-4--
methanesulfonyl-2-piperazinecarboxamide (36 mg) was obtained in
substantially the same manner as in Example 5.
[1089] Mass (ESI): 516 (M-1)
[1090] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.10(3H, s),
2.68-2.80(1H, m), 2.87(3H, s), 3.00 (1H, dd, J=6, 14 Hz),
3.49-3.59(1H, m), 3.70-3.85(3H, m), 4.43-4.50(1H, m), 5.11(2H, s),
7.46(2H, d, J=8 Hz), 7.62(1H, d, J=3 Hz), 7.67(1H, d, J=3 Hz),
7.76(2H, d, J=8 Hz), 9.00(1H, brs)
EXAMPLE 123
[1091]
(2R)-1-[5-(3-Fluoro-4-methoxyphenyl)thiophene-2-sulfonyl]-4-methane-
sulfonyl-N-hydroxy-2-piperazinecarboxamide (315 mg) was obtained in
substantially the same manner as in Example 5.
[1092] Mass (ESI-): 492 (M-H) .sup.1H-NMR (300 MHz, DMSO-d.sub.6,
.delta.): 2.68-2.80(1H, m), 2.85(3H, s), 2.92-3.02(1H, m), 3.53(1H,
d, J=12 Hz), 3.70-3.78(2H, m), 3.81(1H, d, J=12 Hz), 3.89(3H, s),
4.44(1H, s), 7.25(1H, dd, J=11, 11 Hz), 7.48-7.59(2H, m), 7.65(1H,
d, J=4 Hz), 7.70(1H, d, J=11 Hz), 9.01(1H, s)
EXAMPLE 124
[1093] (2R)-N-Hydroxy-4-methanesulfonyl-1
-[5-(3-methoxyphenyl)thiophene-2-
-sulfonyl]-2-piperazinecarboxamide (239 mg) was obtained in
substantially the same manner as in Example 5.
[1094] Mass (ESI): 474 (M-1)
[1095] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.69-2.80(1H,
m), 2.87(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.53(1H, d, J=14 Hz),
3.70-3.81(3H, m), 3.85(3H, s), 4.45-4.50(1H, m), 7.00(1H, d, J=8
Hz), 7.30(1H, d, J=8 Hz), 7.40(1H, t, J=8 Hz), 7.73(1H, d, J=3 Hz),
7.78(1H, d, J=3 Hz), 9.00(1H, brs)
EXAMPLE 125
[1096] (2R)-1-[5-(4-Dimethylaminosulfonylphenyl)
thiophene-2-sulfonyl]-N-h-
ydroxy-4-methanesulfonyl-2-piperazinecarboxamide (264 mg) was
obtained in substantially the same manner as in Example 5.
[1097] Mass (ESI): 551 (M-1)
[1098] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.64(6H, s),
2.71-2.82(1H, m), 2.88(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.56(1H,
d, J=14 Hz), 3.71-3.87(3H, m), 4.47-4.51(1H, m), 7.72(1H, d, J=3
Hz), 7.79-7.86(3H, m), 8.03(2H, d, J=8 Hz), 9.00(1H, brs)
EXAMPLE 126
[1099] (2R)-N-Hydroxy-1-[5-(4-methanesulfonyloxyphenyl)
thiophene-2-sulfonyl]-4-methanesulfonyl-2-piperazinecarboxamide
(241 mg) was obtained in substantially the same manner as in
Example 5.
[1100] Mass (ESI): 538 (M-1)
[1101] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.80(1H,
m), 2.86(3H, s), 2.99(1H, dd, J=6, 14 Hz), 3.43(3H, s), 3.53(1H, d,
J=14 Hz), 3.68-3.84(3H, m), 4.45-4.50(1H, m), 7.46(2H, d, J=8 Hz),
7.63(1H, d, J=3 Hz), 7.70(1H, d, J=3 Hz), 7.88(2H, d, J=8 Hz),
9.00(1H, s)
EXAMPLE 127
[1102]
(2R)-1-[5-(2,4-Difluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-met-
hanesulfonyl-2-piperazinecarboxamide (251 mg) was obtained in
substantially the same manner as in Example 5.
[1103] Mass (ESI): 480 (M-1)
[1104] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.80(1H,
m), 2.88(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.53(1H, d, J=14 Hz),
3.67-3.90(3H, m), 4.47-4.51(1H, m), 7.22-7.30(1H, m), 7.45-7.50(1H,
m), 7.67(1H, d, J=3 Hz), 7.72(1H, d, J=3 Hz), 7.94-8.04(1H, m),
9.00(1H, brs)
EXAMPLE 128
[1105]
(2R)-1-[5-(4Cyanomethoxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-4-me-
thanesulfonyl-2-piperazinecarboxamide (69 mg) was obtained in
substantially the same manner as in Example 5.
[1106] Mass (ESI): 499 (M-1)
[1107] .sup.1H-NMR (300 t, DMSO-d.sub.6, .delta.): 2.67-2.80(1H,
m), 2.86(3H, s), 3.98(1H, dd, J=6, 14 Hz), 3.52(1H, d, J=14 Hz),
3.69-3.88(3H, m), 4.43-4.50(1H, m), 5.26(2H, s), 7.12(2H, d, J=8
Hz), 7.54(1H, d, J=3 Hz), 7.67(1H, d, J=3 Hz), 7.77(2H, d, J=8 Hz),
9.00(1H, brs)
EXAMPLE 129
[1108]
(2R)-N-Hydroxy-4-methanesulfonyl-1-[5-(4-methoxycarbonylphenyl)-thi-
ophene-2-sulfonyl]-2-piperazinecarboxamide (175 mg) was obtained in
substantially the same manner as in Example 5.
[1109] Mass (ESI): 502 (M-1)
[1110] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 , .delta.): 2.69-2.83(1H,
m), 2.88(3H, s), 3.00(1H, dd, J=6, 14 Hz), 3.54(1H, d, J=14 Hz),
3.70-3.86(3H, m), 3.90(3H, s), 4.45-4.52(1H, m), 7.71(1H, d, J=3
Hz), 7.78(1H, d, J=3 Hz), 7.92(2H, d, J=8 Hz), 8.05(2H, d, J=8 Hz),
9.00(1H, brs)
EXAMPLE 130
[1111]
(2R)-1-[5-(4-Biphenylyl)thiophene-2-sulfonyl]-4methanesulfonyl-N-hy-
droxy-2-piperazinecarboxamide (233 mg) was obtained in
substantially the same manner as in Example 5.
[1112] Mass (ESI-): 520 (M-H)
[1113] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.71-2.82(1H,
m), 2.87(3H, s), 2.99(1H, dd, J=4, 8 Hz), 3.52(1H, d, J=12 Hz),
3.70-3.77(2H, m), 3.80(1H, d, J=12 Hz), 4.48(1H, s), 7.41(1H, d,
J=8 Hz), 7.48(1H, dd, J=8, 8 Hz), 7.62-7.85(6H, m)
EXAMPLE 131
[1114]
(2R)-1-[5-(4-Pyridyl)thiophene-2-sulfonyl]-4-methanesulfonyl-N-hydr-
oxy-2-piperazinecarboxamide (225 mg) was obtained in substantially
the same manner as in Example 5.
[1115] Mass (ESI-): 486 (M-H)
[1116] .sup.1H-NM (300 MHz, DMSO-d.sub.6, .delta.): 2.74-2.86(1H,
m), 2.85(3H, s), 3.03-3.09(1H, m), 3.58(1H, d, J=12 Hz),
3.69-3.90(2H, m), 4.56(1H, s), 7 84(1H, d, J=4 Hz), 8.25(1H, d, J=4
Hz), 8.36(2H, d, J=8 Hz), 8.94(1H, d, J=8 Hz)
EXAMPLE 132
[1117] (2R)-1-[5-(2, 3-Dihydrobenzofuran-5-yl)
thiophene-2-sulfonyl)
-4-methanesulfonyl-N-hydroxy-2-piperazinecarboxamide (191 mg) was
obtained in substantially the same manner as in Example 5.
[1118] Mass (ESI-): 486 (M-H)
[1119] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.70-2.83(2H,
m), 2.87(3H, s), 2.96(1H, dd, J=4, 8 Hz), 3.23(2H, t, J=10 Hz),
3.53(1H, d, J=12 Hz), 3.70-3.77(2H, m), 3 81(1H, d, J=12 Hz),
4.43(1H, s), 4.59(2H, t, J=10 Hz), 6.82(1H, d, J=8 Hz), 7.40(1H, d,
J=4 Hz), 7.47(1H, d, J=8 Hz), 7.62(1H, d, J=8 Hz), 7.63(1H, s),
8.97(1H, bs)
EXAMPLE 133
[1120]
(2R)-1-[5-(4-Phenoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfonyl--
N-hydroxy-2-piperazinecarboxamide (250 mg) was obtained in
substantially the same manner as in Example 5.
[1121] Mass (ESI-): 536 (M-H)
[1122] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.80(2H,
m), 2.86(3H, s), 2.98(1H, dd, J=5, 13 Hz), 3.53(1H, d, J=13 Hz),
3.70-3.77(2H, m), 3.81(2H, d, J=12 Hz), 4 22(1H, d, J=13 Hz),
4.47(1H, bs), 7.03-7.09(4H, m), 7.20(1H, dd, J=8, 8 Hz), 7.42(2H,
dd, J=8, 8 Hz), 7.52(1H, d, J=4 Hz), 7.67(1H, d, J=4 Hz), 7.77(2H,
d, J=8 Hz), 8.99(1H, s)
EXAMPLE 134
[1123]
(2R)-1-[5-(5-Methyl-1,3,4-oxadiazol-2-yl)thiophene-2-sulfonyl]-N-hy-
droxy-4-methanesulfonyl-2-piperazinecarboxamide (84 mg) was
obtained in substantially the same manner as in Example 5.
[1124] Mass (ESI): 450 (M-1)
[1125] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.59(3H, s),
2.68-2.80(1H, m), 2.88(3H, s), 2.98-3.06(1H, m), 3.50-3.59(1H, m),
3.68-3.85(3H, m), 4.48-4.52(1H, m), 7.72-7.75(1H, m), 7.78-7.82(1H,
m), 8.97(1H, brs)
EXAMPLE 135
[1126]
(2R)-i-[5-(5-Phenyl-1,3,4-oxadiazol-2-yl)thiophene-2-sulfonyl]-N-hy-
droxy-4-methanesulfonyl-2-piperazinecarboxamide (137 mg) was
obtained in substantially the same manner as in Example 5.
[1127] Mass (ESI): 512 (M-1)
[1128] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.70-2.83(1H,
m), 2.88(3H, s), 3.04(1H, dd, J=6, 14 Hz), 3.57(1H, d, J=14 Hz),
3.68-3.90(3H, m), 4.51-4.56(1H, m), 7.60-7.72(3H, m), 7.84(1H, d,
J=3 Hz), 8.01(1H, d, J=3 Hz), 8.13(H, d, J=8 Hz), 9.00(1H, brs)
EXAMPLE 136
[1129] (2R)-N-Hydroxy-4-methanesulfonyl-1-(5-(2-thiazolyl)
thiophene-2-sulfonyl]-2-piperazinecarboxamide (93 mg) was obtained
in substantially the same manner as in Example 5
[1130] Mass (ESI): 451 (M-1)
[1131] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.82(1H,
m), 2.88(3H, s), 3.02(1H, dd, J=6, 14 Hz), 3.64(1H, d, J=14 Hz),
3.70-3.87(3H, m), 4.47-4.51(1H, m), 7.67(1H, d, J=3 Hz), 7.74(1H,
d, J=3 Hz), 7.90(1H, d, J=2 Hz), 7.93(1H, d, J=2 Hz), 9.00(1H,
brs)
EXAMPLE 137
[1132]
(2R)-N-Hydroxy-4-methanesulfonyl-1-[5-phenyl-1,3,4-thiadiazol-2-sul-
fonyl]-2-piperazinecarboxamide (71 mg) was obtained in
substantially the same manner as in Example 5.
[1133] Mass (ESI): 446 (M-1)
[1134] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.82-2.95(4H,
m), 3.17(1H, dd, J=6, 14 Hz), 3.61(1H, d, J=14 Hz), 3.73(1H, dt,
J=6, 14 Hz), 3.88-4.01(2H, m), 4.58-4.63(1H, m), 7.69-7.70(3H, m),
8.10(2H, d, J=8 Hz), 9.05(1H, brs)
EXAMPLE 138
[1135]
(2R)-N-Hydroxy-4-methanesulfonyl-1-[4-(thiophene-2-yl)-benzenesulfo-
nyl]-2-piperazinecarboxamide (166 mg) was obtained as crystals in
substantially the same manner as in Example 5.
[1136] m.p.: 201-202.degree. C.
[1137] Mass (ESI-): 444 (M-H)
[1138] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.66(1H, dt,
J=2, 11 Hz), 2.83(3H, s), 2.93(1H, dd, J=2, 11 Hz), 3.49(1H, d,
J=11 Hz), 3.63(1H, dt, J=2, 11 Hz), 3.70-3.85(2H, m), 4.46(1H,
brs), 7.21(1H, t, J=2 Hz), 7.67-7.77(2H, m), 7.81(2H, d, J=8 Hz),
7.88(2H, d, J=8 Hz), 8.97(1H, s)
EXAMPLE 139
[1139]
(2R)-N-Hydroxy-4-[5-(isoxazol-3-yl)thiophene-2-sulfonyl]-1-(5-pheny-
lthiophene-2-sulfonyl)-2-piperazinecarboxamide (153 mg) was
obtained in substantially the same manner as in Example 5.
[1140] m.p.: 204.degree. C.
[1141] Mass (ESI-): 579 (M-H)
[1142] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.12-2.28(1H,
m), 2.38(1H, dd, J=6, 14 Hz), 3.48-3.59(1H, d, J=14 Hz),
3.62-3.78(1H, m), 3.80-4.01(2H, m), 4.58-4.62(1H, m), 6.95(1H, s),
7.34-7.42(3H, m), 7.45(1H, d, J=6 Hz), 7.52-7.78(5H, m), 8.72(1H,
s), 9.08(1H, brs)
EXAMPLE 140
[1143]
(2R)-N-Hydroxy-1-(5-phenylthiophene-2-sulfonyl)-4-(1-piperidinesulf-
onyl)-2-piperazinecarboxamide (126 mg) was obtained as an amorphous
powder in substantially the same manner as in Example 5.
[1144] Mass (ESI-): 513 (M-H)
[1145] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.24-1.48(6H,
m), 2.48-2.62(1H, m), 2.73(1H, dd, J=3, 12 Hz), 2.94-3.08(4H, m),
3.37-3.98(1H, m), 3.52-3.97(3H, m), 4.49(1H, brs), 7.38-7.52(3H,
m), 7.58-7.68(1H, m), 7.72-7.80(3H, m), 8.98(1H, brs)
EXAMPLE 141
[1146] (2R)-N-Hydroxy-4-(N-methylpropylaminosulfonyl)-1
-(5-phenylthiophene-2-sulfonyl)-2-piperazinecarboxamide (140 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 5.
[1147] Mass (ESI-): 501 (M-H)
[1148] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.78(3H, t,
J=8 Hz), 1.37-1.50(2H, m), 2.52-2.70(1H, m), 2.16(3H, s), 2.78(1H,
dd, J=4, 12 Hz), 3.00(2H, t, J=8 Hz), 3.30-3.45(1H, m),
3.56-3.97(3H, m), 4.48(1H, brs), 7.38-7.52(3H, m), 7.59-7.67(1H,
m), 7.70-7.79(3H, m), 8.97(1H, s)
EXAMPLE 142
[1149] (2R)-4-(N,N-Dimethylaminosulfonyl)-N-hydroxy-1
-(5-phenylthiophene-2-sulfonyl)-2-piperazinecarboxamide (124 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 5.
[1150] Mass (ESI-): 473 (M-H)
[1151] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.62-2.74(1H,
m), 2.68(6H, s), 2.82-2.91(1H, m), 3.39-3.49(1H, m), 3.60-3.82(3H,
m), 4.46(1H, brs), 7.38-7.52(3H, m), 7.58-7.65(1H, m),
7.68-7.78(3H, m), 8.97(1H, s)
EXAMPLE 143
[1152] (2R)-N-Hydroxy-1-(5-phenylthiophene-2-sulfonyl)
-4-13-(thiazolyl-2-thio)propanesulfonyl]-2-piperazinecarboxamide
(109 mg) was obtained in substantially the same manner as in
Example 5.
[1153] Mass (ESI-): 587 (M-H) .sup.1H-NMR (300 MHz, DMSO-d.sub.6,
.delta.): 2.03(2H, m), 2.80(1H, dt, J=2, 11 Hz), 3.02(1H, dd, J=2,
11 Hz), 3.15(2H, t, J=4 Hz), 3.25(2H, t, J=4 Hz), 3.56(1H, d, J=11
Hz), 3.60-3.80(2H, m), 3.84(1H, d, J=11 Hz), 4.47(1H, brs),
7.38-7.53(3H, m), 7.62(1H, d, J=2 Hz), 7.65-7.70(2H, m),
7.71-7.79(3H, m)
EXAMPLE 144
[1154]
(2R)-N-Hydroxy-4-[3-(4-methyl-1,2,4-triazolyl-3-thio)-propanesulfon-
yl3-1-(5-phenylthiophene-2-sulfonyl)-2-piperazinecarboxamide
hydrochloride (91 mg) was obtained in substantially the same manner
as in Example 5.
[1155] Mass (ESI-): 585 (M-H)
[1156] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.) 2.00(2H, m),
2.80(1H, dt, J=2, 11 Hz), 3.03(1H, dd, J=2, 11 Hz), 3.10-3.24(4H,
m), 3.56(1H, d, J=11 Hz), 3.60(3H, s), 3.64-3.80(2H, m), 3.85(1H,
d, J=11 Hz), 4.48(1H, brs), 7.38-7.53(3H, m), 7.63(1H, d, J=2 Hz),
7.69(1H, d, J=2 Hz), 7.71-7.79(2H, m), 8.98(1H, s)
EXAMPLE 145
[1157]
(2R)-N-Hydroxy-4-[3-(imidazolyl-2-thio)propanesulfonyl)-1-(5-phenyl-
thiophene-2-sulfonyl)-2-piperazinecarboxamide hydrochloride (90 mg)
was obtained in substantially the same manner as in Example 5.
[1158] Mass (ESI-): 570 (M-H)
[1159] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.86(2H, m),
2.81(1H, dt, J=2, 11 Hz), 3.04(1H, dd, J=2, 11 Hz), 3.15(2H, t, J=4
Hz), 3.23(2H, t, J=4 Hz), 3.30-3.70(1H, overlapping with H.sub.2O),
3.65-3.80(2H, m), 3.84(1H, d, J=11 Hz), 4.48(1H, brs),
7.38-7.50(3H, m), 7.63(1H, d, J=2 Hz), 7.68(1H, d, J=2 Hz),
7.70-7.79(4H, m)
EXAMPLE 146
[1160]
(2R)-N-Hydroxy-4-methoxycarbonyl-1-(5-phenylthiophene-2-sulfonyl)-2-
-piperazinecarboxamide (110 mg) was obtained as an amorphous powder
in substantially the same manner as in Example 5.
[1161] Mass (ESI-): 424 (M-H)
[1162] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.85-3.07(1H,
m), 3.12-3.25(1H, m), 3.52(3H, s), 3.56-3.93(3H, m), 4.01-4.11(1H,
m), 4.29(1H, brs), 7.36-7.52(3H, m), 7.57-7.68(2H, m), 7.77(2H, d,
J=8 Hz), 8.95(1H, brs)
EXAMPLE 147
[1163]
(2R)-4-Ethylaminocarbonyl-N-hydroxy-1-(5-phenylthiophene-2-sulfonyl-
)-2-piperazinecarboxamide (108 mg) was obtained as an amorphous
powder in substantially the same manner as in Example 5.
[1164] Mass (ESI-): 437 (M-H)
[1165] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.93(3H, t,
J=7 Hz), 2.76-3.10(4H, m), 3.50-3.78(3H, m), 3,95-4.08(1H, m),
4.28(1H, brs), 6.35-6.47(1H, m), 7.35-7.52(2H1, m), 7.61(1H, d, J=3
Hz), 7.68(1H, d, J=3 Hz), 7.75(2H, d, J=8 Hz), 8.93(1H, brs)
EXAMPLE 148
[1166]
(2R)-1-(5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(1,2-
,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (102 mg) was obtained in substantially the same
manner as in Example 5
[1167] Mass (ESI-): 589 (M-H)
[1168] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.99(2H, m),
2.79(1H, dt, J=2, 11 Hz), 3.03(1H, dd, J=2, 11 Hz), 3.05-3.20(4H,
m), 3.55(1H, d, J=11 Hz), 3.60-3.70(2H, m), 3.84(1H, d, J=11 Hz),
4.46(1H, brs), 7.33(2H, t, J=8 Hz), 7.59(1H, d, J=2 Hz), 7.68(1H,
d, J=2 Hz), 7.80(2H, dd, J=4, 8 Hz), 8.45(1H, s)
EXAMPLE 149
[1169]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-((4--
methyl-1 , 2,4-triazolyl-3-thio) propanesulfonyl)
-2-piperazinecarboxamide hydrochloride (88 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[1170] Mass (ESI-): 603 (M-H)
[1171] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.93-2.08(21H,
m), 2.72-2.88(1H, m), 3.03(1H, dd, J=6, 14 Hz), 3.10-3.25(4H, m),
3.48-3.90(4H, m), 3.62(3H, s), 4.48(1H, brs), 7.33(2H, t, J=8 Hz),
7.60(1H, d, J=4 Hz), 7.69(1H, d, J=4 Hz), 7.77-7.86(2H, m),
8.98(1H, s)
EXAMPLE 150
[1172]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-1-[3-(imi-
dazolyl-2-thio) propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (73 mg) was obtained in substantially the same manner
as in Example 5.
[1173] Mass (ESI-): 588 (M-H)
[1174] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.87(2H, m),
2.82(1H, dt, J=2, 11 Hz), 3.04(1H, dd, J=2, 11 Hz), 3.17(21, t, J=4
Hz), 3.25(2H, t, J=4 Hz), 3.50-3.90(4H, m), 4.48(1H, s), 7.34(2H,
t, J=8 Hz), 7.60(1H, d, J=2 Hz), 7.68(1H, d, J=2 Hz), 7.73(2H, s),
7.82(2H, dd, J=4, 8 Hz)
EXAMPLE 151
[1175]
(2R)-4-[3-(Benzimidazolyl-2-thio)propanesulfonyl]-1-[5-(4-fluorophe-
nyl)thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide
hydrochloride (79 mg) was obtained in substantially the same manner
as in Example 5.
[1176] Mass (ESI-): 638 (M-H)
[1177] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.08(2H, m),
2.83(1H, dt, J=2, 11 Hz), 3.06(1H, dd, J=2, 11 Hz), 3.23(2H, t, J=4
Hz), 3.44(2H, t, J=4 Hz), 3.58(1H, d, J=11 Hz), 3.64-3.80(2H, m),
3.85(1H, d, J=11 Hz), 4.47(1H, s), 7.25-7.37(4H, m), 7.54-7.63(2H,
m), 7.66(1H, d, J=2 Hz), 7.80(2H, dd, J=4, 8 Hz)
EXAMPLE 152
[1178] (2R)-1-[5-(4-Fluorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-4-(pyrid-
ine-3-sulfonyl)-2-piperazinecarboxamide (110 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[1179] Mass (ESI-): 525 (M-H)
[1180] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.98-2.12(1H,
m), 1.98-2.11(1H, m), 2.20-2.31(1H, m), 3.65-3.85(2H, m), 3.96(1H,
d, J=15 Hz), 4.49-4.56(1H, m), 7.35(2H, t, J=8 Hz), 7.44(1H, d, J=5
Hz), 7.47-7.54(1H, m), 7.62(1H, d, J=5 Hz), 7.71(1H, d, J=5 Hz),
7.73(1H, d, J=5 Hz), 8.01(1H, m), 8.62(1H, d, J=5 Hz), 8.78(1H,
brs)
EXAMPLE 153
[1181] (2R)-4-(N-Ethylaminosulfonyl) - 1-[5-(4-fluorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (143 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 5.
[1182] Mass (ESI): 491 (M-H)
[1183] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.94(3H, t,
J=7 Hz), 2.45(1H, dd, J=3, 8 Hz), 2.72-2.87(2H, m), 3.23-3.42(1H,
m), 3.58-3.91(3H, m), 4.15-4.41(1H ,m), 4.48(1H, brs),
7.26-7.38(2H, m), 7.61(1H, d, J=3 Hz), 7.72(1H, d, J=3 Hz),
7.76-7.85(2H, m), 8.94(1H, s)
EXAMPLE 154
[1184]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2sulfonyl]-N-hydroxy-4-(1-piper-
idinesulfonyl)-2-piperazinecarboxamide (157 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[1185] Mass (ESI-): 531 (M-H)
[1186] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.) 1.28-1.52(6H,
m), 2.52-2.64(1H, m), 2.75(1H, dd, J=3, 12 Hz), 2.95-3.08(4H, m),
3.85-3.96(1H, m), 3.50-3.96(3H, m), 4.45-4.51(1H, m), 7.33(2H, t,
J=8 Hz), 7.62(11H, d, J=6 Hz), 7.74(1H, d, J=6 Hz), 7.82(1H, d, J=6
Hz), 7.85(1H, d, J=6 Hz), 8.98(1H, brs)
EXAMPLE 155
[1187]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl)-N-hydroxy-4-(N-meth-
yl-N-(methoxycarbonylmethyl)aminosulfonyl]-2-piperazinecarboxamide
(68 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 5.
[1188] Mass (ESI-): 549 (M-H)
[1189] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.58-2.73(1H,
m), 2.76(3H, s), 2.82-2.93(1H, m), 3.41-3.51(1H, m), 3.58-3.83(3H,
m), 3.36(3H, s), 4.45(1H, brs), 7.33(2H, t, J=8 Hz), 7.56-7.64(1H,
m), 7.67-7.73(1H, m), 7.75-7.86(2H, m), 8.97(1H, brs)
EXAMPLE 156
[1190]
(2R)-4-[N-(Aminocarbonylmethyl)aminocarbonyl]-1-[5-(4-fluorophenyl)-
thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (69 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[1191] Mass (ESI-): 484 (M-H)
[1192] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.89(1H, dt,
J=2, 11 Hz), 3.06(1H, dd, J=2, 12 Hz), 3.50-3.60(2H, m),
3.50-3.71(2H, m), 3.83(1H, d, J=12 Hz), 4.10(1H, d, J=12 Hz),
4.28(1H, brs), 6.81(1H, t, J=4 Hz), 6.95(1H, s), 7.08(1H, s),
7.33(2H, t, J=8 Hz), 7.59(1H, d, J=2 Hz), 7.68(1H, d, J=8 Hz),
7.82(2H, dd, J=4, 8 Hz), 8.95(1H, s)
EXAMPLE 157
[1193] (2R)- 1-[5-(4-Fluorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-4-[N-(2-
-hydroxyethyl)aminocarbonyl]-2-piperazinecarboxamide (138 mg) was
obtained in substantially the same manner as in Example 5.
[1194] Mass (ESI-): 471 (M-H)
[1195] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.85(1H, dt,
J=2, 11 Hz), 2.95-3.05(3H, m), 3.25-3.40(2H, m), 3.52-3.65(2H, m),
3.74(1H, d, J=11 Hz), 4.06(1H, d, J=11 Hz), 4.28(1H, t, J=2 Hz),
6.46(1H, t, J=4 Hz), 7.32(2H, t, J=8 Hz), 7.58(1H, d, J=2 Hz),
7.67(1H, d, J=2 Hz), 7.81(2H, dd, J=4, 8 Hz), 8.94(1H, s)
EXAMPLE 158
[1196]
(2R)-4-Ethylaminosulfonyl-N-hydroxy-1-[5-(4-trifluoromethyl-phenyl)-
thiophene-2-sulfonyl]-2-piperazinecarboxamide (32 mg) was obtained
as an amorphous powder in substantially the same manner as in
Example 5.
[1197] Mass (ESI-): 541 (M-H)
[1198] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.95(3H, t,
J=8 Hz), 2.40-2.49(1H, m), 2.60-2.69(1H, m), 2.73-2.85(2H, m),
3.33-3.42(1H, m), 3.59-3.87(3H, m), 4.48-4.54(1H, m), 7.32(1H, t,
J=8 Hz), 7.74-7.88(4H, m), 7.94-8.02(2H, m), 8.96(1H, brs)
EXAMPLE 159
[1199]
(2R)-N-Hydroxy-4-(N-methylpropylaminosulfonyl)-1-[5-(4-trifluoromet-
hylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (170 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 5.
[1200] Mass (ESI-): 569 (M-H)
[1201] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.88(3H, t,
J=8 Hz), 1.48-1.65(2H, m), 2.59-2.75(2H, m), 2.78(3H, s), 3.14(2H,
t, J=8 Hz), 3.38-3.52(2H, m), 3.93-4.10(2H, m), 4.70(1H, brs),
7.38(1H, d, J=3 Hz), 7.66(1H, d, J=3 Hz), 7.71(4H, m), 9.43(1H,
s)
EXAMPLE 160
[1202]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-hydroxy-1-(5-(4-trifluoromethy-
lphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (106 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[1203] Mass (ESI-): 541 (M-H)
[1204] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.77(1H,
m), 2.69(6H, s), 2.92(1H, dd, J=3, 12 Hz), 3.42-3.51(1H, m),
3.61-3.82(3H, m), 4.49(1H, brs), 7.75(1H, d, J=4 Hz), 7.79-7.87(4H,
m), 7.95-8.02(2H, m), 8.97(1H, brs)
EXAMPLE 161
[1205]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-(N,N-dimethylamin-
osulfonyl)-N-hydroxy-2-piperazinecarboxamide (136 mg) was obtained
as an amorphous powder in substantially the same manner as in
Example 5.
[1206] Mass (ESI-): 507, 509 (M-H)
[1207] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.60-2.76(1H,
m), 2.76(6H, s), 2.88(1H, dd, J=4, 12 Hz), 3.40-3.51(1H, m),
3.56-3.81(3H, m), 4.46(1H, brs), 7.55(2H, d, J=8 Hz), 7.62-7.73(2H,
m), 7.80(2H, d, J=8 Hz), 8.97(1H, s)
EXAMPLE 162
[1208] (2R)-1-1-
5-(4-Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-(N-me-
thylethylaminosulfonyl)-2-piperazinecarboxamide (110 mg) was
obtained in substantially the same manner as in Example 5.
[1209] m.p.: 170-172.degree. C.
[1210] Mass (ESI-): 521, 523 (M-H)
[1211] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.02(3H, t,
J=7 Hz), 2.53-2.64(1H, m), 2.67(3H, m), 2.78(1H, dd, J=3, 12 Hz),
3.08(2H, q, J=7 Hz), 3.35-3.45(1H, m), 3.58-3.82(3H, m),
4.44-4.49(1H, m), 7.54(2H, d, J=8 Hz), 7.68(1H, d, J=3 Hz),
7.73(1H, d, J=3 Hz), 7.76-7.83(2H, m), 8.97(1H, brs)
EXAMPLE 163
[1212]
(2R)-1-[5-(4Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(1,2,-
4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (122 mg) was obtained as an amorphous powder in
substantially the same manner as in Example 5.
[1213] Mass (ESI-): 605, 607 (M-H)
[1214] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.92-2.08(2H,
m), 2.78-2.89(1H, m), 3.04(1H, dd, J=6, 14 Hz), 3.07-3.20(4H, m),
3.50-3.88(4H, m), 4.47(1H, brs), 7.55(2H, d, J=8 Hz), 7.60-7.72(2H,
m), 7.78(2H, d, J=8 Hz), 8.46(1H, brs)
EXAMPLE 164
[1215]
(2R)-1-t5-(4Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(4-me-
thyl-1,2,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (70 mg) was obtained as an amorphous powder in
substantially the same manner as in Example 5.
[1216] Mass (ESI-): 619, 621 (M-H)
[1217] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.92-2.08(2H,
m), 2.72-2.90(1H, m), 3.03(1H, dd, J=6, 14 Hz), 3.10-3.26(4H, m),
3.50-3.90(4H, m), 3.61(3H, s), 4.48(1H, brs), 7.53(2H, d, J=8 Hz),
7.61-7.72(2H, m), 7.79(2H, d, J=8 Hz), 9.04(1H, brs)
EXAMPLE 165
[1218]
(2R)-1-[5-(4Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(imid-
azolyl-2-thio) propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (67 mg) was obtained as an amorphous powder in
substantially the same manner as in Example 5.
[1219] Mass (ESI-): 604, 606 (M-H)
[1220] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.79-1.94(2H,
m), 2.74-2.90(1H, m), 3.06(1H, dd, J=6, 14 Hz), 3.12-3.29(4H, m),
3.35-3.88(4H, m), 4.99(1H, brs), 7.54(2H, d, J=8 Hz), 7.62-7.75(4H,
m), 7.82(2H, d, J=8 Hz)
EXAMPLE 166
[1221]
(2R)-4-[3-(Benzimidazolyl-2-thio)propanesulfonyl]-1-[5-(4-chlorophe-
nyl) thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide
hydrochloride (75 mg) was obtained as an amorphous powder in
substantially the same manner as in Example 5.
[1222] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.98-2.16(2H,
m), 2.78-2.93(1H, m), 3.09(1H, dd, J=6, 14 Hz), 3.17-3.28(2H, m),
3.38-3.51(2H, m), 3.54-3.92(4H, m), 4.49(1H, brs), 7.30-7.39(2H,
m), 7.55(2H, d, J=8 Hz), 7.58-7.71(4H, m), 7.75-7.82(2H, m)
[1223] Mass (ESI-): 654, 656 (M-H)
EXAMPLE 167
[1224]
(2R)-1-t5-(4-Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-methoxy-
carbonyl-2-piperazinecarboxamide (98 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[1225] Mass (ESI-): 458, 460 (M-H)
[1226] .sup.1H-NMR-(300 MHz, DMSO-d.sub.6, .delta.): 2.83-3.08(1H,
m), 3.12-3.27(1H, m), 3.49-3.92(3H, m), 3.50(3H, s), 4.00-4.13(1H,
m), 4.22-4.34(1H, m), 7.54(2H, d, J=8 Hz), 7.66(2H, s), 7.78(2H, d,
J=8 Hz), 8.95(1H, brs)
EXAMPLE 168
[1227]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-[5-(4-ethoxyphenyl)-thiophenes-
ulfonyl]-N-hydroxy-2-piperazinecarboxamide (254 mg) was obtained in
substantially the same manner as in Example 5.
[1228] Mass (ESI-): 517 (M-H)
[1229] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.18(3H, t,
J=7 Hz), 2.69-2.79(2H, m), 2.85(3H, s), 3.50-3.59(1H, m),
3.70-3.86(3H, m), 4.03(2H, q, J=7 Hz), 4.45(1H, bs), 7.23(1H, dd,
J=10, 10 Hz), 7.49-7.59(2H, m), 7.63(1H, d, J=4 Hz), 7.70(1H, d,
J=10 Hz), 9.00(1H, s)
EXAMPLE 169
[1230]
(2R)-1-[5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(1,2-
,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (107 mg) was obtained in substantially the same
manner as in Example 5.
[1231] Mass (ESI-): 615 (M-H)
[1232] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.35(3H, t, J=4
Hz), 1.99(2H, m), 2.28(1H, dt, J=2, 11 Hz), 3.02(1H, dd, J=2, 12
Hz), 3.05-3.20(4H, m), 3.54(1H, d, J=12 Hz), 3.63-3.79(2H, m),
3.84(1H, d, J=12 Hz), 4.0(2H, q, J=4 Hz), 4.45(1H, brs), 7.01(2H,
d, J=8 Hz), 7.47(1H, d, J=2 Hz), 7.64(1H, d, J=2 Hz), 7.67(2H, d,
J=8 Hz), 8.45(1H, s)
EXAMPLE 170
[1233]
(2R)-1(-5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(4-m-
ethyl-1,2,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (84 mg) was obtained in substantially the same manner
as in Example 5.
[1234] Mass (ESI-): 629 (M-H)
[1235] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.35(3H, t, J=4
Hz), 1.99(2H, m), 2.28(1H, dt, J=2, 11 Hz), 3.02(1H, dd, J=2, 12
Hz), 3.10-3.24(4H, m), 3.54(1H, d, J=12 Hz), 3.58(3H, s),
3.63-3.79(2H, m), 3.84(1H, d, J=12 Hz), 4.0(2H, q, J=4 Hz),
4.46(1H, brs), 7.01(2H, d, J=8 Hz), 7.48(1H, d, J=2 Hz), 7.65(1H,
d, J=2 Hz), 7.68(2H, d, J=8 Hz), 8.88(1H, s)
EXAMPLE 171
[1236]
(2R)-1-[5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[3-(imi-
dazolyl-2-thio) propanesulfonyl]-2-piperazinecarboxamide
hydrochloride (91 mg) was obtained in substantially the same manner
as in Example 5.
[1237] Mass (ESI-): 614 (M-H)
[1238] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.35(3H, t,
J=4 Hz), 1.86(2H, m), 2.80(1H, dt, J=2, 11 Hz), 3.02(1H, dd, J=2,
11 Hz), 3.18(2H, t, J=4 Hz), 3.23(2H, t, J=4 Hz), 3.30-3.60(1H,
overlapping with H.sub.2O), 3.60-3.75(2H, m), 3.83(1H, d, J=11 Hz),
4.08(2H, q, J=4 Hz), 4.47(1H, brs), 7.01(2H, d, J=8 Hz), 7.48(1H,
d, J=2 Hz), 7.64(1H, d, J=2 Hz), 7.66(2H, d, J=8 Hz), 7.70(2H,
s)
EXAMPLE 172
[1239]
(2R)-1-[5-(4-Cyanophenyl)thiophene-2-sulfonyl]-4-(N,N-dimethylamino-
sulfonyl)-N-hydroxy-2-piperazinecarboxamide (72 mg) was obtained as
an amorphous powder in substantially the same manner as in Example
5.
[1240] Mass (ESI-): 498 (M-H)
[1241] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68(6H, s),
2.71-2.79(1H, m), 2.92(1H, dd, J=4, 14 Hz), 3.42-3.52(1H, m),
3.59-3.83(3H1, m), 4.46(1H, brs), 7.74(1H, d, J=3 Hz), 7.82(1H, d,
J=3 Hz), 7.96(4H, s), 8.96(1H, s)
EXAMPLE 173
[1242] (2R)-1-[5-(4Cyanomethylphenyl)thiophene-2-sulfonyl]
-4-(N,N-dimethylaminosulfonyl)-N-hydroxy-2-piperazinecarboxamide
(62 mg) was obtained in substantially the same manner as in Example
5.
[1243] m.p.: 170-172.degree. C.
[1244] Mass (ESI-): 512 (M-H)
[1245] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.13-2.25(1H,
m), 2.18(6H, s), 2.88(1H, dd, J=4, 14 Hz), 3.41-3.51(11H m),
3.62-3.82(3H, m), 4.11(2H, s), 4.43-4.49(1H, m), 7.47(2H, d, J=8
Hz), 7.65(1H, d, J=4 Hz), 7.72(1H, d, J=4 Hz), 7.80(2H, d, J=8 Hz),
8.97(1H, s)
EXAMPLE 174
[1246]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-[5-(3-fluoro-4-methoxyphenyl)--
thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (295 mg)
was obtained in substantially the same manner as in Example 5.
[1247] ESI Mass : 521 (M-1)
[1248] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.61-2.73(1H,
m), 2.69(6H, s), 2.88(1H, dd, J=4, 14 Hz), 3.45(1H, d, J=14 Hz),
3.61-3.80(3H, m), 3.90(1H, s), 4.43-4.48(1H, m), 7.26(1H, t, J=8
Hz), 7.54(1H, d, J=8 Hz), 7.59(1H, d, J=3 Hz), 7.69(1H, d, J=3 Hz),
7.72(1H, d, J=10 Hz), 8.98(1H, s)
EXAMPLE 175
[1249]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-hydroxy-1-(4-methoxybenzene-su-
lfonyl)-2-piperazinecarboxamide (70 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
5.
[1250] Mass (ESI-): 421 (M-H)
[1251] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.42-2.58(1H,
m), 2.68(6H, s), 2.69-2.76(1H, m), 3.33-3.43(1H, m), 3.48-3.62(1H,
m), 3.66-3.76(2H, m), 3.86(3H, s), 4.40(1H, brs), 7.12(2H, d, J=8
Hz), 7.76(2H, d, J=8 Hz), 8.90(1H, brs)
EXAMPLE 176
[1252]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-hydroxy-1-(4-phenoxybenzene-su-
lfonyl)-2-piperazinecarboxamide (102 mg) was obtained in
substantially the same manner as in Example 5.
[1253] m.p.: 153-155.degree. C.
[1254] Mass (ESI-): 483 (M-H)
[1255] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.52-2.63(1H,
m), 2.69(6H, s), 2.77(1H, dd, J=4, 14 Hz), 3.35-3.43(1H, m),
3.49-3.78(3H, m), 4.38-4.42(1H, m), 7.06-7.18(4H, m), 7.28(1H, dd,
J=7, 7 Hz), 7.43-7.52(2H, m), 7.78-7.85(2H, m), 8.92(1H, s)
EXAMPLE 177
[1256]
(2R)-1-[5-(4-Cyanophenyl)thiophene-2-sulfonyl]-4-ethylamino-carbony-
l-N-hydroxy-2-piperazinecarboxamide (72 mg) was obtained in
substantially the same manner as in Example 5.
[1257] Mass (ESI-): 462 (M-H)
[1258] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.92(31, t,
J=4 Hz), 2.79-3.10(3H, m), 3.03(1H, dd, J=2, 12 Hz), 3.53-3.67(2H,
m), 3.71(1H, d, J=12 Hz), 4.05(1H, d, J=12 Hz), 4.27(1H, brs),
6.43(1H, m), 7.23(1H, d, J=2 Hz), 7.33(1H, d, J=2 Hz), 7.95(4H,
s)
EXAMPLE 178
[1259] A mixture of
(2R)-4-[2-(acetylamino)ethanesulfonyl]-N-tert-butoxy-1-
-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide
(130 mg) in anisole (1 ml), trifluoroacetic acid (1 ml) and H.sub.2
(0.02 ml) was stirred at ambient temperature overnight, and then at
50.degree. C. for 5 hours. The mixture was concentrated in vacuo,
and the residue was purified by SiO.sub.2 column chromatography,
eluted with MeOH in CHCl.sub.3=2% then 5%. The fractions containing
the desired product were combined and concentrated in vacuo. The
residue was triturated with diisopropyl ether to give 88 mg of
(2R)-4-[2-(acetylamino)ethanesulfonyl]-
-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxam-
ide.
[1260] Mass (ESI-): 533 (M-H)
[1261] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.78(3H, s),
2.80(1H, dt, J=2, 11 Hz), 3.04(1H, dd, J=2, 11 Hz), 3.12(2H, t, J=4
Hz), 3.20-3.40(3H, m), 3.50-3.80(2H, m), 3.83(1H, d, J=11 Hz),
4.44(1H, s), 7.33(2H, t, J=8 Hz), 7.58(1H, d, J=2 Hz), 7.67(1H, d,
J=2 Hz), 7.81(1H, dd, J=4, 8 Hz), 8.03(1H, t, J=4 Hz), 8.98(1H,
s)
EXAMPLE 179
[1262]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl)-N-hydroxy-4-[2-(met-
hanesulfonylamino)ethanesulfonyl]-2-piperazinecarboxamide (132 mg)
was obtained in substantially the same manner as in Example
178.
[1263] Mass (ESI-): 569 (M-H)
[1264] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.84(1H, m),
2.93(3H, s), 3.09(1H, dd, J=2, 11 Hz), 3.15-3.35(4H, m), 3.57(1H, d
,J=11 Hz), 3.63-3.80(2H, m), 3.84(1H, d, J=11 Hz), 4.45(1H, brs),
7.18(1H, t, J=4 Hz), 7.33(2H, t, J=8 Hz), 7.58(1H, d, J=2 Hz),
7.67(1H, d, J=2 Hz), 7.81(2H, dd, J=4, 8 Hz), 9.00(1H, s)
EXAMPLE 180
[1265]
(2R)-N-Hydroxy-4-[2-(methanesulfonylamino)ethanesulfonyl]-1-(5-phen-
ylthiophene-2-sulfonyl)-2-piperazinecarboxamide (157 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 178.
[1266] Mass (ESI-): 551 (M-H)
[1267] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.84(1H, dt,
J=2, 11 Hz), 2.93(3H, s), 3.09(1H, dd, J=2, 11 Hz), 3.12-3.35(4H,
m), 3.58(1H, d ,J=11 Hz), 3.63-3.80(2H, m), 3.84(1H, d, J=11 Hz),
4.46(1H, brs), 7.18(1H, t, J=4 Hz), 7.37-7.53(3H, m), 7.62(1H, d,
J=2 Hz), 7.68(1H, d, J=2 Hz), 7.71-7.79(2H, m), 8.99(1H, s)
EXAMPLE 181
[1268]
(2R)-N-Hydroxy-4-[2-(methanesulfonylamino)ethanesulfonyl]-1-[5-(4-t-
rifluoromethylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide
(106 mg) was obtained as crystals in substantially the same manner
as in Example 178.
[1269] m.p.: 105-108.degree. C.
[1270] Mass (ESI-): 619 (M-H)
[1271] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.86(1H, dt,
J=2, 11 Hz), 2.94(3H, s), 3.11(11H, dd, J=2, 11 Hz), 3.15-3.35(4H,
m), 3.58(1H, d ,J=11 Hz), 3.63-3.83(2H, m), 3.84(1H, d, J=11 Hz),
4.46(1H, brs), 7.18(1H, t, J=4 Hz), 7.73(1H, d, J=2 Hz), 7.78(1H,
d, J=2 Hz), 7.83(2H, d, J=8 Hz), 7.98(2H, d, J=8 Hz), 9.00(1H,
s)
EXAMPLE 182
[1272]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[2-(met-
hanesulfonylamino)ethanesulfonyl]-2-piperazinecarboxamide (160 mg)
was obtained as crystals in substantially the same manner as in
Example 178.
[1273] m.p.: 118-122.degree. C.
[1274] Mass (ESI-): 585, 587 (M-H)
[1275] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.84(1H, dt,
J=2, 11 Hz), 2.93(3H, s), 3.10(1H, dd, J=2, 11 Hz), 3.15-3.35(4H,
m), 3.58(1H, d, J=11 Hz), 3.63-3.79(2H, m), 3.84(1H, d, J=11 Hz),
4.45(1H, brs), 7.18(1H, t, J=4 Hz), 7.54(1H, d, J=8 Hz), 7.63(1H,
d, J=2 Hz), 7.68(2H, d, J=2 Hz), 7.79(2H, d, J=8 Hz), 9.00(1H,
s)
EXAMPLE 183
[1276]
(2R)-1-[5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[2-(met-
hanesulfonylamino)ethanesulfonyl]-2-piperazinecarboxamide (157 mg)
was obtained in substantially the same manner as in Example 178
[1277] Mass (ESI-): 595 (M-H)
[1278] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.35(3H, t,
J=5 Hz), 2.84(1H, m), 2.93(3H, s), 3.09(1H, dd, J=2, 11 Hz),
3.15-3.35(4H, m), 3.56(1H, d ,J=11 Hz), 3.63-3.75(2H, m), 3.83(1H,
d, J=11 Hz), 4.09(2H, q, J=5 Hz), 4.44(1H, brs), 7.01(2H, d, J=8
Hz), 7.18(1H, t, J=4 Hz), 7.47(1H, d, J=2 Hz), 7.63(1H, d, J=2 Hz),
7.66(2H, d, J=8 Hz), 8.99(1H, s)
EXAMPLE 184
[1279]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-{2-[(py-
ridine-3-sulfonyl)amino]ethanesulfonyl}-2-piperazinecarboxamide (87
mg) was obtained in substantially the same manner as in Example
178.
[1280] Mass (ESI-): 648, 650 (M-H)
[1281] .sup.1H-NMR (300 MHz, CDCl.sub.3-CD.sub.3OD 10:1, .delta.):
2.70-2.85(2H, m), 3.28(4H, brs), 3.40-3.57(2H, m), 3.96(1H, d, J=12
Hz), 4.12(1H, d, J=12 Hz), 4.63(1H, brs), 5.42(1H, br), 7.26(1H, d,
J=2 Hz), 7.41(2H, d, J=8 Hz), 7.49-7.57(1H, m), 7.54(1H, d, J=8
Hz), 7.58(1H, d, J=2 Hz), 8.22(1H, d, J=6 Hz), 8.78(1H, d, J=3 Hz),
9.08(1,H, s)
EXAMPLE 185
[1282] (2R)-1-[5-(4-Chlorophenyl)
thiophene-2-sulfonyl]-N-hydroxy-4-2-[(N,-
N-dimethylaminosulfonyl)amino]ethanesulfonyl]-.sup.2-piperazinecarboxamide
(86 mg) was obtained in substantially the same manner as in Example
178.
[1283] Mass (ESI-): 614, 616 (M-H)
[1284] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.65(6H, s),
2.84(1H, dt, J=2, 11 Hz), 3.08(1H, dd, J=2, 11 Hz), 3.19(4H, s),
3.57(1H, d, J=11 Hz), 3.63-3.75(2H, m), 3.83(1H, d, J=11 Hz),
4.46(1H, brs), 7.33(1H, t, J=4 Hz), 7.54(2H, d, J=8 Hz), 7.65(1H,
d, J=2 Hz), 7.68(1H, d, J=2 Hz), 7.79(2H, d, J=8 Hz), 8.98(1H,
s)
EXAMPLE 186
[1285] (2R)-
1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[2-(me-
thoxycarbonylamino)ethanesulfonyl]-2-piperazinecarboxamide (107 mg)
was obtained in substantially the same manner as in Example
178.
[1286] Mass (ESI-): 565, 567 (M-H)
[1287] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.81(1H, dt,
J=2, 11 Hz), 3.05(11H, dd, J=2, 11 Hz), 3.13(2H, t, J=4 Hz),
3.20-3.35(2H, m), 3.53(3H, s), 3.56(1H, d, J=11 Hz), 3.63-3.78(2H,
m), 3.83(1H, d, J=11 Hz), 4.45(1H, brs), 7.25(1H, t, J=4 Hz),
7.54(2H, d, J=8 Hz), 7.65(1H, d, J=2 Hz), 7.68(1H, d, J=2 Hz),
7.78(2H, d, J=8 Hz), 8.98(1H, s)
EXAMPLE 187
[1288]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-{2-[(py-
ridine-3-carbonyl)amino]ethanesulfonyl}-2-piperazinecarboxamide (56
mg) was obtained in substantially the same manner as in Example
178
[1289] Mass (ESI-): 596 (M-H)
[1290] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.83(1H, dt,
J=2, 11 Hz), 3.07(1H, dd, J=2, 11 Hz), 3.28(2H, t, J=4 Hz),
3.53-3.80(5H, m), 3.86(1H, d, J=11 Hz), 4.46(1H, s), 7.30(2H, t,
J=8 Hz), 7.50(1H, dd, J=2, 6 Hz), 7.58(1H, d, J=2 Hz), 7.67(1H, d,
J=2 Hz), 7.80(2H, dd, J=4, 8 Hz), 8.14(1H, d, J=6 Hz), 8.71(1H, d,
J=2 Hz), 8.87(1H, t, J=4 Hz), 8.95(1H, s), 8.99(1H, s)
EXAMPLE 188
[1291] (2R)-4-[2-(Benzoylamino) ethanesulfonyl]-1
-[5-(4-fluorophenyl)-thi-
ophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide (68 mg) was
obtained in substantially the same manner as in Example 178.
[1292] Mass (ESI-): 595 (M-H)
[1293] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.83(1H, dt,
J=2, 11 Hz), 3.06(1H, dd, J=2, 11 Hz), 3.26(2H, t, J=4 Hz),
3.52-3.80(2H, m), 3.86(1H, d, J=11 Hz), 4.47(1H, s), 7.29(2H, t,
J=8 Hz), 7.45(2H, t, J=7 Hz), 7.53(1H, t, J=7 Hz), 7.58(1H, d, J=2
Hz), 7.67(1H, d, J=2 Hz), 7.75-7.85(4H, m), 8.65(1H, t, J=4 Hz),
9.00(1H, s)
EXAMPLE 189
[1294]
(2R)-N-Hydroxy-1-(2-phenyl-2-trans-ethenylsulfonyl)-4-methanesulfon-
yl-2-piperazinecarboxamide (159 mg) was obtained as crystals in
substantially the same manner as in Example 5
[1295] m.p.: 94-99.degree. C.
[1296] Mass (ESI-): 388 (M-H)
[1297] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.81(11H, dt,
J=2, 11 Hz), 2.87(3H, s), 3.05(1H, dd, J=2, 11 Hz), 3.40-3.70(3H,
m), 3.92(1H, d, J=11 Hz), 4.39(1H, brs), 7.21(1H, d, J=14 Hz),
7.43(1H, d, J=14 Hz), 7.43-7.51(3H, m), 7.64-7.74(2H, m), 9.03(1H,
s)
EXAMPLE 190
[1298]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-4-[N-(met-
hoxycarbonylmethyl)aminocarbonyl]-2-piperazinecarboxamide (52 mg)
was obtained in substantially the same manner as in Example 5.
[1299] Mass (ESI-): 499 (M-H)
[1300] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.94(1H, m),
3.06(1H, dd, J=2, 12 Hz), 3.55(3H, s), 3.50-3.80(5H, m), 4.03(1H,
d, J=122 Hz), 4.27(1H, m), 6.98(1H, t, J=4 Hz), 7.33(2H, t, J=8
Hz), 7.59(1H, d, J=2 Hz), 7.68(1H, d, J=2 Hz), 7.81(2H, dd, J=4, 8
Hz), 8.95(1H, s)
[1301] Preparation 146
[1302]
(2R)-1-tert-Butoxycarbonyl-4-(9-fluorenylmethyloxycarbonyl)-2-piper-
azinecarboxylic acid (1 5.6 g) was obtained as an amorphous powder
in substantially the same manner as in Preparation 7.
[1303] Mass (ESI-): 451 (M-H)
[1304] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.34, 1.44(9H,
s), 2.78-3.32(4H, m), 3.64-3.96(2H, m), 4.25(2H, s), 4.28-4.78(2H,
m), 7.34(2H, t, J=8 Hz), 7.42(2H, t, J=8 Hz), 7.56-7.72(2H, m),
7.90(2H, d, J=8 Hz)
[1305] Preparation 147
[1306] (2R)-4-(9-Fluorenylmethyloxycarbonyl)
-2-piperazinecarboxylic acid hydrochloride (10.9 g) was obtained in
substantially the same manner as in Preparation 9.
[1307] Mass (ESI-): 351 (M-H)
[1308] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.90-3.04(1H,
m), 3.18-3.40(3H, m), 3.76-3.92(1H, m), 4.12(2H, d, J=12 Hz),
4.24-4.34(1H, m), 4.39(2H, d, J=7.5 Hz), 7.35(2H, t, J=8 Hz),
7.44(2H, t, J=8 Hz), 7.65(2H, d, J=8 Hz), 7.92(2H, d, J=8 Hz)
[1309] Preparation 148
[1310]
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-1-(5-phenylthiophene-2-sulfon-
yl)-2-piperazinecarboxylic acid (15.5 g) was obtained as an
amorphous powder in substantially the same manner as in Preparation
11.
[1311] Mass (ESI-): 573 (M-H)
[1312] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.82-2.97(1H,
m), 3.03-3.44(4H, m), 3.56-3.72(1H, m), 4.04-4.18(1H, m), 4.39(2H,
d, J=8 Hz), 4.52-4.64(1H, m), 7.11-7.52(11H, m), 7.55(2H, d, J=8
Hz), 7.72(2H, d, J=8 Hz)
EXAMPLE 191
[1313] (2R)-4-(9-Fluorenylmethyloxycarbonyl)
-1-(5-phenylthiophene-2-sulfo-
nyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (16.7 g)
was obtained as an amorphous powder in substantially the same
manner as in Preparation 12.
[1314] Mass (ESI-): 672 (M-H)
[1315] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.26-1.70(6H,
m), 2.92-3.20(2H, m), 3.36-3.95(5H, m), 4.02-4.28(4H, m),
4.32-4.44(1H, m), 4.62-4.85(1H, m), 7.23-7.35(2H, m), 7.35-7.52(5H,
m), 7.52-7.68(4H, m), 7.75(2H, d, J=8 Hz), 7.88(2H, d, J=8 Hz)
[1316] Preparation 449
[1317] (2R)-4-(9-Fluorenylmethyloxycarbonyl)
-1-[5-(4-fluorophenyl)-thioph-
ene-2-sulfonyl]-2-piperazinecarboxylic acid (13.3 g) was obtained
as an amorphous powder in substantially the same manner as in
Preparation 11.
[1318] Mass (ESI-): 591 (M-H)
[1319] .sup.1H-NMR (300 MHz, DMSO-.sub.6 , .delta.): 2.82-3.04(1H,
m), 3.11-3.29(1H, m), 3.38-3.50(1H, m), 3.60-3.75(1H, m),
3.85-4.00(1H, m), 4.22(3H, m), 4.32-4.48(1H, m), 4.60(1H, brs),
7.28-7.45(6H, m), 7.28(1H, d, J=3 Hz), 7.35-7.83(2H, m), 7.88(2H,
d, J=8 Hz)
EXAMPLE 192
[1320] (2R)-4-(9-Fluorenylmethyloxycarbonyl)
-1-[5-(4-fluorophenyl)-thioph-
ene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(12.9 g) was obtained as an amorphous powder in substantially the
same manner as in Preparation 12.
[1321] Mass (ESI-): 690 (M-H)
[1322] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.25-1.78(6H,
m), 2.90-3.20(5H, m), 3.72-4.42(7H, m), 4.62-4.85(1H, m),
7.24-7.45(6H, m), 7.50-7.69(4H, m), 7.74-7.85(2H, m), 7.88(2H, d,
J=8 Hz)
[1323] Preparation 150
[1324]
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-1-[5-(4-trifluoromethyl-pheny-
l)thiophene-2-sulfonyl]-2-piperazinecarboxylic acid (1.18 g) was
obtained as an amorphous powder in substantially the same manner as
in Preparation 11.
[1325] Mass (ESI-): 641 (M-H)
[1326] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.82-3.00(1H,
m), 3.12(1H, dd, J=6, 14 Hz), 3.29-3.43(1H, m), 3.61-3.73(1H, m),
4.05-4.18(1H, m), 4.30-4.47(3H, m), 4.54-4.68(2H, m), 7.15-7.50(8H,
m), 7.55-7.68(4H, m), 7.74(2H, d, J=7 Hz)
EXAMPLE 193
[1327]
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-N-(2-tetrahydropyranyloxy)
-1-[5-(4-trifluoromethylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxam-
ide (1.20 g) was obtained as an amorphous powder in substantially
the same manner as in Preparation 12.
[1328] Mass (ESI-): 740 (M-H)
[1329] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.28-2.63(6H,
m), 2.95-3.23(2H, m), 3.38-3.92(5H, m), 4.01-4.28(4H, m),
4.32-4.46(1H, m), 4.60-4.68(1H, m), 7.25-7.45(4H, m), 7.52-7.62(2H,
m), 7.62-7.81(1H, m), 7.76-7.90(5H, m), 7.97(2H, d, J=8 Hz)
[1330] Preparation 151
[1331]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-(9-fluorenylmethy-
loxycarbonyl)-2-piperazinecarboxylic acid (6.16 g) was obtained as
an amorphous powder in substantially the same manner as in
Preparation 11.
[1332] Mass (ESI-): 607, 609 (M-H)
[1333] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.82-3.00(1H,
m), 3.14(1H, dd, J=5, 15 Hz), 3.20-3.42(1H, m), 3.52-3.74(3H, m),
4.06-4.15(1H, m), 4.30-4.43(2H, m), 4.60(1H, brs), 7.05-7.18(1H,
m), 7.22-7.55(11H, m), 7.74(2H, d, J=7 Hz)
EXAMPLE 194
[1334]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-(9-fluorenylmethy-
loxycarbonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(6.67 g) was obtained in substantially the same manner as in
Preparation 12.
[1335] Mass (ESI-): 706, 708 (M-H)
[1336] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.32-1.67(6H,
m), 2.97-3.25(2H, m), 3.38-3.93(5H, m), 4.06-4.28(4H, m),
4.32-4.44(1H, m), 4.62-4.75(1H, m), 7.27-7.46(4H, m), 7.50-7.68(6H,
m), 7.73-7.92(4H, m)
[1337] Preparation 152
[1338]
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-1-(5-(4-ethoxyphenyl)-thiophe-
nesulfonyl]-2-piperazinecarboxylic acid (7.80 g) was obtained in
substantially the same manner as in Preparation 11.
[1339] Mass (ESI-): 617 (M-H)
[1340] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45(3H, t, J=7
Hz), 2.87-2.97(1H, m), 3.10-3.18(2H, m), 3.30-3.43(2H, m),
3.62-3.71(1H, m), 4.00-4.09(2H, q, J=7 Hz), 4.05-4.11(1H, m),
4.39(2H, d, J=6 Hz), 4.63(1H, bs), 6.90(2H, d, J=8 Hz),
7.05-7.10(1H, m), 7.21-7.56(9H, m), 7.73(2H, d, J=8 Hz)
EXAMPLE 195
[1341]
(2R)-4-(9-Fluorenylmethoxycarbonyl)-1-[5-(4-ethoxyphenyl)-thiophene-
sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (8.76
g) was obtained in substantially the same manner as in Preparation
12.
[1342] Mass (ESI-): 716 (M-H)
[1343] H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48(3H, t, J==7 Hz),
1.50-1.88(6H, m), 3.00-3.26(2H, m), 3.39-3.52(2H, m), 3.62-3.97(3H,
m), 4.07(2H, q, J=7 Hz), 4.05-4.11(1H, m), 4.15-4.28(1H, m),
4.35-4.46(1H, m), 4.51(1H, bs), 6.87(2H, d, J=8 Hz), 7.10-7.21(1H,
m), 7.25-7.67(5H, m), 7.70(2H, d, J=8 Hz)
EXAMPLE 196
[1344] A mixture of
(2R)-4-(3-chloropropanesulfonyl)-1-[5-(4-fluorophenyl)-
-thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(200 mg), piperidine (279 mg) and potassium iodide (65 mg) in DMF
(3 ml) was stirred at ambient temperature for 2 days. The mixture
was concentrated in vacuo. The residue was partitioned between
AcOEt and H.sub.2O. The organic layer was washed with saturated
aqueous NaCl solution, dried over MgSO.sub.4, and concentrated in
vacuo. The residue was purified by SiO.sub.2 column chromatography
eluted with MeOH in CHCl.sub.3 gradually from 0% to 5%, to give 165
mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[3-(1
-piperidino)propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarbo-
xamide.
[1345] Mass (ESI+): 659 (M+H)
[1346] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.35-1.47(2H,
m), 1.48-1.68(7H, m), 1.70-1.98(5H, m), 2.27-2.45(6H, m),
2.75-2.95(2H, m), 3.00-3.14(2H, m), 3.30-3.50(1H, m), 3.54-3.70(2H,
m), 3.85-4.03(2H, m), 4.19(1H, d, J=12 Hz), 4.63(1H, brs), 4.94(1H,
s), 7.13(2H, t, J=8 Hz), 7.22(1H, m), 7.53-7.65(3H, m)
EXAMPLE 197
[1347]
(2R)-4-[3-(N,N-Diethylamino)propanesulfonyl]-1-[5-(4-fluorophenyl)--
thiophene-2-sulfonyl3-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(57 mg) was obtained as-an amorphous powder in substantially the
same manner as in Example 196.
[1348] ESI Mass : 647 (M+H)
[1349] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.93-1.07(6H,
m), 1.50-1.92(8H, m), 2.43-2.60(6H, m), 2.76-2.92(2H, m),
3.02-3.15(2H, m), 3.30-3.48(1H, m), 3.55-3.70(2H, m), 3.85-4.03(2H,
m), 4.20(1H, d, J=12 Hz), 4.58-4.68(1H, m), 4.96(1H, brs), 7.13(2H,
t, J=8 Hz), 7.22(1H, d, J=3 Hz), 7.52-7.66(3H, m)
EXAMPLE 198
[1350]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-[3-(1-piperidino)-propanesu-
lfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 196.
[1351] Mass (ESI+): 641 (M+H)
[1352] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.36-1.48(2H,
m), 1.50-1.66(7H, m), 1.72-1.92(5H, m), 2.27-2.44(6H, m),
2.75-2.94(2H, m), 3.01-3.13(2H, m), 3.33-3.52(1H, m), 3.56-3.68(21,
m), 3.85-4.04(2H, m), 4.20(1H, d, J=12 Hz), 4.08-4.18(1H, m),
4.95(1H, brs), 7.27-7.32(1H, m), 7.36-7.49(3H, m), 7.58-7.67(3H,
m)
EXAMPLE 199
[1353] A mixture of
(2R)-4-(3-chloropropanesulfonyl)-1-(5-phenylthiophene--
2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150
mg), 3-mercapto-1,2,4-triazole (28 mg), potassium iodide (42 mg)
and potassium carbonate (53 mg) in DMF (2 ml) was stirred for 14
hours at ambient temperature. The mixture was partitioned between
AcOEt and saturated aqueous NaHCO.sub.3 solution. The organic layer
was separated, washed with saturated aqueous NaHCO.sub.3 solution
and brine, dried over sodium sulfate and evaporated in vacuo. The
residue was purified by preparative thin layer chromatography (10%
MeOH in CHCl.sub.3) to give 134 mgof
(2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[3-(1,2,4-triazolyl-3-thio)-propa-
nesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as
an amorphous solid.
[1354] Mass (ESI): 655 (M-1)
[1355] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.89(6H,
m), 2.04-2.20(2H, m), 2.80-2.99(2H, m), 3.10-3.28(4H, m),
3.31-3.42(1H, m), 3.53-3.72(2H, m), 3.87-4.00(2H, m), 4.10-4.22(1H,
m), 4.60-4.69(1H, m), 5.00-5.07(1H, m), 7.30(1H, d, J=3 Hz),
7.40-7.49(3H, m), 7.58-7.67(3H, m), 8.10(1H, d, J=3 Hz),
9.38-9.53(1H, m)
EXAMPLE 200
[1356] (2R)- 1-(5-Phenylthiophene-2-sulfonyl) -N-
(2-tetrahydropyranyloxy)
-4-[3-(thiazolyl-2-thio)propanesulfonyl]-2-piperazinecarboxamide
(139 mg) was obtained in substantially the same manner as in
Example 199.
[1357] Mass (ESI-): 671 (M-H)
[1358] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.05-2.28(2H, m), 2.75-2.93(2H, m), 3.14-3.48(5H, m),
3.55-3.70(2H, m), 3.84-4.05(2H, m), 4.20(1H, d, J=12 Hz),
4.55-4.67(1H, brs), 4.9, 4.99(1H, brs), 7.21(1H, m), 7.29(1H, d,
J=2 Hz), 7.39-7.50(3H, m), 3.55-3.68(4H, m), 9.19(1H, brs)
EXAMPLE 201
[1359]
(2R)-4-[3-(4-Methyl-1,2,4-triazolyl-3-thio)propanesulfonyl]-1(5-phe-
nylthiophene-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamid-
e (102 mg) was obtained in substantially the same manner as in
Example 199.
[1360] Mass (ESI-): 669 (M-H)
[1361] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.23(2H, m), 2.80-3.00(2H, m), 3.23(2H, t, J=4 Hz), 3.33(2H, t,
J=4 Hz), 3.46(1H, m), 3.53-3.70(2H, m), 3.60(3H, s), 3.84-4.05(2H,
m), 4.17(1H, d, J=12 Hz), 4.64(1H, brs), 4.97(1H, brs), 7.28(1H, d,
J=2 Hz), 7.38-7.49(3H, m), 3.57-3.65(3H, m), 8.13(1H, s), 9.45,
9.50(1H, brs)
EXAMPLE 202
[1362]
(2R)-4-[3-(Imidazolyl-2-thio)propanesulfonyl]-1-(5-phenylthiophene--
2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (108
mg) was obtained in substantially the same manner as in Example
199.
[1363] Mass (ESI-): 656 (M-H)
[1364] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.85(6H,
m), 1.85-2.13(2H, m), 2.77-3.48(7H, m), 3.54-3.70(2H, m),
3.85-4.05(2H, m), 4.12-4.26(1H, m), 4.63, 4.67(1H, brs), 5.04(1H,
m), 7.06(2H, br), 7.30(1H, m), 7.39-7.49(3H, m), 7.58-7.65(3H, m),
9.62(1H, br)
EXAMPLE 203
[1365]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyra-
nyloxy)-4-[3-(1,2,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxam-
ide(121 mg) was obtained in substantially the same manner as in
Example 199.
[1366] Mass (ESI-): 673 (M-H)
[1367] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.90(6H,
m), 2.00-2.20(2H, m), 2.77-2.99(2H, m), 3.05-3.45(5H, m),
3.52-3.73(2H, m), 3.85-4.03(2H, m), 4.10-4.20(1H, m), 4.64(1H,
brs), 5.04(1H, brs), 7.14(2H, t, J=8 Hz), 7.23(1H, d, J=2 Hz),
7.55-7.65(1H, m), 7.58(2H, dd, J=4, 8 Hz), 8.08-8.14(1H, br), 9.40,
9.47(1H, br)
EXAMPLE 204
[1368]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-[3-(4-methyl-1,2,-
4-triazolyl-3-thio)propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazin-
ecarboxamide (128 mg) was obtained in substantially the same manner
as in Example 199.
[1369] Mass (ESI-): 687 (M-H)
[1370] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-2.00(6H,
m), 2.23(2H, m), 2.80-3.00(2H, m), 3.23(2H, t, J=4 Hz), 3.33(2H, t,
J=4 Hz), 3.48(1H, dt, J=2, 12 Hz), 3.54-3.70(2H1 m), 3.60(3H, s),
3.85-4.03(2H, m), 4.17(1H, d, J=12 Hz), 4.64(1H, brs),
4.93-5.00(1H, m), 7.13(2H, t, J=8 Hz), 7.22(1H, d, J=2 Hz),
7.53-7.65(3H, m), 8.18(1H, brs), 9.50-9.65(1H, br)
EXAMPLE 205
[1371] (2R)-1-[5-(4-Fluorophenyl)
thiophene-2-sulfonyl]-4-[3-(imidazolyl-2-
-thio)propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(96 mg) was obtained in substantially the same manner as in Example
199.
[1372] Mass (ESI-): 672 (M-H) .sup.1H-NMR (300 MHz, CDCl.sub.3,
.delta.): 1.50-1.85(6H, m), 1.85-2.13(2H, m), 2.75-3.50(7H, m),
3.57(1H, d, J=11 Hz), 3.66(1H, d, J=11 Hz), 3.86-4.05(2H, m),
4.12-4.27(1H, m), 4.62, 4.66(1H, brs), 5.00-5.09(1H, m), 7.08(2H,
br), 7.15(2H, t, J=8 Hz), 7.23(1H, d, J=2 Hz), 7.55-7.65(3H, m),
9.45-9.60(1H, br)
EXAMPLE 206
[1373]
(2R)-4-[3-(Benzimidazolyl-2-thio)propanesulfonyl]-1-[5-(4-fluorophe-
nyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxami-
de (121 mg) was obtained in substantially the same manner as in
Example 199.
[1374] Mass (ESI-): 722 (M-H)
[1375] .sup.1H-NMR (300 MHz, CDCl.sub.3.delta.): 1.45-1.83(6H, m),
2.05-2.30(2H, m), 2.72-2.93(2H, m), 3.19-3.40(5H, m), 3.50-3.72(2H,
m), 3.86-4.00(2H, m), 4.10-4.24(1, m), 4.54-4.68(1H, brs), 5.02(1H,
brs), 7.13(2H, t, J=8 Hz), 7.15-7.25(3H, m), 7.53-7.65(5H, m),
9.34-9.40(1H, br)
EXAMPLE 207
[1376]
(2R)-1-[5-(4Chlorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyran-
yloxy)-4-[3-(1,2,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxami-
de (149 mg) was obtained in substantially the same manner as in
Example 199.
[1377] Mass (ESI-): 689, 691 (M-H)
[1378] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.13(2H, m), 2.78-3.00(2H, m), 3.08-3.30(4H, m), 3.38(1H, m),
3.55-3.70(2H, m), 3.85-4.00(2H, m), 4.15(1H, d, J=11 Hz), 4.63(1H,
brs), 5.01(11H, s), 7.26(1H, m), 7.41(2H, d, J=8 Hz), 7.53(2H, d,
J=8 Hz), 7.63(1H, m), 8.13(1H, d, J=2 Hz), 9.45-9.62(1H, br)
EXAMPLE 208
[1379]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-[3-(4-methyl-1,2,-
4-triazolyl-3-thio)propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazin-
ecarboxamide (110 mg) was obtained in substantially the same manner
as in Example 199.
[1380] Mass (ESI-): 703, 705 (M-H)
[1381] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.23(2H, m), 2.80-3.00(2H, m), 3.23(2H, t, J=4 Hz), 3.33(2H, t,
J=4 Hz), 3.37(1H, m), 3.55-3.70(2H, m), 3.59(3H, s), 3.85-4.05(2H,
m), 4.15(1H, d, J=11 Hz), 4.64(1H, brs), 4.96(1H, m), 7.26(1H, m)
7.41(2H, d, J=8 Hz), 7.54(2H, d, J=8 Hz), 7.62(1H, m), 8.13(1H, s),
9.50, 9.58(1H, brs)
EXAMPLE 209
[1382]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-[3-(imidazolyl-2--
thio) propanesulfonyl]-N-(2-tetrahydropyranyloxy)
-2-piperazinecarboxamide (100 mg) was obtained in substantially the
same manner as in Example 199.
[1383] Mass (ESI-): 688, 690 (M-H)
[1384] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.85(6H,
m), 1.85-2.13(2H, m), 2.75-3.50(7H, m), 3.54-3.70(2H, m),
3.85-4.04(2H, m), 4.12-4.25(1H, m), 4.63, 4.67(1H, brs), 5.03(1H,
m), 7.08(2H, br), 7.27(1H, m), 7.42(2H, d, J=8 Hz), 7.54(2H, d, J=8
Hz), 7.62(1H, m), 9.60-9.75(1H, br)
EXAMPLE 210
[1385]
(2R)-4-[3-(Benzimidazolyl-2-thio)propanesulfonyl]-1-[5-(4-chlorophe-
nyl)
thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxam-
ide (100 mg) was obtained in substantially the same manner as in
Example 199.
[1386] Mass (ESI-): 738, 740 (M-H)
[1387] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45-1.80(6H,
m), 2.10-2.25(2H, m), 2.73-2.92(2H, m), 3.15-3.43(5H, m),
3.52-3.70(2H, m), 3.85-4.00(2H, m), 4.17(1H, d, J=11 Hz), 4.61,
4.65(1H, brs), 5.01(1H, m), 7.12-7.30(3H, m), 7.30-7.45(1H, m),
7.41(2H, d, J=8 Hz), 7.52(2H, d, J=8 Hz), 7.60(1H, m), 7.66(1H, m),
9.47(1H, brs)
EXAMPLE 211
[1388] (2R)-1-[5-(4-Ethoxyphenyl)
thiophene-2-sulfonyl]-N-(2-tetrahydropyr-
anyloxy)-4-[3-(1,2,4-triazolyl-3-thio)propanesulfonyl]-2-piperazinecarboxa-
mide (122 mg) was obtained in substantially the same manner as in
Example 199.
[1389] Mass (ESI-): 699 (M-H)
[1390] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45(3H, t, J=4
Hz), 1.50-1.90(6H, m), 2.00-2.20(2H, m), 2.78-2.96(2H, m),
3.10-3.40(5H, m), 3.52-3.72(2H, m), 3.85-4.01(2H, m), 4.08(2H, q,
J=4 Hz), 4.16(1H, m), 4.63(1H, brs), 5.04(1H, brs), 6.94(2H, d, J=8
Hz), 7.17(1H, d, J=2 Hz), 7.51(2H, d, J=8 Hz), 7.60(1H, m),
8.11(1H, m), 9.35-9.53(1H, m)
EXAMPLE 212
[1391]
(2R)-1-[5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-4-(3-(4-methyl-1,2,-
4-triazolyl-3-thio)propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazin-
ecarboxamide (94 mg) was obtained in substantially the same manner
as in Example 199.
[1392] Mass (ESI-): 713 (M-H)
[1393] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.44(3H, t, J=4
Hz), 1.50-1.90(6H, m), 2.23(2H, m), 2.78-2.98(2H, m), 3.22(2H, t,
J=4 Hz), 3.33(2H, t, J=4 Hz), 3.44(1H, m), 3.55-3.70(2H, m),
3.58(3H, s), 3.85-4.03(2H, m), 4.08(2H, q, J=4 Hz), 4.17(1H, d,
J=11 Hz), 4.63(1H, brs), 4.97(1H, m), 6.94(2H, d, J=8 Hz), 7.16(1H,
d, J=2 Hz), 7.51(2H, d, J=8 Hz), 7.58(1H, m), 8.13(1H, s), 9.43,
9.47(1H, brs)
EXAMPLE 213
[1394]
(2R)-1(-5-(4-Ethoxyphenyl)thiophene-2-sulfonyl]-4-[3-(imidazolyl-2--
thio)propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(108 mg) was obtained in substantially the same manner as in
Example 199.
[1395] Mass (ESI-): 698 (M-H)
[1396] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45(3H, t, J=4
Hz), 1.50-1.85(6H, m), 1.85-2.15(2H, m), 2.75-3.50(7H, m),
3.52-3.70(2H, m), 3.86-4.05(2H, m), 4.09(2H, q, J=4 Hz),
4.13-4.27(1H, m), 4.62, 4.66(1H, brs), 5.04(1H, m), 6.94(2H, d, J=8
Hz), 7.03(1H, br), 7.12(1H, br), 7.18(1H, d, J=2 Hz), 7.52(2H, d,
J=8 Hz), 7.59(1H, m), 9.50-9.65(1H, brs)
EXAMPLE 214
[1397] To a solution of
(2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[3-(benzyl-
oxycarbonyl)propane]sulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarbox-
amide (350 mg, 0.56 mmol) in MeOH was added dropwise 1N aqueous
sodium hydroxide solution (1.0 ml, 1.12 mmol) at 0.degree. C., and
the solution was stirred for 3 hours at room temperature. The
resulting mixture was evaporated to remove MeOH and acidified with
5% aqueous citric acid solution. This solution was extracted three
times with AcOEt. The combined organic layer was washed with brine,
and dried over MgSO.sub.4. The solvent was evaporated to give 357
mg of (2R)-1-(5-phenylthiophene-2--
sulfonyl)-4-(3-carboxypropane)sulfonyl-N-(2-tetrahydropyranyloxy)-2-pipera-
zinecarboxamide as a colorless oil.
[1398] Mass (ESI-): 600 (M-H)
[1399] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.54-1.91(6H,
m), 1.92-2.08(2H, m), 2.47-2.58(2H, m), 2.76-2.95(1H, m),
3.10-3.21(2H, m), 3.45-3.56(1H, m), 3.62-3.70(2H, m), 3.88-4.07(2H,
m), 4.17-4.25(1H, m), 4.56-4.71(0.5H, m), 4.94-5.02(0.5H, m),
7.24-7.47(3H, m), 7.57-7.67(2H, m), 9.39-9.56(1H, m)
EXAMPLE 215
[1400]
(2R)-4-[N-(Carboxymethyl)aminocarbonyl]-1l-[5-(4-fluorophenyl)-thio-
phene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(608 mg) was obtained in substantially the same manner as in
[1401] Preparation 127.
[1402] Mass (ESI-): 569 (M-H)
[1403] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.):
[1404] 1.35-1.75(6H, m), 2.60-3.95(8H, m), 4.09(1H, t, J=12 Hz),
4.28(1H, d, J=10 Hz), 4.35(1H, t, J=4 Hz), 4.68, 4.75(1H, brs),
6.82, 6.92(1H, t, J=4 Hz), 7.33(2H, t, J=8 Hz), 7.55-7.65(2H, m),
7.75-7.85(2H, m)
EXAMPLE 216
[1405] To a mixture of
(2R)-1-(5-phenylthiophene-2sulfonyl)-4-[3-(benzylox-
ycarbonyl)propane]sulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxam-
ide (352 mg, 0.58 mmol), morpholine (61 mg, 0.70 mmol) and HOBt (87
mg, 0.64 mmol) in DMF (3 ml) was added WSCD.HCl (135 mg, 0.70 mmol)
at 0.degree. C. and the resulting mixture was stirred at room
temperature for 4.5 hours. After evaporation of DMF, the residue
was diluted with AcOEt (10 ml) and the solution was washed with 5%
aqueous citric acid, saturated aqueous NaHCO.sub.3 solution and
brine, and dried over MgSO.sub.4. The solvent was removed under
reduced pressure. The residue was purified by SiO.sub.2 column
chromatography to give 343 mg of
(2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[3-(4-morpholinocarbonyl)propane]-
sulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as a
slightly brown oil (yield 87%).
[1406] Mass (ESI-): 699 (M-H)
[1407] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.55-1.91(6H,
m), 2.00-2.14(2H, m), 2.45-2.54(2H, m), 2.78-2.91(1H, m),
3.12-3.22(2H, m), 3.31-3.48(3H, m), 3.57-3.71(1OH, m),
3.85-4.07(2H, m), 4.20-4.27(1H, m), 4.55-4.68(0.5H, m),
4.94-5.02(0.5H, m), 7.24-7.49(3H, m), 7.60-7.67(2H, m)
EXAMPLE 217
[1408]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-(3-carbamoylpropane)-sulfon-
yl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (324 mg) was
obtained in substantially the same manner as in Example 216.
[1409] Mass (ESI-): 599 (M-H)
[1410] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48-1.88(6H,
m), 1.93-2.04(2H, m), 2.37(2H, t, J=8 Hz), 2.78-2.92(2H, m),
3.06-3.18(2H, m), 3.42-3.69(4H, m), 3.88-4.03(3H, m), 4.20(1H, d,
J=12 Hz), 4.55-4.69(0.5H, m), 4.95-5.02(0.5H, m), 5.57-5.63(0.5H,
m), 6.05-6.20(0.5H, m), 7.27-7.49(5H, m), 7.60-7.67(3H, m),
9.52-9.63(1H, m)
EXAMPLE 218
[1411]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-[3-(N-methylcarbamoyl)-prop-
ane]sulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(330 mg) was obtained in substantially the same manner as in
Example 216.
[1412] Mass (ESI-): 613 (M-H)
[1413] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.50-1.91(6H,
m), 1.93-2.07(2H, m), 2.32(2H, t, J=10 Hz), 2.70-2.95(2H, m),
2.79(3H, s), 3.01-3.18(2H, m), 3.26-3.69(3H, m), 3.85-4.05(3H, m),
4.21(1H, d, J=12 Hz), 4.53-4.76(1H, m), 4.87-5.03(1H, m),
5.85-6.12(1H, br), 7.24-7.50(5H, m), 7.55-7.66(2H, m),
9.26-9.50(1H, br)
EXAMPLE 219
[1414]
(2R)-4-[N-(Aminocarbonylmethyl)aminocarbonyl]-1-[5-(4-fluorophenyl)-
-thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(154 mg) was obtained as amorphous powder in substantially the same
manner as in Preparation 12.
[1415] Mass (ESI-): 568 (M-H)
[1416] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.78(1H, m), 3.02(1H, m), 3.36(1H, m), 3.61(1H, m),
3.70-3.98(4H, m), 4.12(1H, d, J=11 Hz), 4.32(1H, d, J=11 Hz),
4.58(1H, brs), 4.89, 4.97(1H, brs), 5.58(1H, brs), 5.95(1H, brs),
6.58(1H, brs), 7.13(2H, t, J=8 Hz), 7.23(1H, d, J=2 Hz), 7.55(2H,
dd, J=4, 8 Hz), 7.62(1H, d, J=2 Hz)
[1417] Preparation 153
[1418] 2-(2-Pyridyl)ethanesulfonic acid (1.00 g) was suspended in
thionyl chloride (5 ml). Catalytic amount of DMF was added to the
suspension. The mixture was stirred at 50.degree. C for 30 minutes,
and was concentrated in vacuo. The resulting solid was recovered
and washed with Et.sub.2O to give 1.41 g of
2-(2-pyridyl)ethanesulfonyl chloride hydrochloride as a solid.
[1419] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.98(2H, t,
J=14 Hz), 3.34(2H, t, J=4 Hz), 7.88(1H, dd, J=4, 6 Hz), 8.03(1H, d,
J=6 Hz), 8.48(1H, t, J=6 Hz), 8.77(1H, d, J=4 Hz)
EXAMPLE 220
[1420] 2-(2-Pyridyl)ethanesulfonyl chloride hydrochloride (214 mg)
was added to a solution of
(2R)-1-(5-phenylthiophene-2-sulfonyl]-N-(2-tetrahy-
dropyranyloxy)-2-piperazinecarboxamide (200 mg) and triethylamine
(188 mg) in CHCl.sub.3 (3 ml) with cooling on an ice bath. The
reaction mixture was stirred at ambient temperature for 1 hour. The
mixture was concentrated in vacuo, and the residue was purified by
SiO.sub.2 column chromatography eluted with MeOH in CHCl.sub.3 (1%)
to give 184 mg of
(2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[2-(2-pyridyl)-ethanesulfonyl]-N--
(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous
powder.
[1421] Mass (ESI-): 619 (M-H)
[1422] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.45-1.87(6H,
m), 2.73-2.98(2H, m), 3.13-3.25(2H, m), 3.30-3.72(5H, m),
3.81-4.04(2H, m), 4.27(1H, m), 4.64(1H, m), 4.92, 4.98(1H,brs),
7.13(1H, dd, J=3, 6 Hz), 7.17-7.32(2H, m), 7.37-7.48(3H, m),
7.55-7.66(4H, m), 8.49(1H, d, J=3 Hz), 9.24(1H, brs)
EXAMPLE 221
[1423]
(2R)-4-[3-(4-Morpholino)propanesulfonyl]-1-(5-phenylthiophene-2-sul-
fonyl)-N-(.sup.2-tetrahydropyranyloxy)-2-piperazinecarboxamide (380
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 220.
[1424] Mass (ESI+): 643 (M+H)
[1425] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.52-2.12(9H,
m), 2.65-2.73(1H, m), 2.80-2.98(3H, m), 3.10-3.25(1H, m),
3.51-3.92(4H, m), 4.45-4.60(3H, m), 4.65-4.78(1H, m), 7.28-7.36(2H,
m), 7.41-7.54(3H, m), 7.75(2H, d, J=8 Hz), 8.04-8.12(2H, m),
8.45(2H, d, J=3 Hz), 8.90-9.02(1H, m)
EXAMPLE 222
[1426] (2R)-4-(.sup.3Chloropropanesulfonyl)
-1-(5-phenylthiophene-2-sulfon-
yl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (800 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 220.
[1427] Mass (ESI-): 590, 592(M-H)
[1428] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.53-1.86(6H,
m), 2.10-2.28(2H, m), 2.75-2.93(2H, m), 3.14-3.28(2H, m),
3.56-3.70(4H, m), 3.86-4.08(2H, m), 4.16-4.28(1H, m), 4.57-4.69(1H,
m), 4.95-5.02(1H, m), 7.28-7.32(1H, m), 7.40-7.50(3H, m),
7.58-7.66(3H, m), 9.20(1H, brs)
[1429] Preparation 154
[1430]
(2R)-1-[(5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyr-
anyloxy)-2-piperazinecarboxamide (5.90 g) was obtained as an
amorphous powder in substantially the same manner as in Preparation
157 to be mentioned later.
[1431] Mass (ESI-): 468(M-H)
[1432] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.38-1.69(6H,
m), 2.48-2.60(1H, m), 2.68-2.95(2H, m), 3.00-3.12(1H, m),
3.38-3.60(3H, m), 3.81-3.95(1H, m), 4.08-4.22(1H, m), 4.74(1H, d,
J=14 Hz), 7.33(2H, t, J=8 Hz), 7.59(2H, d, J=3 Hz), 7.75-7.84(2H,
m)
EXAMPLE 223
[1433]
(2R)-1-[(5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-[2-(4-pyridyl)-e-
thanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(405 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 220.
[1434] Mass (ESI-): 637(M-H)
[1435] .sup.1H-NMR (300 MHz, DMSO-d.sub.6.delta.): 1.32-1.70(6H,
m), 2.80-2.98(3H, m), 3.05-3.28(1H, m), 3.32-3.95(8H, m),
4.42-4.54(1H, m), 4.66-4.75(1H, m), 7.22-7.38(4H, m), 7.53-7.67(2H,
m), 7.72-7.86(2H, m), 8.39-8.50(2H, m)
EXAMPLE 224
[1436]
(2R)-4-(3-Chloropropanesulfonyl)-1-[5-(4-fluorophenyl)thiophene-2-s-
ulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (1.47
g) was obtained as an amorphous powder in substantially the same
manner as in Example 220.
[1437] Mass (ESI-): 608, 610(M-H)
[1438] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.91(6H,
m), 2.08-2.28(2H, m), 2.75-2.92(2H, m), 3.15-3.26(2H, m),
3.33-3.46(1H, m), 3.57-3.69(4H, m), 3.85-4.08(2H, m), 4.15-4.28(1H,
m), 4.56-4.68(1H, m), 4.93-5.02(1H, m), 7.14(2H, t, J=8 Hz),
7.21-7.26(1H, m), 7.52-7.64(3H, m), 9.23(1H, brs)
EXAMPLE 225
[1439] A solution of phenyl isocyanate (38 mg) in CHCl.sub.3 (1 ml)
was added to a solution of
(2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N--
(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) in
CHCl.sub.3 (3 ml). After stirring for 30 minutes at ambient
temperature, the reaction mixture was concentrated in vacuo to give
203 mg of
(2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[(N-phenyl)aminocarbony-
l]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an
amorphous powder.
[1440] Mass (ESI-): 587 (M-H)
[1441] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.93(6H,
m), 2.70(1H, m), 2.95(1H, dd, J=2, 12 Hz), 3.24(1H, m), 3.65(1H,
m), 3.88-4.03(2H, m), 4.17(1H, d, J=12 Hz), 4.47(1H, d, J=12 Hz),
4.67(1H, m), 4.94, 5.04(total 1H, s), 6.99(1H, m), 7.15(1H, t, J=8
Hz), 7.20-7.35(5H, m), 7.58(2H, dd, J=4, 8 Hz), 7.64(1H, d, J=3
Hz), 7.80-7.90(1H, m), 9.32, 9.41(1H, s)
EXAMPLE 226
[1442]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-[3-(3-pyridyl)-pr-
opionyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (190
mg) was obtained as an amorphous powder in substantially the same
manner as in Preparation 8.
[1443] Mass (ESI): 601(M-H)
[1444] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.32-1.68(6H,
m), 2.52-2.83(4H, m), 3.02-4.12(7H, m), 4.20-4.52(2H, m),
4.61-4.75(1H, m), 7.18-7.38(3H, m), 7.52-7.68(3H, m), 7.75-7.86(2H,
m), 8.32-8.45(2H, m).
EXAMPLE 227
[1445]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-[3-(3-pyridyl)-ac-
rylyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (190 mg)
was obtained as an amorphous powder in substantially the same
manner as in
[1446] Preparation 8.
[1447] Mass (ESI): 561(M-H)
[1448] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.19(6H, t,
J=7 Hz), 1.89-2.06(2H, m), 2.76-2.88(1H, m), 2.95-3.28(1H, m),
3.49-3.80(3H, m), 3.88(1H, d, J=12 Hz), 4.49(1H, brs), 7.33(2H, t,
J=8 Hz), 7.55-7.63(1H, m), 7.69(1H, d, J=3 Hz), 7.78-7.86(2H, m),
9.01(11H, s)
EXAMPLE 228
[1449]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-(N-propylaminocar-
bonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (175 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 225.
[1450] Mass (ESI): 553 (M-H)
[1451] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.74, 0.76(3H,
t, J=7 Hz), 1.23-1.40(2H, m), 1.44-1.72(6H, m), 2.78-2.98(3H, m),
3.02-3.17(1H, m), 3.46-3.96(5H, m), 4.03-4.18(1H, m), 4.22-4.31(1H,
m), 4.69, 4.77(1H, brs), 6.35-6.52(1H, m), 7.34(2H, t, J=8 Hz),
7.57-7.67(2H, m), 7.75-7.85(2H, m)
EXAMPLE 229
[1452]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-(N-methylaminocar-
bonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (165 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 225.
[1453] Mass (ESI): 525 (M-H)
[1454] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.37-1.69(6H,
m), 2.48(3H, d, J=7 Hz), 2.83-2.98(1H, m), 3.02-3.14(1H, m),
3.45-3.96(5H, m), 4.02-4.18(1H, m), 4.22-4.31(1H, m), 4.69,
4.78(1H, brs), 6.32-6.48(1H, m), 7.34(2H, t, J=8 Hz), 7.56-7.67(2H,
m), 7.75-7.85(2H, m)
EXAMPLE 230
[1455] A solution of ethyl chlorocarbonate (42 mg) in CHCl.sub.3 (1
ml) was added dropwise to a solution of
(2R)-1-[5-(4-fluorophenyl)thiophene-2-
-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150
mg) and triethylamine (39 mg) in CHCl.sub.3 (2 ml) with cooling on
an ice bath. The reaction mixture was stirred at said temperature
for 30 minutes and the reaction was quenched by adding
3-(N,N-dimethylamino)propylamine (0.5 ml). The mixture was
concentrated in vacuo, and the residue was partitioned between
AcOEt and 5% aqueous citric acid. The organic layer was washed with
saturated aqueous NaHCO.sub.3 solution and saturated aqueous NaCl
solution, dried over MgSO.sub.4, and concentrated in vacuo. The
residue was purified by SiO.sub.2 column chromatography eluted with
AcOEt in hexane gradually from 40% to 60%, to give 142 mg of
(2R)-4-ethoxycarbonyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tet-
rahydropyranyloxy)-2-piperazinecarboxamide.
[1456] Mass (ESI-): 540 (M-H)
[1457] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.20(3H, t, J=5
Hz), 1.50-1.90(6H, m), 2.90-3.20(2H, m), 3.45(1H, m), 3.64(1H, m),
3.77(1H, m), 3.83-4.00(2H, m), 4.02-4.15(2H, m), 4.37-4.58(2H, m),
4.92, 4.98(1H, s), 7.12(2H, t, J=8 Hz), 7.21(1H, d, J=2 Hz),
7.51-7.65(3H, m),
EXAMPLE 231
[1458] (2R)-4-Butyryl-1-[5-(4-fluorophenyl)
thiophene-2-sulfonyl]-N-(2-tet-
rahydropyranyloxy)-2-piperazinecarboxamide (168 mg) was obtained as
an amorphous powder in substantially the same manner as in
Preparation 8.
[1459] Mass (ESI): 538 (M-H)
[1460] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.92(3H, t, J=8
Hz), 1.50-1.94(8H, m), 2.18-2.38(2H, m), 2.45-2.72(1H, m),
2.94-3.12(1H, m), 3.25-3.41(1H, m), 3.54-3.98(4H, m), 4.28-4.42(1H,
m), 4.46-4.59(1H, m), 4.90-4.98(1H, brs), 7.08-7.28(3H, m),
7.52-7.68(3H, m), 9.20(1H, s)
EXAMPLE 232
[1461]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-[5-(4-fluorophenyl)thiophene-2-
-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (240
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 230.
[1462] Mass (ESI): 575 (M-H)
[1463] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.92(6H,
m), 2.60-2.76(2H, m), 2.82(3H, s), 2.84(3H, s), 3.39-3.52(2H, m),
3.55-3.69(1H, m), 3.82-4.09(3H, m), 4.52-5.64(1H, m), 4.92-5.00(1H,
m), 7.13(2H, t, J=8 Hz), 7.20-7.24(1H, m), 7.51-7.61(3H, m),
9.18(1H, brs)
[1464] Preparation 155
[1465] Sodium hydride (60% in oil dispersion, 1.22 g, 50.9 mmol)
was washed with dry tetrahydrofuran (20 ml.times.3) under nitrogen
atomosphere. Freshly distilled tetrahydrofuran (50 ml) was added
and the mixture was cooled to 0.degree. C. with an ice bath. To
this mixture was added portionwise solution of benzyl alcohol (5 g,
46.2 mmol) in dry tetrahydrofuran (10 ml) and the mixture was
stirred for 1 hour at said temperature. To the resulting mixture
was added .gamma.-thiobutyrolactone (5.2 g, 50.9 mmol) slowly and
the resulting mixture was warned to room temperature. After
stirring for 1 hour, H.sub.2O (30 ml) was added carefully and
tetrahydrofuran was removed under reduced pressure. The residue was
extracted three times with AcOEt. The organic layers were combined,
washed with brine, and dried over magnesium sulfate. The solvent
was evaporated to give 9.96 g of benzyl 4-mercaptobutyrate as a
colorless oil which was taken to the next step without further
purification.
[1466] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.37(1H, t, J=9
Hz), 1.93-2.04(2H, m), 2.50(1H, t, J=9 Hz), 2.59(1H, t, J=9 Hz),
5.13(2H, s), 7.34-7.40(5H, m)
[1467] Preparation 156
[1468] To a mixture of benzyl 4-mercaptobutyrate (9.96 g, 47.4
mmol) and potassium nitrate (12 g, 118 mmol) was added dropwise
sulfuryl chloride (16 g, 118 mmol) at 0.degree. C., and the mixture
was stirred for 10 hours at room temperature. The resulting
suspension was adjusted to pH 7 with saturated NaHCO.sub.3
solution. The organic layer was separated, washed with saturated
NaHCO.sub.3 solution and brine, and dried over MgSO. The solvent
was removed under reduced pressure. The residue was dissolved in
CHCl.sub.3 and the solution was passed through short SiO.sub.2
column to give 9.85 g of benzyl 4-chlorosulfonylbutyrate as a
slightly brown oil.
[1469] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 2.30-2.45(2H,
m), 2.67(2H, t, J=10 Hz), 3.80(2H, t, J=10 Hz), 5.15(2H, s),
7.38(5H, s)
EXAMPLE 233
[1470]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-[3-(benzyloxycarbonyl)-prop-
ane]sulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(1.11 g) was obtained in substantially the same manner as in
Example 220.
[1471] Mass (ESI-): 690 (M-H)
[1472] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.90(6H,
m), 1.95-2.14(2H, m), 2.48-2.56(2H, m), 2.76-2.88(1H, m),
3.09-3.20(2H, m), 3.33-3.46(1H, m), 3.57-3.67(2H, m), 3.86-4.04(2H,
m), 4.17-4.23(1H, m), 4.57-4.65(0.5H, m), 4.93-5.01(0.5H, m),
5.12(2H, s), 7.27-7.48(3H, m), 7.56-7.65(2H, m), 9.19(1H, br)
EXAMPLE 234
[1473]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-(1-propanesulfony-
l)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (95 mg) was
obtained in substantially the same manner as in Example 220.
[1474] Mass (ESI-): 574 (M-H)
[1475] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.02(3H, t, J=7
Hz), 1.52-1.92(8H, m), 2.75-2.91(2H, m), 2.97-3.10(2H, m),
3.35-3.47(1H, m), 3.57-3.70(2H, m), 3.85-4.05(2H, m), 4.14-4.25(1H,
m), 4.57-4.69(1H, br), 4.92-5.00(1H, m), 7.09-7.19(2H, m), 7.21(1H,
d, J=4 Hz), 7.53-7.64(2H, m), 9.15-9.24(1H, m)
[1476] Preparation 157
[1477]
(2R)-4-(9-Fluorenylmethyloxycarbonyl)-1-(5-phenylthiophene-2-sulfon-
yl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (16.5 g) was
dissolved in a solution (160 ml) of20% piperidine in DMF at room
temperature. After stirring for 30 minutes at said temperature, the
solution was concentrated in vacuo. The residue was purified by
SiO.sub.2 column chromatography (eluent: 1% MeOH in CHCl.sub.3,
then 4% MeOH in CHCl.sub.3) to give 9.57 g of
(2R)-1-(5-phenylthiophene-2-sulfonyl)-N-(2--
tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous
powder.
[1478] Mass (ESI-): 450 (M-H)
[1479] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.46-1.90(6H,
m), 2.67-2.92(3H, m), 3.24-3.50(2H, m), 3.52-3.68(1H, m),
3.74-3.82(1H, m), 3.86-3.98(1H, m), 4.38(1H, brs), 4.92-4.98(1H,
m), 7.28(1H, d, J=3 Hz), 7.35-7.48(3H, m), 7.58-7.64(3H, m),
8.02(1H, s)
EXAMPLE 235
[1480]
(2R)-1-(5-Phenylthiophene-2-sulfonyl)-4-[2-(4-pyridyl)-ethanesulfon-
yl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (186 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 220.
[1481] Mass (ESI-): 619 (M-H)
[1482] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.32-1.69(6H,
m), 2.65-2.73(1H, m), 2.80-2.98(3H, m), 3.10-3.25(1H, m),
3.51-3.92(4H, m), 4.45-4.60(3H, m), 4.65-4.78(1H, m), 7.28-7.36(2H,
m), 7.41-7.54(3H, m), 7.75(2H, d, J=8 Hz), 8.04-8.12(2H, m),
8.45(2H, d, J=3 Hz), 8.90-9.02(1H, m)
EXAMPLE 236
[1483]
(2R)-4-(N-Ethylaminocarbonyl)-1-[5-(4-fluorophenyl)thiophene-2-sulf-
onyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (164 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 225.
[1484] Mass (ESI): 539 (M-H)
[1485] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.08(3H, t, J=7
Hz), 1.50-1.68(3H, m), 1.72-1.90(3H, m), 2.58-2.72(1H, m), 2.85(1H,
dd, J=3, 8 Hz), 3.08-3.31(3H, m), 3.57-3.68(1H, m), 3.84-4.08(3H,
m), 4.22-4.34(1H, m), 4.58(1H, brs), 4.96(1H, d, J=2 Hz),
5.18-5.30(1H, m), 7.14(2H, t, J=8 Hz), 7.22(1H, d, J=3 Hz),
7.52-7.76(3H, m), 9.35, 9.42(1H, s)
EXAMPLE 237
[1486]
(2R)-4-[(N-cyclohexyl)aminocarbonyl]-1-[5-(4-fluorophenyl)-thiophen-
e-2-sulfonyl]-N-(2-tetrahydropyranyloxy) -2-piperazinecarboxamide
(190 mg) was obtained in substantially the same manner as in
Example 225.
[1487] Mass (ESI-): 593 (M-H)
[1488] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.04-1.43(6H,
m), 1.50-1.95(10H, m), 2.65(1H, m), 2.84(1H, dd, J=2, 12 Hz),
3.23(1H, m), 3.50(1H, m), 3.63(1H, m), 3.84-4.07(3H, m), 4.28(1H,
m), 4.58(1H, d, J=7 Hz), 4.91, 5.00(1H, s), 5.15(1H, d, J=5 Hz),
7.15(2H, t, J=8 Hz), 7.22(1H, d, J=2 Hz), 7.52-7.65(3H, m), 9.28,
9.42(1H, s)
EXAMPLE 238
[1489]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-methoxycarbonyl-N-
-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (160 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 230.
[1490] Mass (ESI): 526 (M-H)
[1491] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.33-1.68(6H,
m), 2.85-3.22(2H, m), 3.42-4.15(6H, m), 3.49, 3.51(3H, s),
4.22-4.35(1H, m), 4.62, 4.71(1H, brs), 7.33(2H, t, J=8 Hz),
7.59(2H, d, J=3 Hz), 7.74-7.85(2H, m)
EXAMPLE 239
[1492]
(2R)-4-Dimethylcarbamoyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-
-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (179 mg) was
obtained in substantially the same manner as in Example 230.
[1493] Mass (ESI-): 539 (M-H)
[1494] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.93(6H,
m), 2.82(6H, s), 2.85-3.10(2H, m), 3.20-3.50(1H, m), 3.44(1H, d,
J=12 Hz), 3.63(1H, m), 3.82(1H, m), 3.95(1H, m), 4.21(1H, t, J=12
Hz), 4.61(1H, m), 4.96, 4.99(1H, s), 7.12(2H, t, J=8 Hz), 7.19(1H,
d, J=2 Hz), 7.50(2H, dd, J=4, 8 Hz), 7.65(11H, m)
EXAMPLE 240
[1495] (2R)-4-(2-Benzyloxycarbonylaminoethanesulfonyl)
-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazine-
carboxamide (199 mg) was obtained in substantially the same manner
as in Example 220.
[1496] Mass (ESI): 691 (M-1)
[1497] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.61(4H,
m), 1.70-1.87(2H, m), 2.72-2.88(2H, m), 3.20-3.40(3H, m),
3.49-3.69(4H, m), 3.84-4.05(2H, m), 4.14-4.24(1H, m), 4.56-4.67(1H,
m), 4.94-5.00(1H, m), 5.08-5.11(2H, m), 5.49-5.61(1H, m),
7.25-7.31(1H, m), 7.31-7.38(5H, m), 7.40-7.48(3H, m), 7.58-7.63(3H,
m), 9.18-9.28(1H, m)
EXAMPLE 241
[1498]
(2R)-4-[5-(Isoxazol-3-yl)thiophene-2-sulfonyl]-1-(5-phenylthiophene-
-2-sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(285 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 220.
[1499] Mass (ESI-): 663 (M-H)
[1500] .sup.1H-NM (300 MHz, CDCl.sub.3, .delta.): 1.48-1.89(6H, m),
2.42-2.64(2H, m), 3.45-3.70(3H, m), 3.84-4.07(2H, m), 4.27-4.40(1H,
m), 4.65-4.72(1H, m), 4.92-5.00(1H, m), 6.40(1H, d, J=8 Hz),
7.17-7.12(1H, m), 7.28-7.60(8H, m), 8.28(1H, s), 9.05(1H, brs)
EXAMPLE 242
[1501] (2R) 1-(5-Phenylthiophene-2-sulfonyl)-4-(1
-piperidinesulfonyl)-N-(-
2-tetrahydropyranyloxy)-2-piperazinecarboxamide (192 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 220.
[1502] Mass (ESI-): 597 (M-H)
[1503] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.47-1.93(14H,
m), 2.58-2.77(2H, m), 3.09-3.28(4H, m), 3.33-3.68(3H, m),
3.82-4.13(3H, m), 4.55-4.67(1H, m), 4.96(1H, d, J=8 Hz),
7.24-7.32(1H, m), 7.36-7.48(3H, m), 7.55-7.66(3H, m), 9.19(1H,
brs)
EXAMPLE 243
[1504] (2R)-4-(N-Methylpropylaminosulfonyl)
-1-(5-phenylthiophene-2-sulfon-
yl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (175 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 220.
[1505] Mass (ESI-): 585 (M-H)
[1506] .sup.1H-NMR (300 MHz, CDCl.sub.3,.delta.): 0.88, 0.89(3H, t,
J=8 Hz), 1.48-1.93(8H, m), 2.58-2.75(2H, m), 2.78, 2.81(3H, s),
3.06-3.21(2H, m), 3.36-3.52(2H, m), 3.55-3.70(1H, m), 3.84-4.08(3H,
m), 4.54-4.55(1H, m), 4.92-4.99(1H, m), 7.28-7.31(1H, m),
7.37-7.48(3H, m), 7.57-7.63(3H, m), 9.08(1H, brs)
EXAMPLE 244
[1507]
(2R)-4-(N,N-Dimethylaminosulfonyl)-1-(5-phenylthiophene-2-sulfonyl)-
-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (172 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 220.
[1508] Mass (ESI-): 557 (M-H)
[1509] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.92(6H,
m), 2.62-2.76(2H, m), 2.81(3H, s), 2.84(3H, s) 3.36-3.51(2H, m),
3.55-3.70(1H, m), 3.82-4.09(3H, m), 4.52-4.65(1H, m), 4.91-5.00(1H,
m), 7.28-7.32(1H, m), 7.35-7.48(3H, m), 7.55-7.64(3H, m), 9.18(1H,
brs)
EXAMPLE 245
[1510]
(2R)-4-Methoxycarbonyl-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tetrah-
ydropyranyloxy)-2-piperazinecarboxamide (150 mg) was obtained as an
amorphous powder in substantially the same manner as in Example
220.
[1511] Mass (ESI-): 508 (M-H)
[1512] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.88-3.16(2H, m), 3.48-3.52(1H, m), 3.56-4.00(4H, m), 3.63,
3.66(3H, s), 4.41-4.59(2H, m), 4.89-5.02(1H, m), 7.28(1H, d, J=3
Hz), 7.35-7.48(3H, m), 7.56-7.65(3H, m), 9.14(1H, brs)
EXAMPLE 246
[1513]
(2R)-4-Ethylaminocarbonyl-1-(5-phenylthiophene-2-sulfonyl)-N-(2-tet-
rahydropyranyloxy)-2-piperazinecarboxamide (160 mg) was obtained as
an amorphous powder in substantially the same manner as in Example
220.
[1514] Mass (ESI-): 521 (M-H)
[1515] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.10(3H, t, J=7
Hz), 1.52-1.91(6H, m), 2.58-2.72(1H, m), 2.85(1H, dd, J=3, 16 Hz),
3.08-3.30(3H, m), 3.56-3.68(1H, m), 3.85-4.10(3H, m), 4.22-4.33(1H,
m), 4.55-4.62(1H, m), 4.88-5.01(1H, m), 5.18-5.30(1H, m), 7.30(1H,
d, J=3 Hz), 7.37-7.48(3H, m), 7.56-7.65(3H, m), 9.34, 9.40(1H,
brs)
EXAMPLE 247
[1516]
(2R)1)-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-(pyridine-3-sulfo-
nyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (213 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 220.
[1517] Mass (ESI-): 609 (M-H)
[1518] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.91(6H,
m), 2.46-2.68(2H, m), 3.38-3.52(1H, m), 3.55-3.68(2H, m),
3.82-4.00(2H, m), 4.20-4.38(1H, m), 4.58-4.68(1H, m), 4.86,
4.94(1H, brs), 7.10-7.20(3H, m), 7.33-7.45(1H, m), 7.49-7.59(3H,
m), 7.97-8.06(1H, m), 8.64-8.76(1H, m), 8.89-8.97(1H, m), 9.07(1H,
brs)
EXAMPLE 248
[1519] (2R)-4-(N-Ethylaminosulfonyl)-1-[5-(4-fluorophenyl)
thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(203 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 230
[1520] Mass (ESI): 575 (M-H)
[1521] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.17, 1.18(3H,
t, J=7 Hz), 1.50-1.92(6H, m), 2.18-2.32(2H, m), 2.98-3.13(2H, m),
3.45-3.70(2H, m), 3.84-4.02(2H, m), 4.12-4.28(1H, m), 4.32-4.67(2H,
m), 4.88-4.98(1H, m), 7.08-7.18(2H, m), 7.20-7.25(1H, m),
7.52-7.62(3H, m), 9.24(1H, brs)
EXAMPLE 249
[1522] (2R)-1-[5-(4-Fluorophenyl)
thiophene-2-sulfonyl]-4-(1-piperidinesul-
fonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (240 mg)
was obtained as an amorphous powder in substantially the same
manner as in Example 220.
[1523] Mass (ESI-): 615 (M-H)
[1524] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48-1.93(14H,
m), 2.18-2.26(2H, m), 3.10-3.28(4H, m), 3.36-3.70(3H, m),
3.86-4.12(3H, m), 4.55-4.67(1H, m), 4.92-5.00(1H, m), 7.14(2H, t,
J=8 Hz), 7.19-7.25(1H, m), 7.52-7.62(3H, m), 9.16(1H, brs)
EXAMPLE 250
[1525]
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-4-[N-methyl-N-(meth-
oxycarbonylmethyl)aminosulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazineca-
rboxamide (120 mg) was obtained as an amorphous powder in
substantially the same manner as in Example 220.
[1526] Mass (ESI-): 633 (M-H)
[1527] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 2.66-2.82(2H, m), 2.88, 2.92(3H, s) 3.38-3.68(3H, m), 3.75(3H,
s), 3.85-4.22(5H, m)), 4.58-4.70(1H, m), 4.92-5.01(1H, m), 7.14(2H,
t, J=8 Hz), 7.22(1H, d, J=3 Hz), 7.52-7.65(3H, m), 9.26, 9.32(1H,
brs)
EXAMPLE 251
[1528]
(2R)-4-[N-(Ethoxycarbonylmethyl)aminocarbonyl]-1-[5-(4-fluorophenyl-
)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(829 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 225.
[1529] Mass (ESI-): 597 (M-H)
[1530] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.25(3H, t, J=4
Hz), 1.50-1.90(6H, m), 2.23(1H, t, J=12 Hz), 2.93(1H, d, J=12 Hz),
3.27(1H, t, J=12 Hz), 3.64(1H, m), 3.75-4.08(5H, m), 4.16(2H, q,
J=4 Hz), 4.88(1H, m), 4.61(1H, d, J=8 Hz), 5.01(1H, s), 5.74(1H,
m), 7.15(2H, t, J=8 Hz), 7.23(1H, m), 7.52-7.65(3H, m), 9.33,
9.40(1H, s)
EXAMPLE 252
[1531] Phenyl chloroformate (60 mg) in CHCl.sub.3 (1 ml) was added
to
(2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy-
)-2-piperazinecarboxamide (150 mg) in pyridine (0.5 ml) and
CHCl.sub.3 (0.5 ml) dropwise with cooling on an ice bath. The
reaction mixture was stirred at said temperature for 2 hours. The
mixture was concentrated in vacuo, and the residue was partitioned
between AcOEt and 5% aqueous citric acid. The organic layer was
washed with 5% aqueous citric acid, saturated aqueous NaHCO.sub.3
solution and saturated aqueous NaCl solution, dried over
MgSO.sub.4O, and concentrated in vacuo to give 202 mg of
(2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-.sup.4-phenoxycarbo-
nyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
[1532] Mass (ESI-): 588 (M-H)
[1533] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.50-1.90(6H,
m), 3.00-3.40(2H, m), 3.50-3.70(3H, m), 3.75-4.20(3H, m),
4.44-5.03(3H, m), 7.00-7.35(8H, m), 7.58(2H, dd, J=4, 8 Hz),
7.52-7.70(1H, m), 9.13(11H, brs)
[1534] Preparation 158
[1535]
(2R)-N-(2-Tetrahydropyranyloxy)-1-[5-(4-trifluoromethylphenyl)-thio-
phene-2-sulfonyl]-2-piperazinecarboxamide (770 mg) was obtained as
an amorous powder in substantially the same manner as in
[1536] Preparation 157.
[1537] Mass (ESI+): 520 (M+H)
[1538] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.46-1.88(6H,
m), 2.78-2.90(2H, m), 2.93-3.07(1H, m), 3.25-3.48(2H, m),
3.52-3.68(1H, m), 3.72-3.83(1H, m), 3.86-3.99(1H, m), 4.34-4.42(1H,
m), 4.74, 4.95(1H, brs), 7.35(1H, d, J=3 Hz), 7.58-7.75(5H, m)
EXAMPLE 253
[1539] (2R)-4-Ethylaminosulfonyl-N-(2-tetrahydropyranyloxy)
-1-[5-(4-trifluoromethylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxam-
ide (68 mg) was obtained as an amorphous powder in substantially
the same manner as in Example 220.
[1540] Mass (ESI-): 625 (M-H)
[1541] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.18, 1.23(3H,
t, J=8 Hz), 1.49-1.88(6H, m), 2.28-2.87(2H, m), 2.99-3.15(2H, m),
3.52-3.68(2H, m), 3.86-4.03(2H, m), 4.12-4.15(1H, m), 4.28-4.45(1H,
m), 4.55-4.68(1H, m), 4.86-5.00(1H, m), 7.30-7.40(1H, m),
7.60-7.78(5H, m), 9.17(1H, brs)
EXAMPLE 254
[1542]
(2R)-4-(Methylpropylaminosulfonyl)-N-(2-tetrahydropyranyloxy)-1-[5--
(4-trifluoromethylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide
(235 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 220.
[1543] Mass (ESI-): 653 (M-H)
[1544] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 0.90(3H, t, J=7
Hz), 1.48-1.93(8H, m), 2.61-2.76(2H, m), 2.79, 2.82(3H, s),
3.08-3.22(2H, m), 3.38-3.70(3H, m), 3.85-4.08(3H, m), 4.65(1H,
brs), 4.92-5.00(1H, m), 7.33-7.40(1H, m), 7.58-7.67(1H, m),
7.71(4H, s), 9.18(1H, brs)
EXAMPLE 255
[1545]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-(2-tetrahydropyranyloxy)-1-[5--
(4-trifluoromethylphenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide
(150 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 220.
[1546] Mass (ESI-): 625 (M-H)
[1547] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.92(6H,
m), 2.62-2.77(2H, m), 2.85(3H, s), 2.87(3H, s), 3.40-3.72(3H, m),
3.88-4.09(3H, m), 4.57-4.67(1H, m), 4.92-5.00(1H, m), 7.38(1H, d,
J=3 Hz), 7.60-7.76(5H, m), 9.16(1H, brs)
[1548] Preparation 159
[1549]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyra-
nyloxy)-2-piperazinecarboxamide (4.20 g) was obtained as an
amorphous powder in substantially the same manner as in
[1550] Preparation 157
[1551] Mass (ESI+): 486, 488 (M+H)
[1552] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48-1.98(6H,
m), 2.66-3.04(3H, m), 3.23-3.49(2H, m), 3.53-3.68(1H, m),
3.73-3.83(1H, m), 3.86-3.98(1H, m), 4.38(1H, brs), 4.76, 4.97(1H,
brs), 7.22-7.28(2H, m), 7.36-7.44(2H, m), 7.48-7.62(3H, m)
EXAMPLE 256
[1553]
(2R)-1-[5-(4Chlorophenyl)thiophene-2-sulfonyl]-4-(N,N-dimethylamino-
sulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (210
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 220.
[1554] Mass (ESI-): 591, 593 (M-H)
[1555] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.93(6H,
m), 2.62-2.77(2H, m), 2.84(3H, s), 2.86(3H, s), 3.38-3.70(3H, m),
3.84-4.10(3H, m), 4.54-4.67(1H, m), 4.93-5.00(1H, m), 7.28(1H, d,
J=3 Hz), 7.41(2H, d, J=8 Hz), 7.54(2H, d, J=8 Hz), 7.57-7.62(1H,
m), 9.18(1H, brs)
EXAMPLE 257
[1556]
(2R)-1-[5-(.sup.4-Chlorophenyl)thiophene-2-sulfonyl]-4-(N-methyleth-
ylaminosulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(181 mg) was obtained as an amorphous powder in substantially the
same manner as in Example 220.
[1557] Mass (ESI-): 605, 607 (M-H)
[1558] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.18(3H, t, J=7
Hz), 1.50-1.92(6H, m), 2.57-2.75(2H, m), 2.80, 2.82(3H, s),
3.18-3.32(2H, m), 3.35-3.70(3H, m), 3.85-4.08(3H, m), 4.53-4.66(1H,
m), 4.90-4.99(1H, m), 7.28(1H, d, J=3 Hz), 7.42(2H, d, J=8 Hz),
7.53(2H, d, J=8 Hz), 7.61(1H, d, J=3 Hz), 9.14(1H, brs)
EXAMPLE 258
[1559]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-(3-chloropropanes-
ulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (840
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 220.
[1560] Mass (ESI-): 624, 626 (M-H)
[1561] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.51-1.91 (6H,
m), 2.10-2.27(2H, m), 2.76-2.90(2H, m), 3.15-3.27(2H, m),
3.32-3.48(1H, m), 3.58-3.70(4H, m), 3.86-4.08(2H, m), 4.15-4.27(1H,
m), 4.56-4.68(1H, m), 4.92-5.00(1H, m), 7.28(1H, d, J=3 Hz),
7.42(2H, d, J=8 Hz), 7.54(2H, d, J=8 Hz), 7.57-7.66(1H, m),
9.18(1H, brs)
EXAMPLE 259
[1562]
(2R)-1-[5-(4-Chlorophenyl)thiophene-2-sulfonyl]-4-methoxycarbonyl-N-
-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (138 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[1563] Mass (ESI-): 542, 544 (M-H)
[1564] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.48-1.88(6H,
m), 2.90-3.18(2H, m), 3.37-3.54(1H, m), 3.58-3.69(1H, m), 3.65,
3.68(3H, s), 3.70-4.00(3H, m), 4.40-4.58(2H, m), 4.88-5.01(1H, m),
7.25(1H, d, J=3 Hz), 7.40(2H, d, J=8 Hz), 7.52(2H, d, J=8 Hz),
7.57-7.65(1H, m), 9.16(1H, brs)
[1565] Preparation 160
[1566]
(2R)-1-[5-(4-Ethoxyphenyl)thiophenesulfonyl]-N-(2-tetrahydropyranyl-
oxy)-2-piperazinecarboxamide (3.76 g) was obtained in substantially
the same manner as in Preparation 157.
[1567] Mass (ESI-): 494 (M-H)
[1568] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.42(3H, t, J=7
Hz), 1.49-1.88(6H, m), 2.65-2.85(2H, m), 2.88-3.01(1H, m),
3.24-3.49(2H, m), 3.52-3.67(1H, m), 3.72-3.82(1H, m), 3.86-3.97(1H,
m), 4.05(2H, q, J=7 Hz), 4.34(1H, bs), 4.78(1H, bs), 6.91(2H, d,
J=8 Hz), 7.13(1H, d, J=4 Hz), 7.52(2H, d, J=8 Hz), 7.56(1H, d, J=4
Hz)
EXAMPLE 260
[1569] (2R)-4-(N,
N-Dimethylaminosulfonyl)-1-[5-(4-ethoxyphenyl)-thiophene-
sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (350
mg) was obtained as an amorphous powder in substantially the same
manner as in Example 230.
[1570] Mass (ESI-): 601 (M-H)
[1571] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.47(3H, t, J=7
Hz), 1.52-1.95(6H, m), 2.65-2.87(2H, m), 2.88(3H, s), 2.90(3H, s),
3.35-3.51(2H, m), 3.56-3.70(2H, m), 3.85-3.96(1H, m), 3.97-4.10(3H,
m), 4.09(2H, q, J=7 Hz), 4.62(1H, bs), 4.97(1H, bs), 6.91(2H, d,
J=8 Hz), 7.17(1H, d, J=4 Hz), 7.51(2H, d, J=8 Hz), 7.57(1H, d, J=4
Hz)
EXAMPLE 261
[1572] (2R)-4-(3Chloropropanesulfonyl)-1-[5-(4-ethoxyphenyl)
thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide
(658 mg) was obtained in substantially the same manner as in
Example 220.
[1573] Mass (ESI-): 634, 636 (M-H)
[1574] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.44(3H, t, J=4
Hz), 1.50-1.92(6H, m), 2.08-2.25(2H, m), 2.75-2.90(2H, m), 3.20(2H,
t, J=4 Hz), 3.38(1H, m), 3.55-3.70(4H, m),
[1575] 3.85-4.10(2H, m), 4.08(2H, q, J=4 Hz), 4.21(1H, m), 4.59,
4.63(1H, brs), 4.98(1H, m), 6.94(2H, d, J=8 Hz), 7.17(1H, m),
7.51(2H, d, J=8 Hz), 7.59(1H, m), 9.20(1H, s)
EXAMPLE 262
[1576] 2-Aminoethanol (129 mg) was added to a solution of
(2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-phenoxycarbonyl-N-(2-te-
trahydropyranyloxy)-2-piperazinecarboxamide (250 mg) in DMF (2 ml).
The reaction mixture was stirred at 80.degree. C. overnight. The
mixture was concentrated in vacuo, and the residue was partitioned
between AcOEt and H.sub.2O. The organic layer was washed with
saturated aqueous NaCl solution, dried over MgSO.sub.4, and
concentrated in vacuo. The residue was purified by SiO.sub.2 column
chromatography eluted with MeOH in CHCl.sub.3=2%, then 4%, to give
138 mg of (2R)-1-[5-(.sup.4-fluorophenyl)-
-thiophene-2-sulfonyl]-4-[N-(2-hydroxyethyl)-aminocarbonyl]-N-(2-tetrahydr-
opyranyloxy)-2-piperazinecarboxamide.
[1577] Mass (ESI-): 555 (M-H)
[1578] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.52-1.90(6H,
m), 2.68(1H, t, J=11 Hz), 2.93(1H, d, J=2, 11 Hz), 3.20-3.50(4H,
m), 3.57-3.70(3H, m), 3.85-4.00(2H, m), 4.10(1H, d, J=11 Hz),
4.30(1H, d, J=11 Hz), 4.93, 4.99(1H, brs), 5.62-5.78(1H, m),
7.15(2H, t, J=8 Hz), 7.24(1H, d, J=2 Hz), 7.57(2H, dd, J=4, 8 Hz),
7.60(1H, d, J=2 Hz), 9.40, 9.45(1H, s)
EXAMPLE 263
[1579]
(2R)-1-[5-(4-Hydroxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-4-methan-
esulfonyl-2-piperazinecarboxamide (35 mg) was obtained in
substantially the same manner as in Example 5.
[1580] Mass (ESI): 460 (M-1)
[1581] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.66-2.80(1H,
m), 2.87(3H,s), 2.97(1H, dd, J=6, 14 Hz), 3.51(1H, d, J=14 Hz),
3.68-3.77(1H, m), 3.80(1H, d, J=14 Hz), 4.52-4.48(1H, m), 6.84(2H,
d, J=8 Hz), 7.40(1H, d, J=3 Hz), 7.57(2H, d, J=8 Hz), 7.61(1H, d,
J=3 Hz), 9.00(1H, brs), 9.93(1H, brs)
EXAMPLE 264
[1582]
(2R)-1-[5-(4-Hydroxymethylphenyl)thiophene-2-sulfonyl]-N-hydroxy-4--
methanesulfonyl-2-piperazinecarboxamide (27 mg) was obtained in
substantially the same manner as in Example 5.
[1583] Mass (ESI): 474 (M-1)
[1584] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.68-2.80(1H,
m), 2.86(3H,s), 2.99(1H, dd, J=6, 14 Hz), 3.53(1H, d, J=14 Hz),
3.70-3.78(2H, m), 3.81(1H, d, J=14 Hz), 4.43-4.49(1H, m), 4.54(2H,
d, J=8 Hz), 5.30(1H, t, J=8 Hz), 7.41(2H, d, J=8 Hz), 7.58(1H, d,
J=3 Hz), 7.67(1H, d, J=3 Hz), 7.71(2H, d, J=8 Hz), 9.00(1H,
brs)
EXAMPLE 265
[1585]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-hydroxy-1-[5-(4-hydroxyphenyl)-
thiophene-2-sulfonyl]-2-piperazinecarboxamide (80 mg) was obtained
as an amorphous powder in substantially the same manner as in
Example 5.
[1586] Mass (ESI-): 489 (M-H)
[1587] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.58-2.67(1H,
m), 2.68(6H, s), 2.83(1H, dd, J=4, 14 Hz), 3.38-3.49(1H, m),
3.56-3.81(3H, m), 4.45(1H, brs), 6.84(2H, d, J=8 Hz), 7.42(1H, d,
J=3 Hz), 7.57(2H, d, J=8 Hz), 7.64(1H, d, J=3 Hz), 8.96(1H, s)
EXAMPLE 266
[1588]
(2R)-4-(N,N-Dimethylaminosulfonyl)-N-hydroxy-1-[5-(4-hydroxymethylp-
henyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (63 mg) was
obtained as an amorphous powder in substantially the same manner as
in Example 5.
[1589] Mass (ESI-): 503 (M-H)
[1590] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.60-2.75(1H,
m), 2.69(6H,s), 2.88(1H, dd, J=4, 14 Hz), 3.40-3.50(1H, m),
3.60-3.82(3H, m), 4.44-4.49(1H, m), 4.54(2H, d, J=6 Hz), 5.30(1H,
t, J=6 Hz), 7.42(2H, d, J=8 Hz), 7.62(1H, d, J=4 Hz), 7.68-7.76(3H,
m), 8.97(1H,s)
EXAMPLE 267
[1591]
(2R)-4-Ethylaminocarbonyl-N-hydroxy-1-[5-(4-hydroxyphenyl)-thiophen-
e-2-sulfonyl]-2-piperazinecarboxamide (19 mg) was obtained in
substantially the same manner as in Example 5.
[1592] Mass (ESI-): 453 (M-H)
[1593] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 0.93(3H, t,
J=4 Hz), 2.77-3.05(4H, m), 3.50-3.73(3H, m), 4.01(11H, d, J=21 Hz),
4.23(1H,m), 6.40(1H,m), 6.83(2H, d, J=8 Hz), 7.40(1H, d, J=2 Hz),
7.55(2H, d, J=8 Hz), 7.60(1H, d, J=2 Hz), 8.93(1H, s)
EXAMPLE 268
[1594]
(2R)-N-Hydroxy-1-[5-(4-hydroxyphenyl)thiophene-2-sulfonyl]-4-{2-[(p-
yridine-3-carbonyl)amino]ethanesulfonyl}-2-piperazinecarboxamide
(32 mg) was obtained in substantially the same manner as in Example
178.
[1595] Mass (ESI-): 594 (M-H)
[1596] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.82(1H, dt,
J=2, 11 Hz), 3.05(1H, dd, J=2, 11 Hz), 3.27(2H, t, J=4 Hz),
3.53-3.80(5H, m), 3.86(1H, d, J=11 Hz), 4.45(1H, s), 6.84(2H, d,
J=8 Hz), 7.39(1H, d, J=2 Hz), 7.51(1H, dd, J=2, 6 Hz), 7.56(2H, d,
J=8 Hz), 7.61(1H, d, J=2 Hz), 8.14(1H, d, J=6 Hz), 8.71(1H, d, J=2
Hz), 8.88(1H, t, J=4 Hz), 8.97(1H, s), 8.99(1H, s), 9.92(1H, s),
10.79(1H, s)
EXAMPLE 269
[1597]
(2R)-4-[2-(Benzoylamino)ethanesulfonyl]-N-hydroxy-1-[5-(4-hydroxyph-
enyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (22 mg) was
obtained in substantially the same manner as in Example 178.
[1598] Mass (ESI-): 593 (M-H)
[1599] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.81(1H, dt,
J=2, 11 Hz), 3.05(1H, dd, J=2, 11 Hz), 3.25(2H, t, J=4 Hz),
3.52-3.80(5H, m), 3.86(1H, d, J=11 Hz), 4.45(1H, s), 6.83(2H, d,
J=8 Hz), 7.38(1H, d, J=2 Hz), 7,42-7.58(51H, m)), 7.61 (1H, d, J=2
Hz), 7.80(2H, d, J=8 Hz), 8.65(1H, t, J=4 Hz), 8.99(1H, s),
9.92(1H, s), 10.79(1H, s)
EXAMPLE 270
[1600]
(2R)-1-[5-(3-Fluoro-4-hydroxyphenyl)thiophene-2-sulfonyl]-N-hydroxy-
-4methanesulfonyl-2-piperazinecarboxamide (121 mg) was obtained in
substantially the same manner as in Example 5.
[1601] Mass (ESI): 478 (M-1)
[1602] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.67-2.81 (1H,
m), 2.87(3H, s), 2.98(1H, dd, J=6, 14 Hz), 3.52(1H, d, J=14 Hz),
3.68-3.85(3H, m), 4.43-4.50(1H, m), 7.03(1H, t, J=9 Hz), 7.39(1H,
d, J=8 Hz), 7.50(1H, d, J=3 Hz), 7.59-7.68(2H, m), 9.00(1H, brs),
10.28-10.85(1H, m)
EXAMPLE 271
[1603]
(2R)-N-Hydroxy-4-methanesulfonyl-1-[5-(4-methoxycarbonylmethoxy-phe-
nyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (69 mg) was
obtained in substantially the same manner as in Example 5.
[1604] Mass (ESI): 532 (M-1)
[1605] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 2.64-2.80(1H,
m), 2.86(3H, s), 3.98(1H, dd, J=6, 14 Hz), 3.52(1H, d, J=14 Hz),
3.65-3.85(6H, m), 4.42-4.50(1H, m), 4.89(2H, s), 7.03(2H, d, J=8
Hz), 7.49(1H, d, J=3 Hz), 7.63(1H, d, J=3 Hz), 7.70(2H, d, J=8 Hz),
9.00(1H, brs)
[1606] Preparation 161
[1607] 2-(4-Isopropoxyphenyl)thiophene (1.88 g) was obtained in
substantially the same manner as in Preparation 43.
[1608] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.36(6H, d, J=7
Hz), 4.54(1H, m), 6.88(2H, d, J=8 Hz), 7.00-7.03(1H, m),
7.18-7.21(2H, m), 7.49(2H, d, J=8 Hz)
[1609] Preparation 162
[1610] Sodium 5-(4-isopropoxyphenyl)-2-thiophenesulfonate (1.28 g)
was obtained in substantially the same manner as in Preparation
56.
[1611] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.32(6H, d,
J=7 Hz), 4.45(1H, m), 7.06(1H, d, J=4 Hz), 7.13(1H, d, J=4 Hz),
7.42(2H, d, J=8 Hz), 7.55(2H, d, J=8 Hz)
[1612] Preparation 163
[1613] 5-(4-Isopropoxyphenyl)-2-thiophenesulfonyl chloride (1.35 g)
was obtained in substantially the same manner as in Preparation
44.
[1614] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.35(6H, d, J=6
Hz), 4.61(1H, m), 6.92(2H, d, J=8 Hz), 7.19(1H, d, J=4 Hz),
7.54(2H, d, J=8 Hz), 7.78(1H, d, J=4 Hz)
EXAMPLE 272
[1615]
(2R)-1-[5-(4-Isopropoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfon-
yl-N-(2-tetrahydropyranyloxy) -2-piperazinecarboxamide (246 mg) was
obtained in substantially the same manner as in Example 4.
[1616] Mass (ESI-): 586 (M-H)
[1617] .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta.): 1.37(6H, d, J=7
Hz), 1.55-1.91(6H, m), 2.74-2.90(2H, m), 2.88(1.5H, s), 2.93(1.5H,
s), 3.35-3.49(1H, m), 3.58-3.72(2H, m), 3.85-4.03(2H, m), 4.24(1H,
d, J=13 Hz), 4.55-4.64(2H, m), 4.92-5.01(1H, m), 6.90(2H, d, J=8
Hz), 7.14(1H, d, J=4 Hz), 7.48(2H, d, J=8 Hz), 7.57(1H, d, J=4 Hz),
9.15-9.27(1H, m)
EXAMPLE 273
[1618]
(2R)-1-[5-(4-Isopropoxyphenyl)thiophene-2-sulfonyl]-4-methanesulfon-
yl-N-hydroxy-2-piperazinecarboxamide (195 mg) was obtained in
substantially the same manner as in Example 5.
[1619] Mass (ESI-1): 502 (M-H)
[1620] .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta.): 1.34(6H, d,
J=7 Hz), 2.60-2.74(1H, m), 2.81(3H, s), 3.35-3.49(2H, m), 3.60(1H,
d, J=13 Hz), 3.77-3.95(2H, m), 4.22(1H, d, J=13 Hz), 4.54-4.62(1H,
m), 4.70(1H, bs), 6.90(21H, d, J=8 Hz), 7.14(1H, d, J=4 Hz),
7.48(2H, d, J=8 Hz), 7.68(1H, d, J=48 Hz)
[1621] This application is based on application Nos. PO 4249, PO
7156 and PO 8568 filed in Australia, the contents of which are
incorporated hereinto by reference.
* * * * *