U.S. patent application number 10/050789 was filed with the patent office on 2002-12-19 for anthranilic acid derivatives as inhibitors of the cgmp-phosphodiesterase.
This patent application is currently assigned to Fujisawa Pharmaceutical Co. Ltd.. Invention is credited to Inoue, Takayuki, Kayakiri, Natsuko, Kuroda, Akio, Mizutani, Tsuyoshi, Oku, Chikako, Oku, Noriko, Oku, Teruo, Oku, Tomohito, Sawada, Kozo, Sawada, Yuki.
Application Number | 20020193614 10/050789 |
Document ID | / |
Family ID | 27158074 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020193614 |
Kind Code |
A1 |
Oku, Teruo ; et al. |
December 19, 2002 |
Anthranilic acid derivatives as inhibitors of the
CGMP-phosphodiesterase
Abstract
Novel anthranilic acid derivatives having an inhibiting activity
of cGMP-PDE are represented by the formula I where A is a lower
alkylene group: 1 The anthranilic acid derivatives show
pharmacological activity and may be used in pharmaceutical
compositions as medications. The anthranilic acid derivatives can
be formed by the reaction of a fluoro precursor with an amine.
Pharmaceutical compositions containing the anthranilic acid
derivatives can be used to treat or prevent human health
disorders.
Inventors: |
Oku, Teruo; (Tokyo, JP)
; Oku, Noriko; (Tokyo, JP) ; Oku, Chikako;
(Tokyo, JP) ; Oku, Tomohito; (Tokyo, JP) ;
Sawada, Kozo; (Tsukuba-shi, JP) ; Kuroda, Akio;
(Tsukuba-shi, JP) ; Inoue, Takayuki; (Tsukuba-shi,
JP) ; Kayakiri, Natsuko; (Osaka, JP) ; Sawada,
Yuki; (Ushiku-shi, JP) ; Mizutani, Tsuyoshi;
(Tsukuba-shi, 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-shi
JP
541-8514
|
Family ID: |
27158074 |
Appl. No.: |
10/050789 |
Filed: |
January 18, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10050789 |
Jan 18, 2002 |
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09509541 |
Apr 23, 2001 |
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6384080 |
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Current U.S.
Class: |
549/480 ; 560/24;
560/312; 564/148 |
Current CPC
Class: |
C07C 2601/14 20170501;
A61P 9/10 20180101; A61P 27/06 20180101; A61P 15/10 20180101; A61P
17/00 20180101; A61P 9/00 20180101; C07D 307/22 20130101; C07C
2601/08 20170501; A61P 15/00 20180101; C07D 207/14 20130101; A61P
9/04 20180101; C07D 333/20 20130101; A61P 13/12 20180101; A61P
11/02 20180101; A61P 11/00 20180101; A61P 37/08 20180101; C07D
231/12 20130101; C07D 235/14 20130101; C07D 249/08 20130101; C07C
227/30 20130101; C07C 227/32 20130101; C07D 317/58 20130101; A61P
11/06 20180101; A61P 9/12 20180101; C07D 233/56 20130101; C07D
213/40 20130101; C07D 207/48 20130101; A61P 43/00 20180101; A61P
1/00 20180101; C07D 211/58 20130101 |
Class at
Publication: |
549/480 ; 560/24;
560/312; 564/148 |
International
Class: |
C07D 307/02; C07C
271/26 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 20, 1998 |
AU |
PP3085 |
Sep 11, 1998 |
AU |
PP5851 |
Dec 18, 1998 |
AU |
PP7781 |
Apr 15, 1999 |
WO |
PCT/JP99/02028 |
Claims
1. A compound of the formula (I): 10wherein R.sup.1 is hydrogen
atom or a halogen atom; R.sup.2 is an electron withdrawing group;
R.sup.3 is hydrogen atom; hydroxy group; a lower alkoxy group; a
cycloalkyl group; a substituted or unsubstituted aryl group; or an
unsaturated heterocyclic group optionally substituted with lower
alkyl; A is a lower alkylene group; R.sup.4 is a lower alkoxy
group, a substituted or unsubstituted, saturated or unsaturated
heterocyclic group, an amino group optionally substituted with
halo(lower)alkyl or lower alkyl, a group --CH.sub.2--R.sup.5
wherein R.sup.5 is a cycloalkyl group or an unsaturated
heterocyclic group, or a group --CR.sup.6R.sup.7R.sup.8 wherein
R.sup.6 and R.sup.7 are each independently carboxy group, a
protected carboxy group, a carbamoyl group optionally substituted
with lower alkyl, or a lower alkyl group optionally substituted
with one or more substituents selected from the group consisting of
halogen atom; hydroxy group; cyano group; azido group; lower alkoxy
group; lower alkylthio group; protected carboxy group; lower
alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group;
aryl group; aryloxy group which may be substituted with cyano;
unsaturated heterocyclic group which may be substituted with lower
alkyl; guanidino group which may be substituted with lower alkyl,
cyano and/or halogen; isothioureido group which may be substituted
with lower alkyl and/or cyano; and amino group which may be
substituted with acyl, protected carboxy, lower alkanesulfonyl,
lower alkanesulfonyloxy or aryloxycarbonyl, or R.sup.6 and R.sup.7
together with the carbon atom to which R.sup.6 and R.sup.7 are
attached may form a substituted or unsubstituted, saturated
carbocyclic group, or an unsaturated carbocyclic group optionally
substituted with hydroxy, and R.sup.8 is hydrogen atom; a lower
alkoxy group; or a lower alkyl group optionally substituted with
hydroxy or a lower alkoxy; provided that when R.sup.4 is the group
--CR.sup.6R.sup.7R.sup.8 wherein R.sup.6 is a lower alkyl group
optionally substituted with halogen, R.sup.7 is a lower alkyl group
optionally substituted with halogen, and R.sup.8 is hydrogen atom
or a lower alkyl group, or when R.sup.4 is the group
--CH.sub.2--R.sup.5 wherein R.sup.5 is the same as the above,
R.sup.3 should be hydrogen atom, hydroxy group or a cycloalkyl
group; and a pro-drug thereof, and a salt thereof.
2. A compound of claim 1, wherein the electron withdrawing group
for R.sup.2 is selected from a group consisting of nitro group;
cyano group; acyl group; halo(lower)alkyl group; sulfamoyl group;
carbarnoyl group optionally substituted with lower alkyl; halogen
atom; lower alkenyl group optionally substituted with protected
carboxy; lower alkanesulfonyl group; saturated heterocyclic
sulfonyl group optionally substituted with protected carboxy; and
unsaturated heterocyclic group, the substituent(s) on the aryl
group for R.sup.3 is/are selected from a group consisting of lower
alkyl group; halo(lower)alkyl group; lower alkylthio group; halogen
atom; hydroxy group; lower alkylenedioxy group; cyano group; nitro
group; carboxy group; protected carboxy group; sulfarnoyl group;
acyl group; aryl group; ar(lower)alkoxy group; aryloxy group; lower
alkoxy group which may be substituted with lower alkoxy or
cycloalkyl; amino group which may be substituted with acyl,
protected carboxy or lower alkyl and carbamoyl group which may be
substituted with lower alkyl, the substituent(s) on the saturated
or unsaturated heterocyclic group for R.sup.4 is/are selected from
a group consisting of oxo group; acyl group; protected carboxy
group; lower alkanesulfonyl group; sulfamoyl group which may be
substituted with protected carboxy; ar(lower)alkyl group; lower
alkyl group which may be substituted with hydroxy or aryl; ureido
group which may be substituted with lower alkyl; guanidino group
which may be substituted with protected carboxy; arnidino group
which may be substituted with protected carboxyl; and carbamoyl
group which may be substituted with lower alkyl, and the
substituent(s) on the saturated carbocyclic group formed by
combination of R.sup.6 and R.sup.7 is/are selected from a group
consisting of lower alkyl group; halogen atom; hydroxy group; lower
alkoxy group; acyloxy group; carboxy group; protected carboxy
group; oxo group; amidino group which may be substituted with
protected carboxy; ureido group which may be substituted with lower
alkyl or aryl; guanidino group which may be substituted with
protected carboxy; amino group which may be substituted with acyl,
lower alkanesulfonyl or protected carboxy; and carbamoyl group
which may be substituted with lower alkyl or hydroxy(lower)
alkyl.
3. A compound of claim 1, wherein R.sup.3 is a substituted or
unsubstituted aryl group; R.sup.4 is a group
--CR.sup.6R.sup.7R.sup.8 wherein R.sup.6 and R.sup.7 together with
the carbon atom to which R.sup.6 and R.sup.7 are attached may form
a substituted or unsubstituted, saturated carbocyclic group, and
R.sup.8 is hydrogen atom.
4. A compound of claim 3, wherein R.sup.2 is nitro group, cyano
group or a halo(lower)alkyl group; R.sup.3 is an aryl group
optionally substituted with one or more substituent(s) selected
from halogen and lower alkoxy; R.sup.4 is a group
--CR.sup.6R.sup.7R.sup.8 wherein R.sup.6 and R.sup.7 together with
the carbon atom to which R.sup.6 and R.sup.7 are attached may form
a saturated carbocyclic group optionally substituted with hydroxy
or amino which may be substituted with acyl; and R.sup.8 is
hydrogen atom.
5. A compound of claim 4 which is
N-(2-chlorobenzyl)-2-cyclopentylamino-5-- nitrobenzamide,
N-(3-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,
N-(4-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,
2-(cyclopentylamino)-N-(2,4-dichlorobenzyl)-5-nitrobenzamide,
2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-5-nitrobenzamide,
2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)
benzamide,
2-(cyclopentylamino)-N-(4-fluorobenzyl)-5-nitrobenzamide,
2-(cyclopentylamino)-N-(4-methoxybenzyl)-5-nitrobenzamide,
N-(2-chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,
N-(4-bromobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,
2-(cvclopentylamino)-5-nitro-N-phenethylbenzamide,
2-(cyclopentylamino)-5-nitro-N-(3-ph enylpropyl)benzamide,
N-benzyl-2-(cyclobutylamino)-5-nitrobenzamide,
N-benzyl-2-cycloheptylamin- o-5-nitrobenzamide,
N-benzyl-2-(cyclohexylamino)-5-nitrobenzamide,
N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-
benzamide, 2-(cyclopentylamino)-N-(2,4-difluoro
benzyl)-5-nitrobenzamide,
N-benzyl-2-(cyclopropylamino)-5-nitrobenzamide,
N-benzyl-2-(2-hydroxy cyclohexylamino)-nitrobenzamide,
N-benzyl-2-(trans-2-hydroxycyclopentylam- ino)-5-nitrobenzamide,
2-(cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5--
ylmethyl)benzamide,
2-(trans-2-hydroxycyclopentylarino)-5-nitro-N-(1,3-ben-
zodioxol-5-ylmethyl)benzamide,
2-[cis-4-(benzoyloxy)cyclohexylamino]-N-(3,-
4-dimethoxybenzyl)-5-nitrobenzamide,
2-(cis-4-benzoyloxycyclohexylamino)-5-
-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,
N-(3,4-dimethoxybenzyl)-2--
(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,
2-(cis-4-hydroxycyclohe-
xylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,
N-benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide,
2-[3-(benzoyloxy)cyclopentylamino]-N-benzyl-5-nitrobenzamide,
N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide-
,
2-(trans-2-aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)b-
enzamide,
N-(3-chloro-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5--
nitrobenzamide,
2-[cis4-(benzoyloxy)cyclohexylamino]-N-(3-chloro-4-methoxy-
benzyl)-5-nitrobenzamide,
N-(3-chloro-4-methoxybenzyl)-2-(trans-4-hydroxyc-
yclohexylamino)-5-nitrobenzamide,
N-(3,4-dimethoxybenzyl)-2-(trans-2-hydro-
xycyclopentylamino)-5-nitrobenzamide, 5
N-(3,5-dichloro-4-methoxybenzyl)-2-
-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,
N-(3,4-ethylenedioxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitroben-
zamide,
2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(3,4,5-trimethoxybenzyl-
)benzamide, 2-[cis-4-(acetoxy)
cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-- nitrobenzamide,
2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-
-5-nitrobenzamide,
2-(cis-4-hydroxycyclohexylamino)-N-(1-naphthylmethyl)-5-
-nitrobenzamide,
2-(trans-4-acetamidocyclohexylamino)-N-(3,4-dimethoxybenz-
yl)-5-nitrobenzamide,
N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohe- xyl)
amino]-5-nitrobenzamide,
N-(2-chloro-5-methoxybenzyl)-2-(cis-4-hydrox-
ycyclohexylamino)-5-nitrobenzamide,
2-(cis-4-benzoyloxycyclohexylamino)-N--
(3-filuoro-4-methoxybenzyl)-5-nitrobenzamide,
N-(3-ethoxy-4-methoxybenzyl)-
-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,
N-(4-chloro-4-ethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitro-benz-
amide,
N-(4-ethoxy-3-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nit-
robenzamide,
2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-
-5-nitrobenzamide,
N-(4-ethoxy-3-methoxybenzyl)-2-(trans4-fonnamidocvclohe-
xylamino)-5-nitrobenzamide,
5-cyano-2-(trans-4-hydroxycyclohexylamino)-N-(-
1,3-benzodioxol-5-ylmethyl)benzamide,
2-(cis-4-formamidocyclohexylamino)-N-
-(3,4-dimethoxybenzyl)-5-nitrobenzamide,
2-(cis-4-hydroxycyclohexylamino)--
5-nitro-N-[(1S)-1-phenylethyl]benzamide,
5-bromo-N-(3-chloro-4-methoxybenz-
yl)-2-(cyclopentylamino)benzamide,
5-chloro-2-(cyclopentylamino)-N-(1,3-be-
nzodioxo-5-ylmethyl)benzamide,
4-chloro-N-(3,4-dimethoxybenzyl)-5-fluoro-2-
-(trans-4-hydroxycyclohexylarninc)benzamide, or
2-(cis-4-aminocyclohexylam-
ino)-N-(3,4-dirnethoxybenzyl)-5-nitrobenzamide, or a salt
thereof.
6. A compound of claim 1, wherein R.sup.3 is a substituted or
unsubstituted aryl group; R.sup.4 is a group
--CR.sup.6R.sup.7R.sup.8 wherein R.sup.6 is a lower alkyl group
substituted with hydroxy, R.sup.7 is a lower alkyl which may be
substituted with hydroxy, and R.sup.8 is hydrogen atom or a lower
alkyl group which may be substituted with hydroxy.
7. A compound of claim 6, wherein R.sup.2 is nitro group, cyano
group or a halo(lower)alkyl group; and R.sup.3 is an aryl group
optionally substituted with one or more substituent(s) selected
from halogen and lower alkoxy.
8. A compound of claim 7 which is
N-benzyl-2-[2-hydroxy-1-(hydroxymethyl)e-
thylamino]-5-nitrobenzamide,
(R)-2(1-ethyl-2-hydroxyethylamino)-5-nitro-N--
(1,3-benzodioxol-5-ylmethyl)benzamide,
(S)-2-[1-(hydroxymethyl)propylamino-
]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,
(R)-2-(2-hydroxy-1-meth-
ylethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl) benzamide,
2-[2-hydroxy-1,1-bis(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-
-5-ylmethyl)benzamide,
2-(2-hydroxy-1,1-dimethylethylamino)-5-nitro-N-(1,
3-benzodioxol-5-ylmethyl)benzamide,
2-[2-hydroxy-1-(hydroxymethyl)ethylam-
ino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,
2-[2-hydroxy-1-(hydroxymethyl)-1-methylethylamino]-5-nitro-N-(1,3-benzodi-
oxol-5-ylmethyl)benzamide,
(S)-2-[1-(hydroxymethyl)-2-methylpropylamino]-5-
-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide, 2-[(1R,
2R)-2-hydroxy-1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5--
ylmethyl)benzamide,
N-(3-chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-m-
ethyl)ethylamino]-5-nitrobenzamide,
2-[1-(hydroxyethyl)pentylamino]-5-nitr-
o-N-(1,3-benzodioxol-5-ylmethyl)benzamide,
(R)-N-(3,4-dimethoxybenzyl)-2-(-
2-hydroxy-1-methylethylamino)-5-nitrobenzamide,
(S)-N-(3,4-dimethoxybenzyl-
)-2-[1-(hydroxymethyl)propylamino]-5-nitrobenzamide,
N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1,1-dimethylethylamino)-5-nitrobenza-
mide,
N-(3-fluoro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamin-
o]-5-nitrobenzamide,
N-(4-chloro-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxym- ethyl)
ethylamino]-5-nitrobenzamide,
2-[2-hydroxy-1-(hydroxymethyl)ethylam-
ino]-N-(2-naphthylmethyl)-5-nitrobenzamide,
2-[2-hydroxy-1-(hydroxymethyl)-
ethylamino]-N-[2-(2-methoxyphenyl)ethyl]-5-nitrobenzamide,
N-(3-chloro-4-fluorobenzyl)-2-[2-hydroxy-1-(hydroxymethyl)
ethylamino]-5-nitrobenzamide,
(S)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1--
methylethylamino)-5-nitrobenzamide,
(S)-N-(3,5-dimethoxybenzyl)-2-(2-hydro- xy-1-methylethyl)
amino-5-nitrobenzamide, N-(3-chioro-4-methoxybenzyl)-2-[-
2-hydroxy-1-(hydroxymethyl)ethylamino]-5-(trifluoromethyl)benzamide,
(R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethy-
l)benzamide,
(S)-S-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethy-
lamino)benzamide,
(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methy-
lethylamino)benzamide, or
(R)-N-(4-chloro-3-methoxybenzyl)-5-cyano-2-(hydr-
oxy-1-methylethylamino)benzamide, or a salt thereof.
9. A compound of claim 1 for use as a medicament.
10. A process for preparing a compound of the formula: 11wherein
R.sup.1 is hydrogen atom or a halogen atom; R.sup.2 is an electron
withdrawing group; R.sup.3 is hydrogen atom; hydroxy group; a lower
alkoxy group; a cycloalkyl group; a substituted or unsubstituted
aryl group; or an unsaturated heterocyclic group optionally
substituted with lower alkyl; A is a lower alkylene group; R.sup.4
is a lower alkoxy group, a substituted or unsubstituted, saturated
or unsaturated heterocyclic group, an amino group optionally
substituted with halo(lower)alkyl or lower alky, a group
--CH.sub.2--R.sup.5 wherein R.sup.5 is a cycloalkyl group or an
unsaturated heterocyclic group, or a group --CR.sup.6R.sup.7R.sup.8
wherein R.sup.6 and R.sup.7 are each independently carboxy group, a
protected carboxy group, a carbamoyl group optionally substituted
with lower alkyl, or a lower alkyl group optionally substituted
with one or more substituents selected from the group consisting of
halogen atom; hydroxy group; cyano group; azido group; lower alkoxy
group; lower alkylthio group; protected carboxy group; lower
alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group;
aryl group; aryloxy group which may be substituted with cyano;
unsaturated heterocyclic group which may be substituted with lower
alkyl; guanidino group which may be substituted with lower alky,
cyano and/or halogen; isothioureido group which may be substituted
with lower alkyl and/or cyano; and amino group which may be
substituted with acyl, protected carboxy, lower alkanesulfonyl,
lower alkanesulfonyloxy or an aryloxycarbonyl, or R.sup.6 and
R.sup.7 together with the carbon atom to which R.sup.6 and R.sup.7
are attached may form a substituted or unsubstituted, saturated
carbocyclic group, or an unsaturated carbocyclic group optionally
substituted with hydroxy, and R.sup.8 is hydrogen atom; a lower
alkoxy group; or a lower alkyl group optionally substituted with
hydroxy or lower alkoxy; provided that when R.sup.4 is the group
--CR.sup.6R.sup.7R.sup.8wherein R.sup.6 is a lower alkyl group
optionally substituted with halogen, R.sup.7 is a lower alkyl group
optionally substituted with halogen, and R.sup.8 is hydrogen atom
or a lower alkyl group, or when R.sup.4 is the group
--CH.sub.2-R.sup.5 wherein R.sup.5 is the same as the above,
R.sup.3 should be hydrogen atom, hydroxy group or a cycloalkyl
group; and a salt thereof, which comprises (1) reacting a compound
of the formula (II): 12or its salt, with a compound of (III)
H.sub.2N--R.sup.4 (III) or its salt, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and A are as defined above, or (2) reacting a
compound of the formula (IV): 13or its salt, with a compound of the
formula (V): H.sub.2N--A--R.sup.3 (V) or its salt, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and A are as defined above, or (3)
subjecting a compound of the formula (VI): 14or its salt, to
reductive alkylation with a compound of formula (VII): 15or its
salt, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7 and A are
as defined above.
11. A pharmaceutical composition which comprises, as an active
ingredient, a compound of claim 1 or a pharmaceutically acceptable
salt thereof in admixture with a pharmaceutically acceptable
carrier.
12. A pharmaceutical composition comprising a compound of claim 1,
as an active ingredient, in association with a pharmaceutically
acceptable, substantially non-toxic carrier or excipient.
13. A composition of claim 11 for the use of the treatment and/or
prevention of angina, hypertension, pulmonary hypertension,
congestive heart failure, glomerular diseases, renal
tubulo-intestitinal diseases, renal failure, atherosclerosis,
conditions of reduced blood vessel patency, peripheral vascular
disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria,
glaucoma, diseases characterized by disorders of gut motility,
electile dysfunction, female sexual dysfunction, impotence,
diabetic complications, micturition disorder, or incontinence or
storage of urine disorder.
14. A composition of claim 11 for the use of the treatment of
electile dysfunction or impotence.
15. A use of the compound of claim 1 for the manufacture of a
medicament for inhibiting cGMP-PDE.
16. A use of the compound of claim 1 for the manufacture of a
medicament for treatment and/or prevention of angina, hypertension,
pulmonary hypertension, congestive heart failure, glomerular
diseases, renal tubulo-intestitinal diseases, renal failure,
atherosclerosis, conditions of reduced blood vessel patency,
peripheral vascular disease, stroke, bronchitis, asthma, allergic
rhinitis, urticaria, glaucoma, diseases characterized by disorders
of gut motility, electile dysfunction, female sexual dysfunction,
impotence, diabetic complications, micturition disorder, or
incontinence or storage of urine disorder.
17. A method for the treatment and/or prevention of angina,
hypertension, pulmonary hypertension, congestive heart failure,
glomerular diseases, renal tubulo-intestitinal diseases, renal
failure, atherosclerosis, conditions of reduced blood vessel
patency, peripheral vascular disease, stroke, bronchitis, asthma,
allergic rhinitis, urticaria, glaucoma, diseases characterized by
disorders of gut motility, electile dysfunction, female sexual
dysfunction, impotence, diabetic complications, micturition
disorder, or incontinence or storage of urine disorder, by
administering the compound of claim 1.
Description
TECHNICAL FIELD
[0001] This invention relates to novel anthranilic acid derivatives
having pharmacological activity, to a process for their production,
to a pharmaceutical composition containing the same, and to their
use as a medicament.
BACKGROUND ART
[0002] It is known that a cyclic guanosine-3',5'-monophosphate
(hereinafter referred to as cGMP) derived from a
guanosine-5'-triphosphat- e possesses a relaxant activity of smooth
muscle and that a cyclic guanosine-3',5'-monophosphate
phosphodiesterase (hereinafter refereed to as cGMP-PDE) acts to
catalyze the degradation of cGMP to a guanosine-5'-monophosphate.
The compounds having an inhibitory activity of cGMP-PDE are
disclosed in European Patent Publication Nos. 579,496; 534,443;
526,004; 636,626; U.S. Pat. Nos. 3,819,631; 5,294,612; 5,488,055;
International Patent Publication Nos. 93/07,124; 94/19,351;
95/18,097; 96/32,379; Japan Patent Publication Nos. 05-222,000;
07-330,777; and so on.
DISCLOSURE OF INVENTION
[0003] This invention relates to novel anthranilic acid
derivatives, which have pharmaceutical activity such as inhibiting
activity of cGMP-PDE, to a process for their production, to a
pharmaceutical composition containing the same and to a use
thereof.
[0004] Accordingly, one object of this invention is to provide the
novel anthranilic acid derivatives, which have an inhibiting
activity of cGMP-PDE.
[0005] Another object of this invention is to provide a process for
production of the anthranilic acid derivatives.
[0006] A further object of this invention is to provide a
pharmaceutical composition containing, as an active ingredient, an
anthranilic acid derivative.
[0007] Still further object of this invention is to provide a use
of the anthranilic acid derivatives for treating or preventing
various diseases.
[0008] The new anthranilic acid derivatives of this invention can
be represented by the following formula (I) 2
[0009] wherein
[0010] R.sup.1 is hydrogen atom or a halogen atom;
[0011] R.sup.2 is an electron withdrawing group;
[0012] R.sup.3 is hydrogen atom; hydroxy group; a lower alkoxy
group; a cycloalkyl group; a substituted or unsubstituted aryl
group; or an unsaturated heterocyclic group optionally substituted
with lower alky;
[0013] A is a lower alkylene group;
[0014] R.sup.4 is a lower alkoxy group,
[0015] a substituted or unsubstituted, saturated or unsaturated
heterocyclic group,
[0016] an amino group optionally substituted with halo(lower)alkyl
or lower alky,
[0017] a group --CH.sub.2--R.sup.5
[0018] wherein R.sup.5 is a cycloalkyl group or an unsaturated
heterocyclic group, or
[0019] a group --CR.sup.6R.sup.7R.sup.8 wherein
[0020] R.sup.6 and R.sup.7 are each independently carboxy
group,
[0021] a protected carboxy group,
[0022] a carbamoyl group optionally substituted with lower alkyl,
or
[0023] a lower alkyl group optionally substituted with one or more
substituents selected from the group consisting of halogen atom;
hydroxy group; cyano group; azido group; lower alkoxy group; lower
alkylthio group;
[0024] protected carboxy group; lower alkanesulfonyl group; acyloxy
group; lower alkanesulfonyloxy group; aryl group; aryloxy group
which may be substituted with cyano; unsaturated heterocyclic group
which may be substituted with lower alkyl; guanidino group which
may be substituted with lower alkyl, cyano and/or halogen;
isothioureido group which may be substituted with lower alkyl
and/or cyano; and amino group which may be substituted with acyl,
protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or
aryloxycarbonyl, or
[0025] R.sup.6 and R.sup.7 together with the carbon atom to which
R.sup.6 and R.sup.7 are attached may form a substituted or
unsubstituted, saturated carbocyclic group, or an unsaturated
carbocyclic group optionally substituted with hydroxy, and
[0026] R.sup.8 is hydrogen atom; a lower alkoxy group; or a lower
alkyl group optionally substituted with hydroxy or lower
alkoxy;
[0027] provided that
[0028] when R.sup.4 is the group --CR.sup.6R.sup.7R.sup.8
wherein
[0029] R.sup.6 is a lower alkyl group optionally substituted with
halogen,
[0030] R.sup.7 is a lower alkyl group optionally substituted with
halogen,
[0031] and R.sup.8 is hydrogen atom or a lower alkyl group, or
[0032] when R.sup.4 is the group --CH.sub.2--R.sup.5 wherein
R.sup.5 is the same as the above, R.sup.3 should be hydrogen atom,
hydroxy group or a cycloalkyl group; and a pro-drug thereof, and a
salt thereof.
[0033] The compounds of the formula (I) may contain one or more
asymmetric centers and thus they can exist as enantiomers or
diastereoisomers.
[0034] The compounds of the formula (I) may also exist in
tautomeric forms and the invention includes both mixtures and
separate individual tautomers.
[0035] It is further to be noted that isomerization or
rearrangement of the compounds (I) may occur by the effect of
light, acid, base or the like, and the compounds obtained as the
result of said isomerization or rearrangement are also included
within the scope of the present invention.
[0036] The compounds of the formula (I) and its salts can be in the
form of a solvate, which is included within the scope of the
present invention.
[0037] The solvate preferably include a hydrate and an
ethanolate.
[0038] Also included in the scope of invention are radiolabelled
derivatives of compounds of formula (I) which are suitable for
biological studies.
[0039] According to this invention, the object compounds (I) or its
salts can be prepared by the following process.
[0040] Process 1 3
[0041] Process 2 4
[0042] Process 3 5
[0043] In the above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.7 and A are the same as those defined in the
above.
[0044] Some of the starting materials are novel and can be prepared
by the following processes.
[0045] Process A 6
[0046] Process B 7
[0047] Process C 8
[0048] Process D 9
[0049] In the above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.7and A are the same as those defined in the above, R
is hydrogen atom or a lower alkyl group.
[0050] In the above and subsequent descriptions of the present
specification, suitable examples and illustrations of the various
definitions which the present invention includes within the scope
are explained in detail in the following.
[0051] The term "lower" is intended to mean a group having 1 to 6
carbon atom(s), unless otherwise indicated.
[0052] Suitably the lower alkyl groups and lower alkyl moieties in
the terms of the halo(lower)alkyl, lower alkanesulfonyl, lower
alkanesulfonyloxy, lower alkoxy, lower alkylthio,
hydroxy(lower)alkyl, ar(lower) alkyl, ar(lower)alkoxy and
ar(lower)alkoxycarbonyl groups may include straight or branched
ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, hexyl or the like, more suitably the ones having 1 to 4
carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl or
isobutyl.
[0053] Suitably the examples of the lower alkenyl groups include
straight or branched ones having 2 to 6 carbon atoms, such as
ethenyl, propenyl (i.e., alkyl or 1-propenyl), butenyl, isobutenyl,
pentenyl, hexenyl or the like.
[0054] Suitable lower alkylene groups and lower alkylene moieties
in the lower alkylenedioxy group may include straight or branched
ones having 1 to 6 carbon atoms, such as methylene,
methylmethylene, ethylene, methylethylene, trimethylene,
tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene
or the like, more suitably the ones having 1 to 3 carbon atoms.
[0055] Suitable examples of the acyl groups and acyl moieties in
the term of the acyloxy group include aliphatic acyl groups such as
lower alkanoyls (e.g., formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl) and
acyl groups containing an aromatic or heterocyclic ring such as
aroyls (e.g., benzoyl, toluoyl, xyloyl or naphthoyl),
ar(lower)alkanoyls (e.g., phenylacetyl or phenylpropionyl),
ar(lower)alkoxycarbonyls (e.g., benzyloxycarbonyl or
phenethyloxycarbonyl), heterocyclic carbonyls (e.g., thenoyl or
furoyl) and the like.
[0056] The cycloalkyl groups may include the ones having 3 to 7
carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl or the like.
[0057] Suitably the aryl groups and aryl moieties in the terms of
the ar(lower)alkyl, ar(lower)alkoxy, aryloxy, aryloxycarbonyl and
aroyloxy groups may be an aromatic group having 6 to 12 carbon
atoms. Specific examples thereof are phenyl, naphthyl, indenyl,
azulenyl, biphenylenyl, fluorenyl and anthracenyl.
[0058] Suitable examples of the saturated carbocyclic groups may be
the cycloalkyl groups as exemplified in the above.
[0059] Suitable examples of unsaturated carbocyclic groups may
include cyclopentenyl, cyclohexenyl, cycloheptenyl,
2,3-dihydro-1H-indenyl, benzocyclohexyl and the like.
[0060] Suitable examples of the halogen atoms and halo moiety of
the halo(lower)alkyl group may be fluorine, chlorine, bromine or
iodine.
[0061] Suitable examples of the unsaturated heterocyclic group may
include mono- or poly-cyclic groups containing at least one hetero
atom selected from nitrogen, sulfur and oxygen atoms, such as
[0062] (1) unsaturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl]
tetrazolyl [e.g., 1H-tetrazoly or 2H-tetrazolyll or the like.;
[0063] (2) unsaturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing an oxygen atom, for example,
pyranyl or furyl;
[0064] (3) unsaturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 2 sulfur atoms, for
example, thienyl or the like;
[0065] (4) unsaturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl]
or the like;
[0066] (5) unsaturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or
the like;
[0067] (6) unsaturated condensed heterocyclic groups containing 1
to 2 nitrogen atoms, for example, indolyl, indazolyl, quinolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, benzimidazolyl or the
like;
[0068] (7) unsaturated condensed heterocyclic groups containing 1
to 2 oxygen atoms, for example, benzofuryl or the like;
[0069] (8) unsaturated condensed heterocyclic groups containing 1
to 2 sulfur atoms, for example, benzo[b]thienyl or the like;
[0070] (9) unsaturated condensed heterocyclic groups containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,
benzoxazolyl, benzoxadiazolyl, phenoxazinyl or the like;
[0071] (10) unsaturated condensed heterocyclic groups containing 1
to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,
benzothiazolyl, benzoisothiazolyl, phenothiazinyl or the like.
[0072] Suitable examples of the saturated heterocyclic group and
heterocyclic moiety in the saturated heterocyclic sulfonyl group
include monocyclic groups containing at least one hetero atom
selected from nitrogen, sulfur and oxygen atoms, such as
[0073] (1) saturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.,
pyrrolidinyl, imidazolidinyl, piperidyl or piperazinyl];
[0074] (2) saturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g., morpholinyl];
[0075] (3) saturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms [e.g., thiazolidinyl or thiomorpholinyl];
[0076] (4) saturated 3 to 7-membered, preferably 5 or 6-membered
heteromonocyclic groups containing 1 to 2 sulfur atoms and/or 1 to
2 oxygen atoms [e.g., tetrahydrothiophenyl, tetrahydrothiopyranyl,
1-oxotetrahydrothiopyranyl, 1, 1-dioxotetrahydrothiopyranyl,
dioxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dioxanyl);
or the like.
[0077] Suitably carboxy protective groups in the protected carboxy
group may include lower alkyl groups (e.g., methyl, ethyl or
tert-butyl), halo(lower)alkyl groups (e.g., 2-iodomethyl or
2,2,2-trichloroethyl), ar(lower)alkyl groups (e.g., benzyl, trityl,
4-methoxybenzyl, 4-nitrobenzyl, 25 phenethyl,
bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl or
4-hydroxy-3,5-di-tert-butylbenzyl), aryl groups (e.g., phenyl,
naphthyl, tolyl or xylyl), and the like, more suitably the lower
alkyl groups such as methyl, ethyl or tert-butyl and ar(lower)alkyl
groups such as benzyl.
[0078] Specific examples of the each group containing the
above-mentioned moiety and having substituent(s) are as
follows.
[0079] As the halo(lower) alkyl group, fluoromethyl, iodomethyl,
chloromethyl, trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 2,2,2-trichloroethyl or the like may be
mentioned.
[0080] The lower alkanesulfonyl group is methanesulfonyl(mesyl),
ethanesulfonyl, propanesulfonyl or the like.
[0081] The lower alkanesulfonyloxy group is methan sulfonyloxy(me
syloxy), ethanesulfonyloxy, propanesulfonyloxy or the like.
[0082] The lower alkoxy group is methoxy, ethoxy, propoxy,
n-butoxy, tert-butoxy of the like.
[0083] The lower alkylthio group is methylthio, ethylthio,
propylthio, butylthio, isobutylthio or the like.
[0084] The acyloxy group is formyloxy, acetyloxy, propionyloxy,
benzoyloxy, toluoyloxy, naphthoyloxy, phenylacetyloxy, theonyloxys
or the like.
[0085] The hydroxy(lower)alkyl group is hydroxymethyl, hydroxyethyl
or the like.
[0086] The ar(lower)alkyl group is benzyl, 4-methoxybenzyl,
4-nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl,
3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl) or the
like.
[0087] The ar(lower)alkoxy group is benzyloxy, 4-methoxybenzyloxW,
4-nitrobenzyloxy, phenethyloxy, trityloxy,
bis(methoxyphenyl)methoxy, 3,4-dimethoxybenzyloxy,
4-hydroxy-3,5-di-tert-butylbenzyloxy or the like.
[0088] The lower alkylenedioxy group is methylenedioxy,
ethylenedioxy and the like.
[0089] The aryloxy group is phenoxy, naphthoxy, tolyloxy, xylyloxy
or the like.
[0090] The aroyloxy group is benzoyloxy, naphthoyloxy or the
like.
[0091] The saturated heterocyclic sulfonyl group is
piperazinesulfonyl, piperizinesulfonyl, morpholinesulfonyl,
pyrazolidinesulfonyl or the like.
[0092] Preferred embodiments of the compounds (I) are those
represented by the formula (I),
[0093] wherein
[0094] R.sup.1 is hydrogen atom or a halogen atom;
[0095] R.sup.2 is an electron withdrawing group;
[0096] R.sup.3 is hydrogen atom; hydroxy group; a lower alkoxy
group; a cycloalkyl group; a substituted or unsubstituted aryl
group; or an unsaturated heterocyclic group optionally substituted
with lower alkyl;
[0097] A is a lower alkylene group;
[0098] R.sup.4 is a lower alkoxy group,
[0099] a substituted or unsubstituted, saturated or unsaturated
heterocyclic group,
[0100] an amino group optionally substituted with halo(lower)alkyl
or lower alkyl,
[0101] a group --CH.sub.2--R.sup.5 wherein R.sup.5 is a cycloalkyl
group or an unsaturated heterocyclic group, or
[0102] a group --CR.sup.6R.sup.7R.sup.8 wherein
[0103] R.sup.6 and R.sup.7 are each independently
[0104] carboxy group,
[0105] a protected carboxy group,
[0106] a carbamoyl group optionally substituted with lower alkyl,
or
[0107] a lower alkyl group optionally substituted with one or more
substituents selected from the group consisting of halogen atom;
hydroxy group; cyano group; azido group; lower alkoxy group; lower
alkylthio group; protected carboxy group; lower alkanesulfonyl
group; acyloxy group; lower alkanesulfonyloxy group; aryl group;
aryloxy group which may be substituted with cyano; unsaturated
heterocyclic group which may be substituted with lower alkyl;
guanidino group which may be substituted with lower alkyl, cyano
and/or halogen; isothioureido group which may be substituted with
lower alkyl and/or cyano; and amino group which may be substituted
with acyl, protected carboxy, lower alkanesulfonyl, lower
alkanesulfonyloxy or aryloxycarbonyl, or
[0108] R.sup.6 and R.sup.7 together with the carbon atom to which
R.sup.6 and R.sup.7 are attached may form a substituted or
unsubstituted, saturated carbocyclic group, or
[0109] an unsaturated carbocyclic group optionally substituted with
hydroxy, and
[0110] R.sup.8 is hydrogen atom; a lower alkoxy group; or a lower
alkyl group optionally substituted with hydroxy or a lower
alkoxy;
[0111] provided that
[0112] when R.sup.4 is the group --CR.sup.6R.sup.7R.sup.8
wherein
[0113] R.sup.6 is a lower alkyl group optionally substituted with
halogen,
[0114] R.sup.7 is a lower alkyl group optionally substituted with
halogen,
[0115] and R.sup.8 is hydrogen atom or a lower alkyl group, or
[0116] when R.sup.4 is the group --CH.sub.2--R.sup.5 wherein
R.sup.5 is the same as the above, Rshould be hydrogen atom, hydroxy
group or a cycloalkyl group, the electron withdrawing group for
Rbeing selected from a group consisting of nitro group; cyano
group; acyl group; halo(lower)alkyl group; sulfamoyl group;
carbamoyl group optionally substituted with lower alkyl; halogen
atom; lower alkenyl group optionally substituted with protected
carboxy; lower alkanesulfonyl group; saturated heterocyclic
sulfonyl group optionally substituted with protected carboxy; and
unsaturated heterocyclic group,
[0117] the substituent(s) on the aryl group for R.sup.3 being
selected from a group consisting of lower alkyl group;
halo(lower)alkyl group; lower alkylthio group; halogen atom;
hydroxy group; lower alkylenedioxy group; cyano group; nitro group;
carboxy group; protected carboxy group; sulfamoyl group; acyl
group; aryl group; ar(lower)alkoxy group; aryloxy group; lower
alkoxy group which may be substituted with lower alkoxy or
cycloalkyl; amino group which may be substituted with acyl,
protected carboxy or lower alkyl; and carbamoyl group which may be
substituted with lower alkyl,
[0118] the substituent(s) on the saturated or unsaturated
heterocyclic group for R.sup.4 being selected from a group
consisting of oxo group; acyl group; protected carboxy group; lower
alkanesulfonyl group; sulfamoyl group which may be substituted with
protected carboxy; ar(lower)alkyl group; lower alkyl group which
may be substituted with hydroxy or aryl; ureido group which may be
substituted with lower alkyl; guanidino group which may be
substituted with protected carboxy; amidino group which may be
substituted with protected carboxyl; and carbamoyl group which may
be substituted with lower alkyl, and
[0119] the substituent(s) on the saturated carbocyclic group formed
by combination of R.sup.6 and R.sup.7 being selected from a group
consisting of lower alkyl group; halogen atom; hydroxy group; lower
alkoxy group; acyloxy group; carboxy group; protected carboxy
group; oxo group; amidino group which may be substituted with
protected carboxy; ureido group which may be substituted with lower
alkyl or aryl; guanidino group which may be substituted with
protected carboxy; amino group which may be substituted with acyl,
lower alkanesulfonyl or protected carboxy; and carbamoyl group
which may be substituted with lower alkyl or
hydroxy(lower)alkyl;
[0120] and a pro-drug thereof, and a salt thereof.
[0121] Another preferred embodiments are as follows:
[0122] compounds of the formula (I),
[0123] wherein
[0124] R.sup.1 is hydrogen atom or a halogen atom;
[0125] R.sup.2 is an electron withdrawing group;
[0126] R.sup.3 is a substituted or unsubstituted aryl group;
[0127] A is a lower alkylene group; and
[0128] R.sup.4 is a group --CR.sup.6R.sup.7R.sup.8 wherein
[0129] R.sup.6 and R.sup.7 together with the carbon atom to which
R.sup.6 and R.sup.7 are attached may form a substituted or
unsubstituted, saturated carbocyclic group, and
[0130] R.sup.8 is hydrogen atom; and
[0131] compounds of the formula (I), wherein
[0132] R.sup.1 is hydrogen atom or a halogen atom;
[0133] R.sup.2 is an electron withdrawing group;
[0134] R.sup.3 is a substituted or unsubstituted aryl group;
[0135] A is a lower alkylene group; and
[0136] R.sup.4 is a group --CR.sup.6R.sup.7R.sup.8 wherein
[0137] R.sup.6 is a lower alkyl group substituted with hydroxy,
[0138] R.sup.7 is a lower alkyl which may be substituted with
hydroxy, and
[0139] R.sup.8 is hydrogen atom or a lower alkyl group which may be
substituted with hydroxy.
[0140] Further preferred embodiments are as follows:
[0141] compounds of the formula (I), wherein
[0142] R.sup.1 is hydrogen atom or a halogen atom;
[0143] R.sup.2 is nitro group, cyano group or a halo(lower)alkyl
group;
[0144] R.sup.3 is an aryl group optionally substituted with one or
more substituent(s) selected from halogen and lower alkoxy;
[0145] A is a lower alkylene group; and
[0146] R.sup.4 is a group --CR.sup.6R.sup.7R.sup.8 wherein
[0147] R.sup.6 and R.sup.7 together with the carbon atom to which
R.sup.6 and R.sup.7 are attached may form a saturated carbocyclic
group optionally substituted with hydroxy or amino which may be
substituted with acyl; and
[0148] R.sup.8 is hydrogen atom; and
[0149] compounds of the formula (I), wherein
[0150] R.sup.1 is hydrogen atom or a halogen atom;
[0151] R.sup.2 is nitro group, cyano group or a halo(lower)alkyl
group;
[0152] R.sup.3 is an aryl group optionally substituted with one or
more substituent(s) selected from halogen and lower alkoxy;
[0153] A is a lower alkylene group; and
[0154] R.sup.4 is a group --CR.sup.6R.sup.7R.sup.8 wherein
[0155] R.sup.6 is a lower alkyl group substituted with hydroxy,
[0156] R.sup.7 is a lower alkyl group which may be substituted with
hydroxy, and
[0157] R.sup.8 is hydrogen atom or a lower alkyl group which may be
substituted with hydroxy.
[0158] In accordance with the invention, it includes salts of the
compounds (I). The salts may be conventional non-toxic
pharmaceutically acceptable salts, for example, a salt with an
alkali metal (e.g., sodium or potassium) and an alkaline earth
metal (e.g., calcium or magnesium), an ammonium, an organic base
(e.g., trimethylamine, triethylamine, pyridine, picoline,
dicyclohexylamine or dibenzylethylenediamine), an organic acid
(e.g., acetic acid, benzoic acid, succinic acid, fumaric acid,
maleic acid, lactic acid, citric acid, tartaric acid, gluconic
acid, methanesulfonic acid, benzenesulfonic acid, formic acid,
p-toluenesulfonic acid or trifluoroacetic acid), inorganic acid
(e.g., hydrogen chloride, hydrogen bromide, sulfuric acid or
phosphoric acid), an amino acid (e.g., arginine, aspartic acid or
glutarnic acid) or the like.
[0159] The processes for preparing the starting compounds and the
object compounds (I) of the present invention are explained in
detail in the following.
[0160] Process 1
[0161] A compound (I) or its salt can be prepared by reacting a
compound (II) or its salt with a compound (III) or its salt.
[0162] This reaction is usually carried out in the presence of an
inorganic or an organic base.
[0163] Suitable inorganic base may include an alkali metal [e.g.,
sodium or potassium], an alkali metal hydroxide [e.g., sodium
hydroxide or potassium hydroxide], an alkali metal hydrogen
carbonate [e.g., sodium hydrogen carbonate or potassium hydrogen
carbonate], an alkali metal carbonate [e.g., sodium carbonate], an
alkali earth metal carbonate [e.g., calcium carbonate], an alkali
metal hydride [e.g., sodium hydride or potassium hydridel and the
like.
[0164] Suitable organic base may include tri(lower)alkylamines
[e.g., triethylamine or N,N-diisopropylethylamine], alkyl lithiums
[e.g., methyl lithium or butyl lithium], lithium diisopropylamide,
lithium hexamethyldisilazido and the like.
[0165] The reaction is usually carried out in a conventional
solvent such as water, alcohols [e.g., methanol, ethanol or
isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene
chloride, chloroform, N,N-dimethylformamide or any other organic
solvent which does not adversely affect the reaction, or a mixture
thereof.
[0166] The reaction is preferably carried out at a temperature
under cooling to warming. However, the reaction temperature is not
limited.
[0167] Process 2
[0168] A compound (I) or its salt can be prepared by reacting a
compound (IV) or its reactive derivative at the carboxy group, or
its salt, with a compound (V) or its reactive derivative at the
amino group, or its salt, according to a procedure known in the
art.
[0169] Suitable reactive derivatives at the carboxy group of the
compound (IV) may include the acid chloride, azide, acid anhydride,
activated amide, activated ester and the like.
[0170] Suitably the acid anhydride may include anhydrides with an
acid such as substituted phosphoric acid (e.g., dialkylphosphoric
acid, phenylphosphoric acid, diphenylphosphoric acid,
dibenzylphosphoric acid or halogenated phosphoric acid),
dialkylphosphorous acid, sulfuric acid, thiosulfuric acid,
alkanesulfonic acid (e.g., methanesulfonic acid or ethanesulfonic
acid), alkanoic acid (e.g., pivalic acid, pentanoic acid or
isopentanoic acid), aromatic carboxylic acid (e.g., benzoic acid,
chlorobenzoic acid, fluorobenzoic acid or nitrobenzoic acid),or the
like.
[0171] Suitably the active amide may include the imidazoylylamide,
4-substituted imidazoylylamide, dimethylpyrazolylamide,
triazolylamide tetrazolylamide or the like.
[0172] Suitably the active ester may include the
dimethyliniinomethyl [(CH.sub.3).sub.2N.sup.30=CH.sup.-]ester,
vinyl ester, propargyl ester, 4-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl
ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl
thioester, p-nitrophenyl thioester, carboxymethyl thioester,
pyranyl ester, pyridyl ester, 8-quinolyl thioester, an ester with a
N-hydroxy compound (e.g., N,N-dimethylhydroxylamine,
1-hydroxy-2H-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole
or N-hydroxyphthalimide) or the like.
[0173] Suitably the reactive derivative at amino group of the
compound (V) may include Schiffs base type imino or its tautomeric
enamine type isomer formed by the reaction of the compound (V) with
a carbonyl compound such as aldehyde, ketone or the like; a silyl
derivative formed by the reaction of the compound (V) with a
silylating reagent such as trimethylsilylchloride,
N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the
like.
[0174] Each reactive derivative of compounds (IV) and (V) can
optionally be selected from the above according to the kinds of the
compounds (IV) and (V) to be used, respectively.
[0175] When the compound (IV) is used in a free acid form or its
salt form in the reaction, the reaction is preferably carried out
in the presence of a condensing agent.
[0176] Suitable condensing agent may include carbodiimides (e.g.,
N,N-dicyclohexylcarbodiimide,
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)c- arbodimide or
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide or its
hydrochloride), diphenylphosphinic azide, diphenylphosphinic
chloride, diethylpho sphoryl cyamide,
bis(2-oxo-3-oxazolidinyl)phosphinic chloride,
N,N'-carbonyldiimidazole,
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, cyanuric chloride
or the like.
[0177] The reaction may be also carried out in the presence of an
organic or inorganic base such as an alkali metal carbonate,
tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine or the
like.
[0178] The reaction is usually carried out in a conventional
solvent such as water, acetone, alcohols [e.g., methanol, ethanol
or isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene
chloride, chloroform, N,N'-dimethylformamide or any other organic
solvent which does not adversely affect the reaction, or a mixture
thereof.
[0179] The reaction is preferably carried out at a temperature
under cooling to warming. However, the reaction temperature is not
limited.
[0180] Process 3
[0181] A compound (I-1) or its salt can be prepared by reacting a
compound (VI) or its salt with a ketone compound(VII) in the
presence of an inorganic acid (e.g., sulfuric acid or hydrogen
chloride) or an organic acid (e.g., acetic acid) and a reducing
agent.
[0182] Suitable reducing agent may include sodium cyanoborohydride,
sodium triacetoxyborohydride, sodium borohydride, borane-pyridine
complex and the like.
[0183] The reaction is usually carried out in a conventional
solvent such as alcohols (e.g., methanol or ethanol),
tetrahydrofuran, dioxane, toluene or any other organic solvent
which does not adversely affect the reaction, or a mixture
thereof.
[0184] The reaction is preferably carried out at a temperature
under cooling to ambient temperature. However, the reaction
temperature is not limited.
[0185] Instead of the ketone compound(VII), its corresponding
aldehyde may be used in this reaction.
[0186] Process A
[0187] The process A can be carried out in a manner similar to
Process 2 by using a 2-fluorobenzoic acid derivative (VIII) and an
amine compound (V) to obtain the compound (II).
[0188] Process B
[0189] The process B can be carried out in a manner similar to
Process 3 by using an aminobenzoate derivative (IX) and a ketone
compound (VII) to obtain the compound (IV-1).
[0190] Process C
[0191] The process C can be carried out in a manner similar to
Process 1 by using a 5-fluorobenzoate derivative (X) and an amine
compound (III) to obtain the compound (IV).
[0192] Process D
[0193] The compound (VI) can be prepared by reacting an isatoic
anhydride derivative (XI) with an amine compound (V).
[0194] This reaction is usually carried out in a conventional
solvent such as acetone, tetrahydrofuran, dioxane, toluene,
methylene chloride, chloroform, N,N'-dimethylformamide or any other
organic solvent which does not adversely affect the reaction, or a
mixture thereof.
[0195] The reaction is preferably carried out at a temperature
under cooling to amibient temperature. However, the reaction
temperature is not limited.
[0196] A pharmaceutically acceptable salt of the compound (I) can
be prepared by treating a compound (I) with an appropriate base or
acid in accordance with the conventional method.
[0197] The compounds (I) and pharmaceutically acceptable salts
thereof possess inhibitory activity of cGMP-PDE (especially PDE-V),
relaxant activity of smooth muscle, bronchodilator activity,
vasodilative activity, relaxant activity of the penile corpus
cavernosum, inhibitory activity of smooth muscle cells
proliferation, inhibitory activity of allergy, and so on.
[0198] The compounds (I) and pharmaceutically acceptable salts
thereof, therefore, are useful for the treatment and/or prevention
of various diseases, such as angina, hypertension, pulmonary
hypertension, congestive heart failure, glomerular diseases (e.g.,
diabetic glomerulosclerosis), renal tubulo-intestitinal diseases
(e.g., nephropathy induced by tacrolimus, cyclosporin or the like),
renal failure, atherosclerosis, conditions of reduced blood vessel
patency (e.g., post-percutaneous transluminal coronary
angioplasty), peripheral vascular disease, stroke, chronic
reversible obstructive lung diseases (e.g., bronchitis or asthma
(chronic asthma, allergic asthma)), allergic rhinitis, urticaria,
glaucoma, diseases characterized by disorders of gut motility
(e.g., irritable bowel syndrome), electile dysfunction (e.g.,
organic electile dysfunction or psychic electile dysfunction),
female sexual dysfunction, impotence, or diabetic complications
(e.g., diabetic gangrene, diabetic arthropathy, diabetic
glomerulosclerosis, diabetic dermopathy, diabetic neuropathy,
diabetic cataract or diabetic retinopathy).
[0199] Further, the compounds (I) and pharmaceutically acceptable
salts thereof are also useful for the treatment and/or prevention
of micturition disorder, incontinence or storage of urine disorder
(such as the ones ascribed to nerve regressive affection,
inflammation, injury, neoplasm, diabetes mellitus, cerebral
vascular accident, surgery, prostatomegaly, urethra relaxation
incompetence, dysuria).
[0200] It is to be noted that improvement of sexual performance is
also included in the treatment of electile dysfunction or
impotence.
[0201] The compounds (I) and their salts of the present invention
have much advantages, such as stronger activity, more suitable
half-life, decreased adverse effect, or the like, compared to the
known anthranilic acid derivatives having an inhibitory activity of
cGMP-PDE, which are shown in the prior arts.
[0202] In order to exhibit the usefulness of the present invention,
the activities of the compounds (I) are shown in the following.
[0203] [I] Test Compound:
[0204] The test compounds are shown in Tables 1 and 2 and test
methods 2 and 3.
[0205] [II] Test Method 1: cGMP-Phosphodiesterase (PDE) Assay
[0206] Human platelet cGMP-PDE was separated from other isozymes in
human platelets by a modification of the method of Thompson et. al.
(see Cyclic Nucleotide Phosphodiesterase (PDE), in Methods of
Enzymatic analysis, Vol 4, pl27-234, 1984). In enzyme inhibition
assays, the test compounds were dissolved in DMSO and then diluted
with assay buffer (50 mM Tris-HCl, 0.077 mg/ml dithiothreitol and
10 mg/ml snake venom, 1 mM EGTA, pH 8.0), at final concentrations
ranging from 10.sup.-10 to 10.sup.-6 M. Assays were performed at
0.1 .mu.M substrate ([.sup.3H]-cGMP) concentration, at 30.degree.
C. for 10 minutes using enzymne dilutions which gave 10-20%
hydrolysis of substrate. Each assay was initiated by addition of
substrate and terminated by addition of anion exchange resin
(Dowex.RTM. 1-X8, 250 mg/mg) followed by centrifugation for 10
minutes (3000 rpm, at 4.degree. C.). Radioactivity of supernatant
(.sup.3H-GMP) was assayed by liquid scintillation counting.
[0207] The obtained results in enzymatic inhibitory test against
human platelet PDE-V are shown in Table 1.
1TABLE 1 Inhibitory activity Test Compounds (nM) IC.sub.50(nM)
2-(cyclopentylamino)-N-hexyl-- 5-nitrobenzamide <10
N-(2-chlorobenzyl)-2-cyclopentylamino-5-nit- robenzamide <10
N-(3-chlorobenzyl)-2-(cyclopentylamino)-5-nitrob- enzamide <10
N-(4-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenz- amide <10
2-(cyclopentylamino)-N-(2,4-dichlorobenzyl)-5- <10
nitrobenzamide 2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-- 5-
<10 nitrobenzamide 2-(cyclopentylamino)-N-(4-fluoroben-
zyl)-5-nitrobenzamide <10
2-(cyclopentylamino)-N-(4-methylbenzyl- )-5-nitrobenzamide <10
2-(cyclopentylamino)-N-(4-methoxybenzyl)-- 5- <10 nitrobenzamide
2-(cyclopentylamino)-5-nitro-N-[4-(- trifluoromethyl)benzyl]-
<10 benzamide
N-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide <10
N-(4-amino-2-chlorobenzyl)-2-(cyclopentylamino)-5- <10
nitrobenzamide N-(2-chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-
- <10 nitrobenzamide 2-(cyclopentylamino)-5-nitro-N-(4-ni-
trobenzyl)benzamide <10
N-(4-bromobenzyl)-2-(cyclopentylamino)-5- -nitrobenzamide <10
2-(cyclopentylamino)-N-furfuryl-5-nitrobenza- mide <10
2-(cyclopentylamino)-5-nitro-N-(2-thienyl-methyl)-benza- mide
<10 2-(cyclopentylamino)-N-(4-hydroxy-3-methoxybenzyl)-5- <10
nitrobenzamide 2-(cyclopentylamino)-5-nitro-N-phenet- hylbenzamide
<10 2-(cyclopentylamino)-5-nitro-N-(3-phenyl-propyl- )benzamide
<10 N-benzyl-2-(cyclobutylamino)-5-nitrobenzamide <10
N-benzyl-2-(cyclohexylamino)-5-nitrobenzamide <10
2-(cyclopentylamino)-N-(2,4-difluorobenzyl)-5- <10
nitrobenzamide N-[(2-benzimidazolyl)methyl]-2-(cyclopentylamino)-5-
- <10 nitrobenzamide N-benzyl-2-(cyclopropylamino)-5-nitr-
obenzamide <10 N-benzyl-2-(trans-2-hydroxycyclopentylamino)-5-
<10 nitrobenzamide 5-nitro-N-(1,3-benzodioxol-5-ylmethyl-
)-2-(tetrahydro-2H- <10 thiopyran-4-ylamino)benzamide
2-(tert-butylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)- <10
benzamide 2-[1-(ethoxycarbonyl)piperidin-4-ylamino]-5-nitro-N-(1,3-
- <10 benzodioxol-5-ylmethyl)benzamide
2-(1-benzylpiperidin-4-ylamino)-5-nitro-N-(1,3- <10
benzodioxol-5-ylmethyl)benzamide (R)-2-(1-ethyl-2-hydroxyethylamin-
o)-5-nitro-N-(1,3- <10 benzodioxol-5-ylmethyl)benzamide
(R)-5-Nitro-2-(tetrahydro-3-furanylamino)-N-(1,3- <10
benzodioxol-5-ylmethyl)benzamide 2-(1,1-dioxotetrahydro-2H-thiopyr-
an-4-ylamino)-5-nitro-N- <10
(1,3-benzodioxol-5-ylmethyl)-benzam- ide
2-[4-(methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3- <10
benzodioxol-5-ylmethyl)benzamide 2-(4-carboxycyclohexylamino)-
-5-nitro-N-(1,3-benzodioxol- <10 5-ylmethyl)benzamide
2-(4-carbamoylcyclohexylamino)-5-nitro-N-(1,3- <10
benzodioxol-5-ylmethyl)benzamide (R)-2-[1-(methoxycarbonyl)ethylam-
ino]-5-nitro-N-(1,3- <10 benzodioxol-5-ylmethyl)benzamide
N-benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide <10
2-[3-(benzoyloxy)cyclopentylamino]-N-benzyl-5- <10
nitrobenzamide 2-[1-(hydroxymethyl)cyclopentylamino]-5-nitro-N-(1,-
3- <10 benzodioxol-5-ylmethyl)benzamide
(S)-2-[1-(hydroxymethyl)-2-methylpropylamino]-5-nitro-N- <10
(1,3-benzodioxol-5-ylmethyl)-benzamide 5-nitro-2-(4-oxocyclohexyla-
mino)-N-(1,3-benzodioxol-5- <10 ylmethyl)benzamide
2-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl-amino]-5- <10
nitro-N-(1,3-benzodioxol-5-yl-methyl)benzamide
2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-5-nitro-N- <10
(1,3-benzodioxol-5-ylmethyl)-benzamide 5-nitro-2-(4-piperidinylami-
no)-N-(1,3-benzodioxol-5- <10 ylmethyl)benzamide
2-[1-(hydroxyethyl)pentylamino]-5-nitro-N-(1,3- <10
benzodioxol-5-ylmethyl)benzamide 2-(1-acetyl-4-piperidinylamino)-5-
-nitro-N-(1,3-benzodioxol- <10 5-ylmethyl)benzamide
2-(1-methyl-4-piperidinylamino)-5-nitro-N-(1,3- <10
benzodioxol-5-ylmethyl)benzamide 2-(1-formyl-4-piperidinylamino)-5-
-nitro-N-(1,3-benzodioxol- <10 5-ylmethyl)benzamide
N-(3-fluoro-4-methoxybenzyl)-2-[2-hydroxy-1- <10
(hydroxymethyl)ethylamino]-5-nitrobenzamide
2-(trans-4-hydroxycyclohexyl)amino-N-[4- <10
(methylthio)benzyl]-5-nitrobenzamide N-(3,5-dichloro-4-methoxybenz-
yl)-2-(trans-4- <10 hydroxycyclohexylamino)-5-nitrobenzamide
N-(3,4-ethylenedioxybenzyl)-2-(trans-4- <10
hydroxycyclohexylamino)-5-nitrobenzamide N-(3-chloro-4-fluorobenzy-
l)-2-[2-hydroxy-1- <10
(hydroxymethyl)ethylamino]-5-nitrobenzami- de
(S)-N-(3-chloro-4-methylbenzyl)-2-(2-hydroxy-1- <10
methylethylamino)-5-nitrobenzamide 2-[2-hydroxy-1-(hydroxymethyl)e-
thylamino]-N-(3-methoxy- <10 4-methylbenzyl)-5-nitrobenzamide
N-cyclohexylmethyl-2-(cis-4-hydroxycyclohexylamino)-5- <10
nitrobenzamide (S)-2-[1-(chloromethyl)propylamino]-5-nitro-N-(1,3-
<10 benzodioxol-5-ylmethyl)benzamide
(R)-N-(4-chloro-3-nitrobenzyl)-2-[1-(hydroxy- <10
methyl)propylamino]-5-nitrobenzamide N-(3,4-dimethylbenzyl)-2-(cis-
-4-hydroxycyclohexylamino)-5- <10 nitrobenzamide
2-(cis-4-chlorocyclohexylamino)-5-nitro-N-(1,3-benzodioxol- <10
5-ylmethyl)benzamide 2-[cis-4-(acetoxy)cyclohexylamino]-N-(3,4-
<10 dimethoxybenzyl)-5-nitrobenzamide
2-[(trans-4-aminocyclohexyl)amino]-N-(3,4- <10
dimethoxybenzyl)-5-nitrobenzamide 2-[2-chloro-1-(chloromethyl)ethy-
lamino]-5-nitro-N-(1,3- <10 benzodioxol-5-ylmethyl)benzamide
N-(2-chloro-5-methoxybenzyl)-2-(cis-4- <10
hydroxycyclohexylamino)-5-nitrobenzamide N-(3-chloro-4-methoxybenz-
yl)-2-[2-hydroxy-1- <10
(hydroxymethyl)ethylaminol]-5-(trifluoro- methyl)-benzamide
N-(3,4-dimethoxylbenzyl)-2-[(1R,2S)-2-hydroxy-1-m- ethyl- <10
2-phenylethyl]amino-5-nitrobenzamide
N-(3,4-dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan-5- <10
ylamino)-5-nitrobenzamide N-(3,4-dimethoxybenzyl)-5-nitro-2-[trans-
-4-(3- <10 propylureido)cyclohexylamino]benzamide
N-(3,4-dimethoxybenzyl)-5-nitro-2-(2-oxo-1,3-dioxan-5- <10
ylamino)benzamide N-(4-chloro-4-ethoxybenzyl)-2-(cis-4- <10
hydroxycyclohexylamino)-5-nitrobenzamide
N-(4-ethoxy-3-methoxybenzyl)-2-(cis-4- <10
hydroxycyclohexylamino)-5-nitrobenzamide 2-{trans-4-[2,3-bis(tert--
butoxycarbonyl)-guanidino]cyclo- <10 hexylamino}-N-(3
,4-dimethoxybenzyl)-5-nitrobenzamide 2-[1-(tert-butoxycarbonyl)pip-
eridin-4-ylamino]-N-(3,4- <10 dimethoxybenzyl)-5-nitrobenzamide
(R)-2-(2-hydroxy-1-methylethyl)amino-5-nitro-N-(4- <10
phenoxybenzyl)benzamide N-(4-ethoxy-3-methoxybenzyl)-2-(trans-4-
<10 formamidocyclohexylamino)-5-nitrobenzamide
N-(3,4-dimethoxybenzyl)-5-nitro-2-(4-piperidinyl- <10
amino)benzamide N-(3,4-dimethoxybenzyl)-2-(trans-4-guanidino-
<10 cyclohexylamino)-5-nitrobenzamide hydrochloride
(R)-2-(2-hydroxy-1-methylethyl)amino-5-nitro-N-(4- <10
phenybenzyl)benzamide N-(benzo[b]thiophen-2-ylmethyl)-2-(cis-4-
<10 hydroxycyclohexylamino)-5-nitrobenzamide
2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(4- <10
phenylbenzyl)benzamide N-(3,4-dimethoxylbenzyl)-2-[(R)-1-hydroxyme-
thyl-3- <10 (methylthio)propylamino]-5-nitrobenzamide
N-(benzofuran-2-ylmethyl)-2-(cis-4-hydroxy- <10
cyclohexylamino)-5-nitrobenzamide 2-(cis-4-formamidocyclohexylamin-
o)-N-(3,4- <10 dimethoxybenzyl)-5-nitrobenzamide
2-[1-[1,3-bis(tert-butoxycarbonyl)amidino]-piperidin-4- <10
ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide
2-(1-amidinopiperidin-4-ylamino)-N-(3,4-dimethoxybenzyl)- <10
5-nitrobenzamide hydrochloride 5-bromo-N-(3-chloro-4-methoxybenzyl-
)-2- <10 (cyclopentylamino)benzamide hydrochloride
2-[(1S,2R)-2-carbamoyl-2-hydroxypropyl-amino]-N-(3,4- <10
dimethoxybenzyl)-5-nitro-benzamide 2-(cis-4-hydroxycyclohexylamino-
)-N-[3-methoxy-4-(2- <10 methoxyethoxy)benzyl]-5-nitrobenzamide
N-(4-cyclobutylmethoxy-3-methoxybenzyl)-2-[2-hydroxy-1- <10
(hydroxymethyl)ethylamino]-5-nitrobenzamide
(S)-N-(3,4-dimethoxybenzyl)-2-[1-(formamidomethyl)-2- <10
hydroxyethylamino]-5-nitrobenzamide
[0208] As shown in the above Table 1, the compounds (1) of the
present invention have superior inhibitory activity against
cGMP-PDE.
[0209] Test Method 2: The Effect on Erection Function
[0210] (a) Effect of Test Compound on Nitroprusside or Ach-Induced
Relaxation in Isolated Rat Corpora Cavernosa.
[0211] Male SD rats were anesthetized with sodium pentobarbital 50
mg/kg intraperitoneally, and the corpora cavernosa was excised. The
tunica albuginea was dissected according to the methods described
by Italiano et al. (Pharmacological Research, 30, No.4, 1994) and
used for in vitro pharmacological study. The erectile tissue strip
was placed in a 25 ml organ bath containing Krebs-Ringer solution.
The bath was maintained at 37.degree. C. and bubbled with 95%
O.sub.2 and 5% CO.sub.2. The strip was stretched with a resting
force of 0.25 g, and isometric contraction were recorded via force
development transducer on a recorder.
[0212] The strip was equilibrated in the Krebs-Ringer solution for
about 60 minutes, and preconstructed by 0.1 mM norepinephrine to
ascertain the responsibility of each preparation. The strip was
washed several times, and then constricted by 0.1 mM
norepinephrine. After getting stable constrictile response to
norepinephrine, the first dose-response curve for sodium
nitroprusside or Ach(acetylcholine) was obtained. After washing a
few times for 60 minutes, the strip was constricted by
norepinephrine again, and the second dose-response curve for sodium
nitroprusside or Ach was obtained. The test compound, i.e.,
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenza-
mide which was selected as a representative compound of this
invention was added 30 minutes before adding norepinephrine.
Relaxant response elicited by 10 .mu.M nitroprusside was 20% in
control preparation, but this relaxant response increased to 32% in
the presence of the test compound (5.times.10.sup.-8 M).
[0213] Said compound at 5.times.10.sup.-8 M also potentiated
Ach-induced relaxation of corpora cavernosa. 100 .mu.M Ach-induced
relaxant response to the contractile response induced by 10.sup.-4
M norepinephrine was only 5.0% in control preparation, but this
relaxant response to Ach increased to 18.0% in the presence of said
compound (5.times.10.sup.-8 M).
[0214] (b) Effect of Test Compounds on the Relaxation Elicited by
Electrical Field Stimulation in Rabbit Corpora Cavernosa.
[0215] The rabbit erectile tissue strip prepared according to the
method described by Italiano et al. (Pharmacological Research, 30,
No4, 1994) was placed 25 ml organ bath containing Krebs-Ringer
solution. The bath was maintained at 37.degree. C. and bubbled with
95% O.sub.2 and 5% CO.sub.2. The solution also contained atropine
(1.mu.M) and guanethidine (50 .mu.M). The erectile tissue strip was
stretched with a resting force of 0.25 g, and isometric contraction
were recorded via force development transducer on a recorder. The
bipolar platinum electrode connected to the electric stimulator was
placed around the strip.
[0216] The strip was equilibrated in the Krebs-Ringer solution for
about 60 minutes and preconstructed by 0.1 mM norepinephrine to
ascertain the responsibility of each preparation. The strip was
washed several times, and then constricted by 0.1 mM
norepinephrine. After getting stable contractile response to
norepinephrine, the first electrical field stimulation (1 to 30 Hz,
20V, 0.5 msec duration, 90 sec interval) was delivered. 30 minutes
after adding the tested compound, the second electrical field
stimulation was delivered.
[0217] The compounds i.e.,
N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohe-
xylamino)-5-nitrobenzamide and
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1--
methyl-ethylamino)-5-nitrobenzamide which were selected as
representative compounds of this invention, at 5.times.10.sup.-8 M
potentiated relaxation of corpora cavernosa elicited by electrical
field stimulation in rabbit corpora cavernosa.
[0218] Relaxant response elicited by 30 Hz was only 70% in control
preparation, but this relaxant response increased to 100% in the
presence of 5.times.10.sup.-8 M said compounds.
[0219] (c) Male beagle weighing 8.0-12.0 kg were anesthetized with
pentobarbital sodium (35 mg/kg, i.v.). After tracheotomy, the
animal was artificially ventilated using a volume-cycled
ventilator. The femoral artery was cannulated for continuous blood
pressure and heart rate monitoring. The femoral vein was cannulated
for maintenance of anesthesia and administration of tested
compound.
[0220] Either the left or right cavernous nerve was exposed
posterolaterally to the prostate and a cuff electrode was placed
around the nerve for electrical stimulation. A 21-gauge butterfly
needle was placed in the corpus cavernousum and connected to a
pressure transducer for intracavernous pressure. After a period of
stabilization of all parameters, erection was induced by cavernous
nerve electrically stimulation (7 Hz, 10 V) and the following was
measured: the duration of detumescence (time (T75) from cessation
of stimulation to 75% reduction of intracavernous pressure). The
test compounds, i.e.,
N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide
and
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nitro-
benzamide were each dissolved in 50% PEG400. As shown in Table 2,
T75 after the cessation of electrical stimulation was prolonged by
the administration of the compounds (0.1 mg/kg, i.v.) which were
selected as representative compounds of this invention.
2 TABLE 2 mean of prolongation of test compounds T75 (second)
N-(3,4-dimethoxybenzyl)-2- -(cis-4- 52
hydroxycyclohexylamino)-5-nitrobenzamide
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1- 44
methylethylamino)-5-nitrobenzamide
[0221] Test Method 3: Toxicities of Compound (I)
[0222] Test on the toxicity by repetitive oral administration of
the compounds, i.e.,
N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-
-5-nitrobenzamide and
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methyleth-
ylamino)-5-nitrobenzamide which were selected as representative
compounds of this invention, in SD rat was conducted. The dead at
dose of 32 mg/kg once a day for 14 consecutive days could not be
observed.
[0223] The compound (1) or its salt can be administered alone or in
a form of a mixture, preferably, with a pharmaceutical vehicle or
carrier.
[0224] The active ingredient of this invention can be used in a
form of a pharmaceutical preparation, for example, in solid,
semisolid or liquid form, which contains a compound (I), as an
active ingredient, in admixture with an organic or inorganic
carrier or excipient suitable for external, enteral, intravenous,
intramuscular, parenteral or intramucous applications. The active
ingredient may be compounded, for example, with the conventional
non-toxic, pharmaceutically acceptable carriers for ointment,
cream, plaster, tablets, pellets, capsules, suppositories, solution
(saline, for example), emulsion, suspension (olive oil, for
example), aerosols, pills, powders, syrups, injections, troches,
cataplasms, aromatic waters, lotions, buccal tablets, sublingual
tablets, nasal drops and any other form suitable for use. The
carriers which can be used are water, wax, glucose, lactose, gum
acacia, gelatin, mannitol, starch paster, magnesium trisilicate,
talc, corn starch, keratin, paraffin, colloidal silica, potato
starch, urea and other carriers suitable for use in manufacturing
preparations, in solid, semisolid, or liquid form, and in addition
auxiliary, stabilizing, thickening and coloring agents and perfumes
may be used. The active compound is included in a pharmaceutical
composition in an effective amount sufficient to produce the
desired effect upon the process or condition of the diseases.
[0225] The active ingredient may be compounded into, for example,
preparations for oral application, preparations for injection,
preparations for external application, preparations for inhalation,
preparations for application to mucous membranes (oral mucous
membrane, fascia penis, facies urethralis penis, etc.).
[0226] Mammals which may be treated by the present invention
include livestock mammals such as cows, horses, etc., domestic
animals such as dogs, cats, rats, etc. and humans, preferably
humans.
[0227] While the dosage of therapeutically effective amount of a
compound (I) varies from and also depends upon the age and
condition of each individual patient to be treated, in case of the
systemic administration, a daily dose of about 0.01-1000 mg,
preferably 0.1-500 mg and more preferably 0.5-100 mg of the active
ingredient is generally given for treating the diseases, and an
average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg,
100 mg, 250 mg and 500 mg is generally administered. Daily doses
for chronic administration in humans will be in the range of about
0.3 mg/body to 1,000 mg/body.
[0228] The patents, patent applications and publications cited
herein above are incorporated by reference. (to be continued on the
next page)
BEST MODE FOR CARRYING OUT THE INVENTION
[0229] The following Examples are given only for the purpose of
illustrating the present invention in more detail.
[0230] Preparation 1
[0231] A mixture of 2-fluoro-5-nitrobenzoic acid (1.00 g),
(1,3-benzodioxol-5-ylmethyl)amine (980 mg),
1-[3-(dimethylamino)propyl]-3- -ethylcarbodiimide hydrochloride
(1.55 g) and 1-hydroxybenzotriazole (1.09 g) in anhydrous
dimethylformamide (10 mL) was stirred for 40 hours at ambient
temperature. The mixture was partitioned between water and ethyl
acetate. The separated organic layer was washed with an aqueous
saturated sodium bicarbonate solution, 1N-hydrochloric acid, water
and brine. Then, the resultant was dried over magnesium sulfate and
evaporated in vacuo. The residue was triturated with diisopropyl
ether to give
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow
powders (1.48 g).
[0232] NMR (DMSO-d.sub.6, .delta.): 4.38 (2H, d, J=7 Hz), 5.99 (2H,
s), 6.80-6.98 (3H, m), 7.62 (1H, m), 8.39 (2H, m), 9.12 (1H,
br)
[0233] Mass m/z: 317 (M.sup.+)
EXAMPLE 1(1)
[0234] To a solution of
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)ben- zamide (150 mg)
in anhydrous pyridine (3 mL) was added trans-4-aminocyclohexanol
(81.4 mg), and the mixture was stirred for 15 hours at ambient
temperature, and then for 3 hours at 60.degree. C. The mixture was
partitioned between ethyl acetate and water. The separated organic
layer was washed with water and brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with a mixture of chloroform and
methanol (20:1). The eluent was concentrated and the residue was
triturated with diisopropyl ether to give
2-(trans4-hydroxycyclohexylamin-
o)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow
powders (164 mg).
[0235] NMR (CDCl.sub.3, .delta.): 1.38-1 .60 (4H, br), 2.00-2.24
(4H, br), 3.44 (1H, br), 3.76 (1H, br), 4.49 (2H, d, J=7 Hz), 5.97
(2H, s), 6.44 (1H, br), 6.67 (1H, d, J=8 Hz), 6.80 (3H, m), 8.14
(1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 8.86 (1H br)
[0236] Mass m/z: 412 (M.sup.+).
EXAMPLE 1(2)
[0237] To a solution of
2-(trans-4-hydroxycyclohexylarino)-5-nitro-N-(1,3--
benzodioxol-5-ylmethyl)benzamide (100 mg) in dichloromethane (3 mL)
and acetonitrile (0.4 mL) were added tetrapropylammonium
perruthenate (4.25 mg), 4-methylmorpholine N-oxide (42.5 mg) and
molecular sieves (4 .ANG., 0.2 g). The resulting mixture was
stirred for 2 hours at ambient temperature. The mixture was
subjected to a silica gel chromatography eluting with ethyl acetate
to give 5-nitro-2-(4-oxocyclohexylamino)-N-(1,-
3-benzodioxol-5-ylmethyl)benzamide (92 mg) as a solid
substance.
[0238] NMR (DMSO-d.sub.6, .delta.): 1.70-1.87 (2H, m), 2.12-2.53
(4H, m), 2.49-2.60 (2H, m), 4.06 (1H, m), 4.35 (2H, d, J=6 Hz),
5.98 (2H, s), 6.75-6.91 (3H, m), 7.03 (1H, d, J=9 Hz), 8.16 (1H,
dd, J=2, 9 Hz), 8.63 (1H, d, J=2 Hz), 9.22 (1H, d, J=8 Hz), 9.36
(1H, t, J=6 Hz)
[0239] Mass m/z: 410 (M.sup.+-1).
EXAMPLE 2(1)
[0240]
(S)-2-[1-(Hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-y-
lmethyl)benzamide (69 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzod- ioxol-5-ylmethyl)benzamide (72 mg)
and (S)-2-amino-1-butanol (42.4 mg) in a manner similar to Example
1(1).
[0241] mp: 128-130.degree. C.
[0242] NMR (DMSO-d.sub.6, .delta.): 0.92 (3H, t, J=7 Hz), 1.49 (1H,
m), 1.67 (1H, m), 3.4-3.65 (3H, m), 4.36 (2H, d, J=7 Hz), 4.92 (1H,
t, J=6 Hz), 5.98 (2H, s), 6.75-6.93 (4H, m), 8.09 (1H, dd, J=2, 8
Hz), 8.59 (1H, d, J=2 Hz), 9.16 (1H, d, J=7 Hz), 9.31 (1H, t, J=6
Hz).
EXAMPLE 2(2)
[0243] To a solution of
(S)-2-[1-(hydroxymethyl)propylamino]-5-nitro-N-(1,-
3-benzodioxol-5-ylmethyl)benzamide (127 mg) in 1,2-dichloroethane
(4 mL) and carbontetrachloride (2 mL) was added triphenylphosphine
(215 mg), and the mixture was stirred for an hour under reflux. The
solvent was evaporated in vacuo and the residue was subjected to a
silica gel column chromatography eluting with a mixture of
chloroform and ethyl acetate (9:1) to give
(S)-2-[1-(chloromethyl)propylamino-5-nitro-N-(1,3-benzodiox-
ol-5-ylmethyl)benzamide (71 mg) as a solid substance.
[0244] NMR (DMSO-d.sub.6, .delta.): 0.92 (3H, t, J=7 Hz), 1.52-1.80
(2H, m), 3.82 (2H, m), 3.99 (1H, m), 4.36 (2H, d, J=6 Hz), 5.99
(2H, s), 6.78-6.92 (3H, m), 6.98 (1H, d, J=9 Hz), 8.13 (1H, dd,
J=2, 9 Hz), 8.61 (7H, d, J=2 Hz), 9.19 (1H, d, J=8 Hz), 9.36 (1H,
t, J=6 Hz)
[0245] Mass m/z: 404 (M.sup.+-1).
EXAMPLE 3(1)
[0246]
2-[2-Hydroxy-1-(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxo-
l-5-ylmethyl)benzamide (108 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg)
and 2-amino-1,3-propanediol (42.9 mg) in a manner similar to
Example 1 (1).
[0247] NMR (DMSO-d.sub.6, .delta.): 3.48-3.68 (5H, br), 4.34 (2H,
d, J=7 Hz), 4.93 (2H, t, J=7 Hz), 5.98 (2H, s), 6.78-6.96 (4H, m),
8.12 (1H, dd, J=4 Hz, 8 Hz), 8.58 (1H, d, J=4 Hz), 9.28 (2H,
br)
[0248] Mass m/z: 388 (M.sup.+).
EXAMPLE 3(2)
[0249]
2-[2-Chloro-1-(chloromethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol--
5-ylmethyl)benzamide (36 mg) was obtained from
2-[2-hydroxy-1-(hydroxymeth-
yl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (101
mg) in a manner similar to Example 2(2).
[0250] NMR (DMSO-d.sub.6, .delta.); 3.89 (4H, d, J=6 Hz), 4.36 (2H,
d, J=5 Hz), 4.47 (1H, m), 5.99 (2H, s), 6.78-6.93 (3H, m), 7.08
(1H, d, J=9 Hz), 8.16 (1H, dd, J=2, 9 Hz), 8.64 (1H, d, J=2 Hz),
9.39 (1H, t, J=5 Hz), 9.44 (1H, d, J=8 Hz)
[0251] Mass m/z : 424, 426 (M.sup.+-1).
EXAMPLE 3(3)
[0252] To a solution of
N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymet-
hyl)ethylamino]-5-nitrobenzamide (134 mg) in a mixture of
dichloromethane (1 mL) and pyridine (1 mL) was added triphosgene
(49.1 mg) at -78.degree. C. Then, the resulting mixture was stirred
for an hour at ambient temperature. The mixture was diluted with
ethyl acetate and washed successively with diluted ammonium
chloride, water and brine. The organic layer was dried over sodium
sulfate and evaporated in vacuo. The residue was subjected to a
silica gel column chromatography eluting with a mixture of
chloroform and ethyl acetate (7:3) to give
N-(3,4-dimethoxybenzyl)-5-nitro-2-(2-oxo-1,3-dioxan-5-ylamino)benzamide
(129 mg) as a solid substance.
[0253] NMR (CDCl.sub.3, .delta.): 3.88 (3H, s), 3.90 (3H, s), 4.21
(1H, m), 4.49 (2H, m), 4.53 (2H, d, J=8 Hz), 4.69 (2H, m),
6.60-6.72 (2H, m), 6.84-6.96 (3H, m), 8.23 (1H, dd, J=2, 9 Hz),
8.39 (1H, d, J=2 Hz), 9.44 (1H, m)
[0254] Mass m/z: 430 (M.sup.+-1).
EXAMPLE 3(4)
[0255] To a solution of
N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymet-
hyl)ethylamino]-5-nitrobenzamide (117 mg) in dichloromethane (5.0
mL) were added 2,2-dimethoxypropane (0.36 mL) and 4-toluenesulfonic
acid (10 mg), and the mixture was stirred for 30 minutes under
reflux. The resulting mixture was diluted with ethyl acetate and
washed successively with diluted sodium bicarbonate and brine. The
organic layer was dried over sodium sulfate and evaporated in
vacuo. The residue was triturated with diethyl ether to give
N-(3,4-dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan--
5-ylamino)-5-nitrobenzamide (105 mg) as a solid substance.
[0256] NMR (CDCl.sub.3, .delta.): 1.50 (3H, s), 1.51 (3H, s), 3.68
(1H, m), 3.83 (2H, dd, J=6, 12 Hz), 3.88 (3H, s), 3.90 (3H, s),
4.15 (2H, dd, J=4, 12 Hz), 4.52-4.57 (2H, m), 6.66 (1H, d, J=9 Hz),
6.83-6.95 (3H, m), 6.94 (1H, m), 8.16 (1H, dd, J=2, 9 Hz), 8.39
(1H, d, J=2 Hz)
[0257] Mass m/z: 446 (M.sup.++1).
EXAMPLE 4(1)
[0258]
(S)-2-[1-(tert-Butoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxo-
l-5-ylmethyl)benzamide (131 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-- benzodioxol-5-ylmethyl)benzamide (107 mg)
and (S)-alanine tert-butyl ester hydrochloride (85.5 mg) in a
manner similar to Example 1(1).
[0259] NMR (DMSO-d.sub.6, .delta.); 1.41 (3H, d, J=7 Hz), 1.43 (9H,
s), 4.30-4.38 (3H, m), 5.99 (2H, s), 6.71-6.93 (4H, m), 8.17 (1H,
dd, J=2, 9 Hz), 8.62 (1H, d, J=2 Hz), 9.34-9.43 (2H, m)
[0260] Mass m/z: 442 (M.sup.+-1)
EXAMPLE 4(2)
[0261] To a solution of
(S)-2-[1-(tert-butoxycarbonyl)ethylamino-5-nitro-N-
-(1,3-benzodioxol-5-ylmethyl)benzamide (104 mg) in dichloromethane
(1.5 mL) was added trifluoroacetic acid (0.6 mL), and the mixture
was stirred for 2 hour at ambient temperature. The resulting
mixture was evaporated in vacuo and the residue was triturated with
diethyl ether to give
(S)-2-(1-carboxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzami-
de (76 mg) as a solid substance.
[0262] NMR (DMSO-d.sub.6, .delta.); 1.43 (3H, d, J=7 Hz), 4.31-4.42
(3H, m), 5.99 (2H, s), 6.73-6.93 (4H, m), 8.15 (1H, dd, J=2, 9 Hz),
8.61 (1H, d, J=2 Hz), 9.32-9.41 (2H, m)
[0263] Mass m/z: 386 (M.sup.+-1)
EXAMPLE 5
[0264]
2-(trans-2-Hydroxycyclopentylamino)-S-nitro-N-(1,3-benzodioxol-5-yl-
methyl)benzamide (107 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg)
and trans-2-aminocyclopentanol (47.7 mg) in a manner similar to
Example 1 (1).
[0265] NMR (CDCl.sub.3, .delta.): 1.55-1.75 (2H, m), 1.76-1.95 (2H,
m), 2.00-2.13 (1H, m), 2.26-2.38 (1H, m), 3.78 (1H, br), 4.16 (1H,
br), 4.48 (2H, d, J=7 Hz), 5.96 (2H, s), 6.50 (1H, br) 6.77-6.90
(4H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.30 (1H, d, J=4 Hz), 8.86 (1H,
br)
[0266] Mass m/z: 398 (M.sup.+).
EXAMPLE 6
[0267]
2-(2-Hydroxy-1,1-dimethylethylamino)-5-nitro-N-(1,3-benzodioxol-5-y-
lmethyl)benzamide (80.0 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benz- odioxol-5-ylmethyl)benzamide (100 mg)
and 2-amino-2-methyl-1-propanol(84.0 mg) in a manner similar to
Example 1(1).
[0268] NMR (CDCl.sub.3, .delta.) 1.47 (6H, s), 1.88 (1H, t, J=7
Hz), 3.70 (2H, d, J=7 Hz), 4.50 (2H, d, J=7 Hz), 5.97 (2H, s), 6.45
(1H, br), 6.76-6.95 (4H, m), 8.10 (1H, dd, J=4, 8 Hz), 8.28 (1H, d,
J=4 Hz), 9.13 (1H, br)
[0269] Mass m/z: 388 (M.sup.+).
EXAMPLE 7
[0270]
(R)-2-(2-Hydroxy-1-methylethylamino)-5-nitro-N-(1,3-benzodioxol-5-y-
lmethyl)benzamide (65 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzod- ioxol-5-ylmethyl)benzamide (93 mg)
and (R)-2-amino-1-propanol(44 mg) in a manner similar to Example
1(1).
[0271] mp: 166-168.degree. C.
[0272] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=7 Hz), 3.46 (2H,
m), 3.76 (1H, m), 4.33 (2H, d, J=7 Hz), 4.98 (1H, t, J=6 Hz), 5.98
(2H, s), 6.75-6.93 (4H, m), 8.11 (1H, dd, J=2, 8 Hz), 8.58 (1H, d,
J=2 Hz), 9.15 (1H, d, J=7 Hz), 9.29 (1H, t, J=6 Hz).
EXAMPLE 8
[0273]
5-Nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(2-thiazolylamino)benzamid-
e (28 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl- )benzamide (70 mg)
and 2-aminothiazole (26.4 mg) in a manner similar to Example
1(1).
[0274] NMR (DMSO-d.sub.6, .delta.): 4.43 (2H, d, J=5 Hz), 5.99 (1H,
s), 6.81-6.91 (2H, m), 6.96 (1H, s), 7.27 (1H, d, J=4 Hz), 7.47
(1H, d, J=4 Hz), 8.39 (1H, dd, J=2, 9 Hz), 8.70-8.6 (2H, m), 9.70
(1H, t, J=5 Hz)
[0275] Mass m/z : 397 (M.sup.+-1).
EXAMPLE 9
[0276]
(R)-2-(1-Ethyl-2-hydroxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-yl-
methyl)benzamide (55.8 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzo- dioxol-5-ylmethyl)benzamide (72 mg)
and (R)-2-amino-1-butanol (0.045 mL) in a manner similar to Example
1(1).
[0277] NMR (DMSO-d.sub.6, .delta.): 0.89 (3H, t, J=7 Hz), 1.49 (1H,
m), 1.66 (1H, m), 3.38-3.45 (3H, m), 4.34 (2H, d, J=6 Hz), 4.92
(1H, t, J=5 Hz), 5.98 (2H, s), 6.78-6.92 (4H, m), 8.09 (1H, dd, J
2, 9 Hz), 8.58 (1H, d, J=2 Hz), 9.16 (1H, d, J=8 Hz), 9.30 (1H, t,
J=6 Hz)
[0278] Mass m/z: 386 (M.sup.+-1).
EXAMPLE 10
[0279]
(R)-5-Nitro-2-(tetrahydro-3-furanylamino)-N-(1,3-benzodioxol-5-ylme-
thyl)benzamide (76 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodiox- ol-5-ylmethyl)benzamide (80 mg)
and (R)-3-aminotetrahydrofuran p-toluenesulfonate (78.2 mg) in a
manner similar to Example 1 (1).
[0280] NMR (DMSO-d.sub.6, .delta.): 1.79 (1H, m), 2.31 (1H, m),
3.60 (1H, m), 3.71-3.94 (3H, m), 4.29 (1H, m), 4.37 (2H, d, J=6
Hz), 5.99 (2H, s), 6.81 (1H, d, J=8 Hz), 6.87-6.95 (3H, m), 8.17
(1H, m), 8.63 (1H, d, J=2 Hz), 9.26 (1H, d, J=8 Hz), 9.38 (1H, t,
J=6 Hz)
[0281] Mass m/z: 384 (M.sup.+-1).
EXAMPLE 11
[0282]
(S)-2-[2-Hydroxy-1-(methoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benz-
odioxol-5-ylmethyl)benzamide (73 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (89 mg)
and (S)-serine methyl ester hydrochloride (69.7 mg) in a manner
similar to Example 1 (1).
[0283] NMR (DMSO-d.sub.6, .delta.): 3.67 (3H, s), 3.74 (1H, m),
3.91 (1H, m), 4.36 (2H, d, J=6 Hz), 4.54 (1H, m), 5.34 (1H, t, J=5
Hz), 5.99 (2H, s), 6.76-6.93 (4H, m), 8.11 (1H, dd, J=2, 9 Hz),
8.62 (1H, d, J=2 Hz), 9.34 (1H, t, J=6 Hz), 9.57 (1H, d, J=8
Hz)
[0284] Mass m/z :416 (M.sup.+-1).
EXAMPLE 12
[0285]
(R)-2-[1-(Methoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5--
ylmethyl)benzamide (85 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzo- dioxol-5-ylmethyl)benzamide (92 mg)
and (R)-alanine methyl ester hydrochloride (64.6 mg) in a manner
similar to Example 1(1).
[0286] NMR (DMSO-d.sub.6, .delta.): 1.46 (3H, d, J=7 Hz), 3.69 (3H,
s), 4.36 (2H, d, J=5 Hz), 4.53 (1H, m), 5.99 (2H, s), 6.75-6.93
(4H, m), 8.14 (1H, dd, J 2, 9 Hz), 8.63 (1H, d, J=2 Hz), 9.34-9.44
(2H, m)
[0287] Mass m/z 400 (M.sup.+-1).
EXAMPLE 13
[0288]
2-(2,3-Dihydro-1H-inden-2-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylm-
ethyl)benzamide (82.7 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzod- ioxol-5-ylmethyl)benzamide (90 mg)
and 2-aminoindan hydrochloride (57.6 mg) in a manner similar to
Example 1(1).
[0289] NMR (DMSO-d.sub.6, .delta.): 2.86 (2H, m), 3.43 (2H, m),
4.32 (2H, d, J=6 Hz), 4.52 (1H, m), 5.99 (2H, s), 6.75-6.79 (3H,
m), 6.99 (1H, d, J=9 Hz), 7.15-7.20 (2H, m), 7-21-7.29 (2H, m),
8.17 (1H, dd, J=2, 9 Hz), 8.61 (1H, d, J=2 Hz), 9.26-9.35 (2H,
m)
[0290] Mass m/z: 430 (M.sup.+-1).
EXAMPLE 14
[0291]
2-(trans-2-Aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmet-
hyl)benzamide (73.5 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodio- xol-5-ylmethyl)benzamide (96 mg)
and trans-1,2-diaminocyclohexane (0.072 mL) in a manner similar to
Example 1(1).
[0292] NMR (DMSO-d.sub.6, .delta.): 1.16-1.41 (4H, m), 1.61-1.71
(2H, m), 1.87-2.00 (2H, m), 2.84 (1H, m), 3.46 (1H, m), 4.36 (2H,
m), 4.59 (1H, d, J=4 Hz), 5.98 (2H, s), 6.78-6.92 (3H, m), 7.01
(1H, d, J=9 Hz), 8.10 (1H, dd, J=2, 9 Hz), 8.60 (1H, d, J=2 Hz),
9.10 (1H, d, J=8 Hz), 9.33 (1H, br)
[0293] Mass m/z: 413 (M.sup.++1).
EXAMPLE 15
[0294] 2-[(1R,
2R)-2-Hydroxy-1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3--
benzodioxol-5-ylmethyl)benzamide (81.8 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (93 mg)
and (R)-threoninol (61.4 mg) in a manner similar to Example 1
(1).
[0295] NMR (DMSO-d.sub.6, .delta.): 1.07 (3H, d, J=7 Hz), 3.37-3.56
(3H, m), 4.03 (1H, m), 4.34 (2H, d, J=5 Hz), 4.83 (1H, m), 4.97
(1H, d, J=5 Hz), 5.99 (2H, s), 6.75-6.94 (4H, m), 8.09 (1H, dd,
J=2, 9 Hz), 8.56 (1H, d, J=2 Hz), 9.23-9.30 (2H, m)
[0296] Mass m/z: 402 (M.sup.+-1).
EXAMPLE 16
[0297]
2-[2-(Tetrahydro-2-oxo-3-furanyl)amino]-5-nitro-N-(1,3-benzodioxol--
5-ylmethyl)benzamide (22.8 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-b- enzodioxol-5-ylmethyl)benzamide (54.8
mg) and 2-amino-.gamma.-butyrolacton- e hydrobromide (37.6 mg) in a
manner similar to Example 1(1).
[0298] NMR (DMSO-d.sub.6, .delta.): 2.15-2.3 (1H, m), 2.7-2.86 (1H,
m), 4.29 (1H, m), 4.35 (2H, d, J=5 Hz), 4.42 (1H, t, J=7 Hz), 4.83
(1H, m), 4.97 (1H, d, J=5 Hz), 5.99 (2H, s), 6.75-6.91 (3H, m),
6.97 (1H, d, J=9 Hz), 8.13 (1H, dd, J=2, 9 Hz), 8.61 (1H, d, J=2
Hz), 9.24 (1H, d, J=8 Hz), 9.38 (1H, t, J=6 Hz)
[0299] Mass m/z: 398 (M.sup.+-1).
EXAMPLE 17
[0300]
2-(tert-Butylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide
(94.3 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethy- l)benzamide (100 mg)
and tert-butylamine (115 mg) in a manner similar to Example 1
(1).
[0301] NMR (CDCl.sub.3, .delta.): 1.48 (9H, s), 4.48 (2H, d, J=7
Hz), 5.96 (2H, s), 6.47 (1H, br), 6.77-6.90 (4H, m), 8.11 (1H, dd,
J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 9.08 (1H, br)
[0302] Mass m/z: 370 (M.sup.+).
EXAMPLE 18
[0303]
2-[1-(Ethoxycarbonyl)piperidin-4-ylamino]-5-nitro-N-(1,3-benzodioxo-
l-5-ylmethyl)benzamide (204 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg)
and ethyl 4-amino-1-piperidinecarboxylate (122 mg) in a manner
similar to Example 1(1).
[0304] NMR (CDCl.sub.3, .delta.): 1.28 (3H, t, J=7 Hz), 1.50-1.70
(2H, br), 1.97-2.10 (2H, br), 3.06-3.23 (2H, br), 3.58-3.70 (1H,
br), 3.95-4.10 (2H, br), 4.16 (2H, q, J=7 Hz), 4.48 (2H, d, J=7
Hz), 5.98 (2H, s), 6.50 (1H, br), 6.69 (1H, d, J=8 Hz), 6.77-6.90
(3H, m), 8.16 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 9.00 (1H,
br)
[0305] Mass m/z: 469 (M.sup.+).
EXAMPLE 19
[0306]
2-(1-Benzylpiperidin-4-ylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmeth-
yl)benzamide (123 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg)
and 4-amino-1-benzylpiperidine (122 mg) in a manner similar to
Example 1(1).
[0307] NMR (CDCl.sub.3, .delta.): 1.63-1.78 (2H, br), 1.96-2.08
(2H, br), 2.17-2.33 (2H, br), 2.75-2.90 (2H, br), 3.48 (1H, br),
3.55 (2H, s), 4.50 (2H, d, J=7 Hz), 5.97 (2H, s), 6.40 (1H, br),
6.65 (1H, d, J=8 Hz), 6.77-6.88 (3H, m), 7.23-7.38 (5H, m), 8.13
(1H, dd, J=4, 8 Hz), 8.28 (1H, d, J=4 Hz), 8.93 (1H, br)
[0308] Mass m/z: 489 (M.sup.+).
EXAMPLE 20
[0309]
2-[2-Hydroxy-1,1-bis(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzo-
dioxol-5-ylmethyl)benzamide (14.6 mg) was obtained as brown powders
from 2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100
mg) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (114 mg) in a
manner similar to Example 1(1).
[0310] NMR (DMSO-d.sub.6, .delta.): 3.65 (6H, d, J=7 Hz), 4.33 (2H,
d, J=7 Hz), 4.84 (3H, t, J=7 Hz), 5.98 (2H, s), 6.79-6.93 (3H, m),
7.25 (1H, d, J=8 Hz), 8.02 (1H, dd, J=4, 8 Hz), 8.48 (1H, d, J=4
Hz), 9.18 (1H, br), 9.29 (1H, br)
[0311] Mass m/z: 418 (M.sup.+).
EXAMPLE 21
[0312]
2-[2-Hydroxy-1-(hydroxymethyl)-1-methylethylamino]-5-nitro-N-(1,3-b-
enzodioxol-5-ylmethyl)benzamide (115 mg) was obtained from
2-fluoro-5-nitro-N-(1.,3-benzodioxol-5-ylmethyl)benzamide (150 mg)
and 2-methyl-2-amino-1,3-propanediol (149 mg) in a manner similar
to Example 1 (1).
[0313] NMR (DMSO-d.sub.6, .delta.): 1.26 (3H, s), 3.45-3.60 (4H,
m), 4.32 (2H, d, J=7 Hz), 5.00 (2H, t, J=7 Hz), 5.98 (2H, s),
6.78-6.90 (3H, m), 7.08 (1H, d, J=8 Hz), 8.03 (1H, dd, J=4, 8 Hz),
8.51 (1H, d, J=4 Hz), 9.24 (1H, br), 9.33 (1H, br)
[0314] Mass m/z: 402 (M.sup.+).
EXAMPLE 22
[0315]
2-(tert-Butoxyamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamid-
e (56.0 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmeth- yl)benzamide (150 mg)
and 2-tert-butoxyamine (118 mg) in a manner similar to Example
1(1).
[0316] NMR (CDCl.sub.3, .delta.): 1.35 (9H, s), 4.51 (2H, d, J=7
Hz), 5.97 (2H, s), 6.48 (1H, br), 6.78-6.86 (3H, m), 7.28 (1H, d,
J=8 Hz), 8.19 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz)
[0317] Mass m/z: 386 (M.sup.-).
[0318] Preparation 23
[0319] To a solution of 4-amino-1-cyclohexanecarboxylic acid (500
mg) in dichloromethane (20 mL) and methanol (10 mL) was added 10%
hexane solution of trimethylsilyldiazomethane (638 mg), and the
mixture was stirred for 21 hours at ambient temperature. The
mixture was evaporated in vacuo to give methyl
4-amino-1-cyclohexanecarboxylate as a colorless oil (544 mg).
[0320] NMR (CDCl.sub.3, .delta.): 1.27-1.73 (6H, br), 1.88-2.08
(2H, br), 2.48 (1H, m), 2.85 (1H, m), 3.67 and 3.68 (3H, s).
EXAMPLE 23(1)
[0321]
2-[4-(Methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-
-ylmethyl)benzamide (381 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-ben- zodioxol-5-ylmethyl)benzamide (300 mg)
and methyl 4-amino-1-cyclohexanecar- boxylate (222 mg) in a manner
similar 10 to Example 1(1).
[0322] NMR (CDCl.sub.3, .delta.): 1.70-2.03 (8H, br), 2.52 (1H,
br), 3.63 (1H, br), 3.71 (3H, s), 4.50 (2H, d, J=7 Hz), 5.97 (2H,
s), 6.41 (1H, br), 6.66 (1H, m), 6.78-6.87 (3H, m), 8.14 (1H, m),
8.30 (1H, m), 8.86 and 9.08 (1H, br)
[0323] Mass m/z: 456 (M.sup.+).
EXAMPLE 23(2)
[0324] A mixture of
2-[4-(methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3--
benzodioxol-5-ylmethyl)benzamide (269 mg), methanol (10 mL),
tetrahydrofuran (10 mL) and 1N-sodium hydroxide solution (5 mL) was
20 stirred for an hour at 60.degree. C. The mixture was acidified
with 1N-hydrochloric acid to pH 4 and the organic solvent was
removed by evaporation. The aqueous layer was diluted with water
and extracted with chloroform. The extract was washed with brine,
dried over magnesium sulfate and evaporated in vacuo. The residue
was triturated with diisopropyl ether to give
2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-ben-
zodioxol-5-ylmethyl)benzamide as yellow powders (253 mg).
[0325] NMR (DMSO-d.sub.6, .delta.): 1.20-2.05 (8H, br), 2.42 (1H,
br), 3.77 (1H, br), 4.35 (2H, d, J=7 Hz), 5.96 (2H, s), 6.78-6.95
(4H, m), 8.10 (1H, dd, J=4, 8 Hz), 30 8.60 (1H, d, J=4 Hz), 9.08
and 9.33 (2H, br)
[0326] Mass m/z: 440 (M.sup.-).
EXAMPLE 23(3)
[0327] To a mixture of
2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodi-
oxol-5-ylmethyl)benzamide (80.0 mg),
1-[3-(dimethylamino)propyl]-3-ethylca- rbodiimide hydrochloride
(52.1 mg), 1-hydroxybenzotriazole (36.7 mg) in dimethylformamide (1
mL) was added 28% ammonia solution (10 drops). After stirring for
15 hours at ambient temperature, the mixture was partitioned
between water and ethyl acetate. The separated organic layer was
washed with an aqueous saturated sodium bicarbonate solution, water
and brine. Then, the resultant was dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with 10% methanol in chloroform. The
obtained product was triturated with diisopropyl ether to give
2-(4-carbamoylcyclohexylamino)--
5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders
(60.0 mg).
[0328] NMR (CDCl.sub.3, .delta.): 1.18-1.85 (8H, br), 2.22 (1H,
br), 3.82 (1H, br), 4.37 (2H, d, J=7 Hz), 5.99 (2H, s), 6.70-6.93
(5H, m), 7.23 (1H, br), 8.12 (1H, dd, J=4, 8 Hz), 8.62 (1H, d, 3=4
Hz), 9.06 and 9.43 (1H, br), 9.33 (1H, br)
[0329] Mass m/z: 439 (M.sup.+).
EXAMPLE 24(1)
[0330]
2-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-5-nitro-N-(1,3-benzo-
dioxol-5-ylmethyl)benzamide (539 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (480 mg)
and tert-butyl 4-amino-1-piperidinecarboxylate (604 mg) in a manner
similar to Example 1(1).
[0331] NMR (CDCl.sub.3, .delta.): 1.47 (9H, s), 1.57 (2H, br), 2.00
(2H, br), 3.08 (2H, br), 3.62 (1H, br), 4.00 (2H, br), 4.49 (2H, d,
J=7 Hz), 5.97 (2H, s), 6.50 (1H, br), 6.68 (1H, d, J=8 Hz), 6.82
(3H, m), 8.14 (1H, dd, J-4, 8 Hz), 8.31 (1H, d, J=4 Hz), 9.00 (1H,
d, J=8 Hz)
[0332] Mass m/z: 497 (M.sup.+).
EXAMPLE 24(2)
[0333] To a solution of
2-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-5-n-
itro-N-(1,3-benzodioxol-5-ylmethyl)benzamide(469 mg) in
dichloromethane (6 mL) was added trifluoroacetic acid (1.07 g), and
the mixture was stirred for 4 hours at ambient temperature. The
reaction mixture was washed with 1N-sodium hydroxide solution,
water and brine. Then, the resultant was dried over magnesium
sulfate and evaporated in vacuo. The residue was triturated with
diisopropyl ether to give 5-nitro-2-(4-piperidinylamino)--
N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (335
mg).
[0334] NMR (DMSO-d.sub.6, .delta.): 1.34 (2H, br), 1.89 (2H, br),
2.10 (1H, br), 2.64 (2H, br), 2.93 (2H, br), 3.65 (1H, br), 4.34
(2H, d, J=7 Hz), 5.98 (2H, s), 6.88 (4H, m), 8.11 (1H, dd, J=4, 8
Hz), 8.61 (1H, d, J=4 Hz), 9.14 (1H, d, J=8 Hz), 9.34 (1H, br)
[0335] Mass m/z: 399 (M.sup.+).
EXAMPLE 24(3)
[0336] A mixture of
5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-yl-
methyl)benzamide (80.0 mg), acetic acid (13.3 mg),
1-[3-(dimethylamino)pro- pyl]-3-ethylcarbodiimide hydrochloride
(57.7 mg) and 1-hydroxybenzotriazole (40.7 mg) in anhydrous
dimethylformamide (1 mL) was stirred for 3 hours at ambient
temperature. The mixture was partitioned between water and ethyl
acetate. The organic layer was separated and washed with an aqueous
saturated sodium bicarbonate solution, water and brine. Then, the
resultant was dried over magnesium sulfate and evaporated in vacuo.
The residue was triturated with diisopropyl ether to give
2-(1-acetyl-4-piperidinylamino)-5-nitro-N-(1,3--
benzodioxol-5-ylmethyl)benzamide as yellow powders (81.1 mg).
[0337] NMR (DMSO-d.sub.6, .delta.): 1.27 (1H, br), 1.46 (1H, br),
1.95 (2H, br), 2.01 (3H, s), 2.90 (1H, br), 3.23 (1H, br), 3.75
(1H, br), 3.82 (1H, br), 4.17 (1H, br), 4.34 (2H, d, J=7 Hz), 5.98
(2H, s), 6.81-6.90 (3H, m), 6.98 (1H, d, J=8 Hz), 8.12 (1H, dd,
J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.14 (1H, d, J=8 Hz), 9.35 (1H,
br)
[0338] Mass m/z: 439 (M.sup.+).
EXAMPLE 24(4)
[0339] To a mixture of
5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-
-ylmethyl)benzamide (80.0 mg) and 37% formaldehyde solution (192
mg) in methanol (4 mL) were added sodium cyanoborohydride (37.9 mg)
and acetic acid (4 drops). After stirring for 2 hours at ambient
temperature, the mixture was partitioned between an aqueous
saturated sodium bicarbonate solution and chloroform. The organic
layer was separated and washed with water and brine. Then, the
resultant was dried over magnesium sulfate and evaporated in vacuo.
The residue was triturated with diisopropyl ether to give
2-(1-methyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethy-
l)benzamide as yellow powders (65.0 mg).
[0340] NMR (CDCl.sub.3, .delta.): 1.53-1.80 (2H, br), 2.04 (2H,
br), 2.19 (2H, br), 2.32 (3H, s), 2.75 (2H, br), 3.48 (1H, br),
4.48 (2H, br), 5.97 (2H, s), 6.41 (1H, br), 6.63 (1H, br), 6.80
(3H, br), 8.13 (1H, br), 8.29 (1H, br), 8.93 (1H, br)
[0341] Mass m/z: 413 (M.sup.+).
EXAMPLE 24(5)
[0342]
2-(1-Formyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmeth-
yl)benzamide (70.0 mg) was obtained from
5-nitro-2-(4-piperidinylaminno)-N-
-(1,3-benzodioxol-5-ylmethyl)benzamide (80.0 mg) and formic acid
(10.4 mg) in a manner similar to Example 24(3).
[0343] NMR (DMSO-d.sub.6, .delta.): 1.20-1.48 (2H, br), 1.90-2.08
(2H, br), 2.85-2.97 (1H, br), 3.16-3.30 (1H, br), 3.60-3.73 (1H,
br), 3;80-3.95 (1H, br), 3.98-4.10 (1H, br), 4.34 (2H, d, J=7 Hz),
5.98 (2H, s), 6.75-6.93 (3H, m), 7.00 (1H, d, J=8 Hz), 7.99 (1H,
s), 8.13 (1H, dd, J=4, 8 Hz), 8.62 (1H, d, J=4 Hz), 9.17 (1H, d,
J=8 Hz), 9.35 (1H, br)
[0344] Mass m/z: 425 (M.sup.+).
EXAMPLE 25
[0345]
2-[1-(Hydroxymethyl)cyclopentylamino]-5-nitro-N-(1,3-benzodioxol-5--
ylmethyl)benzamide (130 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benz- odioxol-5-ylmethyl)benzamide (150 mg)
and 1-aminocyclopentanemethanol (81.4 mg) in a manner similar to
Example 1 (1).
[0346] NMR (CDCl.sub.3, .delta.): 1.66-1.86 (5H, m), 1.96 (4H, m),
3.76 (2H, d, J=7 Hz), 4.49 (2H, d, J=7 Hz), 5.97 (2H, s), 6.53 (1H,
br), 6.76-6.85 (4H, m), 8.07 (1H, dd, J=4, 8 Hz), 8.29 (1H, d, J=4
Hz), 9.06 (1H, br)
[0347] Mass m/z: 412 (M.sup.+).
EXAMPLE 26
[0348]
(S)-2-[1-(Hydroxymethyl)-2-rnethylpropylamino]-5-nitro-N-(1,3-benzo-
dioxol-5-ylmethyl)benzamide (127 mg) was obtained from
2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg)
and (S)-2-amino-3-methyl-1-butanol (72.9 mg) in a manner similar to
Example 1(1).
[0349] NMR (CDCl.sub.3, .delta.): 1.03 (6H, t, J=7 Hz), 1.75 (1H,
m), 2.02 (1H, m), 3.55 (1H, br), 3.69 (1H, m), 3.83 (1H, m), 4.50
(2H, m), 5.97 (2H, s), 6.57 (1H, br), 6.77-6.85 (4H, m), 8.09 (1H,
dd, J=4, 8 Hz), 8.29 (1H, d, J=4 Hz), 8.98 (1H, br)
[0350] Mass m/z: 400 (M.sup.+).
EXAMPLE 27
[0351]
2-[1-(Hydroxymethyl)pentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmet-
hyl)benzamide (203 mg) was prepared from
2-fluoro-5-nitro-N-(1,3-benzodiox- ol-5-ylmethyl)benzamide (200 mg)
and 2-amino-1-hexanol (221 mg) in a similar manner to that of
Example 1(1) as yellow crystals. mp 112-115.degree. C.
[0352] NMR (DMSO-d.sub.6, .delta.); 0.85 (3H, t, J=8 Hz), 1.20-1.40
(4H, m), 1.45 (1H, m), 1.65 (1H, m), 3.48 (2H, t, J=6 Hz), 3.63
(1H, m), 4.27-4.44 (2H, m), 4.92 (1H, t, J=6 Hz), 5.99 (2H, s),
6.81 (1H, d, J=8 Hz), 6.86-6.91 (3H, m), 8.10 (1H, dd, J=2, 10 Hz),
8.58 (1H, d, J=2 Hz), 9.13 (1H, d, J=8 Hz), 9.30 (1H, t, J=5
Hz).
[0353] Preparation 28
[0354] 2-(Cyclopropylamino)-5-nitrobenzoic acid (238 mg) was
obtained from 2-fluoro-5-nitrobenzoic acid (275 mg) and
cyclopropylamine (255 mg) in a manner similar to Example 1(1).
[0355] NMR (DMSO-d.sub.6, .delta.): 0.61 (2H, m), 0.90 (2H, m),
2.69 (1H, m), 7.22 (1H, d, J=9 Hz), 8.26 (1H, dd, J=2, 9 Hz), 8.65
(1H, d, J=2 Hz), 8.79 (1H, br).
EXAMPLE 28
[0356] N-Benzyl-2-(cyclopropylamino)-5-nitrobenzamide (151 mg) was
obtained from 2-(cyclopropylamino)-5-nitrobenzoic acid (115 mg) and
benzylamine (0.073 mL) in a manner similar to Preparation 1.
[0357] NMR (DMSO-d.sub.6, .delta.): 0.54 (2H, m), 0.87 (2H, m),
2.62 (1H, m), 4.46 (1H, d, J=6 Hz), 7.18 (1H, d, J=9 Hz), 7.22-7.40
(5H, in), 8.22 (1H, m), 8.64 (1H, d, J=2 Hz), 9.06 (1H, br), 9.44
(1H, t, J=6 Hz)
[0358] Mass m/z: 310 (M.sup.+-1).
[0359] Preparation 29
[0360] 2-(2-Hydroxycyclohexylamino)-5-nitrobenzoic acid (291 mg)
was obtained from 2-fluoro-5-nitrobenzoic acid (235 mg) and
2-aminocyclohexanol (292 mg) in a manner similar to Example
1(1).
[0361] NMR (DMSO-d.sub.6, .delta.): 1.15-1.45 (6H, m), 1.58-1.72
(2H, m), 1.88-2.08 (2H, m), 3.25-3.35 (3H, m), 4.95 (1H, m), 7.02
(1H, d, J=9 Hz), 8.11 (1H, dd, J=2, 9 Hz), 8.64 (1H, d, J=2 Hz),
8.98 (1H, d, J=6 Hz).
EXAMPLE 29
[0362] N-Benzyl-2-(2-hydroxycyclohexylamino)-5-nitrobenzamide (107
mg) was obtained from 2-(2-hydroxycyclohexylamino)-5-nitrobenzoic
acid (134 mg) and benzylamine (0.068 mL) in a manner similar to
Preparation 1.
[0363] NMR (DMSO-d.sub.6, .delta.): 1.38-1.42 (4H, m), 1.55-1.7
(2H, m), 1.8-2.1 (2H, m), 3.3-3.4 (2H, m), 4.43 (2H, d, J=6 Hz),
4.92 (1H, d, J=6 Hz), 6.96 (1H, d, J=9 Hz), 7.2-7.38 (5H, m), 8.09
(1H, dd, J=2, 9 Hz), 8.62 (1H, d, J=2 Hz), 9.28 (1H, d, J=6 Hz),
9.39 (1H, t, J=6 Hz)
[0364] Mass m/z: 368 (M.sup.+-1).
[0365] Preparation 30(1)
[0366] To a solution of ethyl 2-amino-5-nitrobenzoate (5.00 g),
cyclopentanone (9.00 g) and sodium borohydride (4.05 g) in
anhydrous tetrahydrofuran (100 mL) was added sulfuric acid (6 mL)
under ice-water cooling. The mixture was stirred for 9 hours at
0.degree. C. and then for 15 hours at ambient temperature. The
mixture was neutraiized with an aqueous saturated sodium
bicarbonate solution and extracted with ethyl acetate. The extract
was washed with water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with a mixture of hexane and ethyl
acetate (5:1). The obtained product was triturated with hexane to
give ethyl 2-cyclopentylamino-5-nitrobenzoate as yellow powders
(5.94 g).
[0367] NMR (CDCl.sub.3, .delta.): 1.41 (3H, t, J=7 Hz), 1.58-1.90
(6H, m), 2.10 (2H, m), 3.96 (1H, m), 4.36 (2H, q, J=7 Hz), 6.70
(1H, d, J=8 Hz), 8.18 (1H, dd, J=4, 8 Hz), 8.67 (1H, br), 8.87 (1H,
d, J=4 Hz)
[0368] Mass m/z: 279 (M.sup.+).
[0369] Preparation 30(2)
[0370] 2-Cyclopentylamino-5-nitrobenzoic acid (5.16 g) was obtained
as yellow powders from ethyl 2-cylcopentylamino-5-nitrobenzoate
(5.94 g) in a manner similar to Example 23(2).
[0371] NMR (DMSO-d.sub.6, .delta.): 1.47 (2H, m), 1.58-1.78 (4H,
br), 2.10 (2H br) 4.05 (1H, m) 6.93 (1H, d, J=8 Hz), 8.18 (1H, dd,
J=4, 8 Hz), 8.65 (1H, d, J=4 Hz), 8.83 (1H, br)
[0372] Mass m/z: 249 (M.sup.+).
EXAMPLE 30
[0373] To a mixture of 2-cyclopentylamino-5-nitrobenzoic acid (1.00
g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(1.15 g), 1-hydroxybenzotriazole (810 mg) in anhydrous
dimethylformamide (10 mL) was added
(1,3-benzodioxol-5-ylmethyl)amine (725 mg), and the mixture was
stirred for 15 hours at ambient temperature. The mixture was
partitioned between ethyl acetate and water. The organic layer was
separated and washed with an aqueous saturated sodium bicarbonate
solution, water and brine. Then, the resultant was dried over
magnesium sulfate and evaporated in vacuo. The residue was purified
by a silica gel column chromatography eluting with a mixture of
chloroform and methanol (50:1). The obtained product was triturated
with diisopropyl ether and recrystallized from a mixture of hexane
and ethyl acetate to give
2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide
as yellow powders (1.51 g).
[0374] NMR (CDCl.sub.3, .delta.): 1.58-1.86 (6H, m), 2.08 (2H, m),
3.90 (1H, m), 4.50 (2H, d, J=7 Hz), 5.98 (2H, s), 6.46 (1H, br),
6.68 (1H, d, J=8 Hz), 6.83 (3H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.29
(1H, d, J=4 Hz), 8.86 (1H, br)
[0375] Mass m/z: 382 (M.sup.+).
EXAMPLE 31
[0376] 2-(Cyclopentylamino)-N-(4-fluorobenzyl)-5-nitrobenzamide
(138 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and
4-fluorobenzylamine (60.0 mg) in a manner similar to Example
30.
[0377] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.00-2.15 (2H,
m), 3.89 (1H, m), 4.58 (2H, d, J=7 Hz), 6.54 (1H, br), 6.68 (1H, d,
J=8 Hz), 7.06 (2H, m), 7.33 (2H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.30
(1H, d, J=4 Hz), 8.85 (1H, br)
[0378] Mass m/z: 356 (M.sup.+).
EXAMPLE 32
[0379] 2-(Cyclopentylamino)-N-(4-methylbenzyl)-5-nitrobenzamide
(130 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and
4-methylbenzylamine (58.1 mg) in a manner similar to Example
30.
[0380] NMR (CDCl.sub.3, .delta.); 1.59-1.85 (6H, m), 2.03-2.15 (2H,
m), 2.37 (3H, s), 3.90 (1H, m), 4.55 (2H, d, J=7 Hz), 6.45 (1H,
br), 6.67 (1H, d, J=8 Hz), 7.18 (2H, d, J=8 Hz), 7.25 (2H, d, J=8
Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.27 (1H, d, J=4 Hz), 8.87 (1H,
br)
[0381] Mass m/z: 352 (M.sup.+).
EXAMPLE 33
[0382] 2-(Cyclopentylamino)-N-(4-methoxybenzyl)-5-nitrobenzamide
(138 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and
4-methoxybenzylamine (65.8 mg) in a manner similar to Example
30.
[0383] NMR (CDCl.sub.3, .delta.); 1.59-1.85 (6H, m), 2.00-2.15 (2H,
m), 3.82 (3H, s), 3.90 (1H, m), 4.52 (2H, d, J=7 Hz), 6.41 (1H,
br), 6.67 (1H, d, J=8 Hz), 6.90 (2H, d, J=8 Hz), 7.28 (2H, d, J=8
Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.27 (1H, d, J=4 Hz), 8.88 (1H,
br)
[0384] Mass m/z: 368 (M.sup.+).
EXAMPLE 34
[0385]
2-(Cyclopentylamino)-5-nitro-N-[4-(trifluoromethyl)benzyl]benzamide
(155 mg) was obtained as yellow powders from
2-(cyclopentylaniino)-5-nitr- obenzoic acid (100 mg) and
4-(trifluoromethyl)benzylamine (84.0 mg) in a manner similar to
Example 30.
[0386] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.02-2.14 (2H,
m), 3.92 (1H, m), 4.65 (2H, d, J=7 Hz), 6.68 (1H, d, J=8 Hz), 6.69
(1H, br), 7.47 (2H, d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 8.16 (1H, dd,
J=4, 8 Hz), 8.37 (1H, d, J=4 Hz), 8.85 (1H, br)
[0387] Mass m/z: 406 (M.sup.+).
Example 35
[0388] 2-(Cyclopentylamino)-5-nitro-N-(4-nitrobenzyl)benzamide (132
mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and
4-nitrobenzylamine (90.4 mg) in a manner similar to Example 30.
[0389] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.03-2.15 (2H,
m), 3.90 (1H, m), 4.72 (2H, d, J=7 Hz), 6.69 (1H, d, J=8 Hz), 6.90
(1H, br), 7.52 (2H, d, J=8 Hz), 8.16 (1H, dd, J=4, 8 Hz), 8.23 (2H,
d, J=8 Hz), 8.42 (1H, d, J=4 Hz), 8.87 (1H, br)
[0390] Mass m/z: 385 (M.sup.+).
EXAMPLE 36
[0391]
2-(Cyclopentylamino)-N-[4-(dimethylamino)benzyl-5-nitrobenzamide
(121 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitro- benzoic acid (100 mg) and
4-(dimethylamino)benzylamine hydrochloride (107 mg) in a manner
similar to Preparation 1.
[0392] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.03-2.15 (2H,
m), 2.96 (6H, s), 3.91 (1H, m), 4.47 (2H, d, J=7 Hz), 6.32 (1H,
br), 6.66 (1H, d, J=8 Hz), 6.73 (2H, d, J=8 Hz), 7.23 (2H, d, J=8
Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.27 (1H, d, J=4 Hz), 8.87 (1H,
br)
[0393] Mass m/z: 383 (M.sup.+).
EXAMPLE 37
[0394] N-(4-Sulfamoylbenzyl)-2-(cyclopentylamino)-5-nitrobenzamide
(162 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzo- ic acid (100 mg) and
4-sulfamoylbenzylamine hydrochloride (107 mg) in a manner similar
to Preparation 1.
[0395] NMR (DMSO-d.sub.6, .delta.): 1.38-1.52 (2H, m), 1.56-1.74
(4H, m), 1.96-2.10 (2H, m), 3.96 (1H, m), 4.50 (2H, d, J=7 Hz),
6.86 (1H, d, J=8 Hz), 7.33 (2H, s), 7.50 (2H, d, J=8 Hz), 7.78 (2H,
d, J=8 Hz), 8.15 (1H, d, J=8 Hz), 8.67 (1H, d, J=4 Hz), 9.16 (1H,
d, J=8 Hz), 9.50 (1H, br)
[0396] Mass m/z: 417 (M.sup.+).
EXAMPLE 38
[0397] N-(4-Bromobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (160
mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and
4-bromobenzylamine (107 mg) in a manner similar to Preparation
1.
[0398] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.03-2.15 (2H,
m), 3.92 (1H, m), 4.56 (2H, d, J=7 Hz), 6.61 (1H, br), 6.68 (1H, d,
J=8 Hz), 7.23 (2H, d, J=8 Hz), 7.48 (2H, d, J=8 Hz), 8.15 (1H, dd,
J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 8.86 (1H, br)
[0399] Mass m/z: 418 (M.sup.+).
EXAMPLE 39
[0400] 2-(Cyclopentylamino)-N-furfuryl-5-nitrobenzamide (120 mg)
was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and furfurylamine
(46.6 mg) in a manner similar to Preparation 1.
[0401] NMR (CDCl.sub.3, .delta.): 1.58-1.90 (6H, br), 2.03-2.18
(2H, br), 3.91 (1H, m), 4.61 (2H, d, J=7 Hz), 6.33 (2H, m), 6.51
(1H, br), 6.69 (1H, d, J=8 Hz), 7.40 (1H, s), 8.12 (1H, dd, J=4, 8
Hz), 8.32 (1H, d, J=4 Hz), 8.82 (1H, br)
[0402] Mass m/z: 328 (M.sup.+).
EXAMPLE 40
[0403] 2-(Cyclopentylamino)-5-nitro-N-(2-thienylmethyl)benzamide
(130 mg) was obtained as yellow powders from
2-cyclopentylamino-5-nitrobenzoic acid (100 mg) and
2-thiophenemethylamine (54.3 mg) in a manner similar to Preparation
1.
[0404] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.01-2.17 (2H,
m), 3.90 (1H, m), 4.77 (2H, d, J=7 Hz), 6.55 (1H, br), 6.68 (1H, d,
3=8 Hz), 6.98 (1H, m), 7.05 (1H, br), 7.28 (1H, m), 8.15 (1H, dd,
J=4, 8 Hz), 8.30 (1H, d, J=4 Hz), 8.81 (1H, br)
[0405] Mass m/z: 344 (M.sup.+).
EXAMPLE 41
[0406] 2-(Cyclopentylamino)-5-nitro-N-phenethylbenzide (141 mg) was
obtained as yellow powders from 2-(cyclopentylamino)-5-nitrobenzoic
acid (100 mg) and phenethylamine (58.1 mg) in a manner similar to
Preparation 1.
[0407] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.00-2.15 (2H,
m), 2.94 (2H, t, J=7 Hz), 3.68 (2H, m), 3.89 (1H, m), 6.24 (1H,
br), 6.65 (1H, d, J=8 Hz), 7.28 (3H, m), 7.35 (2H, m), 8.13 (1H,
dd, J=4, 8 Hz), 8.19 (1H, d, J=4 Hz), 8.75 (1H, br)
[0408] Mass m/z: 352 (M.sup.+).
EXAMPLE 42
[0409] 2-(Cyclopentylamino)-5-nitro-N-(3-phenylpropyl) benzamide
(120 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and
3-phenylpropylamine (64.8 mg) in a manner similar to Preparation
1.
[0410] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 1.94-2.15 (4H,
m), 2.74 (2H, t, J=7 Hz), 3.47 (2H, m), 3.89 (1H, m), 6.13 (1H,
br), 6.68 (1H, d, J=8 Hz), 7.17-7.33 (5H, m), 8.13 (2H, m), 8.83
(1H, br)
[0411] Mass m/z: 366 (M.sup.+).
EXAMPLE 43
[0412]
N-[1(2-Benzimidazolyl)methyl]-2-(cyclopentylamino)-5-nitrobenzamide
(132 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitro- benzoic acid (100 mg) and
2-(aminomethyl)benzimidazole dihydrochloride hydrate (106 mg) in a
manner similar to Preparation 1.
[0413] NMR (DMSO-d.sub.6, .delta.): 1.40-1.54 (2H, br), 1.54-1.75
(4H, br), 1.95-2.13 (2H, br), 3.96 (1H, br), 4.66 (2H, d, J=7 Hz),
6.89 (1H, d, J=8 Hz), 7.14 (2H, br), 7.45 (1H, br), 7.53 (1H, br),
8.14 (1H, dd, J=4, 8 Hz), 8.73 (1H, d, J=4 Hz), 9.14 (1H, br), 9.53
(1H, br), 12.32 (1H, br)
[0414] Mass m/z: 378 (M.sup.+).
EXAMPLE 44
[0415]
2-(Cyclopentylamino)-N-(4-hydroxy-3-methoxybenzyl)-5-nitrobenzamide
(143 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitro- benzoic acid (100 mg) and
4-hydroxy-3-methoxybenzylamine hydrochloride (90.9 mg) in a manner
similar to Preparation 1.
[0416] NMR (DMSO-d.sub.6, .delta.): 1.39-1.53 (2H, m), 1.55-1.75
(4H, m), 1.98-2.10 (2H, m), 3.76 (3H, s), 3.96 (1H, m), 4.35 (2H,
d, J=7 Hz), 6.72 (2H, s), 6.85 (2H, m), 8.13 (1H, dd, J=4, 8 Hz),
8.59 (1H, d, J=4 Hz), 8.88 (1H, s), 9.12 (1H, d, J=8 Hz), 9.28 (1H,
br)
[0417] Mass m/z: 384 (M.sup.+).
EXAMPLE 45
[0418]
2-(Cyclopentylamino)-N-(3,4-dihydroxybenzyl)-5-nitrobenzamide (109
mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzo- ic acid (100 mg) and
3,4-dihydroxybenzylamine hydrobromide (106 mg) in a manner similar
to Preparation 1.
[0419] NMR (DMSO-d.sub.6, .delta.): 1.38-1.52 (2H, m), 1.54-1.75
(4H, m), 1.97-2.10 (2H, m), 3.98 (1H, m), 4.28 (2H, br), 6.57 (1H,
m), 6.68 (2H, m), 6.87 (1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz),
8.59 (1H, d, J=4 Hz), 8.80 (2H, br), 9.20 (1H, d, J=8 Hz), 9.27
(1H, br).
EXAMPLE 46
[0420] 2-(Cyclopentylamino)-N-(3,4-difluorobenzyl)-5-nitrobenzamide
(130 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzo- ic acid (100 mg) and
3,4-difluorobenzylamine (68.6 mg) in a manner similar to
Preparation 1.
[0421] NMR (CDCl.sub.3, .delta.): 1.58-1.87 (6H, m), 2.03-2.14 (2H,
m), 3.90 (1H, m), 4.55 (2H, d, J=7 Hz), 6.68 (1H, br), 6.69 (1H, d,
J=8 Hz), 7.04-7.22 (3H, m), 8.16 (1H, dd, J=4, 8 Hz), 8.37 (1H, d,
J=4 Hz), 8.88 (1H, br)
[0422] Mass m/z: 374 (M.sup.+).
[0423] Preparation 47(1)
[0424] Ethyl 5-nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoate
(315 mg) was obtained as yellow powders from ethyl
2-amino-5-nitrobenzoate (300 mg) and tetrahydro-2H-thiopyran-4-one
(746 mg) in a manner similar to Preparation 30(1).
[0425] NMR (CDCl.sub.3, .delta.): 1.44 (3H, t, J=7 Hz), 1.75-1.89
(2H, m), 2.28-2.38 (2H, m), 2.70-2.84 (4H, m), 3.49-3.61 (1H, m),
4.38 (2H, q, J=7 Hz), 6.66 (1H, d, J=8 Hz), 8.19 (1H, dd, J=4, 8
Hz), 8.78 (1H, br), 8.87 (1H, d, J=4 Hz)
[0426] Mass m/z: 309 (M.sup.+).
[0427] Preparation 47(2)
[0428] 5-Nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoic acid
(280 mg) was obtained as yellow powders from ethyl
5-nitro-2-(tetrahydro-2H-thiopy- ran-4-ylamino)benzoate (310 mg) in
a manner similar to Preparation 30(2).
[0429] NMR (DMSO-d.sub.6, .delta.): 1.55-1.70 (2H, m), 2.17-2.28
(2H, br), 2.62-2.85 (4H, m), 3.66-3.82 (1H, br), 6.98 (1H, d, J=8
Hz), 8.17 (1H, dd, J=4, 8 Hz), 8.66 (1H, d, J=4 Hz), 8.85 (1H, d,
J=8 Hz)
[0430] Mass m/z: 281 (M.sup.+).
EXAMPLE 47(1)
[0431]
5-Nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahydro-2H-thiopyran-4-
-ylamino)benzamide (170 mg) was obtained as yellow powders from
S-nitro-2-(tetrahydro-2H-thiopyran-4-ylamino)benzoic acid (150 mg)
and (1,3-benzodioxol-5-ylmethyl)amine (96.4 mg) in a manner similar
to Preparation 1.
[0432] NMR (CDCl.sub.3, .delta.): 1.75-1.90 (2H, m), 2.27-2.36 (2H,
m), 2.70-2.82 (4H, m), 3.51 (1H, m), 4.50 (2H, d, J=7 Hz), 5.97
(2H, s), 6.47 (1H, br), 6.64 (1H, d, J=8 Hz), 6.78-6.85 (3H, m),
8.15 (1H, dd, J=4, 8 Hz), 8.31 (1H, d, J=4 Hz), 9.02 (1H, br)
[0433] Mass m/z: 414 (M.sup.+).
EXAMPLE 47(2)
[0434] To a solution of
5-nitro-N-(1,3-benzodioxol-5-ylmethyl)-2-(tetrahyd-
ro-2H-thiopyran-4-ylamino)benzamide (50.0 mg) in anhydrous
dichloromethane (1 mL) was added m-chloroperbenzoic acid (41.5 mg),
and the mixture was stirred for 4 hours at ambient temperature. To
the mixture were added an aqueous saturated sodium thiosulfate
solution and an aqueous sodium bicarbonate solution. The resulting
precipitates were collected by filtration and washed with water,
methanol and ethyl acetate to give
2-(1,1-dioxotetrahydro-2H-thiopyran-4-ylamino)-5-nitro-N-(1,3-benzodioxol-
-5-ylmethyl)benzamide as yellow powders (40.0 mg).
[0435] NMR (CDCl.sub.3, .delta.): 1.88-2.10 (2H, br), 2.20-2.33
(2H, br), 3.04-3.19 (2H, br), 3.29-3.43 (2H, br), 3.98 (1H, br),
4.37 (2H, d, J=7 Hz), 5.98 (2H, s), 6.79-6.98 (4H, m), 8.17 (1H,
m), 8.63 (1H, m), 9.18 (1H, br), 9.37 (1H, br)
[0436] Mass m/z: 446 (M.sup.+).
[0437] Preparation 48(1)
[0438] Methyl 5-cyano-2-(cyclopentylamino)benzoate (2.31 g) was
obtained as yellow powders from methyl 5-cyano-2-aminobenzoate
(2.00 g) and cyclopentanone (3.01 mL) in a manner similar to
Preparation 30(1).
[0439] NMR (CDCl.sub.3, .delta.); 1.53-1.86 (6H, br), 2.00-2.14
(2H, br), 3.87 (3H, s), 3.90 (1H, br), 6.71 (1H, d, J=8 Hz), 7.49
(1H, dd, J=4, 8 Hz), 8.19 (1H, d, J=4 Hz), 8.34 (1H, br).
[0440] Preparation 48(2)
[0441] A mixture of methyl 5-cyano-2-(cyclopentylamino)benzoate
(2.30 g), methanol (100 mL) and 1N-sodium hydroxide solution (20
mL) was heated for 2 hours under reflux. The reaction mixture was
acidified with 1N-hydrochloric acid to pH 4 and the organic solvent
was removed by evaporation. The aqueous layer was diluted with
water and extracted with ethyl acetate. The organic layer was
washed with water and brine and dried over magnesium sulfate. Then,
the resultant was evaporated in vacuo to give
5-cyano-2-(cyclopentylamino)benzoic acid (2.15 g) as pale yellow
powders.
[0442] NMR (DMSO-d.sub.6, .delta.): 1.43 (2H, m), 1.64 (4H, m),
2.03 (2H, m), 3.96 (1H, m), 6.89 (1H, d, J=8 Hz), 7.68 (1H, dd,
J=4, 8 Hz), 8.09 (1H, d, J=4 Hz), 8.51 (1H, d, J=8 Hz)
[0443] Mass m/z: 229 (M.sup.+).
[0444] Preparation 48(3)
[0445] To a solution of 5-cyano-2-(cyclopentylamino)benzoic acid
(40.0 mg) in anhydrous tetrahydrofuran (2 mL) was added 1.5 M
diisobutylaluminium hydride hexane solution (0.34 mL) under dry
ice-acetone cooling, and the mixture was stirred for an hour at
-78.degree. C. and then for 4 hours at ambient temperature. The
reaction was quenched by addition of methanol and an aqueous
saturated ammonium chloride solution. After stirring at ambient
temperature for a half hour, the mixture was partitioned with 5%
sulfuric acid and chloroform. The separated organic layer was
washed with brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by a preparative silica gel
chromatography with 10% methanol in chloroform to give
2-(cyclopentylamino)-5-formylbenzoic acid (25.0 mg) as pale orange
powders.
[0446] NMR (CDCl.sub.3, ): 1.55-1.88 (6H, m), 2.06-2.18 (2H, m),
3.97 (1H, m), 6.81 (1H, d, J=8 Hz), 7.92 (1H, dd, J=4, 8 Hz), 8.41
(1H, br), 8.48 (1H, d, J=4 Hz), 9.73 (1H, s).
EXAMPLE 48
[0447]
2-(Cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5-ylmethyl)benzami-
de (489 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-for- mylbenzoic acid (1.00 g) and
(1,3-benzodioxol-5-ylmethyl)amine (778 mg) in a manner similar to
Example 30.
[0448] NMR (CDCl.sub.3, .delta.): 1.55-1.87 (6H, br), 2.02-2.15
(2H, br), 3.88 (1H, br), 4.48 (2H, d, J=7 Hz), 5.95 (2H, s), 6.44
(1H, br), 6.75 (1H, d, J=8 Hz), 6.77-6.84 (3H, m), 7.74 (1H, d, J=8
Hz), 7.87 (1H, s), 8.70 (1H, br), 9.67 (1H, s)
[0449] Mass m/z: 367 (M.sup.+).
[0450] Preparation 49
[0451] 5-Cyano-2-fluoro-N-(1,3-benzodioxol-5-ylmethyl)benzamide
(534 mg) was obtained from 5-cyano-2-fluorobenzoic acid (300 mg)
and (1,3-benzodioxol-5-ylmethyl)amine (0.26 mL) in a manner similar
to Preparation 1.
[0452] NMR (DMSO-d.sub.6, .delta.): 4.37 (2H, d, J=6 Hz), 6.00 (2H,
s), 6.80-6.93 (3H, m), 7.56 (1H, t, J=9 Hz), 8.04 (1H, m), 8.13
(1H, dd, J=2, 6 Hz), 9.03 (1H, t, J=6 Hz)
[0453] Mass m/z: 297 (M.sup.+-1).
EXAMPLE 49(1)
[0454]
(R)-5-Cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-y-
lmethyl)benzamide (145 mg) was obtained from
5-cyano-2-fluoro-N-(1,3-benzo- dioxol-5-ylmethyl)benzamide (150 mg)
and (R)-2-amino-1-propanol (0.12 mL) in a manner similar to Example
1(1).
[0455] NMR (DMSO-d.sub.6, .delta.): 1.13 (3H, d, J=7 Hz), 3.42 (2H,
t, J=5 Hz), 3.67 (1H, m), 4.32 (2H, d, J=6 Hz), 4.92 (1H, t, J=5
Hz), 5.98 (2H, s), 6.77-6.92 (4H, m), 7.60 (1H, dd, J=2, 9 Hz),
8.04 (1H, d, J=2 Hz), 8.73 (1H, d, J=8 Hz), 8.99 (1H, t, J=6
Hz)
[0456] Mass m/z: 352 (M.sup.+-1).
EXAMPLE 49(2)
[0457] To a solution of
(R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,-
3-benzodioxol-5-ylmethyl)benzamide (76 mg) in ethanol (6 mL) was
added IN-sodium hydroxide (0.65 mL), and the mixture was heated for
6 hours under reflux. The solvent was evaporated in vacuo. The
residue was diluted with ethyl acetate and washed successively with
water and brine. The organic layer was dried over sodium sulfate
and evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with a mixture of chloroform and
methanol (9:1) to give (R)-5-carbamoyl-2-(2-hydroxy
-1-methylethylamino)-N-(1,3-benzodioxol-5-yl- methyl)benzamide (27
mg) as a solid substance.
[0458] NMR (DMSO-d.sub.6, .delta.): 1.13 (3H, d, J=7 Hz), 3.3-3.5
(2H, m), 3.62 (1H, m), 4.33 (2H, d, J=5 Hz), 4.86 (1H, t, J=5 Hz),
5.98 (2H, s), 6.73 (1H, d, J=9 Hz), 6.77-6.90 (3H, m), 7.04 (1H,
br), 7.58 (1H, br), 7.77 (1H, dd, J=2, 9 Hz), 8.14 (1H, d, J=2 Hz),
8.30 (1H, d, J=8 Hz), 8.83 (1H, t, J=5 Hz)
[0459] Mass m/z: 370 (M.sup.+-1).
EXAMPLE 50(1)
[0460]
5-Cyano-2-(trans-4-hydroxycyclohexylamino)-N-1,3-benzodioxol-5-ylme-
thyl)benzamide (142 mg) was obtained from
5-cyano-2-fluoro-N-(1,3-benzodio- xol-5-ylmethyl)benzamide (120 mg)
and trans-4-aminocyclohexanol (139 mg) in a manner similar to
Example 1(1).
[0461] NMR (DMSO-d.sub.6, .delta.): 1.15-1.40 (4H, m), 1.75-1.86
(2H, m), 1.89-2.00 (2H, m), 3.35-3.53 (2H, m), 4.31 (2H, d, J=6
Hz), 4.60 (1H, d, J=4 Hz), 5.98 (2H, s), 6.79 (1H, dd, J=2, 8 Hz),
6.83-6.92 (3H, m), 7.59 (1H, dd, J=2, 9 Hz), 8.05 (1H, d, J=2 Hz),
8.65 (1H, d, J=7 Hz), 9.01 (1H, t, J=6 Hz)
[0462] Mass m/z: 392 (M.sup.+-1).
EXAMPLE 50(2)
[0463]
5-Carbamoyl-2-(trans-4-hydroxycyclohexylamino)-N-(1,3-benzodioxol-5-
-ylmethyl)benzamide (51 mg) was obtained from
5-cyano-2-(trans-4-hydroxycy-
clohexylamino)-N-(1,3-benzodioxo]-5-ylmethyl)benzamide (71 mg) in a
manner similar to Example 49(2).
[0464] NMR (DMSO-d.sub.6, .delta.): 1.13-1.40 (4H, m), 1.75-1.87
(2H, m), 1.89-2.00 (2H, m), 3.3-3.53 (2H, m), 4.33 (2H, d, J=6 Hz),
4.59 (1H, d, J=4 Hz), 5.98 (2H, s), 6.74 (1H, d, J=9 Hz), 6.77-6.90
(3H, m), 7.04 (1H, br), 7.58 (1H, br), 7.77 (1H, dd, J=2, 9 Hz),
8.13 (1H, d, J=2 Hz), 8.24 (1H, d, J=8 Hz), 8.84 (1H, t, J=6
Hz)
[0465] Mass m/z: 410 (M.sup.+-1).
[0466] Preparation 51
[0467] To a solution of 2-fluoro-5-nitrobenzoic acid (235 mg) in
pyridine (1.5 mL) was added trans-4-aminocyclohexanol (292 mg), and
the mixture was stirred for 3 hours at 80.degree. C. After
evaporation of the solvent, the residue was dissolved in water and
neutralized with 1N-hydrochloric acid (1.9 mL). The resulting
precipitates were collected by filtration and washed successively
with water and methanol to give
2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (279 mg) as
a solid substance.
[0468] NMR (DMSO-d.sub.6, .delta.):1.21-1.46 (4H, m), 1.7-1.90 (2H,
m), 1.90-2.08 (2H, m), 3.3-3.65 (2H, m), 4.67 (1H, br), 6.98 (1H,
d, J=8 Hz) 8.14 (1H, dd, J=2, 8 Hz), 8.66 (1H, d, J=2 Hz), 8.74
(1H, d, J=7 Hz).
EXAMPLE 51
[0469] To a solution of
2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) in
dimethylformamide (2 mL) were added 1-hydroxybenzotriazole (96.4
mg), benzylamine (0.063 mL) and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (137
mg). The mixture was stirred for 3 hours at 20.degree. C. The
resulting mixture was diluted with ethyl acetate and washed
successively with diluted hydrochloric acid, aqueous sodium
bicarbonate and brine. The organic layer was dried over sodium
sulfate and evaporated in vacuo. The resulting residue was
triturated with methanol to give
N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (150
mg) as a solid substance.
[0470] mp: 233-234.degree. C.
[0471] NMR (DMSO-d.sub.6, .delta.): 1.17-1.46 (4H, m), 1.72-1.87
(2H, m), 1.92-2.04 (2H, m), 3.4-3.6 (2H, m), 4.42 (2H, d, J=7 Hz),
4.62 (1H, d, J=6 Hz), 6.90 (1H, d, J=8 Hz), 7.22-7.39 (5H, m), 8.13
(1H, dd, J=2, 8 Hz), 8.63 (1H, d, J=2 Hz), 9.10 (1H, d, J=7 Hz),
9.41 (1H, t, J=6 Hz).
EXAMPLE 52(1)
[0472]
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylm-
ethyl)benzamide (173 mg) was obtained as a solid substance from
2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) and
(1,3-benzodioxol-5-ylmethyl)amine (0.072 mL) in a manner similar to
Preparation 1.
[0473] mp: 205-206.degree. C.
[0474] NMR (DMSO-d.sub.6, .delta.) 1.20-1.45 (4H, m), 1.75-1.87
(2H, m), 1.92-2.02 (2H, m), 3.4-3.6 (2H, m), 4.34 (2H, d, J=7 Hz),
4.62 (1H, d, J=6 Hz), 5.99 (2H, s), 6.77-6.93 (4H, m), 8.11 (1H,
dd, J=2, 8 Hz), 8.60 (1H, d, J=2 Hz), 9.08 (1H, d, J=7 Hz), 9.33
(1H, t, J=6 Hz).
EXAMPLE 52(2)
[0475] To a solution of
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3--
benzodioxol-5-ylmethyl)benzamide (100 mg), benzoic acid (32.5 mg)
and diethyl azodicarboxylate (46.3 mg) in anhydrous tetrahydrofuran
(2 mL) was added triphenylphosphine (69.8 mg). The mixture was
stirred for 4 hours at ambient temperature. The mixture was
partitioned between an aqueous saturated sodium bicarbonate
solution and ethyl acetate. The separated organic layer was washed
with water and brine, dried over magnesium sulfate and evaporated
in vacuo. The residue was purified by a silica gel column
chromatography eluting with a mixture of hexane and ethyl acetate
(5:1 to 3:1). The obtained product was triturated with diisopropyl
ether to give 2-[cis-4-(benzoyloxy) cyclohexylamino]-5-nitro--
N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (68.5
mg).
[0476] NMR (CDCl.sub.3, .delta.): 1.78-2.17 (8H, m), 3.60 (1H, br),
4.52 (2H, d, J=7 Hz), 5.27 (1H, br), 5.96 (2H, s), 6.48 (1H, br),
6.71 (1H, d, J=8 Hz), 6.78-6.87 (3H, m), 7.46 (2H, m), 7.58 (1H,
m), 8.07 (2H, d, J=8 Hz), 8.17 (1H, dd, J=4, 8 Hz), 8.33 (1H, d,
J=4 Hz), 9.05 (1H, br)
[0477] Mass m/z: 516 (M.sup.+).
EXAMPLE 52(3)
[0478] A mixture of
2-(cis-4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-ben-
zodioxol-5-ylmethyl)benzamide (64.0 mg), methanol (5 mL),
tetrahydrofuran (5 mL) and 1N-sodium hydroxide solution (1 mL) was
stirred for 2 hours at 60.degree. C. After evaporation of the
organic solvent, the aqueous layer was diluted with water and
extracted with ethyl acetate. The extract was washed with an
aqueous saturated sodium bicarbonate solution, water and brine,
dried over magnesium sulfate and evaporated in vacuo. The residue
was triturated with diisopropyl ether to give
2-(cis-4-hydroxycyclohexyla-
mino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow
powders (50.5 mg).
[0479] NMR (CDCl.sub.3, .delta.): 1.70-1.95 (8H, br), 3.58 (1H,
br), 3.93 (1H, br), 4.51 (2H, d, J=7 Hz), 5.97 (2H, s), 6.43 (1H,
br), 6.67 (1H, d, J=8 Hz), 6.78-6.87 (3H, m), 8.14 (1H, dd, J=4, 8
Hz), 8.30 (1H, d, J=4 Hz), 9.03 (1H, br)
[0480] Mass m/z: 412 (M.sup.+).
EXAMPLE 53
[0481]
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(2-pyrazinylmethyl)ben-
zamide (129 mg) was obtained as yellow powders from
2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (150 mg) and
2-pyrazinylmethylamine (70.1 mg) in a manner similar to Example
51.
[0482] NMR (DMSO-d.sub.6, .delta.): 1.13-1.40 (4H, br), 1.70-1.88
(2H, br), 1.89-2.02 {2H, br), 3.40-3.60 (2H, br), 4.53-4.68 (3H,
br), 6.92 (1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.55 (1H, d,
J=4 Hz), 8.58-8.70 (2H, m), 8.98 (1H, d, J=8 Hz), 9.50 (1H,
br).
EXAMPLE 54
[0483]
2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(3,4,5-trimethoxybenzyl)-
benzamide (106 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (80.0 mg) and
3,4,5-trimethoxybenzylamine (67.6 mg) in a manner similar to
Example 51.
[0484] NMR (DMSO-d.sub.6, .delta.): 1.46-1.75 (8H, br), 3.63 (3H,
s), 3.61-3.72 (2H, br), 3.76 (6H, s), 4.39 (2H, d, J=7 Hz), 4.54
(1H, d, J=4 Hz), 6.67 (2H, s), 6.89 (1H, d, J=8 Hz), 8.12 (1H, dd,
J=4, 8 Hz), 8.62 (1H, d, J=4 Hz), 9.22 (1H, br), 9.33 (1H, br).
[0485] Preparation 55
[0486] To a suspension of 2-fluoro-5-nitrobenzoic acid (313 mg) in
dichloromethane (4 mL) were added thionyl chloride (0.17 mL) and
dimethylformamide (0.05 mL), and the mixture was heated for 36
hours under reflux. After evaporation of the solvent, the residue
was dissolved in dichloromethane (4 mL). To this solution were
added benzylamine (0.19 mL) and triethylamine (0.47 mL), and the
mixture was stirred for 30 minutes at 0.degree. C. After
evaporation of the solvent, the residue was dissolved in ethyl
acetate and washed successively with diluted hydrochloric acid, an
aqueous sodium bicarbonate solution and brine. The organic layer
was dried over sodium sulfate and evaporated tn vacuo. The
resulting residue was triturated with diisopropyl ether to give
N-benzyl-2-fluoro-5-nitrobenzamide (436 mg) as a solid
substance.
[0487] NMR (DMSO-d.sub.6, .delta.): 4.50 (2H, d, J=6 Hz), 7.22-7.40
(5H, m), 7.64 (1H, t, J=8 Hz), 8.38-8.47 (2H, m), 9.19 (1H, t, J=6
Hz).
EXAMPLE 55
[0488] N-Benzyl-2-[2-hydroxy-1-(hydroxymethyl)
ethylamino]-5-nitrobenzamid- e (54.5 mg) was obtained from
N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and
2-amino-1,3-propanediol (59.8 mg) in a manner similar to Example
1(1). mp: 171-173.degree. C.
[0489] NMR (DMSO-d.sub.6, .delta.): 3.45-3.5 (5H, m), 4.43 (2H, d,
J=7 Hz), 4.91 (2H, t, J=6 Hz), 6.92 (1H, d, J=8 Hz), 7.2-7.4 (5H,
m), 8.13 (1H, dd, J=2, 8 Hz), 8.62 (1H, d, J=2 Hz), 9.28 (1H, d,
J=7 Hz), 9.36 (1H, t, J=6 Hz).
EXAMPLE 56
[0490] N-Benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide
(346 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (300
mg) and trans-2-aminocyclohexanol (186 mg) in a manner similar to
Example 1 (1).
[0491] mp: 233-234.degree. C.
[0492] NMR (DMSO-d.sub.6, .delta.): 1.17-1.46 (4H, m), 1.72-1.87
(2H, m), 1.92-2.04 (2H, m), 3.4-3.6 (2H, m), 4.42 (2H, d, J=7 Hz),
4.62 (1H, d, J=6 Hz), 6.90 (1H, d, J=8 Hz), 7.22-7.39 (5H, m), 8.13
(1H, dd, J=2.8 Hz), 8.63 (1H, d, J=2 Hz), 9.10 (1H, d, J=7 Hz),
9.41 (1H, t, J=6 Hz).
EXAMPLE 57
[0493] N-Benzyl-2-(morpholinoamino)-5-nitrobenzamide (41 mg) was
obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and
4-aminomorpholine (40.9 mg) in a manner similar to Example 1
(1).
[0494] NMR (DMSO-d.sub.6, .delta.): 2.63-2.84 (4H, m), 3.22-3.78
(4H, m), 4.42 (2H, d, J=6 Hz), 7.2-7.4 (5H, m), 8.17 (1H, dd, J=2,
8 Hz), 8.63 (1H, d, J=2 Hz), 9.41 (1H, t, J=6 Hz), 9.55 (1H, s)
[0495] Mass m/z: 355 (M.sup.+-1).
EXAMPLE 58
[0496] N-Benzyl-5-nitro-2-(piperidinoamino)benzamide (65 mg) was
obtained from N-benzyl-2-fluoro-5-nitrobenzamide (111 mg) and
4-aminopiperidine (44.6 mg) in a manner similar to Example
1(1).
[0497] NMR (DMSO-d.sub.6, .delta.): 1.55-1.7 (6H, m), 2.4-3.0 (4H,
m), 4.43 (2H, d, J=6 Hz), 7.2-7.4 (5H, m), 8.16 (1H, dd, J=2, 8
Hz), 8.63 (1H, d, J=2 Hz), 9.42 (1H, t, J=6 Hz), 9.56 (1H, s)
[0498] Mass m/z: 353 (M.sup.+-1).
EXAMPLE 59
[0499] N-Benzyl-5-nitro-2-(2-thiazolylamino)benzamide (22.7 mg) was
obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100 mg) and
2-aminothiazole (43.8 mg) in a manner similar to Example 1(1).
[0500] NMR (DMSO-d.sub.6, .delta.): 4.54 (2H, d, J=6 Hz), 7.2-7.5
(6H, m), 7.48 (1H, m), 8.41 (1H, m), 8.73 (1H, d, J=9 Hz), 8.79
(1H, d, J=2 Hz), 9.79 (1H, t, J=6 Hz)
[0501] Mass m/z: 353 (M.sup.+-1).
EXAMPLE 60
[0502]
N-Benzyl-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide (215
mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (181 mg)
and trans-2-aminocyclopentanol (100 mg) in a manner similar to
Example 1(1).
[0503] NMR (CDCl.sub.3, .delta.): 1.54-1.96 (5H, m), 2.00-2.12 (1H,
m), 2.25-2.37 (1H, m), 3.78 (1H, m), 4.16 (1H, m), 4.58 (2H, d, J=7
Hz), 6.60 (1H, br), 6.86 (1H, d, J=8 Hz), 7.28-7.40 (5H, m), 8.15
(1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 8.85 (1H, br)
[0504] Mass m/z: 354 (M.sup.+).
[0505] Preparation 61 (1)
[0506] To a solution of 1,3-cyclopentanediol (500 mg) in pyridine
(10 mL) was added benzoyl chloride (688 mg), and the mixture was
stirred for 18 hours at ambient temperature. After evaporation of
the solvent, the residue was partitioned between ethyl acetate and
water. The separated organic layer was washed with 1N-hydrochloric
acid, water and brine, dried over magnesium sulfate and evaporated
in vacuo. The residue was purified by a silica gel column
chromatography eluting with a mixture of hexane and ethyl acetate
(3:1 to 1:1) to give 3-hydroxycyclopentyl benzoate as a colorless
oil (630 mg).
[0507] NMR (CDCl.sub.3, .delta.): 1.63-1.78 (1H, m), 1.80-2.00 (1H,
br), 2.04-2.20 (3H, m), 2.22-2.40 (1H, m), 4.40 and 4.56 (1H, m),
5.40 and 5.54 (1H, br), 7.42 (2H, m), 7.53 (1H, m), 8.00 (2H, d,
J=8 Hz).
[0508] Preparation 61(2)
[0509] To a solution of 3-hydroxycyclopentyl benzoate (630 mg) in
anhydrous tetrahydrofuran (15 mL) were added diphenylphosphoryl
azide (925 mg), diethyl azodicarboxylate (585 mg) and
triphenylphosphine (881 mg). After stirring for 2 hours at ambient
temperature, the mixture was partitioned between ethyl acetate and
water. The separated organic layer was washed with brine, dried
over magnesium sulfate and evaporated in vacuo. The residue was
purified by a silica gel column chromatography eluting with a
mixture of hexane and ethyl acetate (10:1) to give
3-azidocyclopentyl benzoate as pale yellow oil (531 mg).
[0510] NMR (CDCl.sub.3, .delta.): 1.74-2.46 (6H, br), 4.12-4.28
(1H, br), 5.28-5.54 (1H, br), 7.37-7.50 (2H, br), 7.51-7.62 (1H,
br), 7.94-8.10 (2H, m).
[0511] Preparation 61(3)
[0512] A mixture of 3-azidocyclopentyl benzoate (411 mg) and 10%
palladium on activated carbon (41.1 mg) in methanol (15 mL) was
stirred under hydrogen atmosphere (4 atrn) for 2 hours at ambient
temperature. After removal of the catalyst, the filtrate was
evaporated in vacuo to give 3-aminocyclopentyl benzoate as a pale
yellow oil (354 mg).
[0513] NMR (CDCl.sub.3, .delta.): 1.40-2.20 (5H, br), 2.41 (1H, m),
3.43 (1H, m), 5.38 (1H, br), 7.38-7.65 (3H, br), 8.03 (2H, d, J=8
Hz).
EXAMPLE 61 (1)
[0514] 2-[3-(Benzoyloxy)cyclopentylamino]-N-benzyl-5-nitrobenzamide
(158 mg) was obtained from N-benzyl-2-fluoro-5-nitrobenzamide (100
mg) and 3-aminocyclopentyl benzoate (112 mg) in a manner similar to
Example 1 (1).
[0515] NMR (CDCl.sub.3, .delta.): 1.88-2.30 (5H, br), 2.57 (1H, m),
4.08 (1H, br), 4.59 (2H, d, J=7 Hz), 5.51 (1H, br), 6.48 (1H, br),
6.68 (1H, d, J=8 Hz), 7.20-7.48 (7H, m), 7.52 (1H, m), 8.10 (2H, d,
J=8 Hz), 8.18 (1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 9.20 (1H,
br)
[0516] Mass m/z: 458 (M.sup.+).
EXAMPLE 61(2)
[0517] N-Benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide (129
mg) was obtained from
2-(3-benzoyloxyccyclopentylamino)-N-benzyl-5-nitrobenza- mide (189
mg) in a manner similar to Example 52(3).
[0518] NMR (CDCl.sub.3, .delta.): 1.62 (1H, d, J=7 Hz), 1.74-1.98
(4H, m), 2.09-2.36 (2H, m), 3.99 (1H, m), 4.47 (1H, br), 4.60 (2H,
d, J=7 Hz), 6.47 (1H, br), 6.65 (1H, d, J=8 Hz), 7.28-7.40 (5H, m),
8.16 (1H, dd, J=4, 8 Hz), 8.31 (1H, d, J=4 Hz), 9.05 (1H, br)
[0519] Mass m/z: 356 (M.sup.+).
[0520] Preparation 62
[0521] N-(3-Chloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (320
mg) was obtained as yellow oil from 2-fluoro-5-nitrobenzoic acid
(300 mg) and 3-chloro-4-methoxybenzylamine hydrochloride (405 mg)
in a manner similar to Preparation 1.
[0522] NMR (DMSO-d.sub.6, .delta.): 3.90 (3H, s), 4.60 (2H, d, J=7
Hz), 6.90 (1H, d, J=8 Hz), 6.88-7.00 (1H, br), 7.20-7.40 (3H, m),
8.38 (1H m), 9.00 (1H, m).
EXAMPLE 62
[0523]
N-(3-Chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-methyl)ethylam-
ino]-5-nitrobenzamide (85.0 mg) was obtained from
N-(3-chloro-4-methoxyben- zyl)-2-fluoro-5-nitrobenzamide (105 mg)
and 2-amino-1,3-propanediol (42.4 mg) in a manner similar to
Example 1(1).
[0524] NMR (DMSO-d.sub.6, .delta.): 3.54 (4H, br), 3.62 (1H, br),
3.83 (3H, s), 4.36 (2H, d, J=7 Hz), 4.92 (2H, t, J=7 Hz), 6.92 (1H,
d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.26 (1H, dd, J=4, 8 Hz), 7.38
(1H, d, J=4 Hz), 8.10 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz),
9.30 (2H, br)
[0525] Mass m/z: 408 (M.sup.+).
EXAMPLE 63(1)
[0526]
N-(3-Chloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclo-hexylamino)-5--
nitrobenzamide (200 mg) was obtained from
N-(3-chloro-4-methoxybenzyl)-2-f- luoro-5-nitrobenzamide (210 mg)
and trans4-aminocyclohexanol (107 mg) in a manner similar to
Example 1(1).
[0527] NMR (DMSO-d.sub.6, .delta.): 1.30 (4H, br), 1.80 (2H, br),
1.95 (2H, br), 3.50 (2H, br), 3.82 (3H, s), 4.35 (2H, d, J=7 Hz),
4.60 (1H, d, J=4 Hz), 6.90 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz),
7.25 (1H, dd, J=4, 8 Hz), 7.40 (1H, d, J=4 Hz), 8.10 (1H, dd, J=4,
8 Hz), 8.60 (1H, d, J=4 Hz), 9.04 (1H, d, J=8 Hz), 9.36 (1H,
br)
[0528] Mass m/z: 432 (M.sup.+).
EXAMPLE 63(2)
[0529] 2-[cis-4-(Benzoyloxy)
cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)- -5-nitrobenzamide
(155 mg) was obtained from N-(3-chloro-4-meth
oxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide(197
mg) in a manner similar to Example 52(2).
[0530] NMR (CDCl.sub.3, .delta.): 1.80-2.20 (8H, br), 3.60 (1H,
br), 3.91 (3H, s), 4.54 (2H, d, J=7 Hz), 5.25 (1H, br), 6.53 (1H,
br), 6.72 (1H, d, J=8 Hz), 6.95 (1H, d, J=8 Hz), 7.25 (1H, m),
7.39-7.50 (3H, m), 7.60 (1H, m), 8.07 (2H, d, J=8 Hz), 8.18 (1H,
dd, J=4, 8 Hz), 8.34 (1H, d, J=4 Hz), 9.02 (1H, br).
EXAMPLE 63(3)
[0531]
N-(3-Chloro-4-methoxybenzyl)-2-(cis-4-hydroxy-cyclohexylamino)-5-ni-
trobenzamide (85.0 mg) was obtained from
2-[cis-4-(benzoyloxy)cyclohexylam-
ino]-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide (155 mg) in a
manner similar to Example 52(3).
[0532] NMR (DMSO-d.sub.6, .delta.) 1.43-1.70 (8H, br), 3.66 (2H,
br), 3.83 (3H, s), 4.38 (2H, d, J=7 Hz), 4.54 (1H, d, J=4 Hz), 6.88
(1H, d, J=8 Hz), 7.12 (1H, d, J=8 Hz), 7.28 (1H, dd, J=4, 8 Hz),
7.39 (1H, d, J=4 Hz), 8.11 (1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4
Hz), 9.26 (1H, d, J=8 Hz), 9.36 (1H, br)
[0533] Mass m/z: 432 (M.sup.+).
[0534] Preparation 64
[0535] N-(3,4-Dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (14.2 g)
was obtained from 2-fluoro-5-nitrobenzoic acid (10.0 g) and
3,4-dimethoxybenzylamine (9.30 g) in a manner similar to
Preparation 55.
[0536] NMR (CDCl.sub.3, .delta.): 3.89 (6H, s), 4.63 (2H, d, J=7
Hz), 6.84-6.93 (4H, m), 7.30 (1H, m), 8.35 (1H, m), 9.03 (1H,
m)
[0537] Mass m/z: 333 (M.sup.+).
EXAMPLE 64(1)
[0538]
(R)-N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nit-
robenzamide (156 mg) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-- nitrobenzamide (150 mg) and
(R)-2-amino-1-propanol (50.6 mg) in a manner similar to Example
1(1).
[0539] mp: 125-127.degree. C.
[0540] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=7 Hz), 3.46 (2H,
br), 3.72 (3H, s), 3.74 (3H, s), 3.75 (1H, br), 4.36 (2H, d, J=7
Hz), 4.99 (1H, t, J=7 Hz), 6.83-6.95 (4H, m), 8.09 (1H, dd, J=4, 8
Hz), 8.57 (1H, d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.28 (1H, br)
[0541] Mass m/z: 388 (M.sup.+).
EXAMPLE 64(2)
[0542] To a mixture of
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylet-
hylamino)-5-nitrobenzamide (5.00 g), 4-dimethylaminopyridine (1.57
g, 12.8 mmol) and triethylamine (1.79 mL) in dichloromethane (150
mL) was added acetyl chloride (1.83 mL), and the mixture was
stirred for 5 hours at ambient temperature. The mixture was washed
with 1N-hydrochloric acid, water, an aqueous saturated sodium
bicarbonate solution and brine. Then, the resultant was dried over
magnesium sulfate and evaporated in vacuo. The residue was
triturated with diisopropyl ether. The obtained product was
recrystallized from a mixture of ethyl acetate and hexane (1:1) to
give
(R)-2-(2-acetoxy-1-methylethylamino)-N-(3,4-dimethoxybenzyl)-5-nitro-
benzamide as yellow crystals (5.10 g).
[0543] NMR (DMSO-d.sub.6, .delta.): 1.22 (3H, d, J=7 Hz), 1.99 (3H,
s), 3.73 (3H, s), 3.74 (3H, s), 4.00-4.12 (1H, br), 4.09 (2H, br),
4.37 (2H, d, J=7 Hz), 6.82-6.98 (4H, m), 8.13 (1H, dd, J=4, 8 Hz),
8.60 (1H, d, J=4 Hz), 9.06 (1H, d, J=8 Hz), 9.33 (1H, br)
[0544] Mass m/z: 430 (M.sup.+).
EXAMPLE 64(3)
[0545] To a solution of
(R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methyle-
thylamino)-5-nitrobenzamide (200 mg) in 1,2-dichloroethane (10 mL)
were added trimethyloxonium tetrafluoroborate (91.2 mg) and
2,6-di-tert-butyl-4-methylpyridine (158 mg), and the mixture was
heated for 3 hours under reflux. The mixture was washed with
1N-hydrochloric acid, water, an aqueous saturated sodium
bicarbonate solution and brine. Then, the resultant was dried over
magnesium sulfate and evaporated in vacuo. The residue was purified
by a silica gel column chromatography eluting with a mixture of
hexane and ethyl acetate (3:1 to 1:1). The obtained product was
triturated with diisopropyl ether to give
(R)-N-(3,4-dimethoxybenzyl)-2-(2-methoxy-1-methylethylamino)-5-nitrobenza-
mide as yellow powders (145 mg).
[0546] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=7 Hz), 3.29 (3H,
s), 3.42 (2H, br), 3.73 (3H, s), 3.74 (3H, s), 3.88-4.00 (1H, br),
4.37 (2H, d, J=7 Hz), 6.85-6.96 (4H, m), 8.12 (1H, dd, J=4, 8 Hz),
8.59 (1H, d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.29 (1H, br)
[0547] Mass m/z: 402 (M.sup.+).
EXAMPLE 65
[0548]
(S)-N-(3,4-Dimethoxybenzyl)-2-[1-(hydroxymethyl)-propylamino]-5-nit-
robenzamide (130 mg) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-- nitrobenzamide (150 mg) and
(S)-2-amino-1-butanol (60.0 mg) in a manner similar to Example
1(1).
[0549] mp: 168-169.degree. C.
[0550] NMR (DMSO-d.sub.6, .delta.): 0.90 (3H, t, J=7 Hz), 1.40-1.78
(2H, m), 3.48 (2H, br), 3.57 (1H, br), 3.72 (3H, s), 3.74 (3H, s),
4.38 (2H, br), 4.92 (1H, t, J=7 Hz), 6.83-6.95 (4H, m), 8.08 (1H,
dd, J=4, 8 Hz), 8.57 (1H, d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.29
(1H, br)
[0551] Mass m/z: 402 (M.sup.+).
EXAMPLE 66
[0552]
N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-5-nit-
robenzamide (156 mg) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-- nitrobenzamide (150 mg) and
2-amino-2-methyl-1-propanol (120 mg) in a manner similar to Example
1 (1).
[0553] mp: 161-162.degree. C.
[0554] NMR (DMSO-d.sub.6, .delta.): 1.33 (6H, s), 3.43 (2H, d, J=7
Hz), 3.73 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=7 Hz), S.19 (1H, t,
J=7 Hz), 6.80-6.96 (3H, m), 7.04 (1H, d, J=8 Hz), 8.07 (1H, dd,
J=4, 8 Hz), 8.51 (1H, d, J=4 Hz), 9.27 (2H, br)
[0555] Mass m/z: 402 (M.sup.+).
EXAMPLE 67
[0556]
N-(3,4-Dimethoxybenzyl)-2-(trans-2-hydroxycyclopentylamino)-5-nitro-
benzamide (6.18 g) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-ni- trobenzamide (6.00 g) and
trans-2-aminocyclopentanol (3.63 g) in a manner similar to Example
1(1).
[0557] mp: 154-155.degree. C.
[0558] NMR (DMSO-d.sub.6, .delta.): 1.60-1.96 (5H, m), 2.00-2.14
(1H, m), 2.27-2.40 (1H, m), 3.78 (1H, br), 3.89 (3H, s), 3.90 (3H,
s), 4.16 (1H, br), 4.53 (2H, d, J=7 Hz), 6.50 (1H, br), 6.88 (4H,
br), 8.16 (1H, dd, J=4, 8 Hz), 8.31 (1H, d, J=4 Hz), 8.85 (1H,
br)
[0559] Mass m/z: 414 (M.sup.+).
EXAMPLE 68
[0560]
(S)-N-(3,4-Dimethoxybenzyl)-2-(2-hydroxy-1-methyl-ethylamino)-5-nit-
robenzamide (188 mg) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-- nitrobenzamide (200 mg) and
(S)-2-amino-1-propanol (89.9 mg) in a manner similar to Example
1(1).
[0561] mp: 131-132.degree. C.
[0562] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=7 Hz), 3.46 (2H,
br), 3.72 (3H, s), 3.74 (3H, s), 3.75 (1H, br), 4.36 (2H, d, J=7
Hz), 4.99 (1H, t, J=7 Hz), 6.83-6.95 (4H, m), 8.09 (1H, dd, J=4, 8
Hz), 8.57 (1H, d, J=4 Hz), 9.09 (1H, d, J=8 Hz), 9.28 (1H, br)
[0563] Mass m/z: 388 (M.sup.+).
EXAMPLE 69
[0564]
N-(3,4-Dimethoxybenzyl)-5-nitro-2-[2-(2,2,2-trifluoroethyl)hydrazin-
o]benzamide (27 mg) was obtained as a yellow solid substance from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and
2,2,2-trifluoroethylhydrazine (116 mg) in a manner similar to
Example 1(1).
[0565] mp: 140-142.degree. C.
[0566] NMR (DMSO-d.sub.6, .delta.); 3.47-3.65 (2H, m), 3.73 (3H,
s), 3.74 (3H, s), 4.38 (2H, d, J=5.5 Hz), 5.81 (1H, t, J=4 Hz),
6.85 (1H, d, J=8.5 Hz), 6.91 (1H, d, J=8.5 Hz), 6.96 (1H, s), 7.39
(1H, d, J=8.5 Hz), 8.18 (1H, dd, J=8.5, 1.5 Hz), 8.57 (1H, d, J=1.5
Hz), 9.31 (1H, t, J=5.5 Hz), 9.84 (1H, s)
[0567] Mass m/z: 427 (M.sup.+-1).
EXAMPLE 70
[0568] N-(3,4-Dimethoxylbenzyl)-2-{[(1R,2
S)-cis-2,3-dihydro-2-hydroxy-1H--
inden-1-yl]amino}-5-nitrobenzamide (192 mg) was obtained as yellow
powders from N-(3,4-dimethoxylbenzyl)-2-fluoro-5-nitrobenzamide
(153 mg) and (1R,2S)-cis-1-amino-2-indanol (137 mg) in a manner
similar to Example 1(1).
[0569] mp. 248-250.degree. C.
[0570] NMR (DMSO-d.sub.6, .delta.); 2.86 (1H, d, J=16 Hz), 3.11
(1H, dd, J=16, 5 Hz), 3.71 (3H, s), 3.72 (3H, s), 4.30-4.44 (2H,
m), 4.58 (1H, m), 5.18 (1H, m), 5.37 (1H, d, J=5 Hz), 6.80-6.97
(3H, m), 7.07-7.34 (5H, m), 8.17 (1H, dd, J=10, 2 Hz), 8.63 (1H, d,
J=2 Hz), 9.30 (1H, t, J=6 Hz), 9.55 (1H, d, J=8 Hz)
[0571] Mass m/z: 462 (M.sup.+).
EXAMPLE 71
[0572] N-(3,4-Dimethoxylbenzyl)-2-[(1R,
2S)-2-hydroxy-1-methyl-2-phenyleth- yl]amino-5-nitrobenzamide (167
mg) was obtained as yellow powders from
2-fluoro-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (145 mg) and
(1S,2R)-(+)-Norephedrine (97 mg) in a manner similar to Example 1
(1).
[0573] m.p. 248-250.degree. C.
[0574] NMR (DMSO-d.sub.6, .delta.); 2.86 (1H, d, J=16 Hz), 3.11
(1H, dd, J=16, 5 Hz), 3.71 (3H, s), 3.72 (3H, s), 4.30-4.44 (2H,
m), 4.58 (1H, m), 5.18 (1H, m), 5.37 (1H, d, J=5 Hz), 6.80-6.97
(3H, m), 7.07-7.34 (5H, m), 8.17 (1H, dd, J=10, 2 Hz), 8.63 (1H, d,
J=2 Hz), 9.30 (1H, t, J=6 Hz), 9.55 (1H, d, J=8 Hz)
[0575] Mass m/z: 462 (M.sup.+).
EXAMPLE 72
[0576] 2-[(1S,
2R)-1-(Carbamoyl)-2-hydroxypropylamino]-N-(3,4-dimethoxyben-
zyl)-5-nitrobenzamide (151 mg) was obtained as yellow crystals from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and
L-threoninamide hydrocloride (139 mg) in a manner similar to
Example 1 (1).
[0577] NMR (DMSO-d.sub.6, .delta.): 1.13 (3H, d, J=6 Hz), 3.73 (3H,
s), 3.75 (3H, s), 3.91(1H, m), 4.06 (1H, m), 4.50 (2H, m), 5.23
(1H, d, J=4 Hz), 6.69 (1H, d, J=9 Hz), 6.81 (1H, brd, J=8 Hz), 6.92
(1H, d, J=8 Hz), 6.98 (1H, br), 7.26 (1H, s), 7.44 (1H, s), 8.14
(1H, dd, J=3, 9 Hz), 8.59 (1H, d, J=3 Hz), 9.28 (1H, t, J=5 Hz),
9.38 (1H, d, J=5 Hz)
[0578] Mass (ESI-): 431 (M-H).
EXAMPLE 73(1)
[0579]
2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5-nitrob-
enzamide (12.3 g) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nit- robenzamide (10.0 g) and
trans-1,4-diaminocyclohexane (10.2 g) in a manner similar to
Example 1(1).
[0580] NMR (DMSO-d.sub.6, .delta.): 1.10-1.38 (4H, br), 1.72-1.82
(2H, br), 1.94-2.05 (2H, br), 2.60 (1H, br), 3.46 (1H, br), 3.73
(3H, s), 3.74 (3H, s), 4.36 (2H, d, J=7 Hz), 6.83-6.95 (4H, m),
8.10 (1H, dd, J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 9.01 (1H, d, J=8
Hz), 9.31 (1H, br)
[0581] Mass m/z: 429 (M.sup.+).
EXAMPLE 73(2)
[0582] To a solution of
2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethox-
ybenzyl)-5nitrobenzamide (10 g) in dimethylformamide (60 mL) was
added ethyl formate (200 mL), and the mixture was heated for 8
hours under reflux. The mixture was partitioned between ethyl
acetate and water. The separated organic layer was washed with
water and brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by a silica gel column
chromatography eluting with a mixture of chloroform and methanol
(20:1). The obtained product was recrystallized from ethanol to
give
N-(3,4-dimethoxybenzyl)-2-[(trans4-formamidocyclohexyl)amino]-5-nitr-
obenzamide as yellow crystals (7.21 g)
[0583] NMR (DMSO-d.sub.6, .delta.): 1.25-1.55 (4H, br), 1.79-1.92
(2H, br), 1.95-2.10 (2H, br), 3.47-3.59 (1H, br), 3.60-3.72 (1H,
br), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.85-6.96
(4H, m), 7.95 (1H, s), 8.04 (1H, br), 8.08 (1H, dd, J=4, 8 Hz),
8.60 (1H, d, J=4 Hz), 9.01 (1H, d, J=8 Hz), 9.32 (1H, br)
[0584] Mass m/z: 455 (M.sup.+).
EXAMPLE 73(3)
[0585] Methanesulfonyl chloride (54 mg) and triethylamine (48 mg)
were added to a solution of
2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxyb-
enzyl)-5-nitrobenzamide (134 mg) in chloroform (2 mL). The mixture
was stirred for an hour at ambient temperature.
[0586] Methanesulfonyl chloride (54 mg) and triethylamine (48 mg)
were added to the reaction mixture. After stirring for an hour at
ambient temperature, the mixture was concentrated in vacuo. The
residue was partitioned between ethyl acetate and 3.6% hydrochloric
acid. The separated organic layer was washed with an saturated
aqueous sodium bicarbonate solution and brine, dried over magnesium
sulfate and concentrated in vacuo. The residual crystals were
suspended in hot ethanol and cooled with stirring. The resultant
was collected by filtration and washed with ethanol to give
N-(3,4-dimethoxybenzyl)-2-tran-
s4-(methanesulfonylamino)cyclohexylamino]-5-nitrobenzamide (142 mg)
as yellow crystals.
[0587] NMR (DMSO-d.sub.6, .delta.): 1.25-1.50 (4H, m), 1.88-2.05
(4H, m), 2.92 (3H, s), 3.18 (1H, m), 3.34-3.54 (1H, m), 3.73 (3H,
s), 3.74 (3H, s), 4.37 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz),
6.88-6.97 (3H, m), 7.09 (1H, d, J=7 Hz), 8.10 (1H, dd, J=2, 8 Hz),
8.60 (1H, d, J=2 Hz), 9.00 (1H, dd, J=7 Hz), 9.32 (1H, t, J=6
Hz)
[0588] Mass (ESI-) 505 (M-H).
EXAMPLE 73(4)
[0589]
2-(trans-4-acetamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitr-
obenzamide (110 mg) was obtained as yellow powders from
2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide
(100 mg) and acetic acid (15.4 mg) in a manner similar to
Example24(3).
[0590] NMR (DMSO-d.sub.6, .delta.): 1.22-1.45 (4H, br), 1.79 (3H,
s), 1.75-1.90 (2H, br), 1.96-2.09 (2H, br), 3.44-3.63 (2H, br),
3.73 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=7 Hz), 6.82-6.95 (4H,
m), 7.78 (1H, d, J=8 Hz), 8.10 (1H, dd, J=4, 8 Hz), 8.60 (1H, d,
J=4 Hz), 9.02 (1H, d, J=8 Hz), 9.32 (1H, br)
[0591] Mass m/z: 469(M.sup.+).
EXAMPLE 73(5)
[0592] To a solution of
2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxyb-
enzyl)-5-nitrobenzamide (100 mg) in dichloromethane (3 mL) was
added propyl isocyanate (21.8 mg), and the mixture was stirred for
2 hours at ambient temperature. After evaporation of the solvent,
the residue was triturated with ethyl acetate to give
N-(3,4-dimethoxybenzyl)-5-nitro-2-[-
trans-4-(3-propylureido)cyclohexylamino]benzamide as yellow powders
(118 mg).
[0593] NMR (DMSO-d.sub.6, .delta.): 0.82 (3H, t, J=7 Hz), 1.20-1.45
(6H, m), 1.79-1.90 (2H, br), 1.96-2.10 (2H, br), 2.92 (2H, q, J=7
Hz), 3.40 (1H, br), 3.51 (1H, br), 3.73 (3H, s), 3.74 (3H, s), 4.37
(2H, d, J=7 Hz), 5.70 (2H, br), 6.82-6.96 (4H, m), 8.11 (1H, dd,
J=4, 8 Hz), 8.59 (1H, d, J=4 Hz), 9.02 (1H, d, J=8 Hz), 9.31 (1H,
br)
[0594] Mass m/z: 512 (M.sup.+).
EXAMPLE 73(6)
[0595]
N-(3,4-Dimethoxybenzyl)-5-nitro-2-[trans4-(3-phenylureido)cyclohexy-
lamino]benzamide (158 mg) was obtained as yellow powders from
2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-S-nitrobenzamide
(150 mg) and phenyl isocyanate (45.9 mg) in a manner similar to
Example 73(5).
[0596] NMR (DMSO-d.sub.6, .delta.): 1.28-1.47 (4H, br), 1.87-1.96
(2H, br), 1.96-2.10 (2H, br), 3.45-3.63 (2H, br), 3.73 (3H, s),
3.75 (3H, s), 4.37 (2H, d, J=7 Hz), 6.12 (1H, d, J=8 Hz), 6.83-6.98
(5H, m), 7.21 (2H, m), 7.37 (2H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8
Hz), 8.31 (1H, s), 8.61 (1H, d, J=4 Hz), 9.05 (1H, d, J=8 Hz), 9.33
(1H, br)
[0597] Mass m/z: 546(M.sup.+).
EXAMPLE 73(7)
[0598] To a mixture of
2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybe-
nzyl)-5-nitrobenzamide (300 mg) and
1,3-bis(tert-butoxycarbonyl)-2-methyl-- 2-thiopseudourea (203 mg)
in ethanol (20 mL) was added mercury(II) oxide (152 mg). The
mixture was stirred for 2 hours at ambient temperature. The
resultant precipitates were removed by filtration and the filtrate
was evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with 2% methanol in chloroform. The
obtained product was triturated with diisopropyl ether to give
2-{trans4-[2,3-bis(tert-butoxycarbonyl)guanidino]
cyclohexylamino}-N-(3,4- -dimethoxybenzyl)-5-nitrobenzamide as
yellow powders (432 mg).
[0599] NMR (CDCl.sub.3, .delta.): 1.25-1.45 (4H, br), 1.50 (9H, s),
1.52 (9H, s), 1.95-2.10 (4H, br), 3.28-3.40 (1H, br), 3.89 (3H, s),
3.91 (3H, s), 3.85-4.00 (1H, br), 4.54 (2H, d, J=7 Hz), 6.58 (1H,
d, J=8 Hz), 6.85-6.98 (4H, m), 8.14 (1H, dd, J=4, 8 Hz), 8.28 (1H,
d, J=8 Hz), 8.42 (1H, d, J=4 Hz), 8.89 (1H, d, J=8 Hz)
[0600] Mass m/z: 671 (M.sup.+).
EXAMPLE 73(8)
[0601] To a solution of
2-{trans4-[2,3-bis(tert-butoxycarbonyl)guanidino]c-
yclohexylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (200 mg)
in ethyl acetate (4 mL) was added 4N-hydrochloric acid in ethyl
acetate (8 mL). The mixture was stirred for 15 hours at ambient
temperature. After evaporation of the solvent, the residue was
triturated with ethyl acetate to give
N-(3,4-dimethoxybenzyl)-2-(trans4-guanidinocyclohexylamino)-5-nit-
robenzamide hydrochloride as yellow powders (145 mg).
[0602] NMR (DMSO-d.sub.6, .delta.): 1.22-1.53 (4H, br), 1.86-1.97
(2H, br), 2.00-2.11 (2H, br), 3.22-3.62 (2H, br), 3.73 (3H, s),
3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.84-6.96 (4H, m), 7.72 (1H, d,
J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.02 (1H,
d, J=8 Hz), 9.35 (1H, br)
[0603] Mass m/z: 471 (M.sup.+).
EXAMPLE 73(9)
[0604] A mixture of
2-fluoro-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (200 mg) and
trans-4-formamidocyclohexylamine (170 mg) in pyridine (2 mL) was
stirred for 4 hours at 50.degree. C. The mixture was partitioned
between ethyl acetate and water. The separated organic layer was
washed with 1N HCl and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with 5% methanol in chloroform. The
obtained product was recrystallized from acetone (2 mL) to give
1-(3,4-dimethoxybenzyl)-2-[(trans4-formamidocycloh-
exyl)amino]-5-nitrobenzamide as yellow crystals (164 mg).
[0605] NMR (DMSO-d.sub.6, .delta.): 1.25-1.55 (4H, br), 1.79-1.92
(2H, br), 1.95-2.10 (2H, br), 3.47-3.59 (1H, br), 3.60-3.72 (1H,
br), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.85-6.96
(4H, m), 7.95 (1H, s), 8.04 (1H, br), 8.08 (1H, dd, J=4, 8 Hz),
8.60 (1H, d, J=4 Hz), 9.01 (1H, d, J=8 Hz), 9.32 (1H, br)
[0606] Mass m/z: 455 (M.sup.+).
EXAMPLE 74(1)
[0607]
2-[1-(tert-Butoxycarbonyl)piperidin-4-ylamino]-N-(3,4-dimethoxybenz-
yl)-5-nitrobenzamide (1.06 mg) was obtained as yellow powders from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (1.00 g) and
tert-butyl 4-amino-1-piperidinecarboxylate (899 mg) in a manner
similar to Example 1 (1).
[0608] NMR (CDCl.sub.3, .delta.): 1.48 (9H, s), 1.52-1.65 (2H, br),
1.95-2.10 (2H, br), 3.03-3.17 (2H, br), 3.64 (1H, br), 3.89 (3H,
s), 3.90 (3H, s), 3.94-4.06 (2H, br), 4.52 (2H, d, J=7 Hz), 6.49
(1H, br), 6.69 (1H, d, J=8 Hz), 6.84-6.95 (3H, m), 8.15 (1H, dd,
J=4, 8 Hz), 8.33 (1H, d, J=4 Hz), 8.98 (1H, br)
[0609] Mass m/z: 513 (M.sup.+).
EXAMPLE 74(2)
[0610]
N-(3,4-Dimethoxybenzyl)-5-nitro-2-(4-piperidinylamino)benzamide
(713 mg) was obtained as yellow powders from
2-[1-(tert-butoxycarbonyl)pi-
peridin-4-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (950
mg) in a manner similar to Example 24(2).
[0611] NMR (DMSO-d.sub.6, .delta.): 1.20-1.40 (2H, br), 1.83-1.96
(2H, br), 2.55-2.65 (2H, br), 2.85-2.98 (2H, br), 3.56-3.68 (1H,
br), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=7 Hz), 6.85-6.96
(4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.10 (1H,
d, J=8 Hz), 9.32 (1H, br)
[0612] Mass m/z: 415 (M.sup.+).
EXAMPLE 74(3)
[0613] 2-[1-[1,3-Bis (tert-butoxycarbonyl)
amidino]piperidin-4-ylamino]-N--
(3,4-dimethoxybenzyl)-5-nitrobenzamide (299 mg) was obtained as
yellow powders from
N-(3,4-dimethoxybenzyl)-5-nitro-2-(4-piperidinylamino)benzam- ide
(200 mg) in a manner similar to Example 73(7).
[0614] NMR (CDCl.sub.3, .delta.): 1.49 (9H, s), 1.51 (9H, s),
1.70-1.85 (2H, br), 2.05-2.18 (2H, br), 3.19-3.34 (2H, br),
3.67-3.78 (1H, br), 3.89 (3H, s), 3.90 (3H, s), 3.95-4.15 (2H, br),
4.53 (2H, d, J=7 Hz), 6.59 (1H, br), 6.69 (1H, d, J=8 Hz),
6.84-6.91 (3H, m), 8.16 (1H, dd, J=4, 8 Hz), 8.34 (1H, d, J=4 Hz),
9.01 (1H, d, J=8 Hz)
[0615] Mass m/z: 655 (M.sup.+).
EXAMPLE 74(4)
[0616]
2-(1-Amidinopiperidin-4-ylamino)-N-(3,4-dimethoxybenzyl)-5-nitroben-
zamide hydrochloride (150 mg) was obtained as yellow powders from
2-[1-[1,3-bis(tert-butoxycarbonyl)amidino]piperidin-4-ylamino]-N-(3,4-dim-
ethoxybenzyl)-5-nitrobenzamide (200 mg) in a manner similar to
Example 73(8).
[0617] NMR (DMSO-d.sub.6, .delta.): 1.40-1.58 (2H, br), 2.00-2.11
(2H, br), 3.17-3.30 (2H, br), 3.73 (3H, s), 3.74 (3H, s), 3.77-3.97
(3H, br), 4.37 (2H, d, J=7 Hz), 6.82-7.04 (4H, m), 7.52 (4H, br),
8.14 (1H, dd, J=4, 8 Hz), 8.63 (1H, d, J=4 Hz), 9.09 (1H, d, J=8
Hz), 9.38 (1H, br)
[0618] Mass m/z: 457 (M.sup.+).
EXAMPLE 75(1)
[0619]
N-(3,4-Dimethoxybenzyl)-2(trans-4-hydroxycyclohexylamino)-5-nitrobe-
nzamide (11.8 g) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitr- obenzamide (10.0 g) and
trans-4-aminocyclohexanol (6.89 g) in a manner similar to Example
1(1).
[0620] NMR (DMSO-d.sub.6, .delta.): 1.23-1.41 (4H, m), 1.78-1.88
(2H, br), 1.91-2.01 (2H, br), 3.50 (2H, br), 3.73 (3H, s), 3.74
(3H, s), 4.37 (2H, d, J=7 Hz), 4.62 (1H, d, J=4 Hz), 6.82-6.96 (4H,
m), 8.11 (1H, m), 8.60 (1H, m), 9.04 (1H, br), 9.32 (1H, br)
[0621] Mass m/z: 428 (M.sup.+).
EXAMPLE 75(2)
[0622]
2-cis-4-(Benzoyloxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitr-
obenzamide (9.00 g) was obtained from
N-(3,4-dimethoxybenzyl)-2-(trans-4-h-
ydroxycyclohexylamino)-5-nitrobenzamide (10.0 g) in a manner
similar to Example 52(2).
[0623] NMR (CDCl.sub.3, .delta.): 1.78-2.15 (8H, br), 3.61 (1H,
br), 3.88 (3H, s), 3.89 (3H, s), 4.56 (2H, d, J=7 Hz), 5.26 (1H,
br), 6.48 (1H, br), 6.71 (1H, d, J=8 Hz), 6.85-6.93 (3H, m),
7.42-7.50 (2H, m), 7.58 (1H, m), 8.06 (2H, d, J=8 Hz), 8.18 (1H,
dd, J=4, 8 Hz), 8.33 (1H, d, J=4 Hz), 9.05 (1H, br)
[0624] Mass m/z: 532 (M.sup.+).
EXAMPLE 75(3)
[0625]
N-(3,4-Dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitroben-
zamide (4.56 g) was obtained from 2-[cis-4-(benzoyloxy)
cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (9.00 g)
and in a manner similar to Example 52(3).
[0626] NMR (DMSO-d.sub.6, .delta.): 1.45-1.72 (8H, br), 3.66 (2H,
br), 3.73 (3H, s), 3.75 (3H, s), 4.38 (2H, d, J=7 Hz), 4.55 (1H, d,
J=4 Hz), 6.83-6.97 (4H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.61 (1H, d,
J=4 Hz), 9.26 (1H, br), 9.32 (1H, br)
[0627] Mass m/z: 428 (M.sup.+).
EXAMPLE 75(4)
[0628] To a suspension of
N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohex-
ylamino)-5-nitrobenzamide (1.0 g) in dichloromethane (20 mL) were
added triethylamine (0.49 mL) and 4-dimethylaminopyridine (284 mg),
and then acetyl chloride (0.20 mL) at 20.degree. C. The reaction
mixture was stirred for 2 hours at 20.degree. C. and then, acetyl
chloride (0.05 mL) was added. After stirring for an hour at
20.degree. C., the reaction mixture was partitioned between
chloroform and 1N-hydrochloric acid. The separated organic layer
was washed with water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with a mixture of ethyl acetate and
hexane (1:2). The residual solid was recrystallized from ethyl
acetate to give
2-[cis-4-(acetoxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl-
)-5-nitrobenzamide (429 mg) as yellow crystals.
[0629] mp 147-148.degree. C.
[0630] NMR (DMSO-d.sub.6, .delta.); 1.55-1.90 (8H, br), 2.03 (3H,
s), 3.73 (3H, s), 3.74 (1H, m), 3.75 (3H, s), 4.39 (2H, d, J=8 Hz),
4.82 (1H, m), 6.85 (1H, dd, J=2, 8 Hz), 6.92 (1H, d, J=8 Hz), 6.93
(1H, d, J=10 Hz), 6.97 (1H, d, J=2 Hz), 8.12 (1H, dd, J=3, 10 Hz),
8.63 (1H, d, J=3 Hz), 9.26 (1H, d, J=10 Hz), 9.36 (1H, t, J=6
Hz).
EXAMPLE 76(1)
[0631]
N-(3,4-Dimethoxylbenzyl)-2-[(R)-1-methoxycarbonyl-3-(methylthio)pro-
pylamino]-5-nitrobenzamide (245 mg) was obtained from
2-fluoro-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (210 mg) and
(R)-methionine methyl ester (205 mg) in a manner similar to Example
1(1).
[0632] NMR (DMSO-d.sub.6, .delta.): 2.00-2.22 (2H, m), 2.03 (3H,
s), 2.44-2.60 (2H, m), 3.70 (3H, s), 3.73 (3H, s), 3.75 (3H, s),
4.40 (2H, d, J=5 Hz), 4.61 (1H, dt, J=8, 6 Hz), 6.79-7.00 (4H, m),
8.15 (1H, dd, J=9, 3 Hz), 8.63 (1H, d, J=3 Hz), 9.32-9.43 (2H,
m)
[0633] Mass m/z: 476 (M.sup.+).
EXAMPLE 76(2)
[0634] To a solution of
N-(3,4-dimethoxylbenzyl)-2-[(R)-1-methoxycarbonyl--
3-(methylthio)propylamino]-5-ni trobenzamide (175 mg) in anhydrous
tetrahydrofuran (3 mL) were added lithium chloride (31 mg), and
then sodium borohydride (28 mg) in ethanol (3 mL) at ambient
temperature. The mixture was stirred for one day. After evaporation
of the solvent, the residue was partitioned between ethyl acetate
and 10% citric acid aqueous solution. The separated organic layer
was washed with water and brine and dried over magnesium sulfate.
The residual solid was recrystallized from ethyl acetate-hexane to
give N-(3,4-dimethoxylbenzyl)-2-[(R)-1-hydroxymet-
hyl-3-(methylthio)propylamino]-5-nitrobenzamide (122 mg).
[0635] m.p. 150-152.degree. C.
[0636] NMR (DMSO-d.sub.6, .delta.): 1.73 (1H, m), 1.92 (1H, m),
2.03 (3H, s), 2.40-2.62 (2H, m), 3.50 (2H, m), 3.73 (3H, s), 3.74
(3H, s), 3.78 (1H, m), 4.35 (1H, dd, J=15, 6 Hz), 4.40 (1H, dd,
J=15, 6 Hz), 4.99 (1H, t, J=5 Hz), 6.80-6.99 (4H, m), 8.12 (1H, dd,
J=9, 3 Hz), 8.58 (1H, d, J=3 Hz), 8.58 (1H, d, J=3 Hz), 9.10 (1H,
d, J=8 Hz), 9.30 (1H, dd, J=6, 6 Hz)
[0637] Mass m/z: 448 (M.sup.+).
[0638] Preparation 77(1)
[0639] cis-4-(N-tert-Butoxycarbonylamino)cyclohexylazide (266 mg)
was obtained as an oil from
trans4-(N-tert-butoxycarbonylamino)cyclohexanol (200 mg) in a
manner similar to Preparation 61(2).
[0640] NMR (CDCl.sub.3, .delta.): 1.44 (9H, s), 1.4-1.85 (8H, m),
3.51 (1H, br), 3.71 (1H, br), 4.48 (1H, br).
[0641] Preparation 77(2)
[0642] cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamine (77 mg)
was obtained as an oil from
cis-4-(N-tert-butoxycarbonylamino)cyclohexylazide (252 mg) in a
manner similar to Preparation 61(3).
[0643] NMR (CDCl.sub.3, .delta.): 1.44 (9H, s), 1.5-1.8 (4H, m),
1.8-2.2 (4H, m), 2.91 (1H, br), 3.65 (1H, br), 4.66 (1H, br)
[0644] Mass (ESI+) 215(M+H).
EXAMPLE 77(1)
[0645]
2-[cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamino]-N-(3,4-dimeth-
oxybenzyl)-5-nitrobenzamide (282 mg) was obtained as amorphous
powders from N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200
mg) and cis-4-(N-tert-butoxycarbonylamino)cyclohexylamine (256 mg)
in a manner similar to Example 1(1).
[0646] NMR (CDCl.sub.3, .delta.): 1.45 (9H, s), 1.51-1.70 (2H, m),
1.75-1.94 (6H, m), 3.55-3.80 (2H, m), 3.89 (3H, s), 3.90 (3H, s),
4.54 (2H, d, J=5 Hz), 4.59 (1H, m), 6.49 (1H, m), 6.66 (1H, d, J=9
Hz), 6.82-6.95 (3H, m), 8.15 (1H, d, J=9 Hz), 8.33 (1H, d, J=2 Hz),
9.17 (1H, d, J=7 Hz)
[0647] Mass (ESI-): 527(M-H).
EXAMPLE 77(2)
[0648] 4N-Hydrogen chloride solution in ethyl acetate (2 mL) was
added to a solution of
2-[cis-4-(N-tert-butoxycarbonylamino)cyclohexylamino]-N-(3,-
4-dimethoxybenzyl)-5-nitrobenzamide (270 mg) in ethyl acetate (1
mL). The mixture was stirred for 2 hours at ambient temperature.
The reaction mixture was concentrated in vacuo. To the residue were
added an aqueous saturated sodium bicarbonate solution and ethyl
acetate. The appeared precipitates were collected by filtration and
washed with ethyl acetate and water successively to give
2-(cis-4-aminocyclohexylamino)-N-(3,4-dime-
thoxybenzyl)-5-nitrobenzamide (77 mg) as yellow powders. The
filtrate was separated, and the aqueous layer was extracted with
chloroform. The combined organic layer was dried over magnesium
sulfate and concentrated in vacuo to give a second crop (137.8
mg).
[0649] NMR (DMSO-d.sub.6, .delta.): 1.50-1.90 (8H, m), 3.16 (1H,
m), 3.73 (3H, s), 3.75 (3H, s), 3.80 (1H, m), 4.40 (2H, d, J=5 Hz),
6.83-6.99 (4H, m), 8.14 (1H, dd, J=2, 9 Hz), 8.13 (1H, dd, J=2, 9
Hz), 8.66 (1H, d, J=3 Hz), 9.35-9.44 (2H, m)
[0650] Mass: (ESI+) 429(M+H), (ESI-) 427(M-H).
EXAMPLE 77(3)
[0651]
2-(cis-4-Formamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrob-
enzamide(129 mg) was obtained as yellow crystals from
2-(cis-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide
(180 mg) in a manner similar to Example73(2).
[0652] NMR (DMSO-d.sub.6, .delta.): 1.42-1.60 (2H, m), 1.60-1.83
(6H, m), 3.65-3.78 (1H, m), 3.73 (3H, s), 3.85 (1H, m), 4.39 (2H,
d, J=6 Hz), 6.82-6.98 (4H, m), 7.95 and 8.03 (1H, s), 8.12 (1H, dd,
J=2, 9 Hz), 8.20 (1H, d, J=7 Hz), 8.63 (1H, d, J=2 Hz), 9.27-9.41
(2H, m)
[0653] Mass: (ESI+) 457(M+H), (ESI-) 455(M-H).
[0654] Preparation 78(1)
[0655] Iodomethane (554 mg) was added to a suspension of
(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionoic
acid (1.1 g) and potassium carbonate (539 mg) in
N,N-dimethylformamide (7 mL). The mixture was stirred for 2 hours
at ambient temperature and partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried over
magnesium sulfate and concentrated in vacuo to give methyl
(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)pr-
opionate (1.2 g) as an oil.
[0656] NMR (CDCl.sub.3, .delta.): 1.42 (9H, s), 3.45-3.60 (2H, m),
3.76 (3H, s), 4.41 (1H, m), 4.83 (1H, m), 5.12 (2H, s), 5.79 (1H,
m), 7.30-7.40 (5H, m).
[0657] Preparation 78(2)
[0658] Sodium borohydride (251 mg) was added to a solution of
methyl
(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate
(1.17 g) in methanol (10 mL) at 0.degree. C. The mixture was
stirred for an hour at the same temperature and then for an hour at
ambient temperature. After addition of 3.6% hydrochloric acid, the
mixture was concentrated in vacuo and the residue was partitioned
between ethyl acetate and an aqueous saturated sodium bicarbonate
solution. The organic layer was washed with brine, dried over
magnesium sulfate and concentrated in vacuo. The residual crystals
were suspended in hot diisopropyl ether and cooled to ambient
temperature with stirring. The residual crystals were collected by
filtration and washed with diisopropyl ether to give
(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxyca-
rbonylamino)propanol (945 mg) as white crystals.
[0659] NMR (CDCl.sub.3, .delta.): 1.44 (9H, s), 3.18-3.40 (2H, m),
3.46-3.75 (4H, m), 4.90 (1H, m), 5.09 (2H, s), 5.35 (1H, d, J=5
Hz), 7.30-7.40 (5H, m)
[0660] Mass: (ESI-) 323 (M-H).
[0661] Preparation 78(3)
[0662] 10% Palladium on activated carbon (10 mg) was added to a
solution of
(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanol
(920 mg) in methanol (10 mL) and dioxane (1 mL). The mixture was
stirred under hydrogen atmosphere (3.5 atm) for one and a half days
at ambient temperature. The catalyst was removed by filtration and
the filtrate was concentrated in vacuo. The residue was dissolved
in ethyl acetate, dried over magnesium sulfate, and concentrated in
vacuo to give (S)-2-amino-3-(tert-butoxycarbonylamino)propanol (571
mg) as a white solid substance.
[0663] NMR (CDCl.sub.3, .delta.): 1.45 (9H, s), 2.90 (1H, m), 3.18
(2H, m), 3.49 (2H, m), 4.90 (1H, br)
[0664] Mass: (ESI+) 191(M+H), (ESI-) 189(M-H).
EXAMPLE 78(1)
[0665]
(S)-2-{1-[tert-(Butoxycarbonyl)aminomethyl]-2-hydroxyethylamino}-N--
(3,4-dimethoxybenzyl)-5-nitrobenzamide (719 mg) was obtained as
yellow crystals from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (930 mg) and
(S)-2-amino-3-(tert-butoxycarbonylamino)propanol (556 mg) in a
manner similar to Example 1(1).
[0666] NMR (DMSO-d.sub.6, .delta.): 1.36 (9H, s), 3.08 (2H, m),
3.53 (1H, m), 3.73 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=6 Hz),
4.99 (1H, t, J=6 Hz), 6.84 (1H, brd, J=8 Hz), 6.90-7.06 (4H, m),
8.09 (1H, dd, J=2, 9 Hz), 8.58 (H, d, J=2 Hz), 9.20 (1H, d, J=9
Hz), 9.26 (1H, t, J=6 Hz)
[0667] Mass: (ESI-) 503 (M-H).
EXAMPLE 78(2)
[0668]
(S)-2-{1-[tert-(Butoxycarbonyl)aminomethyl]-2-hydroxyethylamino}-N--
(3,4-dimethoxybenzyl)-5-nitrobenzamide (618 mg) was dissolved in
pyridine (5 mL) and acetic anhydride (2 mL). The mixture was
stirred at ambient temperature overnight, then concentrated in
vacuo. The residue was partitioned between ethyl acetate and 3.6%
hydrochloric acid. The organic layer was washed with an aqueous
saturated sodium bicarbonate solution and brine, dried over
magnesium sulfate and concentrated in vacuo. 4N-Hydrogen chloride
solution in ethyl acetate (5 mL) was added to the residue and the
mixture was stirred at ambient temperature for 2 hours. The mixture
was concentrated in vacuo, and the residue was partitioned between
ethyl acetate and an aqueous saturated sodium bicarbonate solution.
The organic layer was washed with brine, dried over magnesium
sulfate and concentrated in vacuo. The residue was purified by a
silica gel column chromatography eluting with 5% methanol in
chloroform and then a mixture of 28% ammonium hydroxide, methanol
and chloroform (1:10:100) to give (S)-2-l
1-(acetylaminomethyl)-2-hydroxyethylamino]-N-(3,4-dimetho-
xybenzyl)-5-nitrobenzamide (171 mg) as yellow crystals;
[0669] NMR (DMSO-d.sub.6, .delta.): 1.80 (3H, s), 3.09-3.30 (2H,
m), 3.48-3.60 (2H, m), 3.66-3.78 (1H, m), 3.73 (3H, s), 3.75 (3H,
s), 4.37 (2H, d, J=6 Hz), 5.04 (1H, t, J=5 Hz), 6.85 (1H, dd, J=2,
8 Hz), 6.91 (1H, d, J=8 Hz), 6.96 (1H, d, J=2 Hz), 7.08 (1H, d, J=9
Hz), 8.07-8.15 (2H, m), 8.58 (1H, d, J=3 Hz), 9.20 (1H, d, J=8 Hz),
9.28 (1H, t, J=-6 Hz)
[0670] Mass: (ESI+) 447 (M+H), (ESI-) 445 (M-H), and
(S)-2-[1-(aminomethyl)-2-hydroxyethylamino]-N-(3,4-dimethoxybenzyl)-5-nit-
robenzamide (178 mg) as amorphous powders.
[0671] NMR (DMSO-d.sub.6, .delta.): 2.73 (2H, m), 3.47-3.64 (3H,
m), 3.73 (3H, s), 3.74 (3H, s), 4.36 (2H, s), 6.85 (1H, dd, J=2, 8
Hz), 6.90-7.00 (3H, m), 8.09 (1H, dd, J=3, 9 Hz), 8.56 (1H, d, J=3
Hz), 9.15-9.33 (2H, m)
[0672] Mass: (ESI+) 405(M+H).
EXAMPLE 78(3)
[0673]
(S)-N-(3,4-Dimethoxybenzyl)-2-[1-(formamidomethyl)-2-hydroxyethylam-
ino]-5-nitrobenzamide (112 mg) was obtained as yellow crystals from
(S)-2-[1-(aminomethyl)-2-hydroxyethylamino]-N-(3,4-dimethoxybenzyl)-5-nit-
robenzamide (147 mg) in a manner similar to Example 73(2).
[0674] NMR (DMSO-d.sub.6, .delta.): 3.26 (2H, m), 3.54 (2H, m),
3.65-3.84 (1H, m), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H, d, J=6
Hz), 5.06 (1H, t, J=5 Hz), 6.85 (1H, brd, J=8 Hz), 6.91 (1H, d, J=8
Hz), 6.96 (1H, br), 7.06 (1H, d, J=9 Hz), 8.05 (1H, s), 8.11 (1H,
dd, J=3, 9 Hz), 8.25 (1H, t, J=5 Hz), 8.60 (1H, d, J=3 Hz), 9.21
(1H, d, J=7 Hz), 9.29 (1H, t, J=6 Hz)
[0675] Mass: (ESI+) 433 (M+H), (ESI-) 431 (M-H).
[0676] Preparation 79(1)
[0677] Diphenylphosphorylazide (2.60 g) was added dropwise to a
mixture of N-(tert-butoxycarbonyl)nipecotic acid (2.06 g) and
triethylamine (1.00 g) in toluene (20 mL). The reaction mixture was
warnied in an oil bath over 10 minutes at 100.degree. C. Stirring
was continued for 2 hours at 100.degree. C., then the reaction
vessel was taken out from the oil bath. After reflux was ceased,
benzyl alcohol (1.07 g) was added to the reaction mixture. The
mixture was stirred for 3 hours at 100.degree. C., and then poured
into a mixture of 3.6% hydrochloric acid, ice and ethyl acetate.
The separated organic layer was washed with brine, an aqueous
saturated sodium bicarbonate solution and brine, successively. The
resultant was dried over magnesium sulfate and concentrated in
vacuo. The residue was purified by a silica gel column
chromatography eluting with 30% ethyl acetate in hexane to give
3-(benzyloxycarbonylamino)-1-tert-but- oxycarbonylpiperidine (2.66
g) as an oil.
[0678] NMR (CDCl.sub.3, .delta.): 1.44 (9H, s), 1.40-2.00 (4H, m),
3.09-3.45 (3H, m), 3.59 (1H, brd, J=13 Hz), 3.70 (1H, br), 4.70 and
4.88 (1H, m), 5.10 (2H, s), 7.27-7.40 (5H, m)
[0679] Mass: (ESI+) 335(M+H), (ESI-) 333(M-H).
[0680] Preparation 79(2)
[0681] 3-Amino-1-tert-butoxycarbonylpiperidine (1.48 g) was
obtained as syrup from
3-(benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine (2.54 g)
in a manner similar to Preparation 78(3).
[0682] NMR (CDCl.sub.3, .delta.): 1.30 (1H, m), 1.40-1.60 (1H, m),
1.46 (9H, s), 1.70 (1H, m), 1.96 (1H, m), 2.66 (1H, m), 2.75-2.95
(2H, m), 3.80 (1H, m), 3.94 (1H, m)
EXAMPLE 79(1)
[0683]
2-[1-(tert-Butoxycarbonyl)piperidin-3-ylamino]-N-(3,4-dirnethoxyben-
zyl)-5-nitrobenzamide (900 mg) was obtained as amorphous powders
from N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (700 mg) and
3-amino-1-tert-butoxycarbonylpiperidine (503 mg) in a manner
similar to Example 1(1).
[0684] NMR (DMSO-d.sub.6, .delta.): 1.20-2.00 (13H, in), 3.10-3.65
(4H, in), 3.65-3.80 (1H, in), 3.73 (3H, s), 3.74 (3H, s), 4.37 (2H,
d, J=6 Hz), 6.83 (1H, d, J=8 Hz), 6.84-6.96 (3H, m), 8.15 (1H, dd,
J=2, 9 Hz), 8.65 (1H, s), 9.15-9.45 (1H, in), 9.34 (1H, t, J=6
Hz)
[0685] Mass: (ESI+) 515(M+H), (ESI-) 513(M-H).
EXAMPLE 79(2)
[0686] A mixture of
2-[1-(tert-butoxycarbonyl)piperidin-3-ylamino]-N-(3,4--
diinethoxybenzyl)-5-nitrobenzamide (190 mg) and 4 N
hydrogenchloride solution in ethyl acetate (5 mL) was stirred for 2
hours at ambient temperature. The reaction mixture was concentrated
in vacuo. The residual crystals were collected by filtration and
washed with ethyl acetate to give
N-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide
hydrochloride (138 mg) as yellow crystals.
[0687] NMR (DMSO-d.sub.6, .delta.): 1.55-1.96 (3H, in), 2.04 (1H,
m), 2.78-2.92 (2H, m), 3.18-3.40 (2H, m), 3.73 (3H, s), 3.75 (3H,
s), 3.98 (1H, m), 4.39 (2H, d, J=6 Hz), 6.85 (1H, d, J=8 Hz),
6.90-7.00 (3H, m), 8.19 (1H, dd, J=3, 9 Hz), 8.65 (1H, d, J=3 Hz),
9.08 (1H, d, J=8 Hz), 9.41 (1H, t, J=6 Hz)
[0688] Mass: (ESI-) 413(M-H).
EXAMPLE 79(3)
[0689]
N-(3,4-Dimethoxybenzyl)-2-[1-(methanesulfonyl)piperidin-3-ylamino]--
5-nitrobenzamide (100 mg) was obtained as yellow crystals from
N-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide
hydrochloride (100 mg) in a manner similar to Example 73(3).
[0690] NMR (DMSO-d.sub.6, .delta.): 1.50-1.83 (3H, m), 1.87 (1H,
m), 2.89 (3H, s), 2.95-3.15 (1H, m), 3.01 (1H, dd, J=7, 10 Hz),
3.21 (1H, m), 3.41 (1H, dd, J=4, 10 Hz), 3.73 (3H, s), 3.74 (3H,
s), 3.91 (1H, m), 4.38 (2H, d, J=6 Hz), 6.85 (1H, dd, J=2, 8 Hz),
6.90-7.00 (3H, m), 8.16 (1H, dd, J=3, 9 Hz), 8.63 (1H, d, J=3 Hz),
9.25 (1H, d, J=8 Hz), 9.35 (1H, t, J=6 Hz)
[0691] Mass: (ESI+) 493(M+H), (ESI-) 491(M-H).
EXAMPLE 79(4)
[0692]
N-(3,4-Dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide
(550 mg) was obtained as yellow crystals from
2-11-(tert-butoxycarbonyl)p-
iperidin-3-ylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (802
mg) in a manner similar to Example 77(2).
[0693] NMR (DMSO-d.sub.6, .delta.): 1.36-1.64 (2H, in), 1.82 (1H,
m), 2.40-2.65 (2H, m), 2.70 (1H, m), 2.96 (1H, dd, J=4, 10 Hz),
3.63 (1H, m), 3.73 (3H, s), 3.74 (3H, s), 4.38 (2H, d, J=6 Hz),
6.84-6.93 (3H, m), 6.96 (1H, d, J=2 Hz), 8.11 (1H, dd, J=3, 9 Hz),
8.58 (1H, d, J=3 Hz), 9.20 (1H, d, J=8 Hz), 9.29 (1H, t, J=6
Hz)
[0694] Mass: (ESI+) 415(M+H), (ESI-) 413(M-H).
EXAMPLE 79(5)
[0695]
N-(3,4-Dimethoxybenzyl)-2-(1-formylpiperidin-3-ylamino)-5-nitrobenz-
amide (102 mg) was obtained as yellow crystals from
N-(3,4-dimethoxybenzyl)-5-nitro-2-(piperidin-3-ylamino)benzamide
(126 mg) in a manner similar to Example 73(2).
[0696] NMR (DMSO-d.sub.6, .delta.): 1.40-1.76 (3H, m), 1.93-2.05
(1H, m), 3.14-3.86 (5H, m), 3.73 (3H, s), 3.75 (3H, s), 4.37 (2H,
d, J=SHz), 6.84 (1H, d, J=2.8 Hz), 6.90-7.04 (3H, m), 7.96 and 8.06
(1H, s), 8.13 and 8.16 (1H, d, J=3.9 Hz), 8.63 and 8.64 (1H, d, J=3
Hz), 9.19 and 9.23 (1H, d, J=8 Hz), 9.34 and 9.35 (1H, t, J=5
Hz)
[0697] Mass: (ESI+) 443(M+H), (ESI-) 441(M-H).
EXAMPLE 80
[0698]
2-(1H-Benzimidazol-5-ylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzam-
ide (130.9 mg) was obtained as a yellow solid substance from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and
5-amino-1H-benzimidazole (159 mg) in a manner similar to Example
1(1).
[0699] mp. 226.5-227.degree. C.
[0700] NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.75 (3H, s),
4.45 (2H, br), 6.90 (1H, d, J=8.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.00
(1H, s), 7.04 (1H, br), 7.11 (1H, brd, J=8.SHz), 7.51 (1H, br),
7.64 (1H, br), 8.10 (1H, dd, J=8.5, 2.5 Hz), 8.26 (1H, s), 8.69
(1H, d, J=2.5 Hz), 9.50 (1H, br), 10.71 (1H, br), 12.53 (1H,
br)
[0701] Mass m/z: 448 (M.sup.++1).
EXAMPLE 81 (1)
[0702] 2-[(3S,
SS)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-
-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (814 mg) was
obtained from N-(3,4-dimethoxylbenzyl)-2-fluoro-5-nitrobenzamide
(513 mg) and methyl (2S,
4S)-4-aniino-1-(tert-butoxycarbonyl)pyrroridine-2-carboxylate (750
mg) in a manner similar to Example 1 (1).
[0703] NMR (DMSO-d.sub.6, .delta.): 1.35 (9.times.3/5H, s), 1.41
(9.times.2/5H, s), 1.94 (1H, m), 2.70 (1H, m), 3.21 (1H, dd, J=11,
4 Hz), 3.56 (3.times.2/5H, s), 3.58 (3.times.3/5H, s), 3.72 (3H,
s), 3.74 (3H, s), 3.85 (1H, m), 4.25-4.45 (3H, m), 6.83-6.98 (4H,
m), 8.15 (1H, dd, J=9, 2 Hz), 8.61 (1H, d, J=2 Hz), 9.06 (1H, m),
9.34 (1H, t, J=6 Hz)
[0704] Mass m/z: 558 (M.sup.+).
EXAMPLE 81(2)
[0705] A mixture of 2-[(3S,
5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl-
)pyrrolidin-3-ylamino]-N-(3,4-dimethoxlbenzyl)-5-nitrobenzamide
(143 mg) and 30% methanol solution of methylamine (4 mL) was
stirred for one day at ambient temperature. After evaporation of
the solvent, the residue was partitioned between ethyl acetate and
water. The organic layer was separated, washed with brine and dried
over magnesium sulfate. The residue was subjected to a silica gel
column chromatography eluting with ethyl acetate to give 2-[(3S,
5S)-1-(tert-butoxycarbonyl)-5-(methylcarbam- oyl)pyrrolidin
-3-ylamino]-N-(3 4-dinethoxylbenzyl)-5-nitrobenzamide (149 mg).
[0706] NMR (DMSO-d.sub.6, .delta.): 1.48 (9H, s), 2.33-2.70 (2H,
m), 2.79 (3H, d, J=5 Hz), 3.47 (1H, m), 3.88 (3H, s), 3.90 (3H, s),
4.15 (1H, m), 4.40 (1H, m), 4.50 (1H, dd, J=16, 7 Hz), 4.57 (1H,
dd, J=16, 7 Hz), 6.58 (1H, m), 6.62 (1H, d, J=9 Hz), 6.83-6.93 (3H,
m), 8.16 (1H, dd, J=9, 3 Hz), 8.33 (1H, d, J=3 Hz), 8.98 (1H,
m)
[0707] Mass m/z: 558 (M.sup.+).
EXAMPLE 81(3)
[0708] To a solution of 2-[(3S,
5S)-1-(tert-butoxycarbonyl)-5-(methoxycarb-
onyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide
(492 mg) in tetrahydrofuran (5 mL) was added lithium chloride (75
mg), and then a solution of sodium borohydride (67 mg) in ethanol
(10 mL) at ambient temperature. After stirring for one day, the
mixture was evaporated and the residue was partitioned between
ethyl acetate and 10% citric acid aqueous solution. The organic
layer was separated, washed with water and brine and dried over
magnesium sulfate. The residue was subjected to a silica gel column
chromatography eluting with a mixture of ethyl acetate and hexane
(1:1 to 2:1) to give 2-[(3S,
SS)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-ylamino]-N-(3,4-
-dimethoxylbenzyl)-5-nitrobenzamide (399 mg) as pale yellow
foams.
[0709] NMR (DMSO-d.sub.6, .delta.): 1.41 (9H, s), 1.93 (1H, m),
2.44 (1H, m), 3.04 (1H, m), 3.51-3.62 (2H, m), 3.70-3.95 (2H, m),
3.73 (3H, s), 3.74 (3H, s), 4.21 (1H, m), 4.38 (2H, d, J=6 Hz),
4.84 (1H, t, J=5 Hz), 6.81-6.97 (4H, m), 8.15 (1H, dd, J=10, 3 Hz),
8.60 (1H, d, J=3 Hz), 9.18 (1H, d, J=8 Hz), 9.33 (1H, t, J=6
Hz).
EXAMPLE 81(4)
[0710] A mixture of 2-[(3S,
5S)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)p- yrrolidin-3-ylamino
-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (326 mg) and 4N-hydrogen
chloride solution in ethyl acetate (5 mL) was stirred for one day
at ambient temperature. After evaporation of the solvent, the
residue was partitioned between chloroform and an aqueous saturated
sodium bicarbonate solution. The organic layer was separated,
washed with brine and dried over magnesium sulfate. The filtrate
was evaporated to give N-(3,4-dimethoxylbenzyl)-2-[(3S,
5S)-5-(hydroxymethyl)pyrrolidin-3-y- lamino]-5-nitrobenzamide (242
mg) as pale yellow foams.
[0711] NMR (DMSO-d.sub.6, .delta.): 1.32 (1H, m), 2.35 (1H, m),
2.72 (1H, m), 3.13 (1H, m), 3.20-3.41 (2H, m), 3.53 (1H, m), 3.73
(3H, s), 3.74 (3H, s), 4.05 (1H, m), 4.38 (2H, d, J=6 Hz), 4.61
(1H, brt, J=5 Hz), 6.80-6.99 (4H, m), 8.13 (1H, dd, J=9, 3 Hz),
8.60 (1H, m), 9.13 (1H, m), 9.32 (1H, m)
[0712] Mass (ES) m/z: 431 (M.sup.+).
EXAMPLE 81 (5)
[0713] N-(3,4-Dimethoxylbenzyl)-2-[(3S,
5S)--S-(methylcarbamoyl)pyrrolidin- -3-ylamino]-5-nitrobenzamide
(75 mg) was obtained as pale yellow foams from 2-[(3S,
5S)-1-(tert-butoxycarbonyl)-5-(methylcarbamoyl)pyrrolidin-3--
ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (111 mg) in a
manner similar to Example 81(4).
[0714] NMR (DMSO-d.sub.6, .delta.): 1.70 (1H, ddd, J=13, 5, 5 Hz),
2.43 (1H, m), 2.53 (3H, d, J=5 Hz), 2.72 (1H, dd, J=10, 4 Hz), 3.26
(1H, dd, J=10, 5 Hz), 3.60 (1H, m), 3.72 (3H, s), 3.74 (3H, s),
4.07 (1H, m), 4.34 (1H, dd, J=15, 6 Hz), 4.40 (1H, dd, J=15, 6 Hz),
6.81-6.97 (4H, m), 7.85 (1H, q, J=5 Hz), 8.14 (1H, dd, J=9, 2 Hz),
8.59 (1H, d, J=2 Hz), 9.07 (1H, d, J=8 Hz), 9.30 (1H, t, J=6
Hz)
[0715] Mass m/z: 458 (M.sup.+).
[0716] Preparation 82
[0717] To a suspension of cis-4-aminocyclohexanecarboxylic acid
(1.04 g) in methanol (25 mL) was added thionyl chloride (0.583 mL)
under ice-water cooling. The mixture was stirred for an hour at
0.degree. C. and for 17 hours at ambient temperature. After
evaporation of the solvent, the residue was triturated with diethyl
ether to give methyl cis-4-aminocyclohexanecarboxylate
hydrochloride as white powders (1.37 g).
[0718] NMR (DMSO-d.sub.6, .delta.): 1.40-1.68 (4H, m), 1.73-1.85
(2H, br), 1.93-2.07 (2H, br), 2.62 (1H, m), 3.02-3.14 (1H, br),
3.63 (3H, s), 8.00 (3H, br).
EXAMPLE 82(1)
[0719]
N-(3,4-Dimethoxybenzyl)-2-[cis-4-(methoxycarbonyl)cyclohexylamino]--
5-nitrobenzamide (1.38 g) was obtained as yellow powders from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (1.00 g) and
methyl cis-4-aminocyclohexanecarboxylate hydrochloride (985 mg) in
a manner similar to Example 1(1).
[0720] NMR (DMSO-d.sub.6, .delta.): 1.55-1.85 (8H, br), 2.50-2.60
(1H, br), 3.62 (3H, s), 3.73 (3H, s), 3.74 (3H, s), 3.75-3.85 (1H,
br), 4.38 (2H, d, J=7 Hz), 6.82-6.98 (4H, m), 8.12 (1H, dd, J=4, 8
Hz), 8.62 (1H, d, J=4 Hz), 9.28-9.38 (2H, br).
EXAMPLE 82(2)
[0721]
2-(cis-4-Carboxycyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitroben-
zamide (1.12 g) was obtained as yellow powders from
N-(3,4-dimethoxybenzyl)-2-[cis-4-(methoxycarbonyl)
cyclohexylamino]-5-nitrobenzamide (1.27 g) in a manner similar to
Example 23(2).
[0722] NMR (DMSO-d.sub.6, .delta.): 1.55-1.85 (8H, br), 2.39-2.49
(1H, br), 3.73 (3H, s), 3.74 (3H, s), 3.75-3.85 (1H, br), 4.38 (2H,
d, J=7 Hz), 6.80-7.00 (4H, m), 8.12 (1H, dd, J=4 Hz, 8 Hz), 8.61
(1H, d, J=4 Hz), 9.33 (2H, br).
EXAMPLE 82(3)
[0723]
N-(3,4-Dimethoxybenzyl)-2-[cis-4-(dimethylcarbamoyl)cyclohexylamino-
]-5-nitrobenzamide (81.8 mg) was obtained as yellow powders from
2-(cis-4-carboxycyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide
(100 mg) and dimethylamine hydrochloride (21.4 mg) in a manner
similar to Example 23(3).
[0724] NMR (DMSO-d.sub.6, .delta.): 1.52-1.90 (8H, br), 2.66-2.76
(1H, br), 2.80 (3H, s), 3.02 (3H, s), 3.73 (3H, s), 3.74 (3H, s),
3.85-3.95 (1H, br), 4.40 (2H, d, J=7 Hz), 6.83-6.98 (4H, m), 8.12
(1H, dd, J=4, 8 Hz), 8.63 (1H, d, J=4 Hz), 9.33 (1H, br), 9.50 (1H,
d, J=8 Hz)
[0725] Mass m/z: 483 (M.sup.+).
EXAMPLE 82(4)
[0726]
N-(3,4-Dimethoxybenzyl)-2-[cis-4-(2-hydroxyethylcarbamoyl)cyclohexy-
lamino]-5-nitrobenzamide (100 mg) was obtained as yellow powders
from
2-(cis-4-carboxycyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide
(100 mg) and 2-aminoethanol (16.0 mg) in a manner similar to
Example 23(3).
[0727] NMR (DMSO-d.sub.6, .delta.): 1.55-1.72 (8H, br), 2.20-2.30
(1H, br), 3.06-3.16 (2H, m), 3.35-3.41 (2H, m), 3.73 (3H, s), 3.74
(3H, s), 3.78-3.88 (1H, br), 4.39 (2H, d, J=7 Hz), 4.65 (1H, t, J=7
Hz), 6.83-6.98 (4H, m), 7.74 (1H, br), 8.12 (1H, dd, J=4, 8 Hz),
8.63 (1H, d, J=4 Hz), 9.33 (1H, br), 9.43 (1H, d, J=8 Hz)
[0728] Mass m/z: 499 (M.sup.+).
[0729] Preparation 83(1)
[0730] 4-(Benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine
(5.44 g) was obtained as a solid substance from
N-tert-butoxycarbonylisonipecotic acid (4.5 g) in a manner similar
to Preparation 79(1).
[0731] NMR (CDCl.sub.3, .delta.): 1.30 (2H, dq, J=4, 10 Hz), 1.45
(9H, s), 1.94 (2H, br d, J=10 Hz), 2.85 (2H, t, J=10 Hz), 3.66 (1H,
m), 4.01 (2H, br), 4.65 (1H, m), 5.09 (2H, s), 7.27-7.40 (5H,
m).
[0732] Preparation 83(2)
[0733] 4-Amino-1-tert-butoxycarbonylpiperidine (3.83 g) was
obtained as syrup from
4-(benzyloxycarbonylamino)-1-tert-butoxycarbonylpiperidine (5.11 g)
in a manner similar to Preparation 78(3).
[0734] NMR (CDCl.sub.3, .delta.): 1.30 (2H, m), 1.83 (2H, m), 2.56
(2H, m), 2.60-2.95 (3H, m), 4.06 (2H, m)
[0735] Mass: (ESI+) 201(M.sup.++1).
EXAMPLE 83(1)
[0736]
2-[1-(tert-Butoxycarbonyl)piperidin-4-ylamino]-5-cyano-N-(3,4-dimet-
hoxybenzyl)benzamide (360 mg) was obtained as amorphous powders
from 5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (300 mg) and
4-amino-1-tert-butoxycarbonylpiperidine (287 mg) in a manner
similar to Example 1 (1).
[0737] NMR (DMSO-d.sub.6, .delta.): 1.28 (2H, m), 1.90 (2H, m),
3.00 (2H, m), 3.61-3.75 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 3.80
(2H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, dd, J=2, 8 Hz), 6.88-6.94
(3H, m), 7.63 (1H, dd, J=2, 9 Hz), 8.07 (1H, d, J=2 Hz), 8.71 (1H,
d, J=8 Hz), 9.03 (1H, t, J=6 Hz)
[0738] Mass: (ESI-) 493(M-H).
EXAMPLE 83(2)
[0739]
5-Cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-4-ylamino)benzamide
hydrochloride (254 mg) was obtained as white crystals from
2-[1-(tert-butoxycarbonyl)piperidin-4-ylamino]-5-cyano-N-(3,4-dimethoxybe-
nzyl)benzamide (297 mg) in a manner similar to
EXAMPLE 79(2).
[0740] NMR (DMSO-d.sub.6, .delta.): 1.60 (2H, m), 2.10 (2H, m),
3.01 (2H, m), 3.26 (2H, m), 3.64-3.87 (1H, m), 3.73 (3H, s), 3.74
(3H, s), 4.36 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.89-7.00
(3H, m), 7.67 (1H, dd, J=2, 8 Hz), 8.12 (1H, d, J=2 Hz), 8.70-9.05
(2H, m), 9. 11 (1H, t, J=6 Hz)
[0741] Mass: (ESI+) 395(M+H), (ESI-) 393(M-H).
EXAMPLE 83(3)
[0742]
5-Cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-4-ylamino)benzamide
hydrochloride (100 mg) was partitioned between ethyl acetate and an
aqueous saturated sodium bicarbonate solution. The organic layer
was separated, dried over magnesium sulfate and concentrated in
vacuo. The residue was dissolved in N,N-dimethylformamide (1 mL),
and ethyl formate (5 mL) was added to the solution. The mixture was
refluxed under heating overnight and partitioned between ethyl
acetate and water. The organic layer was washed with brine, dried
over magnesium sulfate and concentrated in vacuo. The residue was
crystallized from ethyl acetate to give
5-cyano-N-(3,4-dimethoxybenzyl)-2-(1-formylpiperidin-4-ylamino)benza-
mide (52 mg) as white crystals.
[0743] NMR (DMSO-d.sub.6, .delta.): 1.15-1.44 (2H, m), 1.88-2.03
(2H, m), 2.91 (1H, m), 3.16-3.35 (2H, m), 3.60-3.85 (2H, m), 3.72
(3H, s), 3.74 (3H, s), 4.01 (1H, m), 4.35 (2H, d, J=5 Hz), 6.83
(1H, dd, J=2, 8 Hz), 6.84-6.97 (3H, m), 7.64 (1H, dd, J=2, 9 Hz),
7.99 (1H, s), 8.07 (1H, d, J=2 Hz), 8.74 (1H, d, J=8 Hz), 9.03 (1H,
t, J=5 Hz)
[0744] Mass: (ESI-) 421(M-H).
EXAMPLE 83(4)
[0745]
5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)piperidin-4-y-
lamino)benzamide (78 mg) was obtained as white crystals from
5-cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-4-ylamino)benzamide
hydrochloride (100 mg) in a manner similar to Example 73(3).
[0746] NMR (DMSO-d.sub.6, .delta.): 1.48 (2H, m), 2.02 (2H, m),
2.89 (3H, s), 2.96 (2H, m), 3.50 (2H, m), 3.64 (1H, m), 3.72 (3H,
s), 3.74 (3H, s), 4.35 (2H, d, J=5 Hz), 6.84 (1H, dd, J=2, 8 Hz),
6.88-6.96 (3H, m), 7.65 (1H, d, J=2, 9 Hz), 8.08 (1H, d, J=2 Hz),
8.73 (1H, d, J=8 Hz), 9.04 (1H, t, J=5 Hz)
[0747] Mass: (ESI-) 471(M-H).
EXAMPLE 84(1)
[0748]
2-[1-(tert-Butoxycarbonyl)piperidin-3-ylamino]-5-cyano-N-(3,4-dimet-
hoxybenzyl)benzamide (368 mg) was obtained as amorphous powders
from 5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (300 mg) and
3-amino-1-tert-butoxycarbonylpiperidine (249 mg) in a manner
similar to Example 1(1).
[0749] NMR (DMSO-d.sub.6, .delta.): 1.10-1.75 (12H, m), 1.88 (1H,
m), 2.95-3.65 (5H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35 (2H, d, J=6
Hz), 6.80-6.96 (4H, m), 7.65 (1H, d, J=9 Hz), 8.10 (1H, s),
8.75-9.10 (1H, m), 9.03 (1H, t, J=6 Hz)
[0750] Mass: (ESI-) 493(M-H).
EXAMPLE 84(2)
[0751]
5-Cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-3-ylamino)benzamide
(283 mg) was obtained as an oil from
2-[1-(tert-butoxycarbonyl)piperidin
-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (311 mg) in a
manner similar to Example 77(2).
[0752] NMR (DMSO-d.sub.6, .delta.): 1.44 (2H, m), 1.58 (1H, m),
1.82 (1H, m), 2.45 (1H, dd, J=7, 10 Hz), 2.56 (1H, m), 2.71 (1H,
m), 2.97 (1H, dd, J=4, 10 Hz), 3.52 (1H, in), 3.72 (3H, s), 3.74
(3H, s), 4.36 (2H, d, J=6 Hz), 6.80-6.95 (4H, m), 7.60 (1H, dd,
J=3, 9 Hz), 8.04 (1H, d, J=3 Hz), 8.78 (1H, d, J=8 Hz), 8.98 (1H,
t, J=6 Hz)
[0753] Mass: (ESI+) 395(M+H), (ESI-) 393(M-H).
EXAMPLE 84(3)
[0754]
5-Cyano-N-(3,4-dimethoxybenzyl)-2-(1-formylpiperidin-3-ylamino)benz-
amide (61 mg) was obtained as amorphous powders from
5-cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-3-ylamino)benzamide
(94 mg) in a manner similar to Example 73(2).
[0755] NMR (DMSO-d.sub.6, .delta.): 1.40-1.75 (3H, m), 3.06-3.84
(5H, m), 3.72 (3H, s), 3.74 (3H, s), 4.36 (2H, d, J=6 Hz),
6.80-7.01 (4H, m), 7.63 and 7.67 (1H, d, J=9 Hz), 7.95 and 8.05
(1H, s), 8.08 (1H, br), 8.80 and 8.84 (1H, d, J=8 Hz), 9.04 (1H, t,
J=6 Hz)
[0756] Mass: (ESI+) 423(M+H), (ESI-) 421(M-H).
EXAMPLE 84(4)
[0757]
5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)piperidin-3-y-
lamino]benzamide (83 mg) was obtained as white crystals from
5-cyano-N-(3,4-dimethoxybenzyl)-2-(piperidin-3-ylamino)benzamide
(82 mg) in a manner similar to Example 73(3).
[0758] NMR (DMSO-d.sub.6, .delta.): 1.44-1.94 (4H, m), 2.8-2.96
(1H, m), 2.88 (3H, s), 3.04 (1H, m), 3.22 (1H, m), 3.42 (1H, in),
3.72 (3H, s), 3.74 (3H, s), 3.80 (1H, m), 4.36 (2H, d, J=5 Hz),
6.84 (1H, d, J=2, 8 Hz), 6.88-6.92 (2H, m), 6.94 (1H, d, J=2 Hz),
7.66 (1H, dd, J=2, 9 Hz), 8.08 (1H, d, J=2 Hz), 8.85 (1H, d, J=8
Hz), 9.04 (1H, t, J=5 Hz)
[0759] Mass: (ESI+) 473(M+H), 495(M+Na), (ESI-) 471(M-H).
[0760] Preparation 85(1)
[0761] A solution of di-tert-butyl dicarbonate (5.44 g) in dioxane
(10 mL) was added dropwise to a solution of
(S)-3-benzyloxycarbonylaminopyrrolidi- ne (3.66 g) in dioxane (10
mL) under cooling on an ice bath. The reaction mixture was stirred
at ambient temperature overnight, then the reaction was quenched by
addition of 3-(N,N-dimethylamino)propylamine (5 mL). The mixture
was concentrated in vacuo and the residue was partitioned between
ethyl acetate and 3.6% hydrochloric acid. The organic layer was
washed with an aqueous saturated sodium bicarbonate solution and
brine, dried over magnesium sulfate and concentrated in vacuo. The
residue was purified by a silica gel column chromatography eluting
with 30% ethyl acetate in hexane to give
(S)-3-benzyloxycarbonylamino-1-tert-butoxycarbo- nylpyrrolidine
(1.26 g) as an oil.
[0762] NMR (CDCl.sub.3, .delta.): 1.45 (9H, s), 1.84 (1H, m), 2.14
(1H, m), 3.20 (1H, m), 3.33-3.50 (2H, m), 3.61 (1H, dd, J=2, 10
Hz), 4.25 (1H, m), 4.85 (1H, m), 5.10 (2H, s), 7.27-7.41 (5H,
m)
[0763] Mass: (ESI+) 321(M+H).
[0764] Preparation 85(2)
(S)-3-Amino-1-tert-butoxycarbonylpyrrolidine (2.49 g) was obtained
as syrup from (S)-3-benzyloxycarbonylamino-1-tert-b-
utoxycarbonylpyrrolidine (4.10 g) in a manner similar to
Preparation 78(3).
[0765] NMR (DMSO-d.sub.6, .delta.): 1.39 (9H, s), 1.57 (1H, m),
1.88 (1H, m), 2.89 (1H, dd, J=5, 1 lHz), 3.00-3.40 (3H, m), 3.42
(1H, m)
[0766] Mass: (ESI+) 187(M+H).
EXAMPLE 85(1)
[0767]
(S)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino-5-cyano-N-(3,4-d-
imethoxybenzyl)benzamide (368 mg) was obtained as amorphous powders
from 5-cyano-N-(3,4-dimethoxyb enzyl)-2-fluorobenzamide (500 mg)
and (S)-3-amino-1-tert-butoxycarbonylpyrrolidine (593 mg) in a
manner similar to Example 1(1).
[0768] NMR (DMSO-d.sub.6, .delta.): 1.82 (1H, m), 2.20 (1H, m), 3.
10 (1H, m), 3.25-3.45 (2H, m), 3.61 (1H, m), 3.72 (3H, s), 3.74
(3H, s), 4.18 (1H, m), 4.35 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8
Hz), 6.80-6.94 (3H, m), 7.66 (1H, dd, J=2, 8 Hz), 96 8.09 (1H, d,
J=2 Hz), 8.82 (1H, d, J=7 Hz), 9.05 (1H, t, J=6 Hz).
EXAMPLE 85(2)
[0769]
(S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamid-
e (201 mg) was obtained as amorphous powders from
(S)-2-[1-(tert-butoxycar-
bonyl)pyrrolidin-3-ylamino}-5-cyano-N-(3,4-dimethoxybenzyl)benzamide
(277 mg) in a manner similar to Example 77(2).
[0770] NMR (DMSO-d.sub.6, .delta.): 1.50 (1H, m), 2.11 (1H, m),
2.57 (1H, dd, J=4, 10 Hz), 2.70-2.95 (2H, m), 3.13 (1H, dd, J=6, 10
Hz), 3.72 (3H, s), 3.74 (3H, s), 3.96 (1H, m), 4.34 (2H, d, J=6
Hz), 6.78-6.94 (4H, m), 7.64 (1H, dd, J=2, 8 Hz), 8.06 (1H, d, J=2
Hz), 8.72 (1H, d, J=7 Hz), 9.02 (1H, t, J=6 Hz)
[0771] Mass: (ESI+) 381(M+H), (ESI-) 379(M-H).
EXAMPLE 85(3)
[0772]
(S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)pyrrolidi-
n-3-ylamino)benzamide (81 mg) was obtained as white crystals from
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide
(100 mg) in a manner similar to Example 73(3).
[0773] NMR (DMSO-d.sub.6, .delta.): 1.89 (1H, m), 2.30 (1H, m),
2.90 (3H, s), 3.09 (1H, dd, J=4, 10 Hz), 3.28-3.45 (2H, m), 3.62
(1H, dd, J=6, 10 Hz), 3.72 (3H, s), 3.74 (3H, s), 4.25 (1H, m),
4.36 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.85-6.94 (3H, m),
7.68 (1H, d, J=2, 8 Hz), 8.09 (1H, d, J=2 Hz), 8.84 (1H, d, J=7
Hz), 9.07 (1H, t, J=6 Hz)
[0774] Mass: (ESI+) 459(M+H), (ESI-) 457(M-H).
EXAMPLE 85(4)
[0775]
(S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(1-formylpyrrolidin-3-ylamino-
)benzamide (89 mg) was obtained as amorphous powders from
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide
(100 mg) in a manner similar to Example 73(2).
[0776] NMR (DMSO-d.sub.6, .delta.): 1.86 (1H, m), 2.25 (1H, m),
3.15(ca.0.5H, dd, J=4, 10 Hz), 3.25-3.75 (3H, m), 3.72 (3H, s),
3.74 (3H, s), 3.84(ca.0.5H, dd, J=6, 10 Hz), 4.13-4.29 (1H, m),
4.35 (1H, d, J=6 Hz), 6.83 (1H, d, J=8 Hz), 6.88-6.96 (3H, m), 7.68
(1H, dd, J=2, 8 Hz), 8.10 (1H, d, J=2 Hz), 8.17 and 8.19 (1H, s),
8.82 (1H, d, J=7 Hz), 9.06 (1H, t, J=6 Hz)
[0777] Mass: (ESI+) 409(M+H), (ESI-) 407(M-H).
EXAMPLE 85(5)
[0778] A solution of methyl chloroformate (26 mg) in chloroform (2
mL) was added dropwise to a mixture of (S)-5-cyano-N-(3,4-dimeth
oxybenzyl)-2-(3-pyrrolidinylamino) benzamide (80 mg) and
triethylamine (43 mg) in a mixture of chloroform (2 mL) and
1,3-dimethyl-2-imidazolidin- one (1 mL) under cooling on an ice
bath. The reaction mixture was stirred for 2 hours at same
temperature and the reaction was quenched by addition of
3-(N,N-dimethylamino)propylamine (0.1 mL). The mixture was
concentrated in vacuo, and the residue was partitioned between
ethyl acetate and 3.6% hydrochloric acid. The organic layer was
washed with an aqueous saturated sodium bicarbonate solution and
brine, dried over magnesium sulfate and concentrated in vacuo. The
residue was purified by a silica gel column chromatography eluting
with 70% ethyl acetate in hexane. The obtained crystals were
recrystallized from a mixture of 2-propanol and diisopropyl ether
to give (S)-5-cyano-N-(3,4-dimethoxybenz-
yl)-2-[1-(methoxycarbonyl)pyrrolidin-3-ylamino]benzamide (55 mg) as
white crystals.
[0779] NMR (DMSO-d.sub.6, .delta.): 1.86 (1H, m), 2.21 (1H, m),
3.16 (1H, m), 3.30-3.50 (2H, m), 3.55-3.80 (1H, m), 3.57 and 3.59
(3H, s), 3.72 (3H, s), 3.74 (3H, s), 4.20 (1H, m), 4.35 (2H, d, J=6
Hz), 6.83 (1H, d, J=2, 8 Hz), 6.88-6.94 (3H, m), 7.66 (1H, dd, J=2,
8 Hz), 8.09 (1H, d, J=2 Hz), 8.83 (1H, d, J=7 Hz), 9.06 (1H, t, J=6
Hz)
[0780] Mass: (ESI-) 437(M-H).
EXAMPLE 85(6)
[0781] Acetic anhydride (64 mg) was added to a solution of
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)
benzamide (80 mg) in pyridine (1 mL). The mixture was stirred for
an hour at ambient temperature. The mixture was partitioned between
ethyl acetate and 1% hydrochloric acid. The organic layer was
washed with an aqueous saturated sodium bicarbonate solution and
brine. The resultant was dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by a thin layer
chromatography developed with 5% methanol in chloroform to give
(S)-2-(1-acetylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)-
benzamide (62 mg) as amorphous powders.
[0782] NMR (DMSO-d.sub.6, .delta.): 1.72-1.88 (1H, m), 1.92 and
1.95 (3H, s), 2.13-2.36 (1H, m), 3.20(ca.0.5H, dd, J=3, 12 Hz),
3.27(ca.0.5H, dd, J=5, 10 Hz), 3.35-3.60 (4H, m), 3.63(ca.0.5H, dd,
J=6, 12 Hz), 3.72 (3H, s), 3.74 (3H, s), 3.85(ca.0.5H, dd, J=4, 10
Hz), 4.18 and 4.26 (1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, dd,
J=2, 8 Hz), 6.80-6.96 (3H, m), 7.67 (1H, dd, J=2, 8 Hz), 8.09 (1H,
d, J=2 Hz), 8.81 and 8.86 (1H, d, J=6 Hz), 9.06 (1H, t, J=6 Hz)
[0783] Mass: (ESI+) 423(M+H), (ESI-) 421(M-H).
EXAMPLE 86
[0784]
(R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(tetrahydrofuran-3-ylamino)be-
nzamide (96 mg) was obtained from
5-cyano-N-(3,4-dimethoxybenzyl)-2-fluoro- benzamide (126 mg) and
(R)-3-aminotetrahydrofuran toluene-4-sulfonate (135 mg) in a manner
similar to Example 1(1).
[0785] NMR (DMSO-d.sub.6, .delta.): 1.74 (1H, m), 2.27 (1H, m),
3.54 (1H, dd, J=3, 9 Hz), 3.70-3.92 (3H, m), 3.72 (3H, s), 3.74
(3H, s), 4.20 (1H, m), 4.35 (2H, d, J=6 Hz), 6.81-6.95 (4H, m),
7.66 (1H, dd, J=2, 9 Hz), 8.08 (1H, d, J=2 Hz), 8.81 (1H, d, J=7
Hz), 9.05 (1H, t, J=6 Hz)
[0786] Mass m/z: 380 (M.sup.+-1).
EXAMPLE 87(1)
[0787]
(R)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (918 mg) was obtained as amorphous
powders from 5-cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (700
mg) and (R)-3-amino-1-tert-butoxycarbonylpyrrolidine (830 mg) in a
manner similar to Example 1(1).
[0788] NMR (DMSO-d.sub.6, .delta.): 1.82 (1H, m), 2.20 (1H, m),
3.10 (1H, m), 3.25-3.45 (2H, m), 3.61 (1H, m), 3.72 (3H, s), 3.74
(3H, s), 4.18 (1H, m), 4.35 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8
Hz), 6.80-6.94 (3H, m), 7.66 (1H, dd, J=2, 8 Hz), 8.09 (1H, d, J=2
Hz), 8.82 (1H, d, J=7 Hz), 9.05 (1H, t, J=6 Hz).
EXAMPLE 87(2)
[0789] Trifluoroacetic acid (5 mL) was added to a solution of
(R)-2-[1-(tert-butoxycarbonyl)
pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimet- hoxybenzyl)benzamide
(918 mg) in chloroform (5 mL). The mixture was stirred for 4 hours
at ambient temperature and concentrated in vacuo. The residue was
partitioned between chloroform and an aqueous saturated sodium
bicarbonate solution. The organic layer was dried over magnesium
sulfate and concentrated in vacuo to give
(R)-5-cyano-N-(3,4-dimethoxyben-
zyl)-2-(3-pyrrolidinylamino)benzamide (610 mg) as amorphous
powders.
[0790] NMR (DMSO-d.sub.6, .delta.): 1.50 (1H, m), 2.11 (1H, m),
2.57 (1H, dd, J=4, 10 Hz), 2.7-2.95 (2H, m), 3.13 (1H, dd, J=6, 10
Hz), 3.72 (3H, s), 3.74 (3H, s), 3.96 (1H, m), 4.34 (2H, d, J=6
Hz), 6.78-6.94 (4H, m), 7.64 (1H, dd, J=2, 8 Hz), 8.06 (1H, d, J=2
Hz), 8.72 (1H, d, J=7 Hz), 9.02 (1H, t, J=6 Hz).
EXAMPLE 87(3)
[0791]
(R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methanesulfonyl)pyrrolidi-
n-3-ylamino]benzamide (93 mg) was obtained as white crystals from
(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide
(114 mg) in a manner similar to Example 73(3).
[0792] NMR (DMSO-d.sub.6, .delta.): 1.89 (1H, m), 2.30 (1H, m),
2.90 (3H, s), 3.09 (1H, dd, J=4, 10 Hz), 3.28-3.45 (2H, m), 3.62
(1H, dd, J=6, 10 Hz), 3.72 (3H, s), 3.74 (3H, s), 4.25 (1H, m),
4.36 (2H, d, J=6 Hz), 6.84 (1H, dd, J=2, 8 Hz), 6.85-6.94 (3H, m),
7.68 (1H, d, J=2, 8 Hz), 8.09 (1H, d, J=2 Hz), 8.84 (1H, d, J=7
Hz), 9.07 (1H, t, J=6 Hz).
EXAMPLE 87(4)
[0793]
(R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidi-
n-3-ylamino Jbenzamide (94 mg) was obtained as powders from
(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide
(116 mg) in a manner similar to Example 85(5).
[0794] NMR (DMSO-d.sub.6, .delta.): 1.86 (1H, m), 2.21 (1H, m),
3.16 (1H, m), 3.30-3.50 (2H, m), 3.55-3.80 (1H, m), 3.57 and 3.59
(3H, s), 3.72 (3H, s), 3.74 (3H, s), 4.20 (1H, m), 4.35 (2H, d, J=6
Hz), 6.83 (1H, d, J=2, 8 Hz), 6.88-6.94 (3H, m), 7.66 (1H, dd, J=2,
8 Hz), 8.09 (1H, d, J=2 Hz), 8.83 (1H, d, J=7 Hz), 9.06 (1H, t, J=6
Hz).
EXAMPLE 87(5)
[0795]
(R)-2-(1-Acetylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl-
)benzamide (66 mg) was obtained as amorphous powders from
(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide
(100 mg) in a manner similar to Example 85(6).
[0796] NMR (DMSO-d.sub.6, .delta.): 1.72-1.88 (1H, m), 1.92 and
1.95 (3H, s), 2.13-2.36 (1H, m), 3.20(ca.0.5H, dd, J=3, 12 Hz),
3.27(ca.0.5H, dd, J=5, 10 Hz), 3.35-3.60 (4H, m), 3.63(ca.0.5H, dd,
J=6, 12 Hz), 3.72 (3H, s), 3.74 (3H, s), 3.85(ca.0.5H, dd, J=4, 10
Hz), 4.18 and 4.26 (1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, dd,
J=2, 8 Hz), 6.80-6.96 (3H, m), 7.67 (1H, dd, J=2, 8 Hz), 8.09 (1H,
d, J=2 Hz), 8.81 and 8.86 (1H, d, J=6 Hz), 9.06 (1H, t, J=6
Hz).
EXAMPLE 87(6)
[0797]
(R)-5-Cyano-N-(3,4-dirnethoxybenzyl)-2-(1-formylpyrrolidin-3-ylamin-
o)benzamide (52 mg) was obtained as amorphous powders from
(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide
(100 mg) in a manner similar to Example 73(2).
[0798] NMR (DMSO-d.sub.6, .delta.): 1.86 (1H, m), 2.25 (1H, m),
3.15(ca.0.5H, dd, J=4, 10 Hz), 3.25-3.75 (3H, m), 3.72 (3H, s),
3.74 (3H, s), 3.84(ca.0.5H, dd, J=6, 10 Hz), 4.13-4.29 (1H, m),
4.35 (1H, d, J=6 Hz), 6.83 (1H, d, J=8 Hz), 6.88-6.96 (3H, m), 7.68
(1H, dd, J=2, 8 Hz), 8.10 (1H, d, J=2 Hz), 8.17 and 8.19 (1H, s),
8.82 (1H, d, J=7 Hz), 9.06 (1H, t, J=6 Hz).
EXAMPLE 87(7)
[0799] A solution of potassium cyanate (53 mg) in water (1.5 mL)
was added to a solution of
(R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylami-
no)benzamide (100 mg) in acetic acid (1.5 mL). The mixture was
stirred for 3 hours at 60.degree. C. and then for 2 hours at
90.degree. C. The reaction mixture was concentrated in vacuo and
the residue was partitioned between chloroform and an aqueous
saturated sodium bicarbonate solution. The organic layer was dried
over magnesium sulfate and concentrated in vacuo. The residue was
purified by thin layer chromatography developed with 5% methanol in
chloroform. The obtained product was triturated with diethyl ether
to give (R)-2-(1-carbamoylpyrro-
lidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (22 mg)
as a powders.
[0800] NMR (DMSO-d.sub.6, .delta.): 1.83 (1H, m), 2.20 (1H, m),
3.12(1H, dd, J=4, 10 Hz), 3.20-3.45 (2H, m), 3.57 (1H, dd, J=6, 10
Hz), 3.72 (3H, s), 3.74 (3H, s), 4.19 (1H, m), 4.35 (2H, d, J=6
Hz), 5.80 (2H, s), 6.84 (1H, dd, J=2, 8 Hz), 6.87-6.95 (3H, m),
7.66 (1H, dd, J=2, 8 Hz), 8.09 (1H, d, J=2 Hz), 8.83 (1H, d, J=7
Hz), 9.05 (1H, t, J=6 Hz)
[0801] Mass: (ESI+) 424(M+H).
EXAMPLE 87(8)
[0802] A solution of benzyl alcohol (28 mg) in 1,2-dichloroethane
(1 mL) was added dropwise to a solution of chlorosulfonyl
isocyanate (37 mg) in 1,2-dichloroethane (2 mL) under 5.degree. C.
on an ice-salt bath. The mixture was stirred for one and a half
hours at 4.degree. C. To the mixture was added dropwise a mixture
of (R)-5-cyano-N-(3,4-dimethoxybenzy-
l)-2-(3-pyrrolidinylamino)benzamide (100 mg) and triethylamine (40
mg) in 1,2-dichloroethane (3 mL) under 5.degree. C. After addition,
the reaction mixture was allowed to warm to ambient temperature and
stirred overnight. The reaction mixture was washed with brine,
dried over magnesium sulfate and concentrated in vacuo. The residue
was purified by a thin layer chromatography developed with 5%
methanol in chloroform. The obtained product was triturated with
diethyl ether to give (R)-2-[1-(N-benzyloxyca-
rbonylsulfamoyl)pyrrolidin-3-ylamino
-5-cyano-N-(3,4-dimethoxybenzyl)benza- mide (65 mg) as a syrup.
[0803] NMR (DMSO-d.sub.6, .delta.): 1.84 (1H, m), 2.22 (1H, in),
3.21 (1H, dd, J=4, 10H 3.40-3.55 (2H, m), 3.65-3.80 (1H, m), 3.71
(3H, s), 3.72 (3H, s), 4.20 (1H, m), 4.36 (2H, d, J=6 Hz), 5.08
(2H, s), 6.83 (1H, dd, J=2, 8 Hz), 6.89 (1H, d, J=8 Hz), 6.93 (1H,
d, J=2 Hz), 7.25-7.45 (6H, m), 7.68 (1H, dd, J=2, 8 Hz), 8.11 (1H,
d, J=2 Hz), 8.85 (1H, d, J=7 Hz), 9.06 (1H, t, J=6 Hz)
[0804] Mass: (ESI+) 594(M+H), (ESI-) 593(M-H).
EXAMPLE 87(9)
[0805]
(R)-2-(1-Sulfamoylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxyben-
zyl)benzamide (26 mg) was obtained as white crystals from
(R)-2-[1-(N-benzyloxycarbonylsulfainoyl)pyrrolidin-3-ylamino]-5-cyano-N-(-
3,4-dimethoxybenzyl)benzamide (60 mg) in a manner similar to
[0806] Preparation 78(3).
[0807] NMR (DMSO-d.sub.6, .delta.): 1.79 (1H, m), 2.29 (1H, m),
2.94 (1H, dd, J=5, 10 Hz), 3.15-3.30 (2H, m), 3.51 (1H, dd, J=7, 10
Hz), 3.72 (3H, s), 3.74 (3H, s), 4.22 (1H, m), 4.36 (2H, d, J=6
Hz), 6.80-6.95 (6H, m), 7.67 (1H, dd, J=2, 9 Hz), 8.10 (1H, d, J=2
Hz), 8.85 (1H, d, J=7 Hz), 9.07 (1H, t, J=6 Hz).
[0808] Preparation 88(1)
[0809] To a solution of 5-bromo-2-fluorobenzaldehyde (10 g) in
dimethylformamide (60 mL) were added zinc cyamide (6.92 g) and
tetrakis(triphenylphosphine)palladium(0) (2.28 g), and the mixture
was stirred at 80.degree. C. for 6 hours. The resulting mixture was
diluted with ethyl acetate and washed successively with water and
brine. The organic layer was dried over sodium sulfate and
evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with a mixture of hexane and ethyl
acetate (3:1) to give 5-cyano-2-fluorobenzaldehyde (5.3 g) as a
solid substance.
[0810] NMR (DMSO-d.sub.6, .delta.): 7.35 (1H, t, J=9 Hz), 7.91 (1H,
m), 8.22 (1H, dd, J=2, 7 Hz), 10.36 (1H, s)
[0811] Mass m/z: 150 (M.sup.++1).
[0812] Preparation 8(2)
[0813] To a solution of 5-cyano-2-fluorobenzaldehyde (145 mg) in
acetonitrile (2 mL) were added a sodium dihydrogenphosphate aqueous
solution (23 mg in 1 mL water) and 30% hydrogen peroxide (0.09 mL).
To the resulting mixture was added dropwise a sodium chlorite
aqueous solution (126 mg in 1 mL water) for an hour at 0.degree. C.
The mixture was stirred for an hour at ambient temperature, then a
small amount of sodium sulfite was added. The mixture was diluted
with ethyl acetate and washed successively with 1N-hydrochloric
acid and brine. The organic layer was dried over sodium sulfate and
evaporated in vacuo. The residue was triturated with diisopropyl
ether to give 5-cyano-2-fluorobenzoic acid (137 mg) as a solid
substance.
[0814] NMR (DMSO-d.sub.6, .delta.): 7.29 (1H, t, J=9 Hz), 7.83 (1H,
m), 8.32 (H, dd, J=2, 7 Hz)
[0815] Mass m/z: 164 (M.sup.+-1).
[0816] Preparation 88(3)
[0817] 5-Cyano-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (228 mg)
was obtained from 5-cyano-2-fluorobenzoic acid (130 mg) and
veratrylamine (0.14 mL) in a manner similar to Preparation 1.
[0818] NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.75 (3H, s),
4.40 (2H, d, J=6 Hz), 6.82-6.96 (3H, m), 7.56 (1H, t, J=9 Hz), 8.04
(1H, m), 8.11 (1H, dd, J 2, 6 Hz), 9.02 (1H, t, J=6 Hz)
[0819] Mass m/z: 313 (M.sup.+-1).
EXAMPLE 88(1)
[0820]
(S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino-
)benzamide (112 mg) was obtained from
5-cyano-N-(3,4-dimethoxybenzyl)-2-fl- uorobenzamide (120 mg) and
(S)-2-amino-1-propanol (0.09 mL) in a manner similar to Example
1(1).
[0821] mp 142-143.5.degree. C.
[0822] NMR (DMSO-d.sub.6, .delta.); 1.13 (3H, d, J=6 Hz), 3.42 (2H,
t, J=5 Hz), 3.67 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.34 (2H, d,
J=5 Hz), 4.92 (1H, t, J=5 Hz), 6.81-6.95 (4H, m), 7.60 (1H, dd,
J=2, 9 Hz), 8.03 (1H, d, J=2 Hz), 8.69 (1H, d, J=8 Hz), 8.97 (1H,
t, J=5 Hz)
[0823] Mass m/z: 368 (M.sup.+-1).
EXAMPLE 88(2)
[0824] To a solution of
(S)-5-cyano-N-(3,4-dirnethoxybenzyl)-2-(2-hydroxy--
1-methylethylamino)benzamide (177 mg) in dimethylformamide (4 mL)
was added sodium hydride (19.2 mg) at ambient temperature. After
stirring for 20 minutes, 4-fluorobenzonitrile (63.8 mg) was added
to the mixture. After stirring for an hour at 60.degree. C., the
mixture was diluted with ethyl acetate and washed successively with
water and brine. The organic layer was dried over sodium sulfate
and evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with the mixture of chloroform and
ethyl acetate (9:1) to give
(S)-5-cyano-2-[2-(4-cyanophenoxy)-1-methylethylamino]-N-(3,4-dimethoxyben-
zyl)benzamide (76 mg) as a solid substance.
[0825] NMR (DMSO-d.sub.6, .delta.): 1.28 (3H, d, J=7 Hz), 3.49 (2H,
m), 3.72 (3H, s), 3.73 (3H, s), 4.13 (3H, m), 4.34 (2H, d, J=6 Hz),
6.80-6.95 (4H, m), 7.09 (2H, d, J=9 Hz), 7.63 (1H, dd, J=2, 9 Hz),
7.76 (2H, d, J=9 Hz), 8.06 (1H, d, J=2 Hz), 8.83 (1H, d, J=8 Hz),
9.02 (1H, t, J=6 Hz)
[0826] Mass m/z: 469 (M.sup.+-1).
EXAMPLE 88(3)
[0827] To a solution of
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-
-methylethylamino)benzamide (4 g) in pyridine (20 mL) was added
methanesulfonyl chloride (1.36 g), and the mixture was stirred for
an hour at 0.degree. C. The resulting mixture was diluted with
ethyl acetate and washed successively with water and brine. The
organic layer was dried over sodium sulfate and evaporated in
vacuo. The residue was triturated with diisopropyl ether to give
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(-
methanesulfonyloxy)-1-methylethylamino]benzamide (5.43 g) as an
oil.
[0828] NMR (DMSO-d.sub.6, .delta.): 1.22 (3H, d, J=7 Hz), 3.17 (3H,
s), 3.72 (3H, s), 3.74 (3H, s), 4.08 (1H, m), 4.23 (2H, d, J=5 Hz),
4.36 (2H, d, J=6 Hz), 6.81-6.96 (4H, m), 7.66 (1H, dd, J=2, 9 Hz),
8.08 (1H, d, J=2 Hz), 8.74 (1H, d, J=8 Hz), 9.05 (1H, t, J=6
Hz)
[0829] Mass m/z: 448 (M.sup.++1).
EXAMPLE 88(4)
[0830] Triphenylphosphine (156 mg) was added to a mixture of
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benza-
mide (200 mg) and carbontetrabromide (215 mg) in dichloromethane (4
mL), and the mixture was stirred for an hour at ambient
temperature. After evaporation of the solvent, the residue was
subjected to a silica gel column chromatography eluting with a
mixture of chloroform and ethyl acetate (9:1) to give
(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-d-
imethoxybenzyl)benzamide (161 mg) as a solid substance.
[0831] NMR (DMSO-d.sub.6, .delta.):1.25 (3H, d, J=7 Hz), 3.67 (2H,
m), 3.72 (3H, s), 3.74 (3H, s), 4.04 (1H, m), 4.36 (2H, d, J=6 Hz),
6.82-6.95 (4H, m), 7.65 (1H, dd, J=2, 9 Hz), 8.07 (1H, d, J=2 Hz),
8.79 (1H, d, J=8 Hz), 9.04 (1H, t, J=6 Hz).
EXAMPLE 88(5)
[0832] To a solution of
(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (117 mg) in dimethylsulfoxide (2 mL) was
added sodium cyamide (26.5 mg), and the mixture was stirred for an
hour at 90.degree. C. The resulting mixture was diluted with ethyl
acetate and washed successively with water and brine. The organic
layer was dried over sodium sulfate and evaporated in vacuo. The
residue was subjected to a silica gel column chromatography eluting
with a mixture of chloroform and ethyl acetate (9:1) to give
(S)-5-cyano-2-(2-cyano-1-methylethylamino-
)-N-(3,4-dimethoxybenzyl)benzamide (73 mg) as a solid
substance.
[0833] NMR (DMSO-d.sub.6, .delta.): 1.29 (3H, d, J=7 Hz), 2.83 (2H,
d, J=5 Hz), 3.72 (3H, s), 3.74 (3H, s), 4.08 (1H, m), 4.36 (2H, d,
J=6 Hz), 6.82-6.95 (4H, m), 7.66 (1H, dd, J=2, 9 Hz), 8.09 (1H, d,
J=2 Hz), 8.78 (1H, d, J=8 Hz), 9.07 (1H, t, J=6 Hz)
[0834] Mass m/z: 377 (M.sup.+-1).
EXAMPLE 88(6)
[0835] To a solution of
(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (61 mg) in dimethylsulfoxide (2 mL) was
added imidazole (28.8 mg), and the mixture was stirred for 2 hours
at 100.degree. C. The resulting mixture was diluted with ethyl
acetate and washed successively with sodium bicarbonate solution,
water and brine. The organic layer was dried over sodium sulfate
and evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with 10% methanol in chloroform. The
obtained product was treated with hydrochloric acid to give
(S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(1-imi-
dazolyl)-1-methylethylamino]benzamide hydrochloride (24 mg) as a
solid substance.
[0836] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=7 Hz), 3.73 (3H,
s), 3.75 (3H, s), 4.20-4.45 (5H, m), 6.80-6.97 (4H, m), 7.61 (1H,
dd, J=2, 9 Hz), 7.64 (1H, s), 7.72 (1H, s), 8.08 (1H, d, J=2 Hz),
8.63 (1H, d, J=8 Hz), 9.09 (2H, m)
[0837] Mass m/z: 454 (M.sup.+-1).
EXAMPLE 88(7)
[0838]
(S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[2-(2-methylimidazol-1-yl)-1--
methylethylamino)benzamide hydrochloride (68 mg) was obtained from
(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3
,4-dimethoxybenzyl)benzam- ide (153 mg) and 2-methylimidazole (87.1
mg) in a manner similar to Example 88 (6).
[0839] NMR (DMSO-d.sub.6, .delta.): 1.23 (3H, d, J=7 Hz), 3.70 (1H,
m), 3.73 (3H, s), 3.75 (3H, s), 4.29 (2H, m), 4.36 (1H, d, J=6 Hz),
6.70-6.95 (4H, m), 7.49 (1H, d, J=2 Hz), 7.56 (1H, dd, J=2, 9 Hz),
7.62 (1H, d, J=2 Hz), 8.04 (1H, d, J=2 Hz), 8.57 (1H, d, J=8 Hz),
9.11 (1H, t, J=6 Hz) Mass m/z 468 (M.sup.++1).
EXAMPLE 88(8)
[0840] To a solution of
(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (147 mg) in dimethylsulfoxide (2 mL) was
added benzenesulfinic acid sodium salt (81.6 mg), and the mixture
was stirred for 3 hours at 90.degree. C. The resulting mixture was
diluted with ethyl acetate and washed successively with water and
brine. The organic layer was dried over sodium sulfate and
evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with a mixture of chloroform and
ethyl acetate (9:1) to give (S)-5-cyano-N-(3,4-dimethoxybe-
nzyl)-2-(2-phenylsulfonyl-1-methylethylamino)benzamide (94 mg) as a
solid substance.
[0841] NMR (DMSO-d.sub.6, .delta.): 1.27 (3H, d, J=7 Hz), 3.65 (2H,
m), 3.72 (3H, s), 3.74 (3H, s), 4.07 (1H, m), 4.30 (2H, m), 6.62
(1H, d, J=9 Hz), 6.83 (1H, dd, J=2, 9 Hz), 6.91 (1H, d, J=9 Hz),
6.92 (1H, d, J=2 Hz), 7.48-7.69 (4H, m), 7.79 (1H, d, J=8 Hz), 7.99
(1H, d, J=2 Hz), 8.55 (1H, d, J=8 Hz), 8.93 (1H, t, J=6 Hz)
[0842] Mass m/z: 492 (M.sup.+-1).
EXAMPLE 88(9)
[0843] To a solution of
(S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (101 mg) in a mixture of
dimethylformamide (1.5 mL) and water (0.2 mL) was added sodium
azide (45.6 mg), and the mixture was stirred for 2 hours at
80.degree. C. The resulting mixture was diluted with ethyl acetate
and washed successively with water and brine. The organic layer was
dried over sodium sulfate and evaporated in vacuo The residue was
triturated with diethyl ether to give
(S)-2-(2-azido-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzami-
de (75 mg) as a solid substance.
[0844] NMR (DMSO-d.sub.6, .delta.): 1.18 (3H, d, J=7 Hz), 3.49 (2H,
m), 3.72 (3H, s), 3.74 (3H, s), 3.96 (1H, m), 4.36 (2H, d, J=6 Hz),
6.81-6.95 (4H, m), 7.64 (1H, dd, J=2, 9 Hz), 8.07 (1H, d, J=2 Hz),
8.74 (1H, d, J=8 Hz), 9.03 (1H, t, J=6 Hz)
[0845] Mass m/z: 393 (M.sup.+-1).
EXAMPLE 88(10)
[0846] To a solution of
(S)-2-(2-azido-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (505 mg) in a mixture of ethanol (5 mL)
and dichloromethane (3 mL) was added 10% palladium on activated
carbon (60 mg), and the mixture was stirred under hydrogen
atmosphere (1 atm) for 3 hours at ambient temperature. The
resulting mixture was filtered through celite and washed with
ethanol. The filtrate and the washings were combined and evaporated
in vacuo. The residue was subjected to a silica gel column
chromatography eluting with 10% methanol in chloroform to give
(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzami-
de (393 mg) as a solid substance.
[0847] NMR (DMSO-d.sub.6, .delta.): 1.13 (3H, d, J=7 Hz), 1.58 (2H,
br), 2.55 (1H, m), 2.57 (1H, m), 3.54 (1H, m), 3.72 (3H, s), 3.74
(3H, s), 4.35 (2H, d, J=6 Hz), 6.81-6.95 (4H, m), 7.59 (1H, dd,
J=2, 9 Hz), 8.02 (1H, d, J=2H), 8.66 (1H, d, J=8 Hz), 8.98 (1H, t,
J=6 Hz)
[0848] Mass m/z: 367 (M.sup.+-1).
EXAMPLE 88(11)
[0849]
(S)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-[2-(formamido)-1-methylethyla-
mino]benzamide (73 mg) was obtained from
(S)-2-(2-amino-1-methylethylamino-
)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (100 mg) and ethyl
formate (2.0 g) in a manner similar to Example 73(2).
[0850] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, d, J=7 Hz), 3.05 (1H,
m), 3.28 (1H, m), 3.70 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.35
(2H, d, J=6 Hz), 6.81-6.98 4H, m), 7.63 (1H, dd, J=2, 9 Hz),
8.03-8.07 (2H, m), 8.26 (1H, m), 8.63 (1H, d, J=8 Hz), 9.01 (1H, t,
J=6 Hz).
[0851] Mass m/z: 395 (M.sup.+-1).
EXAMPLE 88(12)
[0852] To a solution of
(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (99 mg) in dichloromethane (3 mL) was
added acetic anhydride (38 mg), and the mixture was stirred for an
hour at ambient temperature. The resulting mixture was evaporated
in vacuo. The residue was triturated with diisopropyl ether to give
(S)-2-[2-(acetamido)-1-methylethylamino]-5-cyano-N-(3,4-dimethoxybenzyl)b-
enzamide (107 mg) as a solid substance.
[0853] NMR (DMSO-d.sub.6, .delta.): 1.15 (3H, d, J=7 Hz), 1.80 (3H,
s), 3.04 (1H, m), 3.23 (1H, m), 3.68 (1H, m), 3.72 (3H, s), 3.74
(3H, s), 4.35 (2H, d, J=6 Hz), 6.81-7.02 (4H, m), 7.63 (1H, dd,
J=2, 9 Hz), 8.05 (1H, d, J=8 Hz), 8.10 (1H, t, J=6 Hz), 8.59 (1H,
d, J=8 Hz), 9.01 (1H, t, J=6 Hz)
[0854] Mass m/z: 409 (M.sup.+-1).
EXAMPLE 88(13)
[0855] To a mixture of
(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-d-
imethoxybenzyl)benzamide (98 mg) and triethylamine (0.074 mL) in
dichloromethane (3 mL) was added methanesulfonyl chloride (0.029
mL), and the mixture was stirred for an hour at ambient
temperature. The resulting mixture was diluted with ethyl acetate
and washed successively with water and brine. The organic layer was
dried over sodium sulfate and evaporated in vacuo. The residue was
triturated with diisopropyl ether to give
(S)--S-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(methanesulfonylamino)-1-methyl-
ethylaminojbenzamide (110 mg) as a solid substance.
[0856] NMR (DMSO-d.sub.6, .delta.): 1.19 (3H, d, J=7 Hz), 2.88 (3H,
s), 2.94 (1H, m), 3.07 (1H, m), 3.68 (1H, m), 3.72 (3H, s), 3.74
(3H, s), 4.35 (2H, d, J=6 Hz), 6.81-6.94 (4H, m), 7.27 (1H, t, J=6
Hz), 7.64 (1H, dd, J=2, 9 Hz), 8.05 (1H, d, J=8 Hz), 8.63 (1H, d,
J=8 Hz), 9.02 (1H, t, J=6 Hz)
[0857] Mass m/z: 445 (M.sup.+-1).
EXAMPLE 88(14)
[0858]
(S)-5-Cyano-2-[2-(ethoxycarbonylamino)-1-methylethylamino]-N-(3,4-d-
imethoxybenzyl)benzamide (60 mg) was obtained from
(S)-2-(2-amino-1-methyl-
ethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)-benzamide (110 mg) and
ethyl chloroformate (0.04 mL) in a manner similar to Example
88(13).
[0859] NMR (DMSO-d.sub.6, .delta.): 1.14 (3H, t, J=7 Hz), 1.15 (3H,
d, J=7 Hz), 2.87 (1H, m), 3.15 (1H, m), 3.67 (1H, m), 3.72 (3H, s),
3.74 (3H, s), 3.98 (2H, q, J=7 Hz), 4.35 (2H, d, J=6 Hz), 6.82-6.99
(4H, m), 7.37 (1H, t, J=6 Hz), 7.63 (1H, dd, J=2, 9 Hz), 8.05 (1H,
d, J=8 Hz), 8.59 (1H, d, J=8 Hz), 9.00 (1H, t, J=6 Hz)
[0860] Mass m/z : 439 (M.sup.+-1).
EXAMPLE 88(15)
[0861] To a solution of
(S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4--
dimethoxybenzyl)benzamide (52 mg) in ethanol (3 mL) was added
dimethyl N-cyanodithioiminocarbonate (22.7 mg), and the mixture was
stirred for 6 hours at ambient temperature. The solvent of the
reaction mixture was evaporated in vacuo. The residue was subjected
to a silica gel column chromatography eluting with a mixture of
chloroform and ethyl acetate (2:1) to give
(S)-5-cyano-2-[2-(N-cyano-S-methylisothioureido)-1-methylet-
hylamino]-N-(3,4-dimethoxybenzyl)benzamide (52 mg) as a solid
substance.
[0862] NMR (DMSO-d.sub.6, .delta.): 1.18 (3H, d, J=7 Hz), 3.29 (1H,
m), 3.34 (3H, s), 3.44 (1H, m), 3.72 (3H, s), 3.75 (3H, s), 3.93
(1H, m), 4.36 (2H, m), 6.81-6.97 (4H, m), 7.62 (1H, dd, J=2, 9 Hz),
8.06 (1H, d, J=8 Hz), 8.49 (1H, br), 8.64 (1H, d, J=8 Hz), 9.02
(1H, t, J=6H)
[0863] Mass m/z: 465 (M.sup.+-1).
EXAMPLE 88(16)
[0864] To a solution of
(S)-5-cyano-2-[2-(N-cyano-S-methylisothioureido)-1-
-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide (48 mg) in
ethanol (2 mL) was added methylamine in methanol (30%, 0.3 mL), and
the mixture was stirred in a sealed tube for 6 hours at 60.degree.
C. The resulting mixture was evaporated in vacuo and the residue
was triturated with diethyl ether to give
(S)-5-cyano-2-[2-(2-cyano-3-methylguanidino)-1-meth-
ylethylamino]-N-(3,4-dimethoxybenzyl)benzamide (32 mg) as a solid
substance.
[0865] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=7 Hz), 2.63 (3H,
d, J=5 Hz), 3.07 (1H, m), 3.27 (1H, m), 3.72 (3H, s), 3.74 (3H, s),
3.83 (1H, m), 4.35 (2H, m), 6.82-7.00 (4H, m), 7.07 (1H, q, J=5
Hz), 7.14 (1H, t, J=5 Hz), 7.60 (1H, dd, J=2, 9 Hz), 8.05 (1H, d,
J=8 Hz), 8.59 (1H, d, J=8 Hz), 9.02 (1H, t, J=6 Hz)
[0866] Mass m/z: 448 (M.sup.+-1).
EXAMPLE 88(17)
[0867]
(R)-5-Cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino-
)benzamide (103 mg) was prepared from
5-cyano-N-(3,4-dimethoxybenzyl)-2-fl- uorobenzainide (115 mg) and
(R)-2-amino-1-propanol (0.085 mL) in a similar manner to Example
1(1).
[0868] NMR (DMSO-d.sub.6, .delta.): 1.13 (3H, d, J=6 Hz), 3.42 (2H,
t, J=5 Hz), 3.67 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.34 (2H, d,
J=5 Hz), 4.92 (1H, t, J=5 Hz), 6.81-6.95 (4H, in), 7.60 (1H, dd,
J=2, 9 Hz), 8.03 (1H, d, J=2 Hz), 8.69 (1H, d, J=8 Hz), 8.97 (1H,
t, J=5 Hz)
[0869] Mass m/z: 368 (M.sup.+-1).
[0870] Preparation 89(1)
[0871] 5-Bromo-N-(3,4-dirnethoxybenzyl)-2-fluorobenzamide (4.01 g)
was obtained from 5-bromo-2-fluorobenzoic acid (3.0 g) and
veratrylamine (2.27 mL) in a in a manner similar to Preparation
1.
[0872] NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.74 (3H, s),
4.38 (2H, d, J=6 Hz), 6.82-6.96 (3H, m), 7.31 (1H, t, J=9 Hz),
7.68-7.76 (2H, m), 8.94 (1H, t, J=6 Hz)
[0873] Mass m/z: 366, 368 (M.sup.+-1).
[0874] Preparation 89(2)
[0875] To a solution of
5-bromo-N-(3,4-dinethoxybenzyl)-2-fluorobenzamide (200 mg) in
dimethylformamide (2 mL) were added methyl acrylate (0.068 mL),
triethylamine (0.09 mL) and
dichlorobis(triphenylphosphine)palladium- (II) (13.4 mg), and the
mixture was stirred for 6 hours at 120.degree. C. in a sealed tube.
The resulting mixture was diluted with ethyl acetate and washed
successively with water and brine. The organic layer was dried over
sodium sulfate and evaporated in vacuo. The residue was subjected
to a silica gel column chromatography eluting with a mixture of
chloroform and ethyl acetate (9:1) to give
N-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-
-2-(methoxycarbonyl)ethenyl]benzamide (117 mg) as a solid
substance.
[0876] NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.74 (3H, s),
3.75 (3H, s), 4.40 (2H, d, J=6 Hz), 6.68 (1H, d, J=16 Hz),
6.82-6.96 (3H, in), 7.36 (1H, t, J=9 Hz), 7.70 (1H, d, J=16 Hz),
7.87-7.96 (2H, m), 8.91 (1H, t, J=6 Hz).
[0877] Mass m/z : 372 (M.sup.++1).
EXAMPLE 89(1)
[0878]
N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(trans-
-2-methoxycarbonylethenyl)benzamide (121 mg) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-[trans-2-(methoxycarbonyl)
ethenyl]benzamide and trans-4-aminocyclohexanol (118 mg) in a
manner similar to Example 1 (1).
[0879] NMR (DMSO-d.sub.6, .delta.): 1.14-1.40 (4H, m), 1.76-1.86
(2H, m), 1.91-2.00 (2H, m), 3.35-3.53 (2H, m), 3.68 (3H, s), 3.72
(3H, s), 3.74 (3H, s), 4.37 (2H, d, J=6 Hz), 4.59 (1H, d, J=4 Hz),
6.41 (1H, d, J=16 Hz), 6.77 (1H, d, J=9 Hz), 6.83 (1H, dd, J=2, 9
Hz), 6.91 (1H, d, J=9 Hz), 6.93 (1H, d, J=2 Hz), 7.52 (1H, d, J=16
Hz), 7.61 (1H, dd, J=2, 9 Hz), 8.02 (1H, d, J=2 Hz), 8.49 (1H, d,
J=8 Hz), 8.91 (1H, t, J=6 Hz).
EXAMPLE 89(2)
[0880] To a solution of
N-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohex-
ylamino)-5-(trans-2-methoxycarbonylethenyl)benzamide (82 mg) in a
mixture of tetrahydrofuran (2 mL) and water (0.1 mL) were added
4-methylmorpholine N-oxide (53.2 mg) and 4% aqueous solution of
osmium tetroxide (0.1 mL). The mixture was stirred for 2 hours
under reflux. To the mixture were added 50% aqueous methanol (2 mL)
and sodium periodate (161 mg). After siring for 20 minutes, the
mixture was diluted with ethyl acetate and washed successively with
water and brine. The organic layer was dried over sodium sulfate
and evaporated in vacuo. The residue was subjected to a silica gel
column chromatography eluting with a mixture of chloroform and
ethyl acetate (1:1) to give N-(3,4-dimethoxybenzyl)-5-form-
yl-2-(trans-4-hydroxycyclohexylamino)benzamide (117 mg) as a solid
substance.
[0881] NMR (DMSO-d.sub.6, .delta.): 1.16-1.42 (4H, m), 1.77-1.87
(2H, m), 1.92-2.02 (2H, m), 3.38-3.54 (2H, m), 3.72 (3H, s), 3.74
(3H, s), 4.36 (2H, d, J=6 Hz), 4.61 (1H, d, J=4 Hz), 6.80-6.95 (4H,
m), 7.75 (1H, dd, J=2, 9 Hz), 8.17 (1H, d, J=2 Hz), 8.79 (1H, d,
J=8 Hz), 9.10 (1H, t, J=6 Hz), 9.65 (1H, s)
[0882] Mass m/z: 411 (M.sup.+-1).
[0883] Preparation 90(1)
[0884] N-(3,4-Dimethoxybenzyl)-2-fluoro-5-formylbenzamide (915.8
mg) was obtained from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-vinylbenzamide (1.1 g) in a
manner similar to Example 89(2) as a colorless solid substance.
[0885] mp. 132-133.degree. C.
[0886] NMR (CDCl.sub.3, .delta.): 3.86 (3H, s), 3.89 (3H, s), 4.64
(2H, d, J=5.5 Hz), 6.85 (1H, d, J=8.0 Hz), 6.91 (1H, s), 6.92 (1H,
d, J=8.0 Hz), 6.89-7.01 (1H, m), 7.29 (1H, dd, J=11.0, 8.5 Hz),
8.06 (1H, m), 8.66 (1H, dd, J=7.0, 2.0 Hz), 10.04 (1H, s)
[0887] Mass m/z: 316 (M.sup.+-1).
[0888] Preparation 90(2)
[0889] N-(3,4-Dimethoxybenzyl)-2-fluoro-5-formylbenzamide (900 mg)
and glyoxal trimeric dihydrate (596 mg) were stirred in methanol (9
mL) at -10.degree. C. Ammonia was bubbled through the solution for
5 minutes and the mixture was stirred for an hour at -10.degree. C.
The mixture was allowed to warm to ambient temperature over 16
hours, then poured into water and extracted twice with chloroform.
The combined extracts were dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was purified by a flash
column chromatography over silica gel with 5% methanol in
chloroform as eluent to give N-(3,4-dimethoxybenzyl)--
2-fluoro-5-(1H-imidazol-2-yl)benzamide (323. 1 mg) as a pale brown
solid substance.
[0890] mp. 164-166.degree. C.
[0891] NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.75 (3H, s),
4.42 (2H, d, J=5.5 Hz), 6.87 (1H, d, J=8.0 Hz), 6.93 (1H, d, J=8.0
Hz), 6.98 (1H, s), 7.03 (1H, s), 7.26 (1H, s), 7.39 (1H, t, J=8.0
Hz), 8.05 (1H, m), 8.17 (1H, dd, J=7.0, 1.5 Hz), 8.92 (1H, t, J=5.5
Hz), 12.61 (1H, s)
[0892] Mass m/z: 354 (M.sup.+-1).
EXAMPLE 90
[0893]
N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(1H-im-
idazol-2-yl)benzamide (18.5 mg) was obtained as a pale gray solid
substance from
N-(3,4-dimethoxybenzyl)-2-fluoro-5-(1H-imidazol-2-yl)benza- mide
(70 mg) and trans-4-aminocyclohexanol (90.8 mg) in a manner similar
to Example 1(1).
[0894] mp. 189-190.degree. C.
[0895] NMR (DMSO-d.sub.6, .delta.): 1.10-1.42 (4H, m), 1.76-1.88
(2H, m), 1.93-2.05 (2H, m), 3.27-3.54 (2H, m), 3.73 (3H, s), 3.74
(3H, s), 4.36 (2H, d, J=5.5 Hz), 4.58 (1H, d, J=4.5 Hz), 6.80 (1H,
d, J=8.5 Hz), 6.85 (1H, d, J=8.0 Hz), 6.92 (1H, d, J=8.0 Hz), 6.97
(1H, s), 7.04 (2H, s), 7.77 (2H, d, J=8.0 Hz), 8.13 (1H, s), 8.83
(1H, t, J=5.5 Hz), 12.18 (1H, s)
[0896] Mass m/z 451 (M.sup.++1).
[0897] Preparation 91(1)
[0898] To a solution of 2-chloro-5-methylphenol (5.00 g) and
potassium carbonate (7.27 g) in anhydrous dimethylformamide (30 mL)
was added methyl iodide (3.27 mL), and the mixture was stirred for
3 hours at ambient temperature. The mixture was partitioned between
water and ethyl acetate. The separated organic layer was washed
with water and brine and dried over magnesium sulfate. The
resultant was evaporated in vacuo to give 4-chloro-3-methoxytoluene
as a colorless oil (5.65 g).
[0899] NMR (CDCl.sub.3, .delta.): 2.34 (3H, s), 3.89 (3H, s), 6.72
(2H, m), 7.22 (1H, d, J=8 Hz).
[0900] Preparation 91(2)
[0901] To a solution of 4-chloro-3-methoxytoluene (5.65 g) and
N-bromosuccinimide (6.74 g) in anhydrous dichloromethane (60 mL)
was added 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (674
mg). After stirring for 3 hours under reflux, the mixture was
washed with water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was triturated with hexane to give
4-chloro-3-methoxybenzyl bromide as white powders (2.00 g).
[0902] NMR (CDCl.sub.3, .delta.): 3.92 (3H, s), 4.46 (2H, s),
6.91-6.96 (2H, m), 7.32 (1H, d, J=8 Hz).
[0903] Preparation 91(3)
[0904] To a solution of 4-chloro-3-methoxybenzyl bromide (7.00 g)
in anhydrous dimethylformamide (50 mL) was added potassium
phthalimide (6.03 g), and the mixture was stirred for 2 hours at
ambient temperature. The mixture was partitioned between ethyl
acetate and water. The separated organic layer was washed with
water and brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was triturated with diisopropyl ether to give
N-(4-chloro-3-methoxybenzyl)phthalimide as white powders (5.88
g).
[0905] NMR (CDCl.sub.3, .delta.): 3.90 (3H, s), 4.80 (2H, s), 6.96
(1H, d, J=8 Hz), 7.05 (1H, s), 7.25-7.31 (1H, m), 7.68-7.75 (2H,
m), 7.82-7.90 (2H, m). Preparation 91(4) To a solution of
N-(4-chloro-3-methoxybenzyl)p- hthalimide (3.00 g) in ethanol (60
mL) was added hydrazine hydrate (2.62 mL), and the mixture was
heated for an hour under reflux. The resulting precipitates were
filtered off and the filtrate was evaporated in vacuo. The residue
was partitioned between chloroform and an aqueous saturated sodium
bicarbonate solution. The separated organic layer was washed with
water and brine, dried over magnesium sulfate and evaporated in
vacuo to give 4-chloro-3-methoxybenzylamine as a yellow oil (1.64
g).
[0906] NMR (CDCl.sub.3, .delta.): 3.86 (2H, s), 3.92 (3H, s), 6.85
(1H, d, J=8 Hz), 6.93 (1H, s), 7.25-7.34 (1H, d, J=8 Hz).
[0907] Preparation 91(5)
[0908] N-(4-Chloro-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (1.97
g) was obtained from 2-fluoro5-nitrobenzoic acid (1.72 g) and
4-chloro-3-methoxybenzylamine (1.64 g) in a manner similar to
Preparation 55.
[0909] NMR (CDCl.sub.3, .delta.): 3.85 (3H, s), 4.50 (2H, d, J=7
Hz), 6.94 (1H, d, J=8 Hz), 7.15 (1H, s), 7.39 (1H, d, J=8 Hz), 7.64
(1H, m), 8.40-8.47 (2H, m), 9.21 (1H, br)
[0910] Mass m/z: 337 (M.sup.+).
EXAMPLE 91
[0911]
N-(4-Chloro-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-methyl)ethylam-
ino]-5-nitrobenzamide (165 mg) was obtained from
N-(4-chloro-3-methoxybenz- yl)-2-fluoro-5-nitrobenzamide (150 mg)
and 2-amino-1,3-propanediol (60.5 mg) in a manner similar to
Example 1(1).
[0912] mp: 176-177.degree. C.
[0913] NMR (DMSO-d.sub.6, .delta.): 3.50 (4H, br), 3.55-3.68 (1H,
br), 3.82 (3H, s), 4.40 (2H, d, J=7 Hz), 4.90 (2H, t, J=7 Hz),
6.86-6.93 (2H, m), 7.11 (1H, s), 7.35 (1H, d, J=8 Hz), 8.10 (1H,
dd, J=4, 8 Hz), 8.58 (1H, d, J=4 Hz), 9.19 (1H, d, J=8 Hz), 9.32
(1H, br)
[0914] Mass m/z 408 (M.sup.+).
[0915] Preparation 92(1)
[0916] To a mixture of 4-(methylthio)benzyl alcohol (2.00 g) and
carbon tetrabromide (6.45 g) in dichloromethane (40 mL) was added
triphenylphosphine (4.08 g), and the mixture was stirred for an
hour at ambient temperature. After evaporation of the solvent, the
residue was purified by a silica gel column chromatography eluting
with a mixture of hexane and ethyl acetate (20:1) to give
4-(methylthio)benzyl bromide (2.00 g) as a colorless oil.
[0917] NMR (CDCl.sub.3, .delta.): 2.49 (3H, s), 4.48 (2H, s), 7.20
(2H, d, J=8 Hz), 7.32 (2H, d, J=8 Hz).
[0918] Preparation 92(3)
[0919] N-[4-(Methylthio)benzyl]phthalimide (2.40 g) was obtained as
colorless powders from 4-(methylthio)benzyl bromide (1.99 g) and
potassium phthalimide (1.87 g) in a manner similar to Preparation
91(3).
[0920] NMR (CDCl.sub.3, .delta.): 2.45 (3H, s), 4.80 (2H, s), 7.19
(2H, d, J=8 Hz), 7.36 (2H, d, J=8 Hz), 7.69 (2H, m), 7.84 (2H, m).
Prepation 92(3) 4-(Methylthio)benzylamine (1. 17 g) was obtained as
a pale yellow oil from N-[4-(methylthio)benzyl]phthalimide (2.04 g)
in a manner similar to Preparation 91(4).
[0921] NMR (CDCl.sub.3, .delta.); 2.48 (3H, s), 3.83 (2H, s), 7.24
(4H, s). Preparation 92(4)
2-Fluoro-N-[4-(methylthio)benzyl]-5-nitrobenzamide (1.45 g) was
obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.35
g) and 4-(methylthio)benzylamine (1.15 g) in a manner similar
to
[0922] Preparation 55.
[0923] NMR (CDCl.sub.3, .delta.): 3.89 (6H, s), 4.63 (2H, d, J=7
Hz), 6.84-6.93 (4H, m), 7.30 (1H, m), 8.35 (1H, m), 9.03 (1H,
m)
[0924] Mass m/z: 333 (M.sup.+).
EXAMPLE 92
[0925] 2-(trans-4-Hydroxycyclohexyl)
amino-N-14-(methylthio)benzyl]-5-nitr- obenzamide (456 mg) was
obtained as yellow powders from
2-fluoro-N-[4-(methylthio)benzyl]-5-nitrobenzamide (400 mg) and
trans4-aminocyclohexanol (288 mg) in a manner similar to Example
1(1).
[0926] NMR (DMSO-d.sub.6, .delta.): 1.20-1.44 (4H, br), 1.75-1.88
(2H, br), 1.90-2.05 (2H, br), 2.45 (3H, s), 3.42-3.59 (2H, br),
4.39 (2H, d, J=7 Hz), 4.61 (1H, d, J=4 Hz), 6.91 (1H, d, J=8 Hz),
7.20-7.30 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.62 (1H, d, J=4 Hz),
9.10 (1H, d, J=8 Hz), 9.38 (1H, br)
[0927] Mass m/z: 414 (M.sup.+).
[0928] Preparation 93(1)
[0929] 3,5-Dichloro-4-methoxytoluene (5.39 g) was obtained as
yellow oil from 2,6-dichloro-4-methylphenol (5.00 g) and methyl
iodide (2.64 mL) in a manner similar to preparation 91(1).
[0930] NMR (CDCl.sub.3, .delta.): 2.27 (3H, s), 3.87 (3H, s), 7.10
(2H, s).
[0931] Preparation 93(2)
[0932] 3,5-Dichloro-4-methoxybenzyl bromide (9.10 g) was obtained
as yellow oil from 3,5-dichloro-4-methoxytoluene (5.39 g) in a
manner similar to preparation 91(2).
[0933] NMR (CDCl.sub.3, .delta.): 3.90 (3H, s), 4.36 (2H, s), 7.33
(2H, s).
[0934] Preparation 93(3)
[0935] N-(3,5-Dichloro-4-methoxybenzyl)phthalimide (6.34 g) was
obtained as colorless powders from 3,5-dichloro-4-methoxybenzyl
bromide (8.00 g) and potassium phthalimide (6.04 g) in a manner
similar to Preparation 91(3).
[0936] NMR (CDCl.sub.3, .delta.): 3.86 (3H, s), 4.74 (2H, s), 7.37
(2H, s), 7.70-7.78 (2H, m), 7.83-7.90 (2H, m).
[0937] Preparation 93(4)
[0938] 3,5-Dichloro-4-methoxybenzylamine (1.50 g) was obtained as
yellow oil from N-(3,5-dichloro-4-methoxybenzyl)phthaliride (3.00
g) in a manner similar to Preparation 91(4).
[0939] NMR (CDCl.sub.3, .delta.): 3.82 (2H, s), 3.90 (3H, s), 7.28
(2H, br).
[0940] Preparation 93(5)
[0941] N-(3,5-Dichloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide
(2.20 g) was obtained as colorless powders from
2-fluoro-5-nitrobenzoic acid (1.31 g) and
3,5-dichloro-4-methoxybenzylamine (1.50 g) in a manner similar to
Preparation 55.
[0942] NMR (DMSO-d.sub.6, .delta.): 3.81 (3H, s), 4.46 (2H, d, J=7
Hz), 7.48 (2H, s), 7.66 (1H, t, J=8 Hz), 8.38-8.45 (1H, m),
8.46-8.53 (1H, m), 9.20 (1H, br).
EXAMPLE 93
[0943]
N-(3,5-Dichloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-
-5-nitrobenzamide (365 mg) was obtained as yellow powders from
N-(3,5-dichloro-4-methoxybenzyl)-2-fluoro-5-nitrobenzamide (400 mg)
and trans-4-aminocyclohexanol (185 mg) in a manner similar to
Example 1(1).
[0944] NMR (DMSO-d.sub.6, .delta.): 1.20-1.43 (4H, m), 1.76-1.89
(2H, br), 1.9 1-2.01 (2H, br), 3.48 (2H, br), 3.81 (3H, s), 4.39
(2H, d, J=7 Hz), 4.61 (1H, d, J=4 Hz), 6.92 (1H, d, J=8 Hz), 7.45
(2H, s), 8.12 (1H, dd, J=4, 8 Hz), 8.63 (1H, d, J=4 Hz), 9.03 (1H,
d, J=8 Hz), 9.37 (1H, br).
[0945] Preparation 94(1)
[0946] 4-Chloro-3-nitrobenzyl bromide (7.90 g) was obtained as
orange oil from 4-chloro-3-nitrotoluene (5.00 g) in a manner
similar to
[0947] Preparation 91(2).
[0948] NMR (CDCl.sub.3, .delta.): 4.47 (2H, s), 7.54 (2H, s), 7.92
(1H, s). Preparation 94(2) N-(4-Chloro-3-nitrobenzyl)phthalimide
(5.49 g) was obtained as colorless powders from
4-chloro-3-nitrobenzyl bromide (7.00 g) and potassium pbthalimide
(5.69 g) in a manner similar to Preparation 91(3).
[0949] NMR (CDCl.sub.3, .delta.): 4.88 (2H, s), 7.50 (1H, d, J=8
Hz), 7.60 (1H, dd, J=4, 8 Hz), 7.75 (2H, m), 7.88 (2H, m), 7.90
(1H, d, J=4 Hz).
[0950] Preparation 94(3)
[0951] 4-Chloro-3-nitrobenzylamine (1.27 g) was obtained as brown
oil from N-(4-chloro-3-nitrobenzyl)phthalimide (3.00 g) in a manner
similar to Preparation 91(4).
[0952] NMR (CDCl.sub.3, .delta.): 3.96 (2H, s), 7.50 (2H, s), 7.89
(1H, s).
[0953] Preparation 94(4)
[0954] N-(4-Chloro-3-nitrobenzyl)-2-fluoro-5-nitrobenzamide (1.72
g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic
acid (1.20 g) and 4-chloro-3-nitrobenzylamine(1.25 g) in a manner
similar to Preparation 55.
[0955] NMR (DMSO-d.sub.6, .delta.): 4.58 (2H, d, J=7 Hz), 7.62-7.73
(2H, m), 7.78 (1H, d, J=8 Hz), 8.06 (1H, s), 8.44 (1H, m), 8.50
(1H, m), 9.29 (1H, br)
[0956] Mass m/z: 352 (M.sup.+).
EXAMPLE 94
[0957]
(R)-N-(4-Chloro-3-nitrobenzyl)-2-[1-(hydroxymethyl)propylamino]-5-n-
itrobenzamide (150 mg) was obtained as yellow powders from
N-(4-chloro-3-nitrobenzyl)-2-fluoro-5-nitrobenzamide (150 mg) and
(R)-2-amino-1-butanol (56.7 mg) in a manner similar to Example
1(1).
[0958] NMR (DMSO-d.sub.6, .delta.): 0.89 (3H, t, J=7 Hz), 1.40-1.56
(1H, m), 1.60-1.77 (1H, m), 3.47 (2H, br), 3.60 (1H, br), 4.51 (2H,
d, J=7 Hz), 4.91 (1H, t, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.67 (1H,
dd, J=4, 8 Hz), 7.76 (1H, d, J=8 Hz), 8.04 (1H, d, J=4 Hz), 8.12
(1H, dd, J=4, 8 Hz), 8.65 (1H, d, J=4 Hz), 9.14 (1H, d, J=8 Hz),
9.46 (1H, br)
[0959] Mass m/z: 421 (M.sup.+).
[0960] Preparation 95(1)
[0961] To a mixture of 4-cyanobenzaldehyde (5.00 g) in ethanol (50
mL) and tetrahydrofuran (20 mL) was added sodium borohydride (2.16
g) under ice-water cooling, and the mixture was stirred for an hour
at 0.degree. C. After evaporation of the solvent, the residue was
partitioned between ethyl acetate and water. The separated organic
layer was washed with water and brine, dried over magnesium sulfate
and evaporated in vacuo to give 4-cyanobenzyl alcohol (4.76 g) as a
colorless oil.
[0962] NMR (CDCl.sub.3, .delta.): 1.98 (1H, t, J=7 Hz), 4.78 (2H,
d, J=7 Hz), 7.48 (2H, d, J=8 Hz), 7.66 (2H, d, J=8 Hz).
[0963] Preparation 95(2)
[0964] 4-Cyanobenzyl bromide (3.16 g) was obtained as colorless
powders from 4-cyanobenzyl alcohol (2.35 g) in a manner similar to
Preparation 92(1).
[0965] NMR (CDCl.sub.3, .delta.): 4.48 (2H, s), 7.50 (2H, d, J=8
Hz), 7.64 (2H, d, J=8 Hz).
[0966] Preparation 95(3)
[0967] N-(4-Cyanobenzyl)phthalimide (3.75 g) was obtained as
colorless powders from 4-cyanobenzyl bromide (3.00 g) and potassium
phthalimide (3.12 g) in a manner similar to Preparation 91(3).
[0968] NMR (CDCl.sub.3, .delta.): 4.89 (2H, s), 7.52 (2H, d, J=8
Hz), 7.63 (2H, d, J=8 Hz), 7.75 (2H, m), 7.86 (2H, m).
[0969] Preparation 95(4)
[0970] 4-Cyanobenzylamine (1.61 g) was obtained as pale yellow oil
from N-(4-cyanobenzyl)phthalimide (3.70 g) in a manner similar to
Preparation 91(4).
[0971] NMR (CDCl.sub.3, .delta.): 3.96 (2H, s), 7.45 (2H, d, J=8
Hz), 7.63 (2H, d. J=8 Hz).
[0972] Preparation 95(5)
[0973] N-(4-Cyanobenzyl)-2-fluoro-5-nitrobenzamide (3.07 g) was
obtained as colorless powders from 2-fluoro-5-nitrobenzoic acid
(2.19 g) and 4-cyanobenzylamine (1.61 g) in a manner similar to
Preparation 55.
[0974] NMR (DMSO-d.sub.6, .delta.): 4.58 (2H, d, J=7 Hz), 7.55 (2H,
d, J=8 Hz), 7.65 (1H, t, J=7 Hz), 7.84 (2H, d, J=8 Hz), 8.39-8.51
(2H, m), 9.29 (1H, br)
[0975] Mass m/z: 298 (M.sup.+).
EXAMPLE 95
[0976]
N-(4-Cyanobenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzami-
de (428 mg) was obtained as yellow powders from
N-(4-cyanobenzyl)-2-fluoro- -5-nitrobenzamide (400 mg) and
trans4-aminocyclohexanol (308 mg) in a manner similar to Example
1(1).
[0977] NMR (DMSO-d.sub.6, .delta.): 1.18-1.45 (4H, br), 1.75-1.88
(2H, br), 1.90-2.00 (2H, br), 3.40-3.58 (2H, br), 4.50 (2H, d, J=7
Hz), 4.62 (1H, d, J=4 Hz), 6.92 (1H, d, J=8 Hz), 7.51 (2H, d, J=8
Hz), 7.82 (2H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.67 (1H, d,
J=4 Hz), 9.07 (1H, d, J=8 Hz), 9.50 (1H, br)
[0978] Mass m/z: 393 (M.sup.+).
[0979] Preparation 96
[0980] 2-Fluoro-5-nitro-N-(2-pyridylmethyl)benzamide (468 mg) was
obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500
mg) and 2-(aminomethyl)pyridine (307 mg) in a manner similar to
Preparation 55.
[0981] NMR (DMSO-d.sub.6, .delta.): 4.60 (2H, d, J=5 Hz), 7.30 (1H,
t, J=5 Hz), 7.40 (1H, d, J=8 Hz), 7.66 (1H, t, J=8 Hz), 7.80 (1H,
t, J=7.5 Hz), 8.39-8.49 (1H, m), 8.49-8.57 (2H, m), 9.24 (1H,
br)
[0982] Mass m/z: 276.1 (M.sup.++1).
EXAMPLE 96
[0983]
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(2-pyridylmethyl)benza-
mide (580 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(2-py- ridylmethyl)benzamide (450 mg) and
trans4-aminocyclohexanol (282 mg) in a manner similar to Example
1(1).
[0984] NMR (DMSO-d.sub.6, .delta.): 1.18-1.43 (4H, m), 1.70-1.88
(2H, m), 1.88-2.04 (2H, m), 3.38-3.59 (2H, m), 4.54 (2H, d, J=5
Hz), 4.61 (1H, d, J=4 Hz), 6.92 (1H, d, J=8 Hz), 7.28 (1H, dd, J=5,
7.5 Hz), 7.33 (1H, d, J=8 Hz), 7.77 (1H, td, J=8, 2 Hz), 8.12 (1H,
dd, J=8, 2 Hz), 8.51 (1H, d, J=5 Hz), 8.68 (1H, d, J=2 Hz), 9.05
(1H, d, J=8 Hz), 9.48 (1H, m)
[0985] Mass m/z: 369.2 (M.sup.+-1).
[0986] Preparation 97
[0987] 2-Fluoro-5-nitro-N-(3-pyridylmethyl)benzamide (510 mg) was
obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500
mg) and 3-(aminomethyl)pyridine (307 mg) in a manner similar to
[0988] Preparation 55.
[0989] NMR (DMSO-d.sub.6, .delta.): 4.52 (2H, d, J=5 Hz), 7.40 (1H,
dd, J=5, 7.5 Hz), 7.64 (1H, t, J=8 Hz), 7.76 (1H, d, J=7.5 Hz),
8.36-8.51 (3H, m), 8.59 (1H, d, J=2 Hz), 9.25 (1H, br)
[0990] Mass m/z: 274.0 (M.sup.+-1).
EXAMPLE 97
[0991]
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(3-pyridylmethyl)benza-
mide (625 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(3-py- ridylmethyl)benzamide (550 mg) and
trans4-aminocyclohexanol (345 mg) in a manner similar to Example
1(1).
[0992] NMR (DMSO-d.sub.6, .delta.): 1.19-1.44 (4H, m), 1.71-1.88
(2H, m), 1.88-2.07 (2H, m), 3.40-3.61 (2H, m), 4.45 (2H, d, J=5
Hz), 4.62 (1H, d, J=4 Hz), 6.92 (1H, d, J=8 Hz), 7.37 (1H, dd, J=5,
7.5 Hz), 7.43 (1H, d, J=7.5 Hz), 8.12 (1H, dd, J=8, 2 Hz), 8.47
(1H, d, J=5 Hz), 8.56 (1H, d, J=2 Hz), 8.63 (1H, d, J=2 Hz), 9.06
(1H, d, J=8 Hz), 9.43 (1H, m)
[0993] Mass m/z: 369.3 (M.sup.+-1).
[0994] Preparation 98
[0995] 2-Fluoro-5-nitro-N-(4-pyridylmethyl)benzamide (534 mg) was
obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (500
mg) and 4-(aminomethyl)pyridine (307 mg) in a manner similar to
Preparation 55.
[0996] NMR (DMSO-d.sub.6, .delta.): 4.53 (2H, d, J=5 Hz), 7.35 (2H,
d, J=5 Hz), 7.66 (1H, t, J=8 Hz), 8.38-8.65 (4H, m), 9.28 (1H)
[0997] Mass m/z: 274.1 (M.sup.+-1).
EXAMPLE 98
[0998]
2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(4-pyridylmethyl)benza-
mide (548 mg) was obtained as yellow powders from
2-fluoro-5-nitro-N-(4-py- ridylmethyl)benzamide (500 mg) and
trans4-aminocyclohexanol (314 mg) in a manner similar to Example
1(1).
[0999] NMR (DMSO-d.sub.6, .delta.): 1.14-1.43 (4H, m), 1.69-1.88
(2H, m), 1.88-2.05 (2H, m), 3.36-3.60 (2H, m), 4.45 (2H, d, J=5
Hz), 4.61 (1H, d, J=4 Hz), 6.93 (1H, d, J=8 Hz), 7.31 (2H, d, J=5
Hz), 8.13 (1H, dd, J=8, 2 Hz), 8.51 (2H, d, J=5 Hz), 8.69 (1H, d,
J=2 Hz), 9.06 (1H, d, J=8 Hz), 9.48 (1H, m)
[1000] Mass m/z: 369.2 (M.sup.+-1).
[1001] Preparation 99(1)
[1002] 2-Naphthalenemethylamine hydrochloride (1.36 g) was obtained
as white powders from N-(2-naphthylmethyl)phthalimide (2.80 g) in a
manner similar to Preparation 91(4).
[1003] NMR (DMSO-d.sub.6, .delta.): 4.19 (2H, s), 7.51-7.60 (2H,
m), 7.63 (1H, dd, J=8, 2 Hz), 7.87-8.05 (4H, m), 8.46 (3H, br).
[1004] Preparation 99(2)
[1005] 2-Fluoro-N-(2-naphthylmethyl)-5-nitrobenzamide (1.73 g) was
obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00
g) and 2-naphthalenemethylamine hydrochloride (1.10 g) in a manner
similar to Preparation 55.
[1006] NMR (DMSO-d.sub.6, .delta.): 4.67 (2H, d, J=5 Hz), 7.44-7.57
(3H, m), 7.64 (1H, t, J=8 Hz), 7.80-7.98 (4H, m), 8.37-8.47 (1H,
m), 8.47-8.55 (1H, m), 9.28 (1H, m).
EXAMPLE 99
[1007] 2-[2-Hydroxy-1-(hydroxymethyl)
ethylamino]-N-(2-naphthylmethyl)-5-n- itrobenzamide (156 mg) was
obtained as yellow powders from
2-fluoro-N-(2-naphthylmethyl)-5-nitrobenzamide (200 mg) and
2-amino-1,3-propanediol (84.3 mg) in a manner similar to Example
1(1).
[1008] NMR (DMSO-d.sub.6, .delta.): 3.45-3.72 (5H, m), 4.61 (2H, d,
J=5 Hz), 4.92 (1H, t, J=5 Hz), 6.93 (1H, d, J=8 Hz), 7.42-7.57 (3H,
m), 7.82 (1H, s), 7.85-7.98 (3H, m), 8.13 (1H, dd, J=8, 2 Hz), 8.67
(1H, d, J=2 Hz), 9.33 (1H, d, J=8 Hz), 9.46 (1H, m)
[1009] Mass m/z: 394.2 (M.sup.+-1).
[1010] Preparation 100
[1011] 2-Fluoro-N-12-(2-methoxyphenyl)ethyl]-5-nitrobenzamide (1.03
g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid
(1.00 g) and (2-methoxyphenyl)ethylamine(613 mg) in a manner
similar to Preparation 55.
[1012] NMR (DMSO-d.sub.6, .delta.): 2.81 (2H, t, J=7.5 Hz), 3.44
(2H, q, J=7.5 Hz), 3.77 (3H, s), 6.86 (1H, t, J=8 Hz), 6.95 (1H, d,
J=8 Hz), 7.11-7.24 (2H, m), 7.57 (1H, t, J=8 Hz), 8.27-8.41 (2H,
m), 8.65 (1H, br).
EXAMPLE 100
[1013] 2-[2-Hydroxy-1-(hydroxymethyl)
ethylamino]-N-[2-(2-methoxyphenyl)et- hyl]-5-nitrobenzamide (198
mg) was obtained as yellow powders from
2-fluoro-N-[2-(2-methoxyphenyl)ethyl]-5-nitrobenzamide (200 mg) and
2-amino-1,3-propanediol (85.9 mg) in a manner similar to Example
1(1).
[1014] NMR (DMSO-d.sub.6, .delta.): 2.83 (2H, t, J=7.5 Hz), 3.42
(2H, q, J=7.5 Hz), 3.48-3.68 (5H, m), 3.79 (3H, s), 4.92 (2H, t,
J=5 Hz), 6.84-6.95 (2H, m), 6.97 (1H, d, J=8 Hz), 7.12-7.27 (2H,
in), 8.10 (1H, dd, J=8, 2 Hz), 8.47 (1H, d, J=2 Hz), 8.83 (1H, m),
9.17 (1H, d, J=8 Hz)
[1015] Mass m/z: 388.3 (M.sup.+-1).
[1016] Preparation 101
[1017] N-(4-Ethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (2.51
g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic
acid (1.50 g) and 4-ethoxy-3-methoxybenzylamine(1.51 g) in a manner
similar to Preparation 55.
[1018] NMR (DMSO-d.sub.6, .delta.); 1.31 (3H, t, J=7 Hz), 3.75 (3H,
s), 3.98 (2H, q, J=7 Hz), 4.42 (2H, d, J=7 Hz), 6.82-6.97 (3H, m),
7.62 (1H, m), 8.39-8.44 (2H, m), 9.11 (1H, br).
EXAMPLE 101(1)
[1019]
2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nit-
robenzamide (314 mg) was obtained as yellow powders from
N-(4-ethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide (300 mg) and
trans-1,4-cyclohexanediamine (295 mg) in a manner similar to
Example 1 (1).
[1020] NMR (DMSO-d.sub.6, .delta.); 1.15-1.35 (4H, br), 1.30 (3H,
t, J=7 Hz), 1.73-1.85 (2H, br), 1.94-2.05 (2H, br), 2.56-2.70 (1H,
br), 3.40-3.50 (1H, br), 3.74 (3H, s), 3.97 (2H, q, J=7 Hz), 4.36
(2H, d, J=7 Hz), 6.80-6.96 (4H, m), 8.11 (1H, dd, J=4, 8 Hz), 8.60
(1H, d, J=4 Hz), 9.02 (1H, d, J=8 Hz), 9.31 (1H, br)
[1021] Mass m/z: 441 (M.sup.+).
EXAMPLE 101(2)
[1022]
N-(4-Ethoxy-3-methoxybenzyl)-2-(trans-4-formamidocyclohexylamino)-5-
-nitrobenzamide (115 mg) was obtained as yellow powders from
2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nitrobenz-
amide (150 mg) in a manner similar to Example 73(2).
[1023] NMR (DMSO-d.sub.6, .delta.); 1.31 (3H, t, J=7 Hz), 1.25-1.45
(4H, br), 1.75-1.90 (2H, br), 1.94-2.10 (2H, br), 3.48-3.55 (1H,
br), 3.52-3.62 (1H, br), 3.75 (3H, s), 3.97 (2H, q, J=7 Hz), 4.36
(2H, d, J=7 Hz), 6.80-6.96 (4H, m), 7.95 (1H, s), 8.03 (1H, br),
8.10 (1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.03 (1H, d, J=8
Hz), 9.32 (1H, br)
[1024] Mass m/z: 469 (M.sup.+).
[1025] Preparation 102 (1)
[1026] A solution of sodium sulphite (10.6 g) in water (20 mL) was
warmed to 80.degree. C. and slowly added with stirring to a
solution of 5-chlorosulfonyl-2-fluorobenzoic acid (10 g) in acetone
(10 mL), saturated aqueous sodium carbonate being added
simultaneously for keeping the liquid in alkaline. The mixture was
stirred at 60.degree. C. for one and a half hours, and concentrated
in vacuo. The residue was suspended in a mixture of ethanol (20 mL)
and water (20 mL), then iodomethane (2.61 mL) was added to the
mixture. The reaction mixture was stirred for 2 hours at 60.degree.
C. and for an hour at 100.degree. C. After cooling to ambient
temperature, ethanol was removed in vacuo. The resultant aqueous
solution was acidified with concentrated hydrochloric acid. The
aqueous solution was extracted with chloroform (3 times), and the
combined organic layer was dried over magnesium sulfate. After
evaporation of the solvent, the residual oil was crystallized from
ethanol to give 2-fluoro-5-methanesulfonylbenzoic acid (563.6 mg)
as a colorless solid.
[1027] mp 194-195.degree. C.
[1028] NMR (DMSO-d.sub.6, .delta.); 3.29 (3H, s), 7.63 (1H, dd,
J=10.5, 8.5 Hz), 8.19 (1H, ddd, J=8.5, 7.0, 2.5 Hz), 8.37 (1H, dd,
J=7.0, 2.5 Hz).
[1029] Mass m/z: 217 (M.sup.+-1)
[1030] Preparation 102(2)
[1031]
N-(4-Chloro-3-methoxybenzyl)-2-fluoro-5-methanesulfonylbenzamide
(313.9 mg) was obtained as an off-white solid substance from
2-fluoro-5-methanesulfonylbenzoic acid (250 mg) and
4-chloro-3-methoxybenzylamine (203 mg) in a manner similar to
[1032] Preparation 55.
[1033] mp. 121-123.degree. C.
[1034] NMR (DMSO-d.sub.6, .delta.); 3.28 (3H, s), 3.85 (3H, s),
4.49 (2H, d, J=6.0 Hz), 6.94 (1H, dd, J=8.0, 2.0 Hz), 7.15 (1H, d,
J=2.0 Hz), 7.40 (1H, d, J=8.0 Hz), 7.63 (1H, dd, J=10.0, 8.5 Hz),
8.10 (1H, m), 8.16 (1H, dd, J=6.5, 2.5 Hz), 9.17 (1H, brt, J=6.0
Hz)
[1035] Mass m/z: 370 (M.sup.+-1).
EXAMPLE 102
[1036]
N-(4-Chloro-3-methoxybenzyl)-2-(trans4-hydroxycyclohex-ylamino)-5-m-
ethanesulfonylbenzamide (57.2 mg) was obtained as an off-white
solid substance from
N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-methanesulfonylben- zamide
(80 mg) and trans-4-aminocyclohexanol (49.6 mg) in a manner similar
to Example 1(1).
[1037] mp. 234-235.5.degree. C.
[1038] NMR (DMSO-d.sub.6, .delta.); 1.15-1.41 (4H, m), 1.76-1.86
(2H, m), 1.90-2.02 (2H, m), 3.10 (3H, s), 3.38-3.53 (2H, m), 3.84
(3H, s), 4.43 (2H, d, J=6 Hz), 4.60 (1H, d, J=4 Hz), 6.89 (1H, dd,
J=9, 2 Hz), 6.91 (1H, d, J=9 Hz), 7.12 (1H, d, J=2 Hz), 7.38 (1H,
d, J=8.5 Hz), 7.70 (1H, dd, J=8.5, 2.5 Hz), 8.11 (1H, d, J=2.5 Hz),
8.49 (1H, d, J=8 Hz), 9.20 (1H, t, J=6 Hz)
[1039] Mass m/z: 465 (M.sup.+-1).
[1040] Preparation 103
[1041] 2-Fluoro-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide (1.34
g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic
acid (1.16 g) and 3-fluoro-4-methoxybenzylamine hydrochloride (1.00
g) in a manner similar to Preparation 55. m.p. 112.degree. C.
[1042] NMR (DMSO-d.sub.6, .delta.): 3.82 (3H, s), 4.42 (1H, d, J=6
Hz), 7.06-7.23 (3H, m), 7.62 (1H, dd, J=9, 9 Hz), 8.37-8.47 (2H,
m), 9.15 (1H, t, J=6 Hz)
[1043] Mass m/z: 321 (M.sup.+).
EXAMPLE 103
[1044]
N-(3-Fluoro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylami-
no]-5-nitrobenzamide (230 mg) was obtained as yellow powders from
2-fluoro-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide (263 mg) and
2-amino-1,3-propanediol (112 mg) in a manner similar to Example 1
(1). m.p. 130-132.degree. C.
[1045] NMR (DMSO-d.sub.6, .delta.): 3.45-3.70 (5H, m), 3.81 (3H,
s), 4.36 (1H, d, J=6 Hz), 4.91 (2H, t, J=5 Hz), 6.92 (1H, d, J=10
Hz), 7.06-7.21 (3H, m), 8.12 (1H, dd, J=10, 2 Hz), 8.59 (1H, d, J=3
Hz), 9.23-9.35 (2H, m)
[1046] Mass m/z: 392 (M.sup.+).
[1047] Preparation 104
[1048] N-(3-Chloro-4-fluorobenzyl)-2-fluoro-5-nitrobenzamide (976
mg) was obtained as pale yellow powders from
2-fluoro-5-nitrobenzoic acid (1000 mg) and
3-chloro-4-fluorobenzylamine (948 mg) in a manner similar to
Preparation 55.
[1049] NMR (DMSO-d.sub.6, .delta.): 4.49 (2H, d, J=6 Hz), 7.32-7.46
(2H, m), 5.57 (1H, d, J=8 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.53
(2H, m), 9.21 (1H, t, J=6 Hz)
[1050] Mass m/z: 325 (M.sup.+).
EXAMPLE 104
[1051]
N-(3-Chloro-4-fluorobenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamin-
o]-5-nitrobenzamide (211 mg) was obtained as yellow powders from
2-fluoro-N-(3-chloro-4-fluorobenzyl)-5-nitrobenzamide (207 mg) and
2-amino-1,3-propanediol (115 mg) in a manner similar to Example
1(1).
[1052] m.p. 235-238.degree. C.
[1053] NMR (DMSO-d.sub.6, .delta.): 3.28-3.70 (5H, m), 4.42 (2H, d,
J=6 Hz), 4.93 (2H, t, J=5 Hz), 6.93 (1H, d, J=10 Hz), 7.30-7.44
(3H, m), 7.54 (1H, dd, J=6, 2 Hz), 8.13 (1H, dd, J=10, 3 Hz), 8.62
(1H, d, J=3 Hz), 9.28 (1H, d, J=8 Hz), 9.37 (1H, t, J=5 Hz)
[1054] Mass m/z: 396 (M.sup.+).
[1055] Preparation 105
[1056] N-(3-Chloro-4-methylbenzyl)-2-fluoro-5-nitrobenzamide (2.25
g) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic
acid (1.65 g) and 3-chloro-4-methylbenzylamine (1.46 g) in a manner
similar to Preparation 55.
[1057] NMR (DMSO-d.sub.6, .delta.): 2.31 (3H, s), 4.46 (2H, d, J=6
Hz), 7.23 (1H, dd, J=8, 1 Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, d,
J=1 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.50 (2H, m), 9.19 (1H, t,
J=6 Hz)
[1058] Mass m/z: 321 (M.sup.+).
EXAMPLE 105
[1059]
(S)-N-(3-Chloro-4-methylbenzyl)-2-(2-hydroxy-1-methylethylamino)-5--
nitrobenzamide (131 mg) was obtained as yellow powders from
N-(3-chloro-4-methylbenzyl)-2-fluoro-5-nitrobenzamide (184 mg) and
(S)-2-amino-1-propanol (64 mg) in a manner similar to Example 1
(1).
[1060] m.p. 178-179.degree. C.
[1061] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, d, J=6 Hz), 2.30 (3H,
s), 3.45 (2H, m), 3.76 (1H, m), 4.40 (2H, d, J=5 Hz), 4.99 (1H, t,
J=5 Hz), 6.90 (1H, d, J=9 Hz), 7.21 (1H, dd, J=8, 1 Hz), 7.32 (1H,
d, J=8 Hz), 8.12 (1H, dd, J=9, 3 Hz), 8.61 (1H, d, J=3 Hz), 9.16
(1H, d, J=8 Hz), 9.36 (1H, t, J=5 Hz)
[1062] Mass m/z: 376 (M.sup.+).
[1063] Preparation 106
[1064] 2-Fluoro-N-(3-methoxy-4-methylbenzyl)-5-nitrobenzamide (3.31
g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid
(2.60 g) and 3-methoxy-4-methylbenzylamine (2.30 g) in a manner
similar to Preparation 55.
[1065] NMR (DMSO-d.sub.6, .delta.): 2.12 (3H, s), 3.78 (3H, s),
4.46 (2H, d, J=6 Hz), 6.83 (1H, d, J=7.5 Hz), 6.94 (1H, s), 7.10
(1H, d, J=7.5 Hz), 7.63 (1H, dd, J=10, 9 Hz), 8.37-8.47 (2H, m),
9.15 (1H, t, J=6 Hz)
[1066] Mass m/z: 317 (M.sup.+).
EXAMPLE 106
[1067] 2-[2-Hydroxy-1-(hydroxymethyl)
ethylamino]-N-(3-methoxy-4-methylben- zyl)-5-nitrobenzamide (173
mg) was obtained as yellow powders from
2-fluoro-N-(3-methoxy-4-methylbenzyl)-5-nitrobenzamide (171 mg)
2-amino-1,3-propanediol (98 mg) in a manner similar to Example
1(1).
[1068] m.p. 160-162.degree. C.
[1069] NMR (DMSO-d.sub.6, .delta.): 2.11 (3H, s), 3.46-3.60 (4H,
m), 3.63 (1H, m), 3.77 (3H, s), 4.40 (2H, d, J=6 Hz), 4.92 (2H, t,
J=5 Hz), 6.80 (1H, br d, J=8 Hz), 6.92 (1H, s), 6.92 (1H, d, J=10
Hz), 7.08 (1H, d, J=8 Hz), 8.12 (1H, dd, J=10, 3 Hz), 8.59 (1H, d,
J=3 Hz), 9.21 (1H, d, J=8 Hz), 9.30 (1H, t, J=6 Hz)
[1070] Mass m/z: 388 (M.sup.+).
[1071] Preparation 107
[1072] N-(3,5-Dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (3.08 g)
was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic
acid (2.12 g) and 3,5-dimethoxybenzylamine (2.01 g) in a manner
similar to Preparation 55.
[1073] NMR (DMSO-d.sub.6, .delta.): 3.73 (6H, s), 4.44 (2H, d, J=6
Hz), 6.40 (1H, dd, J=2, 2 Hz), 6.52 (2H, d, J=2 Hz), 7.64 (1H, dd,
J=9, 9 Hz), 8.37-8.48 (2H, m), 9.16 (1H, t, J=6 Hz)
[1074] Mass m/z: 333 (M.sup.+).
EXAMPLE 107
[1075]
(S)-N-(3,5-Dimethoxybenzyl)-2-(2-hydroxy-1-methylethyl)amino-5-nitr-
obenzamide (178 mg) was obtained as yellow powders from
N-(3,5-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (169 mg) and
(S)-2-amino-1-propanol (57 mg) in a manner similar to Example
1(1).
[1076] m.p. 98-101.degree. C.
[1077] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, d, J=7 Hz), 3.46 (2H,
m), 3.73 (6H, s), 3.75 (1H, m), 4.37 (2H, d, J=6 Hz), 4.99 (1H, t,
J=5 Hz), 6.39 (1H, dd, J=2, 2 Hz), 6.49 (2H, d, J=2 Hz), 6.90 (1H,
d, J=10 Hz), 8.12 (1H, dd, J=10, 2 Hz), 8.61 (1H, d, J=2 Hz), 9.11
(1H, d, J=8 Hz), 9.32 (1H, t, J=6 Hz)
[1078] Mass m/z: 388(M.sup.+).
[1079] Preparation 108
[1080] 2-Fluoro-5-nitro-N-(4-phenoxybenzyl)benzamide (1.22 g) was
obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid (1.00
g) and 4-phenoxybenzylamine (1.13 g) in a manner similar to
Preparation 55.
[1081] NMR (DMSO-d.sub.6, .delta.): 4.49 (2H, d, J=6 Hz), 6.95-7.05
(4H, m), 7.13 (1H, dd, J=7.5, 7.5 Hz), 7.32-7.45 (4H, m), 7.63 (1H,
dd, J=9, 9 Hz), 8.37-8.50 (2H, m), 9.18 (1H, t, J=6 Hz)
[1082] Mass m/z: 365 (M.sup.+).
EXAMPLE 108
[1083] (R)-2-(2-Hydroxy-1-methylethyl)
amino-5-nitro-N-(4-phenoxybenzyl)be- nzamide (197 mg) was obtained
as yellow powders from
2-fluoro-5-nitro-N-(4-phenoxybenzyl)benzamide (207 mg) and
(R)-2-amino-1-propanol (85 mg) in a manner similar to Example
1(1).
[1084] m.p. 127-129.degree. C.
[1085] NMR (DMSO-d.sub.6, .delta.): 1.16 (3H, d, J=7 Hz), 3.46 (2H,
m), 3.76 (1H, m), 4.43 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.90
(1H, d, J=7 Hz), 6.99 (4H, d, J=9 Hz), 7.13 (1H, t, J=8 Hz),
7.30-7.45 (4H, m), 8.12 (1H, dd, J=10, 3 Hz), 8.62 (1H, d, J=3 Hz),
9.20 (1H, d, J=8 Hz), 9.37 (1H, t, J=6 Hz)
[1086] Mass m/z: 420 (M.sup.+).
[1087] Preparation 109
[1088] 2-Fluoro-5-nitro-N-(4-phenylbenzyl)benzamide (1.44 g) was
obtained from 2-fluoro-5-nitrobenzoic acid (827 mg) and
4-phenylbenzylamine (860 mg) in a manner similar to Preparation
55.
[1089] NMR (DMSO-d.sub.6, .delta.): 4.55 (2H, d, J=6 Hz), 7.36 (1H,
dd, J=7.5, 7.5 Hz), 7.40-7.51 (4H, m), 7.57-7.72 (5H, m), 8.37-8.52
(2H, m), 9.23 (1H, t, J=6 Hz)
[1090] Mass m/z: 349 (M.sup.+).
EXAMPLE 109
[1091] (R)-2-(2-Hydroxy-1-methylethyl)
amino-5-nitro-N-(4-phenybenzyl)benz- amide (167 mg) was obtained as
yellow powders from 2-fluoro-5-nitro-N-(4-p- henybenzyl)benzamide
(178 mg) and (R)-2-amino-1-propanol (76 mg) in a manner similar to
Example 1(1).
[1092] m.p. 168.5-170.5.degree. C.
[1093] NMR (DMSO-d.sub.6, .delta.): 1.17 (3H, d, J=6 Hz), 3.46 (2H,
m), 3.77 (1H, m), 4.49 (2H, d, J=6 Hz), 4.99 (1H, t, J=5 Hz), 6.90
(1H, d, J=10 Hz), 7.30-7.52 (5H, m), 7.60-7.71 (4H, m), 8.13 (1H,
dd, J=10, 2 Hz), 8.65 (1H, d, J=2 Hz), 9.21 (1H, d, J=8 Hz), 9.42
(2H, t, J=6 Hz)
[1094] Mass m/z: 404 (M.sup.+).
EXAMPLE 110(1)
[1095]
2-(Cyclopentylamino)-N-(4-ethoxycarbonylbenzyl)-5-nitrobenzamide
(760 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitro- benzoic acid (500 mg) and
4-ethoxycarbonylbenzylamine (430 mg) in a manner similar to Example
30.
[1096] NMR (CDCl.sub.3, .delta.): 1.38 (3H, t, J=7 Hz), 1.59-1.85
(6H, m), 2.00-2.15 (2H, m), 3.91 (1H, m), 4.37 (2H, q, J=7 Hz),
4.66 (2H, d, J=7 Hz), 6.64 (1H, br), 6.69 (1H, d, J=8 Hz), 7.40
(2H, d, J=8 Hz), 8.03 (2H, d, J=8 Hz), 8.16 (1H, dd, J=4, 8 Hz),
8.37 (1H, d, J=4 Hz), 8.84 (1H, br)
[1097] Mass m/z: 410 (M.sup.+).
EXAMPLE 110(2)
[1098] A mixture of
2-(cyclopentylamino)-N-(4-ethoxycarbonylbenzyl)-5-nitr- obenzamide
(645 mg), ethanol (30 mL) and 1N-sodium hydroxide solution (5 mL)
was heated for 2 hours under reflux. The mixture was acidified with
1 N-hydrochloric acid to pH 4 and the organic solvent was removed
by evaporation. The resulting precipitates were collected by
filtration and washed with water and diethyl ether to give
N-(4-carboxybenzyl)-2-(cyclop- entylamino)-5-nitrobenzamide as
yellow powders (541 mg).
[1099] NMR (DMSO-d.sub.6, .delta.): 1.38-1.50 (2H, m), 1.56-1.70
(4H, m), 2.04 (2H, m), 3.97 (1H, m), 4.52 (2H, d, J=7 Hz), 6.87
(1H, d, J=8 Hz), 7.42 (2H, d, J=8 Hz), 7.90 (2H, d, J=8 Hz), 8.13
(1H, dd, J=4, 8 Hz), 8.66 (1H, d, J=4 Hz), 9.16 (1H, d, J=8 Hz),
9.46 (1H, br)
[1100] Mass m/z: 382 (M.sup.+).
EXAMPLE 110(3)
[1101] A mixture of
N-(4-carboxybenzyl)-2-(cyclopentylamino)-5-nitrobenzam- ide (120
mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(90.0 mg) and 1-hydroxybenzotriazole (63.4 mg) in anhydrous
dimethylformamide (2 mL) was stirred for an hour at ambient
temperature. After addition of 28% ammonia solution (10 drops), the
mixture was stirred for 15 hours at ambient temperature and poured
into water. The resulting precipitates were collected by
filtration, washed with water and purified by a silica gel column
chromatography eluting with 10% methanol in chloroform. The
obtained product was triturated with diisopropyl ether to give
N-(4-carbamoylbenzyl)-2-(cyclopentylamino)-5-ni- trobenzamide (107
mg) as yellow powders.
[1102] NMR (DMSO-d.sub.6, .delta.): 1.39-1.52 (2H, m), 1.56-1.73
(4H, m), 1.98-2.10 (2H, m), 3.98 (1H, m), 4.48 (2H, d, J=7 Hz),
6.87 (1H, d, J=8 Hz), 7.31 (1H, br), 7.38 (2H, d, J=8 Hz), 7.85
(2H, d, J=8 Hz), 7.91 (1H, br), 8.13 (1H, dd, J=4, 8 Hz), 8.67 (1H,
d, J=4 Hz), 9.15 (1H, d, J=8 Hz), 9.44 (1H, br)
[1103] Mass m/z: 383 (M.sup.+).
EXAMPLE 111(1)
[1104] N-(4-Aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (270
mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (300 mg) and
4-aminobenzylamine (176 mg) in a manner similar to Example 30.
[1105] NMR (DMSO-d.sub.6, .delta.): 1.40-1.51 (2H, m), 1.55-1.75
(4H, m), 1.98-2.10 (2H, m), 3.97 (1H, m), 4.24 (2H, d, J=7 Hz),
4.97 (2H, br), 6.52 (2H, d, J=8 Hz), 6.86 (1H, d, J=8 Hz), 6.97
(2H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.57 (1H, d, J=4 Hz),
9.10-9.25 (2H, m)
[1106] Mass m/z: 355 (M.sup.+).
EXAMPLE 111(2)
[1107] To a mixture of
N-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenza- mide (126 mg)
and triethylamine (0.119 mL) in anhydrous dichloromethane (20 mL)
was added acetyl chloride (33.5 mg). After stirring for 2 hours at
ambient temperature, the mixture was washed with an aqueous
saturated sodium bicarbonate solution, water and brine. The
resultant was dried over magnesium sulfate and evaporated in vacuo.
The residue was purified by a silica gel column chromatography
eluting with 10% methanol in chloroform. The obtained product was
triturated with diisopropyl ether to give
N-(4-acetamidobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide as
yellow powders (135 mg).
[1108] NMR (DMSO-d.sub.6, .delta.): 1.38-1.54 (2H, m), 1.60-1.75
(4H, m), 1.98-2.10 (5H, br), 3.96 (1H, m), 4.38 (2H, d, J=7 Hz),
6.86 (1H, d, J=8 Hz), 7.25 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz),
8.13 (1H, d, J=8 Hz), 8.62 (1H, s), 9.17 (1H, d, J=8 Hz), 9.35 (1H,
br), 9.92 (1H, s)
[1109] Mass m/z: 395 (M.sup.+).
[1110] Preparation 112(1)
[1111]
N-[4-[Bis(tert-butoxycarbonyl)amino]-2-chlorobenzyl]phthalimide
(2.14 g) was obtained as colorless powders from
4-[bis(tert-butoxycarbony- l)amino]-2-chlorobenzyl bromide (2.00 g)
and potassium phthalimide (969 mg) in a manner similar to
Preparation 91(3).
[1112] NMR (CDCl.sub.3, .delta.): 1.42 (18H, s), 4.99 (2H, s), 7.00
(1H, dd, J=4, 8 Hz), 7.22 (2H, m), 7.75 (2H, m), 7.87 (2H, m).
Preparation 112(2) 4-(tert-Butoxycarbonylamino)-2-chlorobenzylamine
(950 mg) was obtained as colorless oil from
N-[4-[bis(tert-butoxycarbonyl)amino]-2-chl- orobenzyl]phthalimide
(2.00 g) in a manner similar to Preparation 91(4).
[1113] NMR (CDCl.sub.3, .delta.): 1.50 (9H, s), 3.87 (2H, s), 7.14
(1H, m), 7.25 (2H, m)
[1114] Mass m/z: 257 (M.sup.+).
EXAMPLE 112(1)
[1115] N-[4-(tert-Butoxycarbonyl)
amino-2-chlorobenzyl]-2-(cyclopentylamin- o)-5-nitrobenzamide (206
mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitrobenzoic acid (200 mg) and
4-(tert-butoxycarbonylamino)-2-chlorobenzylamine (246 mg) in a
manner similar to Example 51.
[1116] NMR (CDCl.sub.3, .delta.): 1.50 (9H, s), 1.59-1.85 (6H, m),
2.06 (2H, m), 3.90 (1H, m), 4.61 (2H, d, J=7 Hz), 6.48 (1H, br),
6.54 (1H, br), 6.67 (1H, d, J=8 Hz), 7.14 (1H, dd, J=4, 8 Hz), 7.32
(1H, d, J=8 Hz), 7.61 (1H, d, J=4 Hz), 8.13 (1H, dd, J=4, 8 Hz),
8.28 (1H, d, J=4 Hz), 8.77 (1H, br)
[1117] Mass m/z: 487 (M.sup.+).
EXAMPLE 112(2)
[1118] To a solution of
N-[4-(tert-butoxycarbonyl)amino-2-chlorobenzyl]-2--
(cyclopentylamino)-5-nitrobenzamide (141 mg) in anhydrous ethyl
acetate (2 mL) was added 4N-hydrochloric acid ethyl acetate
solution (4 mL). After stirring for 2 hours at ambient temperature,
the mixture was partitioned between 1N-sodium hydroxide solution
and chloroform. The separated organic layer was washed with water
and brine, dried over magnesium sulfate and evaporated in vacuo.
The residue was triturated with diisopropyl ether to give
N-(4-amino-2-chlorobenzyl)-2-(cyclopentylamino)- -5-nitrobenzamide
as yellow powders (102 mg).
[1119] NMR (DMSO-d.sub.6, .delta.): 1.39-1.52 (2H, m), 1.55-1.74
(4H, m), 1.96-2.10 (2H, m), 3.97 (1H, m), 4.33 (2H, d, J=7 Hz),
5.32 (2H, s), 6.49 (1H, dd, J=4, 8 Hz), 6.62 (1H, d, J=4 Hz), 6.85
(1H, d, J=8 Hz), 7.03 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz),
8.59 (1H, d, J=4 Hz), 9.07 (1H, d, J=8 Hz), 9.14 (1H, br)
[1120] Mass m/z: 389 (M.sup.+).
[1121] Preparation 113(1)
[1122] N-(2-Chloro-4-methoxybenzyl)phthalimide (2.40 g) was
obtained as colorless powders from 2-chloro-4-methoxybenzyl bromide
(2.00 g) and potassium phthalimide (1.86 g) in a manner similar to
Preparation 91(3).
[1123] NMR (CDCl.sub.3, .delta.): 3.77 (3H, s), 4.93 (2H, s), 6.74
(1H, dd, J=4, 8 Hz), 6.92 (1H, d, J=4 Hz), 7.22 (1H, d, J=8 Hz),
7.73 (2H, m), 7.86 (2H, m).
[1124] Preparation 113(2)
[1125] 2-Chloro-4-methoxybenzylamine (630 mg) was obtained as pale
yellow oil from N-(2-Chloro-4-methoxybenzyl)phthalimide (1.00 g) in
a manner similar to Preparation 91(4).
[1126] NMR (CDCl.sub.3, .delta.): 3.79 (3H, s), 3.86 (2H, s), 6.78
(1H, dd, J=4, 8 Hz), 6.92 (1H, d, J=4 Hz), 7.27 (1H, m)
[1127] Mass m/z: 154 (M.sup.+).
EXAMPLE 113
[1128]
N-(2-Chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide
(146 mg) was obtained as yellow powders from
2-(cyclopentylamino)-5-nitro- benzoic acid (100 mg) and
2-chloro-4-methoxybenzylamine (82.3 mg) in a manner similar to
Preparation 1.
[1129] NMR (CDCl.sub.3, .delta.): 1.59-1.85 (6H, m), 2.00-2.13 (2H,
m), 3.80 (3H, s), 3.90 (1H, m), 4.62 (2H, d, J=7 Hz), 6.52 (1H,
br), 6.67 (1H, d, J=8 Hz), 6.80 (1H, dd, J=4, 8 Hz), 6.97 (1H, d,
J=4 Hz), 7.34 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz), 8.29 (1H,
d, J=4 Hz), 8.78 (1H, br)
[1130] Mass m/z: 404 (M.sup.+).
[1131] Preparation 114
[1132] A solution of 3-chloro-4-methoxybenzylamine (234 mg) in
N,N-dimethylformamide (5 mL) was added dropwise to a solution of
5-bromoisatoic anhydride (300 mg) in N,N-dimethylformamide (3 mL).
The reaction mixture was stirred for an hour at ambient
temperature. The mixture was poured into a mixture of water and
ethyl acetate. The precipitates were collected by filtration and
washed with 2-propanol to give
2-amino-5-bromo-N-(3-chloro-4-methoxybenzyl)benzamide (245 mg) as
white powders.
[1133] NMR (DMSO-d.sub.6, .delta.): 3.83 (3H, s), 4.32 (2H, d, J=6
Hz), 6.61 (2H, s), 6.68 (1H, d, J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.25
(1H, dd, J=2, 9 Hz), 7.27 (1H, dd, J=2, 9 Hz), 7.35 (1H, d, J=2
Hz), 7.69 (1H, d, J=2 Hz), 8.88 (1H, t, J=6 Hz).
EXAMPLE 114
[1134] A solution of 97% sulfuric acid (79 mg) in tetrahydrofuran
(0.5 mL) was added to a mixture of
2-amino-5-bromo-N-(3-chloro-4-methoxybenzyl)ben- zamide (199 mg),
cyclopentanone (68 mg) and sodium borohydride (31 mg) in
tetrahydrofuran (3 mL). The mixture was stirred for an hour at
ambient temperature. Then cyclopentanone (68 mg), sodium
borohydride (31 mg) and a solution of 97% sulfuric acid (80 mg) in
tetrahydrofuran (0.5 mL) were added to the reaction mixture. After
stirring for additional 2 hours at ambient temperature, the
reaction mixture was diluted with water. The resultant was made
alkaline with an aqueous saturated sodium bicarbonate solution and
extracted with ethyl acetate. The extract was washed with brine,
dried over magnesium sulfate and concentrated in vacuo. The residue
was purified by a preparative silica gel thin layer chromatography
developed by 25% ethyl acetate in hexane. The obtained substance
was dissolved in diethyl ether, and 4 N-hydrogen chloride solution
in ethyl acetate (0.3 mL) was added thereto. The mixture was
concentrated in vacuo and the residue was triturated with diethyl
ether to give
5-bromo-N-(3-chloro-4-methoxybenzyl)-2-(cyclopentylamino)benzamid-
e hydrochloride (198 mg) as white powders.
[1135] NMR (DMSO-d.sub.6, .delta.): 1.38 (2H, m), 1.50-1.70 (4H,
m), 1.95 (2H, m), 3.77 (1H, m), 3.83 (3H, s), 4.32 (1H, d, J=6 Hz),
6.87 (1H, d, J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.25 (1H, dd, J=2, 19
Hz), 7.35 (1H, d, J=2 Hz), 7.40 (1H, dd, J=2, 9 Hz), 7.77 (1H, d,
J=2 Hz), 8.99 (1H, t, J=6 Hz)
[1136] Mass: (ESI+) 437,439 (M+H), (ESI-) 435,437 (M-H).
[1137] Preparation 115
[1138] 2-Amino-5-chloro-N-(1,3-benzodioxol-5-ylmethyl)benzamide
(321 mg) was obtained as white powders from 5-chloroisatoic
anhydride (300 mg) and (1,3-benzodioxol-5-ylmethyl)amine (275 mg)
in a manner similar to Preparation 114.
[1139] NMR (DMSO-d.sub.6, .delta.): 4.30 (2H, d, J=6 Hz), 5.98 (2H,
s), 6.58 (2H, s), 6.72 (1H, d, J=9 Hz), 6.78 (1H, dd, J=1, 8 Hz),
6.86 (1H, d, J=8 Hz), 6.87 (1H, d, J=1 Hz), 7.17 (1H, dd, J=2, 9
Hz), 7.58 (1H, d, J=2 Hz), 8.84 (1H, t, J=6 Hz)
[1140] Mass: (ESI+) 305, 307 (M+H), (ESI-) 303, 305 (M-H).
EXAMPLE 115
[1141]
5-Chloro-2-(cyclopentylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzami-
de hydrochloride (140 mg) was obtained as white crystals from
2-amino-5-chloro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (135 mg)
and cyclopentanone (110 mg) in a manner similar to Example 114.
[1142] NMR (DMSO-d.sub.6, .delta.): 1.32-1.45 (2H, m), 1.50-1.73
(4H, m), 1.90-2.03 (2H, m), 4.30 (2H, d, J=6 Hz), 5.98 (2H, s),
6.73 (1H, d, J=9 Hz), 6.77 (1H, d, J=8 Hz), 6.86 (1H, d, J=8 Hz),
6.88 (1H, s), 7.29 (1H, brd, J=9 Hz), 7.67 (1H, br), 8.95 (1H, t,
J=6 Hz)
[1143] Mass: (ESI+) 373, 375 (M+H), (ESI-) 371, 373 (M-H).
[1144] Preparation 116
[1145] To a suspension of 5-nitroisatoic anhydride (300 mg) in
dimethylformamide (4 mL) was added 2-chlorobenzylamine (245 mg),
and the mixture was stirred for 15 hours at ambient temperature.
The mixture was partitioned between ethyl acetate and water. The
separated organic layer was washed with water and brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
triturated with diisopropyl ether to give
2-amino-N-(2-chlorobenzyl)-5-nitrobenzamide as yellow powders (397
mg).
[1146] NMR (DMSO-d.sub.6, .delta.): 4.50 (2H, d, J=7 Hz), 6.82 (1H,
d, J=8 Hz), 7.27-7.41 (3H, m), 7.47 (1H, d, J=8 Hz), 7.80 (2H, br),
8.05 (1H, dd, J=4, 8 Hz), 8.65 (1H, d, J=4 Hz), 9.28 (1H, br)
[1147] Mass m/z: 304 (M.sup.+).
EXAMPLE 116
[1148] N-(2-Chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide (152
mg) was obtained as yellow powders from
2-amino-N-(2-chlorobenzyl)-5-nitrobenzami- de (150 mg) and
cyclopentanone (61.9 mg) in a manner similar to Preparation
30(1).
[1149] NMR (CDCl.sub.3, .delta.): 1.58-1.84 (6H, m), 2.00-2.15 (2H,
m), 3.88 (1H, m), 4.68 (2H, d, J=7 Hz), 6.60 (1H, br), 6.68 (1H, d,
J=8 Hz), 7.27 (2H, m), 7.42 (2H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.32
(1H, d, J=4 Hz), 8.78 (1H, br).
[1150] Mass m/z: 372 (M.sup.+).
[1151] Preparation 117
[1152] 2-Amino-N-(3-chlorobenzyl)-5-nitrobenzamide (400 mg) was
obtained as yellow powders from 5-nitroisatoic anhydride (300 mg)
and 3-chlorobenzylamine (245 mg) in a manner similar to Preparation
114.
[1153] NMR (DMSO-d.sub.6, .delta.): 4.42 (2H, d, J=7 Hz), 6.80 (1H,
d, J=8 Hz), 7.28-7.40 (4H, m), 7.82 (2H, br), 8.03 (1H, dd, J=4, 8
Hz), 8.59 (1H, d, J=4 Hz), 9.28 (1H, br)
[1154] Mass m/z: 304 (M.sup.+).
EXAMPLE 117
[1155] N-(3-Chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide
(136 mg) was obtained as yellow powders from
2-amino-N-(3-chlorobenzyl)-5-nitroben- zamide (150 mg) and
cyclopentanone (61.9 mg) in a manner similar to Preparation
30(1).
[1156] NMR (CDCl.sub.3, .delta.): 1.58-1.84 (6H, m), 2.00-2.15 (2H,
m), 3.88 (1H, m), 4.58 (2H, d, J=7 Hz), 6.60 (1H, br), 6.68 (1H, d,
J=8 Hz), 7.20-7.35 (4H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.32 (1H, d,
J=4 Hz), 8.85 (1H, br)
[1157] Mass m/z: 372 (M.sup.+).
[1158] Preparation 118
[1159] 2-Amino-N-(4-chlorobenzyl)-5-nitrobenzamide (407 mg) was
obtained as yellow powders from 5-nitroisatoic anhydride (300 mg)
and 4-chlorobenzylamine (245 mg) in a manner similar to Preparation
114.
[1160] NMR (DMSO-d.sub.6, .delta.): 4.42 (2H, d, J=7 Hz), 6.80 (1H,
d, J=8 Hz), 7.32-7.44 (4H, m), 7.82 (2H, br), 8.03 (1H, dd, J=4, 8
Hz), 8.58 (1H, d, J=4 Hz), 9.30 (1H, br)
[1161] Mass m/z: 304 (M.sup.+).
EXAMPLE 118
[1162] N-(4-Chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide
(97.7 mg) was obtained as yellow powders from
2-amino-N-(4-chlorobenzyl)-5-nitroben- zamide (150 mg) and
cyclopentanone (61.9 mg) in a manner similar to Preparation
30(1).
[1163] NMR (CDCl.sub.3, .delta.): 1.58-1.84 (6H, m), 2.00-2.15 (2H,
m), 3.88 (1H, m), 4.57 (2H, d, J=7 Hz), 6.54 (1H, br), 6.68 (1H, d,
J=8 Hz), 7.27-7.36 (4H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.32 (1H, d,
J=4 Hz), 8.78 (1H, br)
[1164] Mass m/z: 372 (M.sup.+).
[1165] Preparation 119
[1166] 2-Amino-N-hexyl-5-nitrobenzamide (1.09 g) was obtained as
yellow powders from 5-nitroisatoic anhydride (1.00 g) and
hexylamine (583 mg) in a manner similar to Preparation 114.
[1167] NMR (DMSO-d.sub.6, .delta.): 0.85 (3H, br), 1.30 (6H, br),
1.52 (2H, br), 3.20 (2H, m), 6.78 (1H, d, J=8 Hz), 7.75 (2H, br),
8.02 (1H, dd, J=4, 8 Hz), 8.48 (1H, d, J=4 Hz), 8.67 (1H, br)
[1168] Mass m/z: 264 (M.sup.+).
EXAMPLE 119
[1169] 2-(Cyclopentylamino)-N-hexyl-5-nitrobenzamide (98.0 mg) was
obtained as yellow powders from 2-amino-N-hexyl-5-nitrobenzamide
(100 mg) and cyclopentanone (47.6 mg) in a manner similar to
Preparation 30(1).
[1170] NMR (CDCl.sub.3, .delta.): 0.90 (3H, br), 1.28-1.48 (6H,
br), 1.58-1.83 (8H, br), 2.07 (2H, br), 3.38 (2H, m), 3.89 (1H,
br), 6.20 (1H, br), 6.63 (1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz),
8.29 (1H, d, J=4 Hz), 8.82 (1H, br)
[1171] Mass m/z: 332 (M.sup.+).
EXAMPLE 120
[1172] N-Hexyl-5-nitro-2-[(2-thienylmethyl)amino]benzamide (124 mg)
was obtained as yellow powders from
2-amino-N-hexyl-5-nitrobenzamide (200 mg) and
2-thiophenecarboxaldehyde (93.0 mg) in a manner similar to
Preparation 30(1).
[1173] NMR (CDCl.sub.3, .delta.): 0.90 (3H, br), 1.28-1.48 (6H,
br), 1.60-1.70 (2H, br), 3.41 (2H, m), 4.66 (2H, d, J=7 Hz), 6.28
(1H, br), 6.72 (1H, d, J=8 Hz), 6.98 (1H, m), 7.03 (1H, m), 7.24
(1H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.33 (1H, d, J=4 Hz), 9.17 (1H,
br)
[1174] Mass m/z: 360(M.sup.+).
EXAMPLE 121
[1175] 2-(Cycloheptylamino)-N-hexyl-5-nitrobenzamide (225 mg) was
obtained as yellow powders from 2-amino-N-he,xyl-5-nitrobenzamide
(200 mg) and cycloheptanone (211 mg) in a manner similar to
Preparation 30(1).
[1176] NMR (CDCl.sub.3, .delta.): 0.89 (3H, br), 1.28-1.45 (6H,
br), 1.48-1.78 (12H, br), 1.93-2.06 (2H, br), 3.40 (2H, m), 3.60
(1H, m), 6.20 (1H, br), 6.57 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8
Hz), 8.30 (1H, d, J=4 Hz), 8.88 (1H, br)
[1177] Mass m/z: 360 (M.sup.+).
[1178] Preparation 122
[1179] 2-Amino-N-(5-hydroxypentyl)-5-nitrobenzamide (167 mg) was
obtained as yellow powders from 5-nitroisatoic anhydride (200 mg)
and 5-amino-1-pentanol (119 mg) in a manner similar to Preparation
114.
[1180] NMR (DMSO-d.sub.6, .delta.): 1.25-1.60 (6H, m), 3.22 (2H,
m), 3.40 (2H, m), 4.37 (1H, t, J=7 Hz), 6.78 (1H, d, J=8 Hz), 7.75
(2H, br), 8.02 (1H, dd, J=4, 8 Hz), 8.49 (1H, d, J=4 Hz), 8.68 (1H,
br)
[1181] Mass m/z: 266 (M.sup.+).
EXAMPLE 122
[1182] 2-(Cyclopentylamino)-N-(5-hydroxypentyl)-5-nitrobenzamide
(83.5 mg) was obtained as yellow powders from
2-amino-N-(5-hydroxypentyl)-5-nitrobe- nzamide (150 mg) and
cyclopentanone (142 mg) in a manner similar to Preparation
30(1).
[1183] NMR (CDCl.sub.3, .delta.): 1.43-1.88 (12H, br), 2.00-2.15
(2H, br), 3.43 (2H, m), 3.69 (2H, t, J=7 Hz), 3.83-3.96 (1H, m),
6.55 (1H, br), 6.65 (1H, m), 8.13 (1H, dd, J=4, 8 Hz), 8.36 (1H, d,
J=4 Hz), 8.86 (1H, br)
[1184] Mass m/z: 334 (M.sup.+).
[1185] Preparation 123
[1186] 2-Amino-N-(3-ethoxypropyl)-5-nitrobenzamide (332 mg) was
obtained as yellow powders from 5-nitroisatoic anhydride (300 mg)
and 3-ethoxypropylamine (178 mg) in a manner similar to Preparation
114.
[1187] NMR (DMSO-d.sub.6, .delta.): 1.10 (3H, t, J-7 Hz), 1.25 (2H,
m), 3.29 (2H, m), 3.42 (4H, m), 6.78 (1H, d, J=8 Hz), 7.76 (2H,
br), 8.01 (1H, dd, J=4, 8 Hz), 8.48 (1H, d, J=4 Hz), 8.68 (1H,
br)
[1188] Mass m/z: 266 (M.sup.+).
EXAMPLE 123
[1189] 2-(Cyclopentylamino)-N-(3-ethoxypropyl)-5-nitrob enzamide
(150 mg) was obtained as yellow powders from
2-amino-N-(3-ethoxypropyl)-5-nitroben- zamide (150 mg) and
cyclopentanone (165 mg) in a manner similar to Preparation
30(1).
[1190] NMR (CDCl.sub.3, .delta.): 1.28 (3H, t, J=7 Hz), 1.61-1.84
(6H, br), 1.93 (2H, m), 2.03-2.12 (2H, m), 3.57 (4H, m), 3.68 (2H,
t, J=7 Hz), 3.91 (1H, m), 6.67 (1H, d, J=8 Hz), 7.45 (1H, br), 8.15
(1H, dd, J=4, 8 Hz), 8.32 (1H, d, J=4 Hz), 9.01 (1H, br)
[1191] Mass m/z: 334 (M.sup.+).
[1192] Preparation 124
[1193] 2-Amino-N-benzyl-5-nitrobenzamide (1.66 g) was obtained as
yellow powders from 5-nitroisatoic anhydride (1.50 g) and
benzylamine (850 mg) in a manner similar to Preparation 114.
[1194] NMR (DMSO-d.sub.6, .delta.): 4.45 (2H, d, J=7 Hz), 6.80 (1H,
d, J=8 Hz), 7.26 (1H, m), 7.33 (4H, m), 7.80 (2H, br), 8.01 (1H,
dd, J=4, 8 Hz), 8.58 (1H, d, J=4 Hz), 9.28 (1H, br)
[1195] Mass m/z: 270 (M.sup.+).
EXAMPLE 124
[1196] N-Benzyl-2-(cyclobutylamino)-5-nitrobenzamide (210 mg) was
obtained as yellow powders from 2-amino-N-benzyl-5-nitrobenzamide
(200 mg) and cyclobutanone (77.5 mg) in a manner similar to
preparation 30(1).
[1197] NMR (CDCl.sub.3, .delta.): 1.80-2.10 (4H, m), 2.44-2.55 (2H,
m), 4.00 (1H, m), 4.61 (2H, d, J=7 Hz), 6.52 (1H, br), 6.53 (1H, d,
J=8 Hz), 7.28-7.42 (5H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.31 (1H, d,
J=4 Hz), 8.89 (1H, br)
[1198] Mass m/z: 324(M.sup.+).
EXAMPLE 125
[1199] N-Benzyl-2-cycloheptylamino-5-nitrobenzamide (165 mg) was
obtained as yellow powders from 2-amino-N-benzyl-5-nitrobenzamide
(200 mg) and cycloheptanone (372 mg) in a manner similar to
Preparation 30(1).
[1200] NMR (CDCl.sub.3, .delta.): 1.44-1.80 (10H, br), 1.95-2.07
(2H, br), 3.63 (1H, m), 4.61 (2H, d, J=7 Hz), 6.47 (1H, br), 6.58
(1H, d, J=8 Hz), 7.29-7.42 (5H, m), 8.15 (1H, dd, J=4, 8 Hz), 8.30
(1H, d, J=4 Hz), 8.90 (1H, br)
[1201] Mass m/z: 366(M.sup.+).
EXAMPLE 126
[1202] N-Benzyl-2-(cyclohexylamino)-5-nitrobenzamide (135 mg) was
obtained as yellow powders from 2-amino-N-benzyl-5-nitrobenzamide
(200 mg) and cyclohexanone (217 mg) in a manner similar to
Preparation 30(1).
[1203] NMR (CDCl.sub.3, .delta.): 1.27-1.70 (6H, br), 1.80 (2H,
br), 2.03 (2H, br), 3.46 (1H, br), 4.59 (2H, d, J=7 Hz), 6.46 (1H,
br), 6.66 (1H, d, J=8 Hz), 7.28-7.40 (5H, m), 8.13 (1H, dd, J=4, 8
Hz), 8.32 (1H, d, J=4 Hz), 8.88 (1H, br)
[1204] Mass m/z: 352(M.sup.+).
[1205] Preparation 127
[1206] 2-Amino-N-(2,4-dichlorobenzyl)-5-nitrobenzamide (437 mg) was
obtained as yellow powders from 5-nitroisatoic anhydride (300 mg)
and 2,4-dichlorobenzylamine (305 mg) in a manner similar to
Preparation 116.
[1207] NMR (DMSO-d.sub.6, .delta.): 4.48 (2H, d, J=7 Hz), 6.83 (1H,
d, J=8 Hz), 7.42 (2H, m), 7.63 (1H, s), 7.81 (2H, br), 8.05 (1H,
dd, J=4, 8 Hz), 8.64 (1H, d, J=4 Hz), 9.29 (1H, br).
EXAMPLE 127
[1208] 2-(Cyclopentylamino)-N-(2,4-dichlorobenzyl)-5-nitrobenzamide
(151 mg) was obtained as yellow powders from
2-amino-N-(2,4-dichlorobenzyl)-5-- nitrobenzamide (150 mg) and
cyclopentanone (111 mg) in a manner similar to Preparation
30(1).
[1209] NMR (CDCl.sub.3, .delta.): 1.58-1.88 (6H, m), 2.08 (2H, m),
3.89 (1H, m), 4.65 (2H, d, J=7 Hz), 6.67 (1H, d, J=8 Hz), 6.65-6.75
(1H, br), 7.25 (1H, m), 7.36 (1H, d, J=8 Hz), 7.43 (1H, d, J=4 Hz),
8.13 (1H, dd, J=4, 8 Hz), 8.33 (1H, d, J=4 Hz), 8.75 (1H, br).
[1210] Preparation 128
[1211] 2-Amino-N-(3,4-dichlorobenzyl)-5-nitrobenzamide (444 mg) was
obtained as yellow powders from 5-nitroisatoic anhydride (300 mg)
and 3,4-dichlorobenzylamine (305 mg) in a manner similar to
Preparation 116.
[1212] NMR (DMSO-d.sub.6, .delta.): 4.43 (2H, d, J=7 Hz), 6.83 (1H,
d, J=8 Hz), 7.33 (1H, d, J=8 Hz), 7.59 (2H, m), 7.83 (2H, br), 8.04
(1H, dd, J=4, 8 Hz), 8.58 (1H, d, J=4 Hz), 9.32 (1H, br).
EXAMPLE 128
[1213] 2-(Cyclopentylamino)-N-(3,4-dichlorobenzyl)-5-nitrobenzamide
(81.8 mg) was obtained as yellow powders from
2-amino-N-(3,4-dichlorobenzyl)-5-- ntrobenzamide (150 mg) and
cyclopentanone (111 mg) in a manner similar to Preparation
30(1).
[1214] NMR (CDCl.sub.3, .delta.): 1.58-1.86 (6H, m), 2.07 (2H, m),
3.90 (1H, m), 4.56 (2H, d, J=7 Hz), 6.63 (1H, br), 6.69 (1H, d, J=8
Hz), 7.18 (1H, d, J=8 Hz), 7.43 (2H, m), 8.17 (1H, dd, J=4, 8 Hz),
8.35 (1H, d, J=4 Hz), 8.85 (1H, br).
[1215] Preparation 129(1)
[1216] Methyl
2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoate(20.4 g) was
obtained as yellow powders from methyl 2-fluoro-5-nitrobenzoate
(15.0 g) and trans-4-aminocyclohexanol (13.0 g) in a manner similar
to Example 1(1).
[1217] NMR (CDCl.sub.3, .delta.): 1.36-1.57 (4H, m), 1.97-2.25 (4H,
m), 3.43-3.56 (1H, m), 3.70-3.84 (1H, m), 3.90 (3H, s), 6.69 (1H,
d, J=8 Hz), 8.19 (1H, dd, J=2, 8 Hz), 8.60 (1H, br d, J=8 Hz), 8.87
(1H, d, J=2 Hz)
[1218] Mass m/z: 294.(EI+).
[1219] Preparation 129 (2)
[1220] Methyl 2-(cis-4-acetoxycyclohexylamino)-5-nitrobenzo ate
(14.6 g) was obtained as yellow powders from methyl
2-(trans4-hydroxycyclohexylami- no)-5-nitrobenzoate (20.0 g) in a
manner similar to Example 52(2).
[1221] NMR (DMSO-d.sub.6, .delta.): 1.56-1.92 (8H, m), 2.04 (3H,
s), 3.74-3.86 (1H, m), 3.89 (3H, s), 4.85 (1H, br), 7.05 (1H, d,
J=8 Hz), 8.20 (1H, dd, J=2, 8 Hz), 8.64-8.73 (2H, m).
[1222] Preparation 129(3)
[1223] 2-(cis-4-Hydroxycyclohexylamino)-5-nitrobenzoic acid (11.7
g) was obtained as yellow powders from methyl
2-(cis-4-acetoxycyclohexylamino)-5- -nitrobenzoate (14.4 g) in a
manner similar to Example 52(3).
[1224] NMR (DMSO-d.sub.6, .delta.): 1.45-1.84 (8H, m), 3.62-3.81
(2H, m), 4.57 (1H, br), 6.95 (1H, d, J=8 Hz), 8.15 (1H, dd, J=2, 8
Hz), 8.66 (1H, d, J=2 Hz), 8.99 (1H, d, J=8 Hz)
[1225] Mass m/z: 279.1 (M.sup.+-1).
[1226] Preparation 129(4)
[1227] To a mixture of 3-methoxy-4-nitrobenzyl alcohol (3.00 g) and
carbon tetrabromide (8.15 g) in dichloromethane (60 mL) was added
triphenylphosphine (5.16 g) under ice-water cooling, and the
mixture was stirred for an hour at ambient temperature. After
evaporation of the solvent, the residue was purified by a silica
gel column chromatography eluting with a mixture of hexane and
ethyl acetate (5:1) to give 3-methoxy-4-nitrobenzyl bromide as pale
yellow powders (4.87 g).
[1228] NMR (CDCl.sub.3, .delta.): 3.99 (3H, s), 4.47 (2H, s), 7.04
(1H, d, J=8 Hz), 7.10 (1H, s), 7.83 (1H, d, J=8 Hz).
[1229] Preparation 129(5) N-(3-Methoxy-4-nitrobenzyl)phthalimide
(4.49 g) was obtained as colorless powders from
3-methoxy-4-nitrobenzylbromide (4.00 g) and potassium phthalimide
(3.31 g) in a manner similar to Preparation 91(3).
[1230] NMR (CDCl.sub.3, .delta.): 3.97 (3H, s), 4.87 (2H, s), 7.07
(1H, d, J=8 Hz), 7.18 (1H, s), 7.72-7.80 (2H, m), 7.81 (1H, d, J=8
Hz), 7.83-7.91 (2H, m). Preparation 129 (6)
3-Methoxy-4-nitrobenzylamine (1.28 g) was obtained as yellow oil
from N-(3-methoxy-4-nitrobenzyl)phthalimide (3.00 g) in a manner
similar to Preparation 91(4).
[1231] NMR (CDCl.sub.3, .delta.): 3.97 (2H, s), 3.98 (3H, s), 6.95
(1H, d, J=8 Hz), 7. 10 (1H, s), 7.84 (1H, d, J=8 Hz).
EXAMPLE 129
[1232] 2-(cis-4-Hydroxycyclohexylamino)-N-(3-methoxy-4-nitrobenzyl)
-5-nitrobenzamide (110 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
3-methoxy-4-nitrobenzylamine (78.0 mg) in a manner similar to
Preparation 1.
[1233] NMR (DMSO-d.sub.6, .delta.): 1.44-1.75 (8H, br), 3.66 (2H,
br), 3.93 (3H, s), 4.54 (3H, br), 6.90 (1H, d, J=8 Hz), 7.06 (1H,
d, J=8 Hz), 7.34 (1H, s), 7.88 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4,
8 Hz), 8.69 (1H, d, J=4 Hz), 9.27 (1H, br), 9.49 (1H, br)
[1234] Mass m/z: 443 (M.sup.+).
[1235] Preparation 130(1)
[1236] N-(2-Chloro-5-methoxybenzyl)phthalimide (7.69 g) was
obtained as colorless powders from 2-chloro-5-methoxybenzyl bromide
(8.30 g) and potassium phthalimide (6.85 g) in a manner similar to
Preparation 91(3).
[1237] NMR (CDCl.sub.3, .delta.): 3.73 (3H, s), 4.95 (2H, s), 6.75
(2H, m), 7.27 (1H, m), 7.75 (2H, m), 7.88 (2H, m).
[1238] Preparation 130(2)
[1239] 2-Chloro-5-methoxybenzylamine (1.67 g) was obtained as
yellow oil from N-(2-chloro-5-methoxybenzyl)phthalimide (3.00 g) in
a manner similar to Preparation 91(4).
[1240] NMR (CDCl.sub.3, .delta.): 3.80 (3H, s), 3.89 (2H, s), 6.73
(1H, dd, J=4, 8 Hz), 6.94 (1H, d, J=4 Hz), 7.25 (1H, d, J=8
Hz).
EXAMPLE 130
[1241]
N-(2-Chloro-5-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nit-
robenzamide (125 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
2-chloro-5-methoxybenzylamine (73.5 mg) in a manner similar to
Preparation 1.
[1242] NMR (DMSO-d.sub.6, .delta.): 1.45-1.75 (8H, br), 3.61-3.72
(2H, br), 3.74 (3H, s), 4.48 (2H, d, J=7 Hz), 4.53 (1H, d, J=4 Hz),
6.88-6.93 (3H, m), 7.39 (1H, d, J=8 Hz), 8.13 (1H, dd, J=4, 8 Hz),
8.67 (1H, d, J=4 Hz), 9.17 (1H, d, J=8 Hz), 9.36 (1H, br)
[1243] Mass m/z: 432 (M.sup.+).
[1244] Preparation 131(1)
[1245] To a solution of 3-hydroxy-4-methoxybenzoic acid (10.0 g) in
methanol (100 mL) was added conc. sulfuric acid (10 mL) under
ice-water cooling, and the mixture was heated for 15 hours under
reflux. After evaporation of the solvent, the residue was
partitioned between ethyl acetate and water. The separated organic
layer was washed with an aqueous saturated sodium bicarbonate
solution, water and brine. The resultant was dried over magnesium
sulfate and evaporated in vacuo to give methyl
3-hydroxy-4-methoxybenzoate as a brown oil (9.43 g).
[1246] NMR (CDCl.sub.3, .delta.): 3.88 (3H, s), 3.95 (3H, s), 5.69
(1H, s), 6.87 (1H, d, J=8 Hz), 7.57-7.64 (2H, m). Preparation
131(2) To a mixture of methyl 3-hydroxy-4-methoxybenzoate (4.00 g)
and potassium carbonate (4.55 g) in dimethylformamide (20 mL) was
added ethyl iodide (2.63 mL) under water-cooling and the mixture
was stirred for 2 hours at ambient temperature. The mixture was
partitioned between water and ethyl acetate. The separated organic
layer was washed with water and brine, dried over magnesium sulfate
and evaporated in vacuo to give methyl 3-ethoxy-4-methoxybenzoate
as pale brown powders (4.55 g).
[1247] NMR (CDCl.sub.3, .delta.): 1.49 (3H, t, J=7 Hz), 3.89 (3H,
s), 3.93 (3H, s), 4.16 (2H, q, J=7 Hz), 6.89 (1H, d, J=8 Hz), 7.54
(1H, d, J=4 Hz), 7.66 (1H, dd, J=4, 8 Hz).
[1248] Preparation 131(3)
[1249] A mixture of methyl 3-ethoxy-4-methoxybenzoate (4.42 g),
methanol (160 mL) and 1N-sodium hydroxide solution (40 mL) was
heated for 2 hours under reflux. The reaction mixture was acidified
with IN-hydrochloric acid to pH 4, and the organic solvent was
removed by evaporation. The aqueous layer was diluted with water
and extracted with ethyl acetate. The extract was washed with
brine, dried over magnesium sulfate and evaporated in vacuo. The
residue was triturated with hexane to give
3-ethoxy-4-methoxybenzoic acid as colorless powders (3.76 g).
[1250] NMR (CDCl.sub.3, .delta.): 1.50 (3H, t, J=7 Hz), 3.95 (3H,
s), 4.17 (2H, q, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.60 (1H, d, J=4
Hz), 7.76 (1H, dd, J=4, 8 Hz)
[1251] Mass m/z: 195 (M.sup.+).
[1252] Preparation 131(4)
[1253] To a mixture of 3-ethoxy-4-methoxybenzoic acid (3.66 g) and
oxalyl chloride (2.12 mL) in dichloromethane (40 mL) was added
dimethylformamide (5 drops), and the mixture was stirred for 2
hours at ambient temperature. After evaporation of the solvent, the
residue was redissolved in dichloromethane (40 mL). The solution
was added to a mixture of 28% ammonia solution (40 mL) and
dichloromethane (40 mL) under ice-water cooling. The mixture was
stirred for an hour at ambient temperature. The resulting
precipitates were collected by filtration and washed with water and
diethyl ether to give 3-ethoxy-4-methoxybenzamide as colorless
powders (3.40 g).
[1254] NMR (DMSO-d.sub.6, .delta.): 1.34 (3H, t, J=7 Hz), 3.80 (3H,
s), 4.04 (2H, q, J=7 Hz), 7.00 (1H, d, 3=8 Hz), 7.18 (1H, br),
7.39-7.51 (2H, m), 7.83 (1H, br).
[1255] Preparation 131(5)
[1256] To a solution of 3-ethoxy-4-methoxybenzamide (3.30 g) in
pyridine (33 mL) was added phosphorus oxychloride (1.73 mL) under
ice-water cooling, and the mixture was stirred for 2 hours at
ambient temperature. After evaporation of the solvent, the residue
was partitioned between ethyl acetate and water under ice-water
cooling. The separated organic layer was washed with
1N-hydrochloric acid, water and brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with a mixture of hexare and ethyl
acetate (5:1 to 4:1) to give 3-ethoxy-4-methoxybenzonitrile as
colorless powders (2.83 g).
[1257] NMR (CDCl.sub.3, .delta.): 1.49 (3H, t, J=7 Hz), 3.93 (3H,
s), 4.10 (2H, q, J=7 Hz), 6.90 (1H, d, J=8 Hz), 7.08 (1H, d, J=4
Hz), 7.27 (1H, dd, J=4, 8 Hz).
[1258] Preparation 131(6)
[1259] To a suspension of lithium aluminum hydride (1.17 g) in
anhydrous tetrahydrofuran (15 mL) was added a solution of
3-ethoxy-4-methoxybenzoni- trile (2.73 g) in tetrahydrofuran (15
mL). The mixture was stirred for an hour under water cooling and
then for an hour at ambient temperature. Potassium sodium
(+)-tartrate aqueous solution was added to the mixture under
ice-water cooling. The mixture was diluted with ethyl acetate and
the insolubles were filtered off. After evaporation of the
filtrate, ethyl acetate was added. The solution was dried over
magnesium sulfate and evaporated in vacuo to give
3-ethoxy-4-methoxybenzylamine as yellow oil (2.81 g).
[1260] NMR (CDCl.sub.3, .delta.): 1.47 (3H, t, J=7 Hz), 3.80 (2H,
s), 3.87 (3H, s), 4.12 (2H, q, J=7 Hz), 6.80-6.90 (3H, m).
EXAMPLE 131
[1261]
N-(3-Ethoxy-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nit-
robenzamide (130 mg) was obtained as yellow powders from
2-(cis-4-hydroxycycloh exylamino)-5-nitrobenzoi c acid (100 mg) and
3-ethoxy-4-methoxybenzylamine (77.6 mg) in a manner similar to
Preparation 1.
[1262] NMR (DMSO-d.sub.6, .delta.): 1.32 (3H, t, J=7 Hz), 1.45-1.80
(8H, br), 3.60-3.75 (2H, br), 3.73 (3H, s), 3.99 (2H, q, J=7 Hz),
4.37 (2H, d, J=7 Hz), 4.55 (1H, d, J=4 Hz), 6.82-6.96 (4H, m), 8.10
(1H, dd, J=4, 8 Hz), 8.60 (1H, d, J=4 Hz), 9.24 (1H, d, J=8 Hz),
9.32 (1H, br)
[1263] Mass m/z: 442(M.sup.+).
[1264] Preparation 132(1)
[1265] 4-Chloro-3-ethoxytoluene (6.08 g) was obtained as pale
yellow oil from 2-chloro-5-methylphenol (5.00 g) and ethyl iodide
(4.21 mL) in a manner similar to Preparation 91 (1).
[1266] NMR (CDCl.sub.3, .delta.): 1.46 (3H, t, J=7 Hz), 2.32 (3H,
s), 4.09 (2H, q, J=7 Hz), 6.66-6.73 (2H, m), 7.22 (1H, d, J=8
Hz).
[1267] Preparation 132(2)
[1268] 4-Chloro-3-ethoxybenzyl bromide (8.75 g) was obtained as
yellow oil from 4-chloro-3-ethoxytoluene (6.00 g) in a manner
similar to Preparation 91(2).
[1269] NMR (CDCl.sub.3, .delta.): 1.48 (3H, t, J=7 Hz), 4.11 (2H,
q, J=7 Hz), 4.44 (2H, s), 6.84-6.95 (2H, m), 7.30 (1H, d, J=8
Hz).
[1270] Preparation 132(3)
[1271] N-(4-Chloro-3-ethoxybenzyl)phthalimide (7.88 g) was obtained
as colorless powders from 4-chloro-3-ethoxybenzyl bromide (8.75 g)
and potassium phthalimide (6.82 g) in a manner similar to
Preparation 91(3).
[1272] NMR (CDCl.sub.3, .delta.): 1.46 (3H, t, J=7 Hz), 4.11 (2H,
q, J=7 Hz), 4.78(2H, s), 6.95 (1H, d, J=8 Hz), 7.04 (1H, s), 7.27
(1H, d, J=8 Hz), 7.72 (2H, m), 7.85 (2H, m).
[1273] Preparation 132(4)
[1274] 4-Chloro-3-ethoxybenzylamine (2.25 g) was,obtained as yellow
oil from N-(4-chloro-3-ethoxybenzyl)phthalimide (4.00 g) in a
manner similar to Preparation 91(4).
[1275] NMR (CDCl.sub.3, .delta.): 1.48 (3H, t, J=7 Hz), 3.82 (2H,
s), 4.12 (2H, q, J=7 Hz), 6.79 (1H, d, J=8 Hz), 6.90 (1H, s), 7.25
(1H, d, J=8 Hz).
EXAMPLE 132
[1276] N-(4-Chloro-3-ethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino
)-5-nitrobenzamide (130 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
4-chloro-3-ethoxybenzylamine (79.5 mg) in a manner similar to
Preparation 1.
[1277] NMR (DMSO-d.sub.6, .delta.): 1.36 (3H, t, J=7 Hz), 1.45-1.80
(8H, br), 3.58-3.65 (2H, br), 4.11 (2H, q, J=7 Hz), 4.44 (2H, d,
J=7 Hz), 4.56 (1H, d, J=4 Hz), 6.86-6.92 (2H, m), 7.12 (1H, s),
7.38 (1H, d, J=8 Hz), 8.12 (1H, dd, J=4, 8 Hz), 8.64 (1H, d, J=4
Hz), 9.25 (1H, d, J=8 Hz), 9.40 (1H, br)
[1278] Mass m/z: 446 (M.sup.+).
[1279] Preparation 133(1)
[1280] Methyl 4-hydroxy-3-methoxybenzoate (25.2 g) was obtained as
colorless powders from 4-hydroxy-3-methoxybenzoic acid (25.9 g) in
a manner similar to Preparation 131 (1).
[1281] NMR (CDCl.sub.3, .delta.): 3.89 (3H, s), 3.94 (3H, s), 6.07
(1H, s), 6.94 (1H, d, J=8 Hz), 7.55 (1H, s), 7.64 (1H, d, J=8
Hz).
[1282] Preparation 133(2)
[1283] Methyl 4-ethoxy-3-methoxybenzoate (4.10 g) was obtained as
colorless powders from methyl 4-hydroxy-3-methoxybenzoate (4.00 g)
and ethyl iodide (2.63 mL) in a manner similar to Preparation
131(2).
[1284] NMR (CDCl.sub.3, .delta.): 1.50 (3H, t, J=7 Hz), 3.89 (3H,
s), 3.93 (3H, s), 4.14 (2H, q, J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.54
(1H, d, J=4 Hz), 7.65 (1H, dd, J=4, 8 Hz).
[1285] Preparation 133(3)
[1286] 4-Ethoxy-3-methoxybenzoic acid (3.46 g) was obtained as
colorless powders from methyl 4-ethoxy-3-methoxybenzoate (3.97 g)
in a manner similar to Preparation 131(3).
[1287] NMR (CDCl.sub.3, .delta.): 1.52 (3H, t, J=7 Hz), 3.92 (3H,
s), 4.18 (2H, q, J=7 Hz), 6.89 (1H, d, J=8 Hz), 7.58 (1H, s), 7.73
(1H, d, J=8 Hz)
[1288] Mass m/z: 195 (M.sup.+).
[1289] Preparation 133(4)
[1290] 4-Ethoxy-3-methoxybenzamide (1.74 g) was obtained as
colorless powders from 4-ethoxy-3-methoxybenzoic acid (3.36 g) in a
manner similar to Preparation 131(4).
[1291] NMR (DMSO-d.sub.6, .delta.): 1.34 (3H, t, J=7 Hz), 3.79 (3H,
s), 4.05 (2H, q, J=7 Hz), 6.97 (1H, d, J=8 Hz), 7.19 (1H, br),
7.44-7.49 (2H, m), 7.85 (1H, br).
[1292] Preparation 133(5)
[1293] 4-Ethoxy-3-methoxybenzonitrile (1.88 g) was obtained as
colorless powders from 4-ethoxy-3-methoxybenzamide (2.21 g) in a
manner similar to Preparation 131(5).
[1294] NMR (CDCl.sub.3, .delta.): 1.52 (3H, t, J=7 Hz), 3.89 (3H,
s), 4.17 (2H, q, J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.07 (1H, d, J=4
Hz), 7.25 (1H, dd, J=4, 8 Hz)
[1295] Mass m/z: 178 (M.sup.+).
[1296] Preparation 133(6)
[1297] 4-Ethoxy-3-methoxybenzylamine (1.77 g) was obtained as
colorless oil from 4-ethoxy-3-methoxybenzonitrile (1.78 g) in a
manner similar to Preparation 131(6).
[1298] NMR (CDCl.sub.3, .delta.): 1.46 (3H, t, J=7 Hz), 3.81 (2H,
s), 3.89 (3H, s), 4.09 (2H, q, J=7 Hz), 6.80-6.90 (3H, m).
EXAMPLE 133
[1299]
N-(4-Ethoxy-3-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nit-
robenzamide (120 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
4-ethoxy-3-methoxybenzylamine (77.6 mg) in a manner similar to
Preparation 1.
[1300] NMR (DMSO-d.sub.6, .delta.): 1.31 (3H, t, J=7 Hz), 1.43-1.75
(8H, br), 3.62-3.72 (2H, br), 3.75 (3H, s), 3.97 (2H, q, J=7 Hz),
4.38 (2H, d, J=7 Hz), 4.55 (1H, d, J=4 Hz), 6.81-6.97 (4H, m), 8.11
(1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.27 (1H, d, J=8 Hz),
9.32 (1H, br)
[1301] Mass m/z: 442(M.sup.+).
[1302] Preparation 134(1)
[1303] Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (5.69 g) was
obtained as colorless powders from ethyl
4-hydroxy-3-methoxybenzoate (5.00 g) and 2-methoxyethyl bromide
(3.59 mL) in a manner similar to Preparation 131(2).
[1304] NMR (CDCl.sub.3, .delta.): 1.39 (3H, t, J=7 Hz), 3.46 (3H,
s), 3.81 (2H, t, J=4 Hz), 3.91 (3H, s), 4.23 (2H, t, J=4 Hz), 4.35
(2H, q, J=7 Hz), 6.91 (1H, d, J=8 Hz), 7.55 (1H, d, J=4 Hz), 7.65
(1H, dd, J=4, 8 Hz).
[1305] Preparation 134(2)
[1306] 3-Methoxy-4-(2-methoxyethoxy)benzoic acid (4.57 g) was
obtained as colorless powders from ethyl
3-methoxy-4-(2-methoxyethoxy)benzoate (5.68 g) in a manner similar
to Preparation 131(3).
[1307] NMR (DMSO-d.sub.6, .delta.): 3.31 (3H, s), 3.68 (2H, t, J=4
Hz), 3.80 (3H, s), 4.15 (2H, t, J=4 Hz), 7.05 (1H, d, J=8 Hz), 7.44
(1H, d, J=4 Hz), 7.53 (1H, dd, J=4, 8 Hz)
[1308] Mass m/z: 225 (M.sup.+).
[1309] Preparation 134(3)
[1310] 3-Methoxy-4-(2-methoxyethoxy)benzamide (3.86 g) was obtained
as colorless powders from 3-methoxy-4-(2-methoxyethoxy)benzoic acid
(4.56 g) in a manner similar to Preparation 131(4).
[1311] NMR (DMSO-d.sub.6, .delta.): 3.31 (3H, s), 3.67 (2H, t, J=4
Hz), 3.80 (3H, s), 4.12 (2H, t, J=4 Hz), 7.00 (1H, d, J=8 Hz), 7.21
(1H, br), 7.46 (2H, m), 7.86 (1H, br).
[1312] Preparation 134(4)
[1313] 3-Methoxy-4-(2-methoxyethoxy)benzonitrile (3.21 g) was
obtained as colorless powders from
3-methoxy-4-(2-methoxyethoxy)benzamide (3.66 g) in a manner similar
to Preparation 131(5).
[1314] NMR (CDCl.sub.3, .delta.): 3.45 (3H, s), 3.81 (2H, t, J=4
Hz), 3.88 (3H, s), 4.20 (2H, t, J=4 Hz), 6.93 (1H, d, J=8 Hz), 7.08
(1H, d, J=4 Hz), 7.25 (1H, dd, J=4, 8 Hz).
[1315] Preparation 134(5)
[1316] 3-Methoxy-4-(2-methoxyethoxy)benzylamine (3.26 g) was
obtained as pale yellow oil from
3-methoxy-4-(2-methoxyethoxy)benzonitrile (3.11 g) in a manner
similar to Preparation 131(6).
[1317] NMR (CDCl.sub.3, .delta.): 3.45 (3H, s), 3.77 (2H, t, J=4
Hz), 3.79 (2H, s), 3.87 (3H, 1H, s), 4.16 (2H, t, J=4 Hz),
6.78-6.92 (3H, m).
EXAMPLE 134
[1318]
2-(cis-4-Hydroxycyclohexylamino)-N-[3-methoxy-4-(2-methoxyethoxy)be-
nzyl]-5-nitrobenzamide (150 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-S-nitrobenzoic acid (120 mg) and
3-methoxy-4-(2-methoxyethoxy)benzylamine (109 mg) in a manner
similar to Preparation 1.
[1319] NMR (DMSO-d.sub.6, .delta.): 1.45-1.75 (8H, br), 3.30 (3H,
s), 3.62 (2H, m), 3.60-3.70 (2H, br), 3.75 (3H, s), 4.03 (2H, m),
4.38 (2H, d, J=7 Hz), 4.56 (1H, d, J=4 Hz), 6.83-6.98 (4H, m), 8.11
(1H, dd, J=4, 8 Hz), 8.61 (1H, d, J=4 Hz), 9.26 (1H, br), 9.32 (1H,
br).
[1320] Preparation 135(1)
[1321] Ethyl 4-cyclobutylmethoxy-3-methoxybenzoate (6.32 g) was
obtained as colorless oil from ethyl 4-hydroxy-3-methoxybenzoate
(5.00 g) and cyclobutylmethyl bromide (4.30 mL) in a manner similar
to Preparation 131(2).
[1322] NMR (CDCl.sub.3, .delta.): 1.41 (3H, t, J=7 Hz), 1.80-2.05
(4H, m), 2.13-2.28 (2H, m), 2.78-2.96 (1H, m), 3.91 (3H, s), 4.04
(2H, d, J=7 Hz), 4.35 (2H, q, J=7 Hz), 6.87 (1H, d, J=8 Hz), 7.54
(1H, d, J=4 Hz), 7.65 (1H, dd, J=4, 8 Hz).
[1323] Preparation 135(2)
[1324] 4-Cyclobutylmethoxy-3-methoxybenzoic acid (5.10 g) was
obtained as colorless powders from ethyl
4-cyclobutylmethoxy-3-methoxybenzoate (6.20 g) in a manner similar
to Preparation 131(3).
[1325] NMR (DMSO-d.sub.6, .delta.): 1.76-1.98 (4H, m), 2.00-2.17
(2H, m), 2.65-2.83 (1H, m), 3.80 (3H, s), 4.00 (2H, d, J=7 Hz),
7.04 (1H, d, J=8 Hz), 7.43 (1H, d, J=4 Hz), 7.54 (1H, dd, J=4, 8
Hz)
[1326] Mass m/z: 235 (M.sup.+).
[1327] Preparation 135(3)
[1328] 4-Cyclobutylmethoxy-3-methoxybenzamide (4.50 g) was obtained
as colorless powders from 4-cyclobutylmethoxy-3-methoxybenzoic acid
(4.90 g) in a manner similar to Preparation 131(4).
[1329] NMR (DMSO-d.sub.6, .delta.): 1.75-2.00 (4H, m), 2.03-2.17
(2H, m), 2.67-2.80 (1H, m), 3.79 (3H, s), 3.98 (2H, d, J=7 Hz),
6.99 (1H, d, J=8 Hz), 7.19 (1H, br), 7.43-7.50 (2H, m), 7.85 (1H,
br).
[1330] Preparation 135(4)
[1331] 4-Cyclobutylmethoxy-3-methoxybenzonitrile (3.21 g) was
obtained as colorless powders from
4-cyclobutylmethoxy-3-methoxybenzamide (4.35 g) in a manner similar
to Preparation 131(5).
[1332] NMR (DMSO-d.sub.6, .delta.): 1.80-2.06 (4H, m), 2.12-2.27
(2H, m), 2.78-2.94 (1H, m), 3.87 (3H, s), 4.03 (2H, d, J=7 Hz),
6.88 (1H, d, J=8 Hz), 7.07 (1H, d, J=4 Hz), 7.25 (1H, dd, J=4, 8
Hz).
[1333] Preparation 135(5)
[1334] 4-Cyclobutylmethoxy-3-methoxybenzylamine (3.61 g) was
obtained as pale yellow oil from
4-cyclobutylmethoxy-3-methoxybenzonitrile (3.54 g) in a manner
similar to Preparation 131(6).
[1335] NMR (CDCl.sub.3, .delta.):1.80-2.00 (4H, m), 2.10-2.25 (2H,
m), 2.76-2.92 (1H, m), 3.81 (2H, s), 3.87 (3H, s), 3.98 (2H, d, J=7
Hz), 6.78-6.86 (3H, m).
[1336] Preparation 135(6)
[1337]
N-(4-Cyclobutylmethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide
(3.17 g) was obtained as yellow powders from
2-fluoro-5-nitrobenzoic acid (2.33 g) and
4-cyclobutylmethoxy-3-methoxybenzylamine(2.87 g) in a manner
similar to Preparation 55.
[1338] NMR (DMSO-d.sub.6, .delta.): 1.75-1.98 (4H, m), 2.02-2.14
(2H, m), 2.63-2.78 (1H, m), 3.75 (3H, s), 3.90 (2H, d, J=7 Hz),
4.42 (2H, d, J=7 Hz), 6.83-6.98 (3H, m), 7.63 (1H, t, J=7 Hz),
8.37-8.44 (2H, m), 9.12 (1H, br)
[1339] Mass m/z: 387 (M.sup.+).
EXAMPLE 135
[1340]
N-(4-Cyclobutylmethoxy-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymeth-
yl)ethylamino]-5-nitrobenzamide (123 mg) was obtained as yellow
powders from
N-(4-cyclobutylmethoxy-3-methoxybenzyl)-2-fluoro-5-nitrobenzamide
(150 mg) and 2-amino-1,3-propanediol (52.8 mg) in a manner similar
to Example 1(1).
[1341] NMR (DMSO-d.sub.6, .delta.): 1.75-1.98 (4H, m), 2.00-2.15
(2H, m), 2.65-2.79 (1H, m), 3.50-3.60 (4H, br), 3.60-3.70 (1H, br),
3.74 (3H, s), 3.89 (2H, d, J=7 Hz), 4.36 (2H, d, J=7 Hz), 4.93 (2H,
t, J=7 Hz), 6.83 (1H, dd, J=4, 8 Hz), 6.89-7.00 (3H, m), 8.12 (1H,
dd, J=4, 8 Hz), 8.57 (1H, d, J=4 Hz), 9.21 (1H, d, J=8 Hz), 9.27
(1H, br).
EXAMPLE 136
[1342] A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic
acid (120 mg), cyclohexanemethylamine (53.3 mg),
1-13-(dimethylamino)propyl]-3- -ethylcarbodiimide hydrochloride
(107 mg) and 1-hydroxybenzotriazole (81.0 mg) in anhydrous
dimethylformamide (3 mL) was stirred for 18 hours at ambient
temperature. The mixture was partitioned between water and ethyl
acetate. The separated organic layer was washed with
1N-hydrochloric acid, water, an aqueous saturated sodium
bicarbonate solution and brine, successively, and dried over
magnesium sulfate. After evaporation of the solvent, the residue
was triturated with diisopropyl ether to give
N-cyclohexylmethyl-2-(cis4-hydroxycyclohexylamino)-5-nitrobenzamide
(157 mg) as yellow powders.
[1343] NMR (DMSO-d.sub.6, .delta.): 0.83-1.04 (2H, m), 1.04-1.31
(3H, m), 1.40-1.82 (14H, m), 3.09 (2H, t, J=7 Hz), 3.65 (2H, br),
4.55 (1H, d, J=4 Hz), 6.86 (1H, d, J=8 Hz), 8.10 (1H, dd, J=2, 8
Hz), 8.55 (1H, d, J=2 Hz), 8.83 (1H, m), 9.25 (1H, d, J=8 Hz)
[1344] Mass m/z: 374.3 (M.sup.+-1).
EXAMPLE 137
[1345]
2-(cis-4-Hydroxycyclohexylamino)-N-(1-naphthylmethyl)-5-nitrobenzam-
ide (165 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexy- lamino)-5-nitrobenzoic acid (120 mg) and
1-naphthalenemethylamine (74.0 mg) in a manner similar to Example
136.
[1346] NMR (DMSO-d.sub.6, .delta.): 1.45-1.80 (8H, m), 3.67 (2H,
br), 4.58 (1H, d, J=4 Hz), 4.94 (2H, d, J=5 Hz), 6.89 (1H, d, J=8
Hz), 7.45-7.66 (4H, m), 7.84-7.93 (1H, m), 7.97 (1H, dd, J=2, 8
Hz), 8.11 (1H, dd, J=2, 9 Hz), 8.17 (1H, d, J=8 Hz), 8.61 (1H, d,
J=2 Hz), 9.26 (1H, d, J=8 Hz), 9.43 (1H, m)
[1347] Mass m/z: 418.2 (M.sup.+-1).
EXAMPLE 138
[1348]
2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(2-quinolinylmethyl)benz-
amide (53.0 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
2-aminomethylqunoline (62.1 mg) in a manner similar to Example
136.
[1349] NMR (DMSO-d.sub.6, .delta.): 1.39-1.76 (8H, m), 3.65 (2H,
br), 4.51 (1H, d, J=4 Hz), 4.74 (2H, d, J=5 Hz), 6.93 (1H, d, J=8
Hz), 7.52-7.64 (2H, m), 7.76 (1H, t, J=8 Hz), 7.95-8.04 (2H, m),
8.14 (1H, dd, J=2, 8 Hz), 8.37 (1H, d, J=8 Hz), 8.78 (1H, d, J=2
Hz), 9.25 (1H, d, J=8 Hz), 9.63 (1H, m)
[1350] Mass m/z: 419.2 (M.sup.+-1).
EXAMPLE 139
[1351] 2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(1
(S)-1-phenylethyl]benzamide (123 mg) was obtained as yellow powders
from 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg)
and (S)-1-phenylethylamine (62.3 mg) in a manner similar to Example
136.
[1352] NMR (DMSO-d.sub.6, .delta.): 1.41-1.72 (11H, m), 3.65 (2H,
br), 4.53 (1H, d, J=4 Hz), 5.10-5.24 (1H, m), 6.87 (1H, d, J=8 Hz),
7.19-7.30 (1H, m), 7.30-7.45 (4H, m), 8.12 (1H, dd, J=2, 8 Hz),
8.71 (1H, d, J=2 Hz), 9.10-9.23 (2H, m)
[1353] Mass m/z: 382.2 (M.sup.+-1).
[1354] Preparation 140(1)
[1355] To a solution of 2-(trifluoromethyl)benzyl bromide (1.50 g)
in ethanol (15 mL) was added a solution of sodium cyamide (461 mg)
in water (15 mL) at ambient temperature, and the mixture was heated
for 3 hours under reflux . After evaporation of the organic
solvent, the aqueous layer was extracted with ethyl acetate. The
extract was washed with water and brine, dried over magnesium
sulfate and evaporated in vacuo to give
[2-(trifluoromethyl)phenyl]acetonitrile (1.08 g) as an oil.
[1356] NMR (CDCl.sub.3, .delta.): 3.97 (2H, s), 7.48 (1H, t, J=8
Hz), 7.62 (1H, t, J=8 Hz), 7.66-7.75 (2H, m).
[1357] Preparation 140(2)
[1358] 2-12-(Trifluoromethyl)phenyl]ethylamine hydrochloride (187
mg) was obtained as pale yellow powders from
[2-(trifluoromethyl)phenyl]acetonitr- ile (1.08 g) in a manner
similar to Preparation 131(6).
[1359] NMR (DMSO-d.sub.6, .delta.): 2.94-3.15 (4H, m), 7.44-7.59
(2H, m), 7.62-7.79 (2H, m), 8.16 (2H, br).
EXAMPLE 140
[1360] A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic
acid (120 mg), [2-(trifluoromethyl)phenyl]ethylamine hydrochloride
(111 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (86.4 mg)
and 1-hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide
(3 mL) was stirred for 18 hours at ambient temperature. The mixture
was partitioned between water and ethyl acetate. The separated
organic layer was washed with 1N-hydrochloric acid, water, an
aqueous saturated sodium bicarbonate solution and brine,
successively, and dried over magnesium sulfate. After evaporation
of the solvent, the residue was purified by a preparative silica
gel thin layer chromatography with a mixture of hexane and ethyl
acetate (2:1). The obtained product was recrystallized from a
mixture of petroleum ether and diethyl ether to give
2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-{[2-(trifluoromethyl)phenyl]et-
hyl}benzamide (157 mg) as yellow powders.
[1361] NMR (DMSO-d.sub.6, .delta.): 1.44-1.75 (8H, m), 3.03 (2H, t,
J=7.5 Hz), 3.51 (2H, q, J=7.5 Hz), 3.66 (2H, br), 4.56 (1H, d, J=4
Hz), 6.87 (1H, d, J=8 Hz), 7.41-7.55 (2H, m), 7.64 (1H, t, J=8 Hz),
7.71 (1H, d, J=8 Hz), 8.11 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz),
9.00 (1H, m), 9.14 (1H, d, J=8 Hz)
[1362] Mass m/z 450.2 (M.sup.+-H).
[1363] Preparation 141(1)
[1364] 4-Bromomethylthiazole (1.80 g) was obtained as an oil from
4-methylthiazole (1.00 g) and N-bromosuccinimide (1.97 g) in a
manner similar to Preparation 91(2).
[1365] NMR (DMSO-d.sub.6, .delta.): 4.65 (2H, s), 7.37 (1H, d, J=2
Hz), 8.82 (1H, d, J=2 Hz).
[1366] Preparation 141(2)
[1367] N-(Thiazol-4-ylmethyl)phthalimide (1.20 g) was obtained as
white powders from 4-bromomethylthiazole (1.80 g) and potassium
phthalimide (1.87 g) in a manner similar to Preparation 91(3).
[1368] NMR (DMSO-d.sub.6, .delta.): 5.06 (2H, s), 7.30 (1H, d, J=2
Hz), 7.68-7.80 (2H, in), 7.84-7.92 (2H, m), 8.76 (1H, d, J=2
Hz).
[1369] Preparation 141(3)
[1370] 4-Aminomethylthiazole hydrochloride (305 mg) was obtained as
white powders from N-(thiazol-4-ylmethyl)phthalimide (1.15 g) in a
manner similar to Preparation 91(4).
[1371] NMR (DMSO-d.sub.6, ): 4.18 (2H, q, J=5 Hz), 7.83 (1H, d, J=2
Hz), 8.52 (3H, br), 9.20 (1H, d, J=2 Hz).
EXAMPLE 141
[1372]
2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(4-thiazolylmethyl)benza-
mide (92 mg) was obtained as yellow powders from
2-(cis4-hydroxycyclohexyl- amino)-5-nitrobenzoic acid (120 mg) and
4-aminomethylthiazole hydrochloride (70.9 mg) in a manner similar
to Preparation 1.
[1373] NMR (DMSO-d.sub.6, .delta.): 1.42-1.76 (8H, m), 3.65 (2H,
br), 4.54 (1H, d, J=4 Hz), 4.59 (1H, d, J=5 Hz), 6.89 (1H, d, J=8
Hz), 7.52 (1H, d, J=2 Hz), 8.12 (1H, dd, J=2, 8 Hz), 8.66 (1H, d,
J=2 Hz), 9.07 (1H, d, J=2 Hz), 9.28 (1H, d, J=8 Hz), 9.45 (1H,
m)
[1374] Mass m/z: 375.2 (M.sup.+-H).
[1375] Preparation 142(1)
[1376] 2-Cyanobenzo[b]thiophene (250 mg) was obtained as an oil
from benzo[b]thiophene-2-carboxamide (500 mg) in a manner similar
to
[1377] Preparation 131(5).
[1378] NMR (CDCl.sub.3, .delta.): 7.48 (1H, t, J=8 Hz), 7.54 (1H,
t, J=8 Hz), 7.84-7.94 (3H, m).
[1379] Preparation 142(2)
[1380] 2-(Aminomethyl)benzo[b]thiophene hydrochloride (281 mg) was
obtained as pale yellow powders from 2-cyanobenzo[b]thiophene (250
mg) in a manner similar to Preparation 131(6).
[1381] NMR (DMSO-d.sub.6, .delta.): 4.35 (2H, s), 7.34-7.45 (2H,
m), 7.57 (1H, s), 7.83-7.90 (1H, m), 7.96-8.04 (1H, m), 8.67 (3H,
br).
EXAMPLE 142
[1382]
N-(Benzo[b]thiophen-2-ylmethyl)-2-(cis4-hydroxycyclohexylamino)-5-n-
itrobenzamide (104 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
2-(aminomethyl)benzo[b]thiophene hydrochloride (78.4 mg) in a
manner similar to Example 140.
[1383] NMR (DMSO-d.sub.6, .delta.): 1.44-1.80 (8H, m), 3.66 (2H,
br), 4.57 (1H, d, J=4 Hz), 4.72 (2H, d, J=5 Hz), 6.91 (1H, d, J=8
Hz), 7.24-7.28 (3H, m), 7.79 (1H, d, J=8 Hz), 7.91 (1H, d, J=8 Hz),
8.13 (1H, dd, J=2, 8 Hz), 8.64 (1H, d, J=2 Hz), 9.26 (1H, d, J=8
Hz), 9.62 (1H, m).
[1384] Preparation 143(1)
[1385] 2-Cyanobenzofuran (402 mg) was obtained as an oil from
benzofuran-2-carboxamide (500 mg) in a manner similar to
Preparation 131(5).
[1386] NMR (CDCl.sub.3, .delta.): 7.37 (1H, t, J=8 Hz), 7.43-7.60
(3H, m), 7.69 (1H, d, J=8 Hz).
[1387] Preparation 143(2)
[1388] 2-(Aminomethyl)benzofuran hydrochloride (333 mg) was
obtained as pale yellow powders from 2-cyanobenzofuran (400 mg) in
a manner similar to Preparation 131(6).
[1389] NMR (DMSO-d.sub.6, .delta.): 4.23 (2H, s), 7.03 (1H, s),
7.28 (1H, t, J=8 Hz), 7.35 (1H, t, J=8 Hz), 7.60 (1H, d, J=8 Hz),
7.69 (1H, d, J=8 Hz), 8.62 (3H, br).
EXAMPLE 143
[1390]
N-(Benzofuran-2-ylmethyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrob-
enzamide (154 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg) and
2-(aminomethyl)benzofuran hydrochloride (86.5 mg) in a manner
similar to Example 140.
[1391] NMR (DMSO-d.sub.6, .delta.): 1.43-1.77 (8H, m), 3.67 (2H,
br), 4.55 (1H, d, J=4 Hz), 4.63 (2H, d, J=5 Hz), 6.81 (1H, s), 6.90
(1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.27 (1H, t, J=8 Hz), 7.56
(1H, d, J=8 Hz), 7.60 (1H, d, J=8 Hz), 8.11 (1H, dd, J=2, 8 Hz),
8.67 (1H, d, J=2 Hz), 9.30 (1H, d, J=8 Hz), 9.49 (1H, m).
EXAMPLE 144
[1392]
N-(3,4-Dimethylbenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenz-
amide (185 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohe- xyl)amino-5-nitrobenzoic acid (200 mg) and
3,4-dimethylbenzylamine (116 mg) in a manner similar to Preparation
1.
[1393] m.p. 157-158.degree. C.
[1394] NMR (DMSO-d.sub.6, .delta.): 1.34-1.74 (8H, m), 2.19 (3H,
s), 2.21 (3H, s), 3.60-3.72 (2H, m), 4.38 (2H, d, J=5 Hz), 4.55
(1H, d, J=4 Hz), 6.88 (1H, d, J=10 Hz), 7.04 (1H, br d, J=8 Hz),
7.07-7.14 (2H, m), 8.11 (1H, dd, J=10, 3 Hz), 8.62 (1H, d, J=3 Hz),
9.30 (1H, d, J=8 Hz), 9.34 (1H, t, J=5 Hz)
[1395] Mass m/z: 396(M.sup.+).
EXAMPLE 145
[1396]
2-(cis-4-Hydroxycyclohexylamino)-5-nitro-N-(4-phenylbenzyl)benzamid-
e (113 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexyl)- amino-5-nitrobenzoic acid (78 mg) and
4-phenylbenzylamine (61 mg) in a manner similar to Preparation
1.
[1397] m.p. 168-170.degree. C.
[1398] NMR (DMSO-d.sub.6, .delta.): 1.43-1.80 (8H, m), 3.59-3.75
(2H, m), 4.50 (2H, d, J=6 Hz), 4.55 (1H, d, J=5 Hz), 6.90 (1H, d,
J=10 Hz), 7.35 (1H, dd, J=7.5, 7.5 Hz), 7.39-7.52 (4H, m), 7.65
(4H, m), 8.12 (1H, dd, J=10, 2 Hz), 8.67 (1H, d, J=2 Hz), 9.33 (1H,
d, J=8 Hz), 9.45 (1H, t, J=6 Hz).
[1399] Preparation 146(1)
[1400] Methyl 3-benzyloxy-4-methoxybenzoate (5.70 g) was obtained
as colorless powders from methyl 3-hydroxy-4-methoxybenzoate (4.00
g) and benzyl bromide (3.13 mL) in a manner similar to Preparation
131(2).
[1401] NMR (CDCl.sub.3, .delta.): 3.87 (3H, s), 3.93 (3H, s), 5.18
(2H, s), 6.90 (1H, d, J=8 Hz), 7.28-7.40 (3H, m), 7.46 (2H, m),
7.61 (1H, d, J=4 Hz), 7.68 (1H, dd, J=4, 8 Hz).
[1402] Preparation 146(2)
[1403] 3-Benzyloxy-4-methoxybenzoic acid (5.06 g) was obtained as
colorless powders from methyl 3-benzyloxy-4-methoxybenzoate (5.60
g) in a manner similar to Preparation 131(3).
[1404] NMR (DMSO-d.sub.6, .delta.): 3.84 (3H, s), 5.13 (2H, s),
7.07 (1H, d, J=8 Hz), 7.30-7.50 (5H, m), 7.53 (1H, d, J=4 Hz), 7.58
(1H, dd, J=4, 8 Hz).
[1405] Preparation 146(3)
[1406] 3-Benzyloxy-4-methox>ybenzamide (4.03 g) was obtained as
colorless powders from 3-benzyloxy-4-methoxybenzoic acid (4.96 g)
in a manner similar to Preparation 131(4).
[1407] NMR (DMSO-d.sub.6, .delta.): 3.81 (3H, s), 5.11 (2H, s),
7.02 (1H, d, J=8 Hz), 7.21 (1H, br), 7.32-7.47 (5H, m), 7.51 (1H,
dd, J=4, 8 Hz), 7.58 (1H, d, J=4 Hz), 7.85 (1H, br).
[1408] Preparation 146(4)
[1409] 3-Benzyloxy-4-methoxybenzonitrile (3.35 g) was obtained as
colorless powders from 3-benzyloxy-4-methoxybenzamide (3.93 g) in a
manner similar to Preparation 131(5).
[1410] NMR (CDCl.sub.3, .delta.): 3.94 (3H, s), 5.15 (2H, s), 6.91
(1H, d, J=8 Hz), 7.10 (1H, d, J=4 Hz), 7.25-7.45 (6H, m).
[1411] Preparation 146(5)
[1412] 3-Benzyloxy-4-methoxybenzylamine (3.51 g) was obtained as
pale yellow oil from 3-benzyloxy-4-methoxybenzonitrile (3.30 g) in
a manner similar to Preparation 131(6).
[1413] NMR (CDCl.sub.3, .delta.): 3.76 (2H, s), 3.88 (3H, s), 5.16
(2H, s), 6.83-6.90 (3H, m), 7.24-7.45 (5H, m).
EXAMPLE 146
[1414]
N-(3-Benzyloxy-4-methoxybenzyl)-2-(cis4-hydroxycyclohexylamino)-5-n-
itrobenzamide (152 mg) was obtained as yellow powders from
2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (100 mg) and
3-benzyloxy-4-methoxybenzylamine (104 mg) in a manner similar to
Preparation 1.
[1415] NMR (DMSO-d.sub.6, .delta.): 1.45-1.77 (8H, br), 3.62-3.72
(2H, br), 3.75 (3H, s), 4.37 (2H, d, J=7 Hz), 4.56 (1H, d, J=4 Hz),
5.06 (2H, s), 6.85-6.97 (3H, m), 7.05 (1H, d, J=2 Hz), 7.24-7.37
(3H, m), 7.40-7.47 (2H, m), 8.12 (1H, dd, J=4, 8 Hz), 8.61 (1H, d,
J=4 Hz), 9.30 (2H, br)
[1416] Mass m/z: 504 (M.sup.+).
[1417] Preparation 147(1)
[1418] 3,4-Ethylenedioxybenzyl bromide (2.31 g) was obtained as
colorless oil from 3,4-ethylenedioxybenzyl alcohol (2.00 g) and
carbon tetrabromide (5.99 g) in a manner similar to Preparation
129(4).
[1419] NMR (CDCl.sub.3, .delta.): 4.25 (4H, s), 4.44 (2H, s),
6.78-6.94 (3H, m).
[1420] Preparation 147(2)
[1421] N-(3,4-Ethylenedioxybenzyl)phthalimide (2.65 g) was obtained
as white powders from 3,4-ethylenedioxybenzyl bromide (2.31 g) and
potassium phthalimide (1.92 g) in a manner similar to preparation
91(3).
[1422] NMR (CDCl.sub.3, .delta.): 4.20 (4H, s), 4.64 (2H, s),
6.72-6.81 (3H, m), 7.80-7.93 (4H, m)
[1423] Mass m/z: 296.1 (M.sup.++1).
[1424] Preparation 147(3)
[1425] 3,4-Ethylenedioxybenzylamine hydrochloride (1.70 g) was
obtained as white powders from
N-(3,4-ethylenedioxybenzyl)phthalimide(2.60 g) in a manner similar
to Preparation 91(4).
[1426] NMR (DMSO-d.sub.6, .delta.): 3.88 (2H, q-like), 4.24 (4H,
s), 6.84-6.97 (2H, m), 7.03 (1H, d, J=2 Hz), 8.29 (3H, br).
[1427] Preparation 147(4)
[1428] N-(3,4-Ethylenedioxybenzyl)-2-fluoro-5-nitrobenzamide (1.39
g) was obtained as yellow powders from 2-fluoro-5-nitrobenzoic acid
(1.00 g) and 3,4-ethylenedioxybenzylamine hydrochloride (1.14 g) in
a manner similar to Preparation 55.
[1429] NMR (DMSO-d.sub.6, .delta.): 4.19 (4H, s), 4.34 (1H, d, J=5
Hz), 6.73-6.84 (3H, m), 7.59 (1H, t, J=8 Hz), 8.34-8.44 (2H, m),
9.07 (1H, m)
[1430] Mass m/z: 331.4 (M.sup.+-1).
EXAMPLE 147
[1431]
N-(3,4-Ethylenedioxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-ni-
trobenzamide (496 mg) was obtained as yellow powders from
N-(3,4-ethylenedioxybenzyl)-2-fluoro-5-nitrobenzamide (400 mg) and
trans-4-aminocyclohexanol (208 mg) in a manner similar to Example 1
(1).
[1432] NMR (DMSO-d.sub.6, .delta.): 1.20-1.43 (4H, m), 1.73-1.88
(2H, m), 1.88-2.05 (2H, m), 3.40-3.59 (2H, m), 4.21 (4H, s), 4.30
(2H, d, J=5 Hz), 4.62 (1H, d, J=4 Hz), 6.74-6.84 (3H, m), 6.90 (1H,
d, J=8 Hz), 8.11 (1H, dd, J=8, 2 Hz), 8.59 (1H, d, J=2 Hz), 9.08
(1H, d, J=8 Hz), 9.30 (1H, m)
[1433] Mass m/z : 426.2 (M.sup.+-1).
[1434] Preparation 148
[1435]
N-(3-Chloro-4-methoxybenzyl)-2-filuoro-5-(trifluoromethyl)benzamide
(2.92 g) was obtained from 2-fluoro-5-(trifluoromethyl)benzoic acid
(1.76 g) and 3-chloro-4-10 methoxybenzylamine (1.45 g) in a in a
manner similar to Preparation 1.
[1436] NMR (DMSO-d.sub.6, .delta.): 3.83 (3H, s), 4.41 (2H, d, J=6
Hz), 7.13 (1H, d, J=9 Hz), 7.29 (1H, dd, J=2, 8 Hz), 7.41 (1H, d,
J=2 Hz), 7.58 (1H, t, J=9 Hz), 7.93 (1H, m), 7.97 (1H, d, J=8 Hz),
9.08 (1H, t, J=6 Hz).
EXAMPLE 148
[1437]
N-(3-Chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylami-
no]-5-(trifluoromethyl)benzamide (91 mg) was obtained from
N-(3-chloro-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide
(194 mg) and 2-amino-1,3-propanediol (147 20 mg) in a manner
similar to Example 1(1).
[1438] NMR (DMSO-d.sub.6, .delta.): 3.4-3.6 (5H, m), 3.83 (3H, s),
4.35 (2H, d, J=6 Hz), 4.83 (2H, m), 6.91 (1H, d, J=9 Hz), 7.11 (1H,
d, J=9 Hz), 7.26 (1H, dd, J=2, 9 Hz), 7.37 (1H, d, J=2 Hz), 7.53
(1H, dd, J=2, 9 Hz), 7.93 (1H, d, J=2 Hz), 8.63 (1H, m), 9.07 (1H,
t, J=6 Hz)
[1439] Mass m/z: 431 (M.sup.+-1).
EXAMPLE 149(1)
[1440]
(R)-2-1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-me-
thoxybenzyl)-5-(trifluoromethyl)benzamide (696 mg) was obtained 30
as amorphous powders from
N-(3-chloro-4-methoxybenzyl)-2-fluoro-5-trifluorom- ethylbenzamide
(700 mg) and (R)-3-amino-1-tert-butoxycarbonylpyrrolidine (721 mg)
in a manner similar to Example 1 (1).
[1441] NMR (DMSO-d.sub.6, .delta.): 1.39 (9H, s), 1.83 (1H, m),
2.20 (1H, m), 3.09 (1H, m), 3.25-3.45 (2H, m), 3.61 (1H, m), 3.83
(3H, s), 4.15 (1H, m), 4.36 (2H, d, J=6 Hz), 6.93 (1H, d, J=8 Hz),
7.10 (1H, d, J=8 Hz), 7.25 (1H, dd, J=2, 8 Hz), 7.36 (1H, d, J=2
Hz), 7.59 (1H, brd, J=8 Hz), 7.98 (1H, br), 8.61 (1H, d, J=7 Hz),
9.17 (1H, t, J=6 Hz)
[1442] Mass: (ESI+) 528(M+H), (ESI-) 526(M-H).
EXAMPLE 149(2)
[1443]
(R)-N-(3-Chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(trifluo-
romethyl)benzamide (448 mg) was obtained as amorphous powders from
(R)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-methoxy-
benzyl)-5-(trifluoromethyl)benzamide (596 mg) in a manner similar
to Example 87(2).
[1444] NMR (DMSO-d.sub.6, .delta.): 1.49 (1H, m), 2.10 (1H, m),
2.55 (1H, dd, J=4, 10 Hz), 2.7-2.95 (2H, m), 3.13 (1H, dd, J=6, 10
Hz), 3.83 (3H, s), 3.93 (1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, d,
J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.26 (1H, dd, J=2, 8 Hz), 7.37 (1H,
d, J=2 Hz), 7.56 (1H, dd, J=2, 8 Hz), 7.95 (1H, d, J=2 Hz), 8.52
(1H, d, J=7 Hz), 9.13 (1H, t, J=6 Hz)
[1445] Mass: (ESI+) 428(M+H), (ESI-) 426(M-H).
EXAMPLE 149(3)
[1446]
(R)-N-(3-Chloro-4-methoxybenzyl)-2-1-(methoxycarbonyl)pyrrolidin-3--
ylamino]-5-triflu oromethylbenzamide (119 mg) was obtained as
amorphous powders from
(R)-N-(3-chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(-
trifluoromethyl) benzamide (109 mg) in amanner similar to Example
85(5).
[1447] NMR (DMSO-d.sub.6, .delta.): 1.86 (1H, m), 2.21 (1H, m),
3.16 (1H, m), 3.30-3.50 (2H, m), 3.58 and 3.59 (3H, s), 3.66 (1H,
m), 3.83 (3H, s), 4.18 (1H, m), 4.36 (2H, d, J=6 Hz), 6.93 (1H, d,
J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.25 (1H, dd, J=2, 9 Hz), 7.36 (1H,
d, J=2 Hz), 7.59 (1H, brd, J=9 Hz), 7.99 (1H, br), 8.62 (1H, d, J=7
Hz), 9.18 (1H, t, J=6 Hz).
EXAMPLE 150 (1)
[1448]
(S)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-m-
ethoxybenzyl)-5-(trifluoromethyl)benzamide (516 mg) was obtained as
amorphous powders from N-(3-chloro-4-methoxybenzyl)-2-fluoro-5
trifluoromethylbenzamide (700 mg) and
(S)-3-amino-1-tert-butoxycarbonylpy- rrolidine (721 mg) in a manner
similar to Example 1 (1).
[1449] NMR (DMSO-d.sub.6, .delta.): 1.39 (9H, s), 1.83 (1H, m),
2.20 (1H, m), 3.09 (1H, m), 3.25-3.45 (2H, m), 3.61 (1H, m), 3.83
(3H, s), 4.15 (1H, m), 4.36 (2H, d, J=6 Hz), 6.93 (1H, d, J=8 Hz),
7.10 (1H, d, J=8 Hz), 7.25 (1H, dd, J=2, 8 Hz), 7.36 (1H, d, J=2
Hz), 7.59 (1H, brd, J=8 Hz), 7.98 (1H, brs), 8.61 (1H, d, J=7 Hz),
9.17 (1H, t, J=6 Hz).
EXAMPLE 150(2)
[1450]
(S)-N-(3-Chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(trifluo-
romethyl)benzamide (262 mg) was obtained as amorphous powders from
(S)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-N-(3-chloro-4-methoxy-
benzyl)-S-(trifluoromethyl)benzamide (430 mg) in a manner similar
to Example 87(2).
[1451] NMR (DMSO-d.sub.6, .delta.): 1.49 (1H, m), 2.10 (1H, m),
2.55 (1H, dd, J=4, 10 Hz), 2.7-2.95 (2H, m), 3.13 (1H, dd, J=6, 10
Hz), 3.83 (3H, s), 3.93 (1H, m), 4.35 (2H, d, J=6 Hz), 6.83 (1H, d,
J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.26 (1H, dd, J=2, 8 Hz), 7.37 (1H,
d, J=2 Hz), 7.56 (1H, dd, J=2, 8 Hz), 7.95 (1H, d, J=2 Hz), 8.52
(1H, d, J=7 Hz), 9.13 (1H, t, J=6 Hz)
[1452] Mass (ESI+) 428(M+H), (ESI-) 426(M-H).
EXAMPLE 150(3)
[1453]
(S)-N-(3-Chloro-4-methoxybenzyl)-2-[1-(methoxycarbonyl)pyrrolidin-3-
-ylamino]-5-(trifluoromethyl)benzamide (105 mg) was obtained as
amorphous powders from
(S)-N-(3-chloro-4-methoxybenzyl)-2-(3-pyrrolidinylamino)-5-(-
triflu oromethyl)benzamide (115 mg) in a manner similar to Example
85(5).
[1454] NMR (DMSO-d.sub.6, .delta.): 1.86 (1H, m), 2.21 (1H, m),
3.16 (1H, m), 3.30-3.50 (2H, m), 3.58 and 3.59 (3H, s), 3.66 (1H,
m), 3.83 (3H, s), 4.18 (1H, m), 4.36 (2H, d, J=6 Hz), 6.93 (1H, d,
J=9 Hz), 7.11 (1H, d, J=9 Hz), 7.25 (1H, dd, J=2, 9 Hz), 7.36 (1H,
d, J=2 Hz), 7.59 (1H, brd, J=9 Hz), 7.99 (1H, br), 8.62 (1H, d, J=7
Hz), 9.18 (1H, t, J=6 Hz).
[1455] Preparation 151
[1456] 4-Chloro-2,5-difluoro-N-(3,4-dimethoxybenzyl)benzamide (1.66
g) was obtained from 4-chloro-2,5-difluorobenzoic acid (1.05 g) and
veratrylamine (0.91 mL) in a in a manner similar to preparation
1.
[1457] NMR (DMSO-d.sub.6, .delta.): 3.73 (3H, s), 3.74 (3H, s),
4.39 (2H, d, J=6 Hz), 6.81-6.97 (3H, m), 7.67 (1H, dd, J-6, 9 Hz),
7.79 (1H, dd, J=6, 9 Hz), 8.96 (1H, t, J=6 Hz).
EXAMPLE 151
[1458]
4-Chloro-N-(3,4-dimethoxybenzyl)-5-fluoro-2-(trans4-hydroxycyclohex-
ylamino)benzamide (27 mg) was obtained from
4-chloro-2,5-difluoro-N-(3,4-d- imethoxybenzyl)benzamide (102 mg)
and trans-4-aminocyclohexanol (103 mg) in a manner similar to
Example
[1459] NMR (DMSO-d.sub.6, .delta.): 1.06-1.39 (4H, m), 1.74-1.84
(2H, m), 1.88-1.97 (2H, m), 3.38-3.53 (2H, m), 3.72 (3H, s), 3.73
(3H, s), 4.33 (2H, d, J=6 Hz), 4.57 (1H, d, J=4 Hz), 6.80-6.93 (4H,
m), 7.66 (1H, d, J=11 Hz), 7.83 (1H, d, J=8 Hz), 8.89 (1I, t, 3=6
Hz).
[1460] Preparation 152(1)
[1461] 5-Bromo-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (3.07
g) was obtained as colorless powders from 5-bromo-2-fluorobenzoic
acid (2.00 g) and 4-chloro-3-methoxybenzylamine (1.72 g) in a
manner similar to Preparation 1.
[1462] NMR (DMSO-d.sub.6, .delta.): 3.85 (3H, s), 4.45 (2H, d, J=7
Hz), 6.91 (1H, dd, J=4, 258 Hz), 7.13 (1H, d, J=4 Hz), 7.32 (1H, t,
J=8 Hz), 7.38 (1H, d, J=8 Hz), 7.69-7.80 (2H, m), 9.05 (1H,
br).
[1463] Preparation 152(2)
[1464] To a solution of
5-bromo-N-(4-chloro-3-methoxybenzyl)-2-fluorobenza- mide (2.00 g)
in toluene (40 mL) were added tetrakis(triphenylphosphine)pa-
lladium (217 mg) and tributylvinyltin (1.87 g), and the mixture was
heated for 4 hours under reflux. After evaporation of the solvent,
the residue was partitioned between ethyl acetate and saturated
potassium fluoride solution. The remaining precipitates were
removed by filtration. The separated organic layer was washed with
water and brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by a silica gel column
chromatography eluting with a mixture of hexane and ethyl acetate
(3:1) to give N-(4-chloro-3-methoxybenzyl)-2-fluoro-5-vinyl-
benzamide as pale yellow powders (1.51 g).
[1465] NMR (CDCl.sub.3, .delta.): 3.90 (3H, s), 4.65 (2H, br), 5.31
(1H, d, J=10 Hz), 5.77 (1H, d, J=15 Hz), 6.65-6.78 (1H, dd, J=10,
15 Hz), 6.84-6.94 (2H, br), 6.96-7.10 (2H, m), 7.33 (1H, d, J=8
Hz), 7.50 (1H, m), 8.12 (1H, dd, J=4, 8 Hz)
[1466] Mass m/z: 318 (M.sup.+).
[1467] Preparation 152(3)
[1468] A mixture of copper(I) chloride (464 mg) and palladium(II)
chloride (83.2 mg) in a mixture of dimethylformamide (42 mL) and
water (6 mL) was stirred for an hour under oxygen atmosphere (1
atm) at ambient temperature. To the mixture was added
N-(4-chloro-3-methoxybenzyl)-2-fluo- ro-5-vinylbenzamide (1.50 g).
After stirring for 6 hours at 60.degree. C., the mixture was
partitioned between ethyl acetate and IN-hydrochoric acid. The
separated organic layer was washed with water, an aqueous saturated
sodium bicarbonate solution and brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was purified by a silica gel
column chromatography eluting with a mixture of hexane and ethyl
acetate (2:1 to 1:1) to give
5-acetyl-2-fluoro-N-(4-chloro-3-methoxybenzyl)benzam- ide as
colorless powders (719 mg).
[1469] NMR (DMSO-d.sub.6, .delta.): 2.61 (3H, s), 3.85 (3H, s),
4.48 (2H, d, J=7 Hz), 6.94 (1H, dd, J=4, 8 Hz), 7.15 (1H, d, J=4
Hz), 7.39 (1H, d, J=8 Hz), 7.47 (1H, t, J=8 Hz), 8.12 (1H, m), 8.19
(1H, dd, J=4, 8 Hz), 9.09 (1H, br)
[1470] Mass m/z :334(M.sup.+).
EXAMPLE 152
[1471] (R)--Acetyl-N-(4-chloro-3-methoxybenzyl)-2
(2-hydroxy--methylethyla- mino)benzamide (68.1 mg) was obtained as
colorless powders from
5-acetyl-N-(4-chloro-3-methoxybenzyl)-2-fluorobenzamide (100 mg)
and (R)-2-amino-1-propanol (44.7 mg) in a manner similar to Example
1 (1).
[1472] NMR (DMSO-d.sub.6, .delta.): 1.14 (3H, d, J=7 Hz), 2.47 (3H,
s), 3.38-3.50 (2H, m), 3.62-3.72 (1H, br), 3.85 (3H, s), 4.43 (2H,
d, J=7 Hz), 4.91 (1H, t, J=7 Hz), 6.80 (1H, d, J=8 Hz), 6.91 (1H,
dd, J=4, 8 Hz), 7.13 (1H, d, J=4 Hz), 7.38 (1H, d, J=8 Hz), 7.86
(1H, dd, J=4, 8 Hz), 8.25 (1H, d, J-4 Hz), 8.63 (1H, d, J=8 Hz),
9.17 (1H, br).
[1473] Preparation 153(1)
[1474] 5-Chlorosulfonyl-2-fluorobenzoic acid (2 g) was dissolved in
dichloromethane (20 mL) under nitrogen atmosphere and cooled to
0.degree. C. tert-Butyl 1-piperazinecarboxylate (3.12 g) was added
portionwise to the solution at 0.degree. C. and stirred for 3 hours
at ambient temperature. The organic solvent was evaporated in
vacuo, and the residue was dissolved in 1N-sodium hydroxide
solution. The aqueous solution was washed with diethyl ether and
acidified with 1N-hydrochloric acid. The precipitates were
collected by filtration and washed with water to give
5-4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-2-fluorobenzoic
acid (2.26 g) as a colorless solid substance.
[1475] mp. 203-204.5.degree. C.
[1476] NMR (DMSO-d.sub.6, .delta.): 1.35 (9H, s), 2.84-3.01 (4H,
m), 3.35-3.54 (4H, m), 7.62 (1H, dd, J=9.0, 8.5 Hz), 7.95-8.04 (1H,
m), 8.14 (1H, dd, J=7.0, 2.5 Hz)
[1477] Mass m/z: 387 (M.sup.+-1)
[1478] Preparation 153(2)
[1479]
5-[4-(tert-Butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-dimethoxyb-
enzyl)-2-fluorobenzamide (1.34 g) was obtained as off-white
amorphous substance from
5-[4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-2-fluoro- benzoic
acid (1.0 g) and 3,4-dimethoxybenzylamine (452 mg) in a manner
similar to Preparation 1.
[1480] NMR (DMSO-d.sub.6, .delta.): 1.34 (9H, s), 2.85-2.94 (4H,
m), 3.36-3.44 (4H, m), 3.73 (3H, s), 3.74 (3H, s), 4.42 (2H, d,
J=6.0 Hz), 6.86 (1H, dd, J=8.0, 1.5 Hz), 6.92 (1H, d, J=8.0 Hz),
6.96 (1H, d, J=1.5 Hz), 7.60 (1H, t, J=9.0 Hz), 7.85-7.92 (2H, m),
9.04 (1H, t, J=6.0 Hz).
EXAMPLE 153(1)
[1481]
5-[4-(tert-Butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-dimethoxyb-
enzyl)-2-(trans-4-hydroxycyclohexylamino)benzamide (191.8 mg) was
obtained as off-white solid substance from
5-14-(tert-butoxycarbonyl)piperazin-1-y-
lsulfonyl]-N-(3,4-dimethoxybenzyl)-2-fluorobenzamide (200 mg) and
trans-4-aminocyclohexanol (129 mg) in a manner similar to Example 1
(1).
[1482] mp. 221-222.degree. C.
[1483] NMR (DMSO-d.sub.6, .delta.): 1.13-1.41 (4H, m), 1.34 (9H,
s), 1.76-1.86(1H, m), 1.90-2.01 (2H, m), 2.77-2.88 (4H, m),
3.30-3.54 (6H, m), 3.72 (3H, s), 3.73 (3H, s), 4.36 (2H, d, J=6.0
Hz), 4.60 (1H, d, J=4.5 Hz), 6.83 (1H, d, J=7.5 Hz), 6.89 (1H, s),
6.93 (2H, d, J=7.5 Hz), 7.52 (1H, d, J=7.5 Hz), 7.91 (1H, s), 8.50
(1H, d, J=7.5 Hz), 9.15 (1H, t, J=6.0 Hz)
[1484] Mass m/z: 631 (M.sup.+-1).
EXAMPLE 153(2)
[1485]
N-(3,4-Dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-(piper-
azinosulfonyl)benzamide (88.3 mg) was obtained as a pale yellow
solid substance from
5-[4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-N-(3,4-d-
imethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)benzamide (125
mg) in a manner similar to Example 77(2).
[1486] m.p. 108-110.degree. C.
[1487] NMR (DMSO-d.sub.6, .delta.): 1.15-1.41 (4H, m), 1.75-1.86
(2H, m), 1.90-2.01 (2H, m), 2.65-2.79 (8H, m), 3.29-3.51 (3H, m),
3.72 (3H, s), 3.73 (3H, s), 4.35 (2H, d, J=6.0 Hz), 4.60 (1H, d,
J=4.5 Hz), 6.81 (1H, dd, J=8.0, 1.0 Hz), 6.90 (2H, d, J=8.0 Hz),
6.94 (1H, d, J=l.OHz), 7.51 (1H, dd, J=8.0, 1.0 Hz), 7.91 (1H, d,
J=1.0 Hz), 8.53 (1H, d, J=7.0 Hz), 9.18 (1H, t, J=6.0 Hz)
[1488] Mass m/z: 533 (M.sup.++1).
EXAMPLE 153(3)
[1489] To a mixture of
N-(3-fluoro-4-methoxybenzyl)-2-(trans4-hydroxycyclo-
hexylamino)-5-nitrobenzamide (262 mg), benzoic acid (115 mg) and
diethyl azodicarboxylate (164 mg) in anhydrous tetrahydrofuran (6
mL) was added triphenylphosphine (247 mg). After stirring for one
day at ambient temperature, the mixture was evaporated in vacuo.
The residue was purified by a silica gel column chromatography
eluting with a mixture of hexane and ethyl acetate (4:1 to 2:1).
Collection of an upper fraction gave
2-(3-cyclohexenylamino)-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamid-
e as yellow powders (40 mg).
[1490] m.p. 140.degree. C.
[1491] NMR (DMSO-d.sub.6, .delta.): 1.61 (1H, m), 1.82-2.26 (4H,
m), 2.45 (1H, m), 3.81 (3H, s), 3.85 (1H, m), 4.37 (2H, d, J=5 Hz),
5.64 (1H, br d, J=9 Hz), 5.73 (1H, br d, J=9 Hz), 6.94 (1H, d, J=9
Hz), 7.06-7.22 (3H, m), 8.12 (1H, dd, J=9, 3 Hz), 8.62 (1H, d, J=3
Hz), 9.19 (1H, d, J=8 Hz), 9.35 (1H, t, J=5 Hz)
[1492] Mass m/z (ES): 398.
[1493] Collection of a lower fraction gave
2-(cis-4-benzoyloxycyclohexylam-
ino)-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide as yellow
powders (249 mg)
[1494] NMR (DMSO-d.sub.6, .delta.): 1.60-1.78 (2H, m), 1.80-1.97
(6H, m), 3.75 (1H, m), 3.81 (3H, s), 4.40 (2H, d, J=6 Hz), 5.14
(1H, br), 6.97 (1H, d, J=10 Hz), 7.07-7.22 (2H, m), 7.45-7.60 (2H,
m), 7.67 (1H, dd, J=7, 7 Hz), 8.01 (2xlH, d, J=7 Hz), 8.44 (1H, dd,
J=10, 2 Hz), 8.64 (1H, d, J=2 Hz), 9.26 (1H, d, J=8 Hz), 9.39 (1H,
t, J=6 Hz)
[1495] Mass m/z (ES):520.
[1496] Preparation 154
[1497] N-(4-Chloro-3-methoxybenzoyl)-5-cyano-2-fluorobenzamide
(4.00 g) was obtained as colorless powders from
5-cyano-2-fluorobenzoic acid (4.57 g) and
4-chloro-3-methoxybenzylamine (150 mg) in a manner similar to
Preparation 1.
[1498] NMR (DMSO-d.sub.6, .delta.): 3.85 (3H, s), 4.46 (2H, d, J=7
Hz), 6.93 (1H, dd, J=4, 8 Hz), 7.13 (1H, d, J=4 Hz), 7.39 (1H, d,
J=8 Hz), 7.58 (1H, t, J=8 Hz), 8.06 (1H, m), 8.13 (1H, dd, J=4, 8
Hz), 9.12 (1H, br).
EXAMPLE 154
[1499]
(R)-N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(2-hydroxy-1-methylethyl-
amino)benzamide (153 mg) was obtained as colorless powders from
N-(4-chloro-3-methoxybenzyl)-5-cyano-2-fluorobenzamide (150 mg) and
(R)-2-amino-1-propanol (70.7 mg) in a manner similar to Example
1(1).
[1500] NMR (DMSO-d.sub.6, .delta.): 1.12 (3H, d, J=7 Hz), 3.42 (2H,
t, J=7 Hz), 3.60-3.74 (1H, br), 3.85 (3H, s), 4.41 (2H, d, J=7 Hz),
4.93 (1H, t, J=7 Hz), 6.84 (1H, d, J=8 Hz), 6.92 (1H, dd, J=4, 8
Hz), 7.12 (1H, d, J=4 Hz), 7.37 (1H, d, J=8 Hz), 7.61 (1H, dd, J=4,
8 Hz), 8.06 (1H, d, J=4 Hz), 8.69 (1H, d, J=8 Hz), 9.07 (1H,
br)
[1501] Mass m/z: 372.
* * * * *