U.S. patent application number 10/173076 was filed with the patent office on 2003-05-01 for amide derivatives.
This patent application is currently assigned to Mitsubishi Chemical Corporation. Invention is credited to Ando, Ryoichi, Chiba, Noriko, Kawamura, Makoto, Watanabe, Kazutoshi.
Application Number | 20030083523 10/173076 |
Document ID | / |
Family ID | 26492175 |
Filed Date | 2003-05-01 |
United States Patent
Application |
20030083523 |
Kind Code |
A1 |
Ando, Ryoichi ; et
al. |
May 1, 2003 |
Amide derivatives
Abstract
A compound represented by the following general formula (I): 1
wherein X represents R.sup.1(R.sup.2)R.sup.3)C- where R.sup.1
represents a C.sub.3-C.sub.8 cycloalkyl group, an optionally
substituted C.sub.6-C.sub.14 aryl group, an optionally substituted
heterocyclic residue, an optionally substituted C.sub.6-C.sub.14
aryloxy group, or an optionally substituted C.sub.7-C.sub.15
arylmethyl group; R.sup.2 and R.sup.3 independently represent
hydrogen atom or a C.sub.1-C.sub.5 alkyl group, or R.sup.2 and
R.sup.3 may combine to represent a C.sub.2-C.sub.7 alkylene group;
or X represents R.sup.7-A- wherein R.sup.7 represents (i) a C1-C10
alkyl group which may optionally be substituted with an optionally
substituted C6-C14 aryl group, an optionally substituted fluorenyl
group or an optionally substituted heterocyclic group, (ii) an
optionally substituted C6-C14 aryl group or (iii) an optionally
substituted heterocyclic group, and A represents an oxygen atom or
-N-R.sup.8 where R.sup.8 represents hydrogen atom or a C1-C5 alkyl
group. Y represents an oxygen atom or a sulfur atom, R.sup.4 and
R.sup.5 independently represent hydrogen atom or a C.sub.1-C.sub.5
alkyl group; and R.sup.6 represents hydrogen atom, a
C.sub.1-C.sub.5 alkyl group which may optionally be substituted
with a hydroxyl group, a hydroxyl group or a C.sub.1-C.sub.5 alkoxy
group, provided that the compounds wherein R.sup.7 is a benzyl
group, A and Y are an oxygen atom, R.sup.4 and R.sup.5 are hydrogen
atom, and R.sup.6 is a propyl group are excluded, or a salt
thereof, or a solvate thereof or a hydrate thereof.
Inventors: |
Ando, Ryoichi; (Kanagawa,
JP) ; Kawamura, Makoto; (Tokyo, JP) ; Chiba,
Noriko; (Kanagawa, JP) ; Watanabe, Kazutoshi;
(Kanagawa, JP) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1941 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Assignee: |
Mitsubishi Chemical
Corporation
Tokyo
JP
|
Family ID: |
26492175 |
Appl. No.: |
10/173076 |
Filed: |
June 18, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10173076 |
Jun 18, 2002 |
|
|
|
09469354 |
Dec 22, 1999 |
|
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6444849 |
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09469354 |
Dec 22, 1999 |
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09103500 |
Jun 24, 1998 |
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Current U.S.
Class: |
564/74 ; 544/224;
544/237; 544/261; 544/277; 544/283; 544/335; 544/336; 544/353;
544/59; 546/113; 546/168; 546/226; 546/313; 546/314; 548/333.5;
548/374.1; 548/530; 549/390; 549/405; 549/420; 549/70; 564/152 |
Current CPC
Class: |
C07D 307/79 20130101;
C07C 2601/08 20170501; C07C 2601/14 20170501; C07C 237/42 20130101;
C07D 317/60 20130101; C07D 209/18 20130101; C07D 333/60
20130101 |
Class at
Publication: |
564/74 ; 564/152;
544/224; 544/237; 544/261; 544/283; 544/336; 544/335; 544/353;
544/277; 546/113; 546/168; 546/313; 546/314; 544/59; 546/226;
548/333.5; 548/530; 548/374.1; 549/70; 549/390; 549/405;
549/420 |
International
Class: |
C07D 279/12; C07D
333/22 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 25, 1997 |
JP |
9-168484 |
Claims
What is claimed is:
1. A compound represented by the following general formula (I):
372wherein X represents R.sup.1(R.sup.2)(R.sup.3)C- where R.sup.1
represents a C.sub.3-C.sub.8 cycloakyl group, an optionally
substituted C.sub.5-C.sub.14 aryl group, an optionally substituted
heterocyclic residue wherein the heterocyclic residue is one of
furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring,
dihydropyran ring, tetrahydropyran ring, benzofuran ring,
dihydrobenzofuran ring, isobenzofuran ring, chromene ring, chroman
ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole
ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline
ring, imidazolidine ring, pyrazole ring, pyrazoline ring,
pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring,
pyridineoxide ring, piperidine ring, pyrazine ring, piperazine
ring, pyrimidine ring, pyridazine ring, indoline ring, indole ring,
indoline ring, isoindole ring, isoindoline ring, indazole ring,
benzimidazole ring, purine ring, quinolizine ring, quinoline ring,
phthalazine ring, naphthylidine ring, quinoxaline ring, quinazoline
ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine
ring, isoxazole ring, isoxazolidine ring, thiazole ring,
thiazylidine ring, isothiazole ring, isothiazolidine ring, dioxane
ring, dithian ring, morpholine ring, and thiomorpholine ring, an
optionally substituted C.sub.6-C.sub.14 aryloxy group, or an
optionally substituted C.sub.7-C.sub.15 arylmethyl group; R.sup.2
and R.sup.3 independently represent hydrogen atom or a
C.sub.1-C.sub.5 alkyl group, or R.sup.2 and R.sup.3 may combine to
represent a C.sub.2-C.sub.7 alkylene group; or X represents
R.sup.7-A- wherein R.sup.7 represents (i) a C1-C10 alkyl group
which may optionally be substituted with an optionally substituted
C6-C14 aryl group, an optionally substituted fluorenyl group or an
optionally substituted heterocyclic group, (ii) an optionally
substituted C6-C14 aryl group or (iii) an optionally substituted
heterocyclic group, and A represents an oxygen atom or -N-R.sup.8
where R.sup.8 represents hydrogen atom or a C1-C5 alkyl group, Y
represents an oxygen atom or a sulfur atom, R.sup.4 and R.sup.5
independently represent hydrogen atom or a C.sub.1-C.sub.5 alkyl
group; and R.sup.6 represents hydrogen atom, a C.sub.1-C.sub.5
alkyl group which may optionally be substituted with a hydroxyl
group, a hydroxyl group or a C.sub.1-C.sub.5 alkoxy group, provided
that the compounds wherein R.sup.7 is a benzyl group, A and Y are
an oxygen atom, R.sup.4 and R.sup.6 are hydrogen atom, and R.sup.6
is a propyl group are excluded, or a salt thereof, or a solvate
thereof or a hydrate thereof.
2. The compound according to claim 1 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.4 is hydrogen
atom.
3. The compound according to claim 1 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.5 is hydrogen
atom.
4. The compound according to claim 3 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.6 is a
C.sub.1-C.sub.5 alkyl group.
5. The compound according to claim 4 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.6 is methyl
group.
6. The compound according to claim 1 or a salt thereof or a solvate
thereof or a hydrate thereof, wherein Y is an oxygen atom.
7. The compound according to claim 6 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein X is
R.sup.1(R.sup.2)(R.sup.3)C-.
8. The compound according to claim 7 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.2 and R.sup.3
are hydrogen atoms.
9. The compound according to claim 7 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.1 is a
C.sub.6-C.sub.14 aryl group which may optionally be
substituted.
10. The compound according to claim 7 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.1 is a residue
of a heterocyclic compound which may optionally be substituted.
11. The compound according to claim 7 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.1 is a
C.sub.6-C.sub.14 aryloxy group which may optionally be
substituted.
12. The compound according to claim 7 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.1 is a
C.sub.7-C.sub.15 arylmethyl group which may optionally be
substituted.
13. The compound according to claim 1 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein X is R.sup.7-A-.
14. The compound according to claim 13 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein A is an oxygen atom
or -N-H.
15. The compound according to claim 13 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.7 is a C1-C10
alkyl group which may optionally be substituted with an optionally
substituted C6-C14 aryl group or an optionally substituted
heterocyclic group.
16. The compound according to claim 15 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.7 is a C1-C5
alkyl group which may optionally be substituted with an optionally
substituted C6-C14 aryl group or an optionally substituted
heterocyclic group.
17. The compound according to claim 16 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.7 is a methyl
group which may optionally be substituted with an optionally
substituted C6-C14 aryl group or an optionally substituted
heterocyclic group.
18. The compound according to claim 17 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.7 is a methyl
group which is substituted with an optionally substituted C6-C14
aryl group.
19. The compound according to claim 17 or a salt thereof, or a
solvate thereof or a hydrate thereof, wherein R.sup.7 is a methyl
group which is substituted with an optionally substituted
heterocyclic group.
20. A compound selected from the group consisting of:
N-(3-methylcarbamoylphenyl)-3-chlorophenylacetamide;
N-(3-methylcarbamoylphenyl)-4-chlorophenylacetamide;
N-(3-methylcarbamoylphenyl)-3-bromophenylacetamide;
N-(3-methylcarbamoylphenyl)-4-bromophenylacetamide:
N-(3-methylcarbamoylphenyl)-3-methylphenylacetamide;
N-(3-methylcarbamoylphenyl)-4-methylphenylacetamide;
N-(3-methylcarbamoylphenyl)-3-methoxyphenylacetamide;
N-(3-methylcarbamoylphenyl)-4-methoxyphenylacetamide;
N-(3-methylcarbamoylphenyl)-3,4,5-trimethoxyphenylacetamide;
N-(3-methylcarbamoylphenyl)-3-benzyloxyphenylacetamide;
N-(3-methylcarbamoylphenyl)-1-naphthylacetamide;
N-(3-methylcarbamoylphen- yl)-2-naphthylacetamide;
N-(3-methylcarbamoylphenyl)-3-inadolylacetamide;
N-(3-methylcarbamoylphenyl)-3-benzothienylacetamide;
N-(3-methylcarbamoylphenyl)-4-benzothienylacetamide;
N-(3-methylcarbamoylphenyl)-3,4-methylenedioxyphenylacetamide;
N-(3-methylcarbamoylphenyl)-2-chlorophenoxyacetamide;
N-(3-methylcarbamoylphenyl)-2,3-chlorophenoxyacetamide;
N-(3-methylcarbamoylpheny)-1-naphthyloxyacetamide;
N-(3-methylcarbamoylphenyl)-2-naphthyloxyacetimide; and
N-(3-methylcarbamoylphenyl)-3-(2-methoxyphenyl)propionamide, or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
21. A compound selected from the group consisting of:
N'-methyl-3-(2-chlorobenzyloxycarbonylamino)benzamide,
N'-methyl-3-(4-chlorobenxyloxycarbonylamino)benzamide;
N'-methyl-3-(2,3-dichlorobenzyloxycarbonylamino)benzamide;
N'-methyl-3-(2,6-dichlorobenzyloxycarbonylamino)benzamide;
N'-methyl-3-(2-bromobenzyloxycarbonylamino)benzamide;
N'-methyl-3-(2-methylbenzyloxycarbonylamino)benzamide;
N'-methyl-3(3-methylbenzyloxycarbonylamino)benzamide;
N-methyl-3-(4-methylbenzyloxycarbonylamino)benzamide;
N'-methyl-3-(1-naphthylmethoxycarbonylamino)benzamide; and
N'-methyl-3-(2-naphthylmethoxycarbonylamino)benzamide; or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
22. N-(3-methylcarbamoylpheny)-1-naphthylacetamide or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
23. N-(3-methylcarbamoylphenyl)-2-naphthylacetamide or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
24. N-(3-methylcarbamoylphenyl)-3-benzothienylacetamide or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
25. N-(3-methylcarbamoylphenyl)-4-benzothienylacetamide or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
26. N-(3-methylcarbamoylphenyl)-1-naphthyloxyacetamide or a
pharmaceutically acceptable salt thereof, or a solvate thereof or a
hydrate thereof.
27. A medicament comprising as an active ingredient a substance
selected from the group consisting of a compound according to claim
1 and a salt thereof, and a solvate thereof and a hydrate
thereof.
28. The medicament according to claim 27 which is in the form of a
pharmaceutical composition comprising said substance as an active
ingredient and one or more pharmaceutical additives.
29. The medicament according to claim 27 which has antibacterial
activity.
30. The medicament according to claim 29 which has antibacterial
activity against a microorganism belonging to the genus
Helicobacter and/or Campylobacter.
31. The medicament according to claim 30 which has
anti-Helicobacter pylori activity and/or anti-Campylobacter jejuni
activity.
32. A process for at least one of preventing and treating a
digestive disease, comprising administering the medicament
according claim 27.
33. The process of claim 32, wherein the digestive disease is one
of gastritis, gastric ulcer, gastric cancer, gastric malignant
lymphoma, MALT lymphoma, duodenal ulcer, duodenal carcinoma, and
enteritis.
34. A process for preventing recurrence of a digestive disease,
comprising administering the medicament according to claim 27.
35. The process of claim 34, wherein the digestive disease is one
of gastric ulcer and duodenal ulcer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of U.S.
application Ser. No. 09/469,354 filed Dec. 22, 1999 which is a
continuation-in-part of U.S. application Ser. No. 09/103,500, filed
Jun. 24, 1998, the disclosures of which are expressly incorporated
by reference herein in their entireties.
TECHNICAL FIELD
[0002] The present invention relates to novel amide derivatives
having strong antibacterial activity against Helicobacter
pylori.
BACKGROUND ART
[0003] Helicobacter pylori is a slightly aerobic gram-negative
bacterium which was recently isolated from human gastric mucosa,
and various published reports suggest its involvement in
inflammation of alimentary tract, formation and recurrence of
ulcer, and moreover, gastric cancer (Molecular Medicine, Vol. 31,
pp.1304-1374, 1994).
[0004] For the treatment of gastrointestinal ulcers, medicaments
such as H.sub.2 blockers or proton-pump inhibitors have been used
so far. Since relation between Helicobacter pylori infection and
gastric ulcer has been being clarified as explained above, an
antibacterial agent such as amoxicillin has become practically used
in combination, particularly from a viewpoint of prevention of
recurrence. However, in most cases, ordinarily used antibacterial
agents fail to achieve complete elimination of the bacteria. In
addition, they may affect on intestinal bacterial flora due to
their broad antibacterial spectra, and they often cause adverse
effects such as diarrhea. Therefore, it has been desired to develop
an antibacterial agent having potent antibacterial activity in
alimentary tract that is specific against Helicobacter pylori.
[0005] The compound represented by the general formula (I) defined
herein below wherein R.sup.7 is a benzyl group, and A and Y are an
oxygen atom, and R.sup.4 and R.sup.5 are a hydrogen atom, and
R.sup.6 is a propyl group, has been reported as intermediates of
receptor models (Journal of American Chemical Society, Vol.115,
pp.3548, 1993). However, it has not been known that this compound
has an antibacterial activity against Helicobacter pylori.
DISCLOSURE OF THE INVENTION
[0006] The inventors of the present invention conducted researches
to provide a novel anti-Helicobacter pylori agent, and as a result,
they found that the compounds represented by the following general
formula have excellent antibacterial activity against Helicobacter
pylori, and can exhibit potent antibacterial activity in alimentary
tract. The present invention was achieved on the bas of these
findings.
[0007] The present invention thus provides amide derivatives
represented by the following general formula (I) and salts thereof
and solvates thereof and hydrates thereof: 2
[0008] wherein X represents R.sup.1(R.sup.2)(R.sup.3)C- where
R.sup.1 represents a C.sub.3-C.sub.8 cycloalkyl group, an
optionally substituted C.sub.6-C.sub.14 aryl group, an optionally
substituted heterocyclic residue wherein the heterocyclic residue
is one of furan ring, dihydrofuran ring, tetrahydrofuran ring,
pyran ring, dihydropyran ring, tetrahydropyran ring, bexizofuran
ring, dihydrobenzofuran ring, isobenzofuran ring, chromene ring,
chroman ring, isochroman ring, thiophene ring, benzothiophene ring,
pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring,
imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline
ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine
ring, pyridineoxide ring, piperidine ring, pyrazine ring,
piperazine ring, pyrimidine ring, pyridazine ring, indolizine ring,
indole ring, indoline ring, isoindole ring, isoindoline ring,
indazole ring, benzinidazole ring, purine ring, quinolizine ring,
quinoline ring, phthalazine ring, naphthylidine ring, quinoxaline
ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole
ring, oxazolidine ring, isoxazole ring, isoxazolidine ring,
thiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine
ring, dioxane ring, dithian ring, morpholine ring, and
thiomorpholine ring, an optionally substituted C.sub.6-C.sub.14
aryloxy group, or an optionally substituted C.sub.7-C.sub.15
arylmethyl group; R.sup.2 and R.sup.3 independently represent
hydrogen atom or a C.sub.1-C.sub.5 alkyl group, or R.sup.2 and
R.sup.3 may combine to represent a C.sub.2-C.sub.7 alkylene group;
or
[0009] X represents R.sup.7A- wherein R.sup.7 represents (i) a
C1-C10 alkyl group which may optionally be substituted with an
optionally substituted C6-C14 aryl group, an optionally substituted
fluorenyl group or an optionally substituted heterocyclic group,
(ii) an optionally substituted C6-C14 aryl group or (iii) an
optionally substituted heterocyclic group, and A represents an
oxygen atom or -N-R.sup.8 where R.sup.6 represents hydrogen atom or
a C1-C5 alkyl group,
[0010] Y represents an oxygen atom or a sulfur atom,
[0011] R.sup.4 and R.sup.5 independently represent hydrogen atom or
a C.sub.1-C.sub.5 alkyl group; and R.sup.6 represents hydrogen
atom, a C.sub.1-C.sub.5 alkyl group which may optionally be
substituted with a hydroxyl group, a hydroxyl group or a
C.sub.1-C.sub.5 alkoxy group,
[0012] provided that the compounds wherein R.sup.7 is a benzyl
group, A and Y are an oxygen atom, R.sup.4 and R.sup.5 are hydrogen
atom, and R.sup.6 is a propyl group are excluded, or a salt
thereof, or a solvate thereof or a hydrate thereof.
[0013] According to another aspect of the present invention, the
present invention provides medicaments, preferably for the
treatment of gastric diseases, e.g., gastritis, gastric ulcer, and
gastric cancer, which comprise as an active ingredient a subs
selected from the group consisting of the aforementioned amide
derivatives and pharmaceutically acceptable salts thereof, and
solvates thereof and hydrates thereof. The medicaments are
preferably provided as pharmaceutical compositions comprising the
aforementioned substance as an active ingredient together with one
or more pharmaceutically acceptable additives. These medicaments
can be used as anti-Helicobacter pylori agents for therapeutic
and/or preventive treatment of digestive diseases related to
Helicobacter pylori infection, for example, gastritis, gastric
ulcer, gastric cancer, stomach malignant lymphoma, MALT lymphoma,
duodenal ulcer, duodenal carcinoma and the like.
[0014] According to further aspects of the present invention, there
are provided a method for treating digestive diseases related to
Helicobacter pylori infection which comprises the step of
administering to a mammal including a human a therapeutically
effective amount of a substance selected from the group consisting
of the aforementioned amide derivatives and pharmaceutically
acceptable salts thereof, and solvates thereof and hydrates
thereof, and a use of a substance selected from the group
consisting of the aforementioned amide derivatives and
pharmaceutically acceptable salts thereof, and solvates thereof and
hydrates thereof for the manufacture of the above medicaments.
BEST MODE FOR CARRYING OUT THE INVENTION
[0015] In the general formula (I), examples of the C.sub.3-C.sub.8
cycloalkyl group represented by R.sup.1 include, for example,
cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl
group, cycloheptyl group, and cyclooctyl group. Examples of the
C.sub.6-C.sub.14 aryl group include, for example, aromatic
hydrocarbon groups consisting of one ring or two to approximately
three condensed aromatic rings such as phenyl group, naphthyl
group, and anthryl group.
[0016] As the residue of a heterocyclic compound, residues of
heterocyclic compounds containing 1 to 4 heteroatoms selected from
oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10
ring-membered atoms in total can be used. More specifically,
examples of the residues of heterocyclic compounds include, for
example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran
ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring,
dihydiobenzofuran ring, isobenzofuran ring, chromene ring, chroman
ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole
ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline
ring, imidazolidine ring, pyrazole ring, pyrazoline ring,
pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring,
pyridineoxide ring, piperidine ring, pyrazine ring, piperazine
ring, pyrimidine ring, pyridazine ring, indolizine ring, indole
ring, indoline ring, isoindole ring, isoindoline ring, indazole
ring, benzimidazole ring, purine ring, quinolizine ring, quinoline
ring, phthalazine ring, naphthylidine ring, quinoxaline ring,
quinazoline ring, cinnoline ring, pteridine ring, oxazole ring,
oxazolidine ring, isoxazole ring, isoxazolidine ring, thiazole
ring, thiazylidine ring, isothiazole ring, isothiazoline ring,
dioxane ring, dithian ring, morpholine ring, and thiomorpholine
ring. Examples of the C.sub.5-C.sub.14 aryloxy group include, for
example, phenyloxy group, naphthyloxy group, and anthryloxy group,
and examples of the C.sub.7-C.sub.15 arylmethyl group include, for
example, benzyl group, naphthylmethyl group, and anthrylmethyl
group.
[0017] The C.sub.1-C.sub.5 alkyl group independently represented by
R.sup.2 and R.sup.3 may be either a straight-or branched-chain
alkyl, and examples include, for example, methyl group, ethyl
group, propyl group, isopropyl group, butyl group, isobutyl group,
pentyl group, and isopentyl group. Examples of the C.sub.2-C.sub.7
alkylene group represented by R.sup.2 combined with R.sup.3
include, for example, ethylene group, trimethylene group,
tetramethylene group, pentamethylene group, bexamethylene group,
and heptamethylene group, and these groups may have one or more
branched chains.
[0018] As the C.sub.1-C.sub.5 alkyl group represented by R.sup.4
and R.sup.5, those explained for R.sup.2 and R.sup.3 can be
independently used. In the present invention, R.sup.4 and R.sup.5
are preferably hydrogen atom.
[0019] As the C.sub.1-C.sub.5 alkyl group represented by R.sup.6,
those explained for R.sup.2 and R.sup.3 can be used, and these
alkyl groups may be substituted with at least one, preferably one
hydroxy group. The C.sub.1-C.sub.5 alkoxy group represented by
R.sup.6 may be a straight or branched chain group, and examples
include, for example, methoxy group, ethoxy group, propoxy group,
isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group,
pentyloxy group, and isopentyloxy group. In the present invention,
R.sup.6 is preferably an alkyl group, more preferably a methyl
group.
[0020] As the C.sub.1-C.sub.10 alkyl group represented by R.sup.7
in the general formula (I) above, those having a straight or
branched chain can be used, and examples include methyl group,
ethyl group, propyl group, isopropyl group, butyl group, isobutyl
group, pentyl group, isopentyl group, hexyl group, isohexyl group,
heptyl group, octyl group, nonyl group, and decyl group. These
alkyl groups may optionally be substituted with a C.sub.6-C.sub.14
aryl group, a fluorenyl group or a heterocyclic group. The
C.sub.6-C.sub.14 aryl group which can be a substituent on the alkyl
group represented by R.sup.7 includes, for example, a
C.sub.6-C.sub.14 aryl group such as phenyl group, naphtyl group or
anthryl group. The heterocyclic group which can be a substituent on
the alkyl group represented by R.sup.7 includes, for example, those
described for R.sup.1.
[0021] As the C.sub.6-C.sub.14 aryl group and the heterocyclic
group represented by R.sup.7, those described for the substituent
on the C.sub.1-C.sub.10 alkyl group can be used.
[0022] R.sup.7 is preferably a C.sub.1-C.sub.10 alkyl group which
may optionally be substituted with an optionally substituted
C.sub.6-C.sub.14 aryl group or an optionally substituted
heterocyclic group, more preferably a C.sub.1-C.sub.5 alkyl group
which may optionally be substituted with an optionally substituted
C.sub.6-C.sub.14 aryl group or an optionally substituted
heterocyclic group, still more preferably a methyl group which may
optionally be substituted with an optionally substituted C6-C14
aryl group or an optionally substituted heterocyclic group. In the
present invention, R.sup.7 is particularly preferably a methyl
group which is substituted with an optionally substituted
C.sub.6-C.sub.14 aryl group or a methyl group which is substituted
with an optionally substituted heterocyclic group.
[0023] A represents an oxygen atom or -N-R.sup.8 wherein R.sup.8
represents hydrogen atom or a C.sub.1-C.sub.5 alkyl group. The
C.sub.1-C.sub.5 alkyl group represented by R.sup.8 includes methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group, pentyl group, and isopentyl group. A is preferably
an oxygen atom or -N-H.
[0024] Y represents an oxygen atom or a sulfur atom. Y is
preferably an oxygen atom.
[0025] The aforementioned aryl group, residue of a heterocyclic
compound, aryloxy group, and arylmethyl group may have one or more
substituents at arbitrary positions on their rings. Examples of
substituents include, for example, a halogen atom such as fluorine
atom, chlorine atom, and bromine atom; a C.sub.1-C.sub.5 alkyl
group such as methyl group, ethyl group, propyl group, isopropyl
group, butyl group, isobutyl group, sec-butyl group, tert-butyl
group, pentyl group, isopentyl group, neopentyl group, and
tert-pentyl group; a C.sub.7-C.sub.15 aralkyl group such as benzyl
group, phenylethyl group, and naphthylmethyl group; trifluoromethyl
group; a C.sub.7-C.sub.15 alkoxy group such as methoxy group,
ethoxy group, propoxy group, isopropoxy group, butoxy group,
isobutoxy group, tert-butoxy group, pentyloxy group, and
isopentyloxy group; a C.sub.7-C.sub.15 aralkyloxy group such as
benzyloxy group, phenylethyloxy group, and naphthylmethyloxy group;
a C.sub.1-C.sub.5 alkylenedioxy group such as methylenedioxy group,
ethylenedioxy group, and propylenedioxy group; hydroxy group; nitro
group; a C.sub.2-C.sub.6 alkylcarbonyloxy group such as acetoxy
group, propionyloxy group, butyryloxy group, and valeryloxy group;
carboxyl group; a C.sub.2-C.sub.6 alkoxycarbonyl group such as
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl
group, tertbutoxycarbonyl group, and pentyloxycarbonyl group; a
C.sub.7-C.sub.16 aralkyloxycarbonyl group such as benzyloxycarbonyl
group, phenylethyloxycarbonyl group, and naphthylmethyloxycarbonyl
group; oxo group; a C.sub.2-C.sub.6 alkylcarbonyl group such as
acetyl group, propioxyl group, butyryl group, and valeryl group;
amino group; a C.sub.1-C.sub.5 monoalkylamino group such as
methylamino group, ethylamino group, propylamino group,
isopropylamino group, butylamino group, isobutylamino group,
tert-butylamino group, pentylamino group, and isopentylamino group;
a C.sub.2-C.sub.10 dialkylamino group such as dimethylamino group,
ethylmethylamino group, diethylamino group, methylpropylamino
group, and diisopropylamino group; a C.sub.2-C.sub.6
alkylcarbonylamimno group such as acetylamino group, propionylamino
group, isopropionylamino group, butyrylamino group, and
valerylamino group; a C.sub.2-C.sub.6 alkoxycarbonylamino group
such as methoxycarbonylamino group, ethoxycarbonylamino group,
propoxycarbonylamino group, isopropoxycarbonylamino group,
butoxycarbonylamino group, isobutoxycarbonylamino group,
tert-butoxycarbonylamino group, and pentyloxycarbonylamino group; a
C.sub.7-C.sub.15 aralkyloxycarbonylamino group such as
benzyloxycarbonylamino group, phenylethyloxycarbonylamino group,
and naphthylmethyloxycarbonylamino group; carbamoyl group; a
C.sub.2-C.sub.6 alkylcarbamoyl group such as methylcarbamoyl group,
ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group,
tert-butylcarbamoyl group, and pentylcarbamoyl group; a
C.sub.6-C.sub.12 aryl group such as phenyl group, and naphthyl
group and the like.
[0026] Among the compounds of the present invention represented by
the above formula (I) wherein X is R.sup.1(R.sup.2)(R.sup.3)C-,
preferred compounds include those wherein R.sup.1 is a
C.sub.6-C.sub.14 aryl group which may optionally be substituted, a
residue of a heterocyclic compound which may optionally be
substituted, a C.sub.6-C.sub.14 aryloxy group which may optionally
be substituted, or a C.sub.7-C.sub.15 arylmethyl group which may
optionally be substituted, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
are hydrogen atoms, R.sup.6 is a C.sub.1-C.sub.6 alkyl group, and Y
is an oxygen atom. More preferred compounds include those wherein
R.sup.1 is a C.sub.6-C.sub.14 aryl group which may optionally be
substituted, a residue of a heterocyclic compound which may
optionally be substituted, a C.sub.6-C.sub.14 aryloxy group which
may optionally be substituted, or a C.sub.7-C.sub.15 arylmethyl
group which may optionally be substituted, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are hydrogen atoms, R.sup.6 is methyl group,
and Y is an oxygen atom.
[0027] Examples of particularly preferred compounds include:
[0028] N-(3-methylcarbamoylphenyl)-3-chlorophenylacetamide;
[0029] N-(3-methylcarbamoylphenyl)-4-chlorophenylacetamide,;
[0030] N-(3-methylcarbamoylphenyl)-3-bromophenylacetamide;
[0031] N-(3-methylcarbamoylphenyl)-4-bromophenylacetamide;
[0032] N-(3-methylcarbamoylphenyl)-3-methylphenylacetamide;
[0033] N-(3-methylcarbamoylphenyl)-4-methylphenylacetamide;
[0034] N-(3-methylcarbamoylphenyl)-3-methoxyphenylacetamide;
[0035] N-(3-methylcarbamoylphenyl)-4-methoxyphenylacetamide;
[0036]
N-(3-methylcarbamoylphenyl)-3,4,5-trimethoxyphenylacetamide;
[0037] N-(3-methylcarbamoylphenyl)-3-benzyloxyphenylacetamide;
[0038] N-(3-methylcarbamoylphenyl)-1-naphthylacetamide;
[0039] N-(3-methylcarbamoylphenyl)-2-naphthylacetamide;
[0040] N-(3-methylcarbamoylphenyl)-3-indoly)acetamide;
[0041] N-(3-methylcarbamoylphenyl)-3-benzothienylacetamide;
[0042] N-(3-methylcarbamoylphenyl)-4-benzothienylacetamide;
[0043]
N-(3-methylcarbamoylphenyl)-3,4-methylenedioxyphenylacetamide;
[0044] N-(3-methylcarbamoylphenyl)-2-chlorophenoxyacetamide;
[0045]
N-(3-methylcarbamoylphenyl)-2,3-dichlorophenoxyacetamide;
[0046] N-(3-methylcarbamoylphenyl)-1-naphthyloxyacetide;
[0047] N-(3-methylcarbamoylphenyl)-2-naphthyloxyacetamide; and
[0048]
N-(3-methylcarbamoylphenyl-3-(2-methoxyphenyl)propionamide.
[0049] Among the compounds of the above formula (I) wherein X is
R.sup.7-A-, preferred compounds include those wherein R.sup.4 and
R.sup.5 are hydrogen atom, A is an oxygen atom or -N-H and Y is an
oxygen atom, or a pharmaceutically acceptable salt thereof, or a
solvate thereof or a hydrate thereof. More preferred compounds
include those wherein R.sup.7 is a methyl group which is
substituted with an optionally substituted C.sub.6-C.sub.4 aryl
group or heterocyclic group, R.sup.4 and R.sup.5 are hydrogen atom,
R.sup.6 is a methyl group, A is an oxygen atom or -N-H and Y is an
oxygen atom, or a pharmaceutically acceptable salt thereof, or a
solvate thereof or a hydrate thereof.
[0050] Particularly preferred compounds include a compound selected
from the group consisting of:
[0051] N'-methyl-3-(2-chlorobenzyloxycarbonylamino)benzamide;
[0052] N'-methyl-3-(4-chlorobenzyloxycarbonylamino)benzamide;
[0053]
N'-methyl-3-(2,3-dichlorobenzyloxycarbonylamino)benzamide;
[0054]
N'methyl-3-(2,6-dichlorobenzyloxycarbonylamino)benzamide;
[0055] N'-methyl-3-(2-bromobenzyloxycarbonylamino)benzamide;
[0056] N'-methyl-3(2-methylbenzyloxycarbonylamino)benzamide;
[0057] N'-methyl-3-(3-methylbenzyloxycarbonylamino)benzamide;
[0058] N-methyl-3-(4-methylbenzyloxycarbonylamino)benzamide;
[0059] N'-methyl-3-(1-naphthylmethoxycarbonylamino)benzamide;
and
[0060] N'-methyl-3-(2-naphthylmethoxycarbonylmino)benzamide;
[0061] or a pharmaceutically acceptable salt thereof, or a solvate
thereof or a hydrate thereof.
[0062] The amide derivatives of the present invention represented
by the above general formula (I) can form a salt. Where one or more
acidic groups exist examples of salts include, for example, metal
sats such as lithium salt, sodium salt, potassium salt, magnesium
salt, and calcium salt, and ammonium salts such as inorganic
ammonium salt, methylammonium salt, dimethylammonium salt,
trimethylammonium salt, and dicyclohexylammonium salt. Where one or
more basic groups exist, examples of salts include, for example,
mineral acid salts such as hydrochloride, hydrobromide, sulfate,
nitrate, and phosphate, and organic acid salts such as
methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate,
propionate, tartrate, fumarate, maleate, malate, oxalate,
succinate, citrate, benzoate, mandelate, cinnamate, and lactate.
Pharmaceutically acceptable salts are preferred as the active
ingredient of the medicaments of the present invention. The amide
derivatives of the present invention represented by the above
general formula (I) and salts thereof may also exist as solvates or
hydrates. Any substances in the form of salts, solvates, or
hydrates as well as compounds in free forms fall within the scope
of the present invention.
[0063] As to the stereochemistry of asymmetric carbon atoms present
in the amide derivatives of the present invention represented by
the general formula (I), the atoms can independently be in (S),
(R), or (RS) configuration. Isomers in pure forms based on one or
more asymmetric carbon atoms, e.g., enantiomers and
diastereoisomers, any mixtures of such isomers, racemates and the
like fall within the scope of the present invention.
[0064] Examples of specific examples of the amide derivatives of
the present invention represented by the above general formula (I)
wherein X is R.sup.1(R.sup.2)(R.sup.3)C-, and Y is an oxygen atom,
include those listed in Table 1.
1TABLE 1 Compd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6
1 3 H H H H CH.sub.3 2 4 H H H H CH.sub.3 3 5 H H H H CH.sub.3 4 6
H H H H CH.sub.3 5 7 H H H H CH.sub.3 6 8 H H H H CH.sub.3 7 9 H H
H H CH.sub.3 8 10 CH.sub.3 H H H CH.sub.3 9 11 CH.sub.3 CH.sub.3 H
H CH.sub.3 10 12 CH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.3 11 13
--(CH.sub.2).sub.4-- H H CH.sub.3 12 14 --(CH.sub.2).sub.5-- H H
CH.sub.3 13 15 H H H H CH.sub.3 14 16 H H H H CH.sub.3 15 17 H H H
H CH.sub.3 16 18 H H H H CH.sub.3 17 19 H H H H CH.sub.3 18 20 H H
H H CH.sub.3 19 21 H H H H CH.sub.3 20 22 H H H H H 21 23 H H
CH.sub.3 H CH.sub.3 22 24 H H H H CH.sub.3 23 25 H H H CH.sub.3
CH.sub.3 24 26 H H H H CH.sub.2CH.sub.3 25 27 H H H H
CH.sub.2CH.sub.2CH.sub.3 26 28 H H H H (CH.sub.2).sub.3CH.sub.3 27
29 H H H H (CH.sub.2).sub.4CH.sub.3 28 30 H H H H
CH.sub.2CH.sub.2OH 29 31 H H H H OH 30 32 H H H H OCH.sub.3 31 33 H
H H H OCH.sub.2CH.sub.3 32 34 H H H CH.sub.2CH.sub.3
CH.sub.2CH.sub.3 33 35 H H H H CH.sub.3 34 36 H H H H CH.sub.3 35
37 H H H H CH.sub.3 36 38 H H H H CH.sub.3 37 39 H H H H CH.sub.3
38 40 H H H H CH.sub.3 39 41 H H H H CH.sub.3 40 42 H H H H
CH.sub.3 41 43 H H H H CH.sub.3 42 44 H H H H CH.sub.3 43 45 H H H
H CH.sub.3 44 46 H H H H CH.sub.3 45 47 H H H H CH.sub.3 46 48 H H
H H CH.sub.3 47 49 H H H H CH.sub.3 48 50 H H H H CH.sub.3 49 51 H
H H H CH.sub.3 50 52 H H H H CH.sub.3 51 53 H H H H CH.sub.3 52 54
H H H H CH.sub.3 53 55 H H H H CH.sub.3 54 56 H H H H CH.sub.3 55
57 H H H H CH.sub.3 56 58 H H H H CH.sub.3 57 59 H H H H CH.sub.3
58 60 H H H H CH.sub.3 59 61 H H H H CH.sub.3 60 62 H H H H
CH.sub.3 61 63 H H H H CH.sub.3 62 64 H H H H CH.sub.3 63 65 H H H
H CH.sub.3 64 66 H H H H CH.sub.3 65 67 H H H H CH.sub.3 66 68 H H
H H CH.sub.3 67 69 H H H H CH.sub.3 68 70 H H H H CH.sub.3 69 71 H
H H H CH.sub.3 70 72 H H H H CH.sub.3 71 73 H H H H H 72 74 H H H H
CH.sub.3 73 75 H H H H CH.sub.3 74 76 H H H H CH.sub.3 75 77 H H H
H CH.sub.3 76 78 H H H H CH.sub.3 77 79 H H H H CH.sub.3 78 80 H H
H H CH.sub.3 79 81 H H H H CH.sub.3 80 82 H H H H CH.sub.3 81 83 H
H H H CH.sub.3 82 84 H H H H CH.sub.3 83 85 H H H H CH.sub.3 84 86
H H H H CH.sub.3 85 87 H H H H CH.sub.3 86 88 H H H H CH.sub.3 87
89 H H H H CH.sub.3 88 90 H H H H CH.sub.3 89 91 H H H H CH.sub.3
90 92 H H H H CH.sub.3 91 93 H H H H CH.sub.3 92 94 H H H H
CH.sub.3 93 95 H H H H CH.sub.3 94 96 H H H H CH.sub.3 95 97 H H H
H CH.sub.3 96 98 H H H H CH.sub.3 97 99 H H H H CH.sub.3 98 100 H H
H H CH.sub.3 99 101 H H H H CH.sub.3 100 102 H H H H CH.sub.3 101
103 H H H H CH.sub.3 102 104 H H H H CH.sub.3 103 105 H H H H
CH.sub.3 104 106 H H H H CH.sub.3 105 107 H H H H CH.sub.3 106 108
H H H H CH.sub.3 107 109 H H H H CH.sub.3 108 110 H H H H CH.sub.3
109 111 H H H H CH.sub.3 110 112 H H H H CH.sub.3 111 113 H H H H
CH.sub.3 112 114 H H H H CH.sub.3 113 115 H H H H CH.sub.3 114 116
H H H H CH.sub.3 115 117 H H H H CH.sub.3 116 118 H H H H CH.sub.3
117 119 H H H H CH.sub.3 118 120 H H H H CH.sub.3 119 121 H H H H
CH.sub.3 120 122 H H H H CH.sub.3 121 123 H H H H CH.sub.3 122 124
H H H H CH.sub.3 123 125 H H H H CH.sub.3 124 126 H H H H CH.sub.3
125 127 H H H H CH.sub.3 126 128 H H H H CH.sub.3 127 129 H H H H
CH.sub.3 128 130 H H H H CH.sub.3 129 131 H H H H CH.sub.3 130 132
H H H H CH.sub.3 131 133 H H H H CH.sub.3 132 134 H H H H CH.sub.3
133 135 H H H H CH.sub.3 134 136 H H H H CH.sub.3 135 137 H H H H
CH.sub.3 136 138 H H H H CH.sub.3 137 139 H H H H CH.sub.3 138 140
H H H H CH.sub.3 139 141 H H H H CH.sub.3 140 142 H H H H CH.sub.3
141 143 H H H H CH.sub.3 142 144 H H H H CH.sub.3 143 145 H H H H
CH.sub.3 144 146 H H H H CH.sub.3 145 147 H H H H CH.sub.3 146 148
H H H H CH.sub.3 147 149 H H H H CH.sub.3 148 150 H H H H CH.sub.3
149 151 H H H H CH.sub.3 150 152 H H H H CH.sub.3 151 153 H H H H
CH.sub.3 152 154 H H H H CH.sub.3 153 155 H H H H CH.sub.3 154 156
H H H H CH.sub.3 155 157 H H H H CH.sub.3 156 158 CH.sub.3 H H H
CH.sub.3 157 159 CH.sub.3 CH.sub.3 H H CH.sub.3 158 160 H H H H
CH.sub.3 159 161 H H H H CH.sub.3 160 162 H H H H CH.sub.3 161 163
H H H H CH.sub.3 162 164 H H H H CH.sub.3 163 165 H H H H CH.sub.3
164 166 H H H H CH.sub.3 165 167 H H H H CH.sub.3 166 168 H H H H
CH.sub.3 167 169 H H H H CH.sub.3 168 170 H H H H CH.sub.3 169 171
H H H H CH.sub.3 170 172 H H H H CH.sub.3 171 173 H H H H CH.sub.3
172 174 H H H H CH.sub.3 173 175 H H H H CH.sub.3 174 176 H H H H
CH.sub.3 175 177 H H H H CH.sub.3 176 178 H H H H CH.sub.3 177 179
H H H H CH.sub.3 178 180 H H H H CH.sub.3 179 181 H H H H CH.sub.3
180 182 H H H H CH.sub.3 181 183 H H H H CH.sub.3 182 184 H H H H
CH.sub.3 183 185 H H H H CH.sub.3 184 186 H H H H CH.sub.3 185 187
H H H H CH.sub.3 186 188 H H H H CH.sub.3 187 189 H H H H CH.sub.3
188 190 H H H H CH.sub.3 189 191 H H H H CH.sub.3 190 192 H H H H
CH.sub.3 191 193 H H H H CH.sub.3 192 194 H H H H CH.sub.3 193 195
H H H H CH.sub.3 194 196 H H H H CH.sub.3 195 197 H H H H CH.sub.3
196 198 H H H H CH.sub.3 197 199 H H H H CH.sub.3 198 200 H H H H
CH.sub.3 200 201 H H H H CH.sub.3 201 202 H H H H CH.sub.3 202 203
H H H H CH.sub.3 203 204 H H H H CH.sub.3 204 205 H H H H CH.sub.3
205 206 H H H H CH.sub.3 206 207 H H H H CH.sub.3 207 208 H H H H
CH.sub.3 208 209 H H H H CH.sub.3 209 210 H H H H CH.sub.3 210 211
H H H H CH.sub.3 211 212 H H H H CH.sub.3 212 213 H H H H CH.sub.3
213 214 H H H H CH.sub.3 214 215 H H H H CH.sub.3 215 216 H H H H
CH.sub.3 216 217 H H H H CH.sub.3 217 218 H H H H CH.sub.3 218 219
H H H H CH.sub.3 219 220 H H H H CH.sub.3 220 221 H H H H CH.sub.3
221 222 H H H H CH.sub.3 222 223 H H H H CH.sub.3 223 224 H H H H
CH.sub.3 224 225 H H H H CH.sub.3 225 226 H H H H CH.sub.3 226 227
H H H H CH.sub.3 227 228 H H H H CH.sub.3 228 229 H H H H CH.sub.3
229 230 H H H H CH.sub.3 230 231 H H H H CH.sub.3 231 232 H H H H
CH.sub.3 232 233 H H H H CH.sub.3 233 234 H H H H CH.sub.3 234 235
H H H H CH.sub.3 235 236 H H H H CH.sub.3 236 237 H H H H CH.sub.3
237 238 H H H H CH.sub.3 238 239 H H H H CH.sub.3 239 240 H H H H
CH.sub.3 240 241 H H H H CH.sub.3 241 242 H H H H CH.sub.3 242 243
H H H H CH.sub.3 243 244 H H H H CH.sub.3 244 245 H H H H CH.sub.3
245 246 H H H H CH.sub.3 246 247 H H H H CH.sub.3 247 248 H H H H
CH.sub.3 248 249 H H H H CH.sub.3 249 250 H H H H CH.sub.3 250 251
H H H H CH.sub.3 251 252 H H H H CH.sub.3 252 253 H H H H
CH.sub.3
[0065] Examples of specific examples of the amide derivatives of
the present invention represented by the above general formula (I)
wherein X is R.sup.7A-, include those listed in Table 2.
2TABLE 2 Compd. No. R.sup.7 A Y R.sup.4 R.sup.5 R.sup.6 1 CH.sub.3
O O H H CH.sub.3 2 NH O 3 4 5 6 254 O O NH NH O S O S H H CH.sub.3
7 8 255 O NH O O H H H 9 10 256 O NH O O H CH.sub.3 CH.sub.3 11 12
257 O NH O O H H CH.sub.2CH.sub.3 13 14 258 O NH O O H H
CH.sub.2CH.sub.2CH.sub.3 15 16 259 O NH O O CH.sub.3 H CH.sub.3 17
18 260 O NH O O H H CH.sub.3 19 20 261 O NH O O H H CH.sub.3 21 22
262 O NH O O H H CH.sub.3 23 24 263 O NH O O H H CH.sub.3 25 26 264
O NH O O H H CH.sub.3 27 28 265 O NH O O H H CH.sub.3 29 30 266 O
NH O O H H CH.sub.3 31 32 267 O NH O O H H CH.sub.3 33 34 268 O NH
O O H H CH.sub.3 35 36 269 O NH O O H H CH.sub.3 37 38 270 O NH O O
H H CH.sub.3 39 40 271 O NH O O H H CH.sub.3 41 42 272 O NH O O H H
CH.sub.3 43 44 273 O NH O O H H CH.sub.3 45 46 274 O NH O O H H
CH.sub.3 47 48 275 O NH O O H H CH.sub.3 49 50 276 O NH O O H H
CH.sub.3 51 52 277 O NH O O H H CH.sub.3 53 54 278 O NH O O H H
CH.sub.3 55 56 279 O NH O O H H CH.sub.3 57 58 280 O NH O O H H
CH.sub.3 59 60 281 O NH O O H H CH.sub.3 61 62 282 O NH O O H H
CH.sub.3 63 64 283 O NH O O H H CH.sub.3 65 66 284 O NH O O H H
CH.sub.3 67 68 285 O NH O O H H CH.sub.3 69 70 286 O NH O O H H
CH.sub.3 71 72 287 O NH O O H H CH.sub.3 73 74 288 O NH O O H H
CH.sub.3 75 76 289 O NH O O H H CH.sub.3 77 78 290 O NH O O H H
CH.sub.3 79 80 291 O NH O O H H CH.sub.3 81 82 292 O NH O O H H
CH.sub.3 83 84 293 O NH O O H H CH.sub.3 85 86 294 O NH O O H H
CH.sub.3 87 88 295 O NH O O H H CH.sub.3 89 90 296 O NH O O H H
CH.sub.3 91 92 297 O NH O O H H CH.sub.3 93 94 298 O NH O O H H
CH.sub.3 95 96 299 O NH O O H H CH.sub.3 97 98 300 O NH O O H H
CH.sub.3 99 100 301 O NH O O H H CH.sub.3 101 102 302 O NH O O H H
CH.sub.3 103 104 303 O NH O O H H CH.sub.3 105 106 304 O NH O O H H
CH.sub.3 107 108 305 O NH O O H H CH.sub.3 109 110 306 O NH O O H H
CH.sub.3 111 112 307 O NH O O H H CH.sub.3 113 114 308 O NH O O H H
CH.sub.3 115 116 309 O NH O O H H CH.sub.3 117 118 310 O NH O O H H
CH.sub.3 119 120 311 O NH O O H H CH.sub.3 121 122 312 O NH O O H H
CH.sub.3 123 124 313 O NH O O H H CH.sub.3 125 126 314 O NH O O H H
CH.sub.3 127 128 315 O NH O O H H CH.sub.3 129 130 316 O NH O O H H
CH.sub.3 131 132 317 O NH O O H H CH.sub.3 133 134 318 O NH O O H H
CH.sub.3 135 136 319 O NH O O H H CH.sub.3 137 138 320 O NH O O H H
CH.sub.3 139 140 321 O NH O O H H CH.sub.3 141 CH.sub.3CH.sub.2 O O
H H CH.sub.3 142 NH O 143 144 322 O NH O O H H CH.sub.3 145 146 323
O NH O O H H CH.sub.3 147 148 324 O NH O O H H CH.sub.3 149 150 325
O NH O O H H CH.sub.3 151 152 326 O NH O O H H CH.sub.3 153 154 327
O NH O O H H CH.sub.3 155 156 328 O NH O O H H CH.sub.3 157 158 329
O NH O O H H CH.sub.3 159 160 330 O NH O O H H CH.sub.3 161 162 331
O NH O O H H CH.sub.3 163 164 332 O NH O O H H CH.sub.3 165 166 333
O NH O O H H CH.sub.3 167 168 334 O NH O O H H CH.sub.3 169 170 335
O NH O O H H CH.sub.3 171 172 336 O NH O O H H CH.sub.3 173 174 337
O NH O O H H CH.sub.3 175 176 338 O NH O O H H CH.sub.3 177 178 339
O NH O O H H CH.sub.3 179 180 340 O NH O O H H CH.sub.3 181 182 183
184 185 186 341 O NH NCH.sub.3O NH NCH.sub.3 O O O S S S H H
CH.sub.3 187 188 342 O NH O O H H H 189 190 343 O NH O O H CH.sub.3
CH.sub.3 191 192 344 O NH O O H H CH.sub.2CH.sub.3 193 194 345 O NH
O O H H CH.sub.2CH.sub.2CH.sub.3 195 196 346 O NH O O CH.sub.3 H
CH.sub.3 197 198 347 O NH O O H H CH.sub.3 199 200 348 O NH O O H H
CH.sub.3 201 202 349 O NH O O H H CH.sub.3 203 204 350 O NH O O H H
CH.sub.3 205 206 351 O NH O O H H CH.sub.3 207 208 352 O NH O O H H
CH.sub.3 209 210 353 O NH O O H H CH.sub.3 211 212 354 O NH O O H H
CH.sub.3 213 214 355 O NH O O H H CH.sub.3 215 216 356 O NH O O H H
CH.sub.3 217 218 357 O NH O O H H CH.sub.3 219 220 358 O NH O O H H
CH.sub.3 221 222 359 O NH O O H H CH.sub.3 223 224 360 O NH O O H H
CH.sub.3 225 226 361 O NH O O H H CH.sub.3 227 228 362 O NH O O H H
CH.sub.3 229 230 363 O NH O O H H CH.sub.3 231 232 364 O NH O O H H
CH.sub.3 233 234 365 O NH O O H H CH.sub.3 235 236 366 O NH O O H H
CH.sub.3 237 238 367 O NH O O H H CH.sub.3 239 240 368 O NH O O H H
CH.sub.3
[0066] The amide derivatives of the present invention represented
by the above general formula (I) wherein X is
R.sup.1(R.sup.2)(R.sup.3)C-, and Y is an oxygen atom, can be
prepared by, for example, the method explained below. 369
[0067] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are the same as those defined above.
[0068] A carboxylic acid derivative represented by the above
general formula (II) is allowed to react with a condensing agent
such as dicyclohexylcarbodiimide, diphenylphospboryl azide,
carbonyldiimidazole, oxalyl chloride, isobutyl chloroformate, and
thionyl chloride, optionally in the presence of a base such as
triethylamine and pyridine as required, to activate a carboxylic
acid, and then the resulting intermediate is allowed to react with
an aniline derivative represented by the above general formula
(III), optionally in the presence of a base such as triethylamine
and pyridine as required, to obtain a compound represented by the
above general formula (I). As a solvent used in the condensation
reaction, a suitable solvent may be appropriately chosen depending
on a type of a condensing agent. Reaction conditions may also be
appropriately chosen so as to be suitable for a condensing agent
used.
[0069] In the above series of reactions, protection and
deprotection of one or more functional groups may sometimes be
required. In such a case, a protective group suitable for each of
the reactive functional group may be chosen, and reaction
procedures can be employed according to known methods described in
the literature.
[0070] The amide derivatives of the present invention represented
by the above general formula (I) wherein X is R.sup.7-A-, can be
prepared by, for example, the method explained below. 370
[0071] wherein R.sup.7, R.sup.4, R.sup.5, and R.sup.6 are the same
as those defined above.
[0072] An alcohol derivative represented by the above general
formula (IV) is dissolved in an inert solvent such as acetonitrile,
methylene chloride or chloroform, and allowed to be reacted with
di(n-succinimidyl)carbonate in the presence of base such as
triethylamine or pyridine to obtain an asymmetric carbonate
compound (V) as an intermediate. The compound (V) is then dissolved
in a polar solvent such as dimethylformamide, N-methylpyrrolidone
or dimethylsulfoxide, and allowed to be reacted with the aniline
derivative (VI) in the presence of base such as triethylamine or
pyridine to obtain the compound (VII) i.e., the compound
represented by the formula (I) wherein A and Y are an oxygen atom.
371
[0073] wherein R.sup.7, R.sup.4, R.sup.5, R.sup.6 and Y are the
same as those defined above.
[0074] The isocyanate derivative (VIII) is dissolved in an inert
solvent such as acetonitrile, methylene chloride or chloroform, and
allowed to be reacted with the aniline derivative (VI) to obtain
the compound (IX), i.e., the compound represented by the formula
(I) wherein A is -NH.
[0075] In the above series of reactions, protection and
deprotection of one or more functional groups may sometimes be
required. In such a case, a protective group suitable for each of
the reactive functional group may be chosen, and reaction
procedures can be employed according to known methods described in
the literature.
[0076] The compounds of the present invention represented by the
above general formula (I) have excellent antibacterial activity
against Helicobacter pylori, and they can exhibit potent
antibacterial activity against Helicobacter pylori in stomach.
Accordingly, the medicaments of the present invention are useful
for therapeutic and/or preventive treatment of various digestive
diseases related to the infection caused by Helicobacter pylori,
for example, a disease selected from the group consisting of
gastritis, gastric ulcer, gastric cancer; gastric malignant
lymphoma, MALT lymphoma, duodenal ulcer, and duodenal carcinoma.
More specifically, the compounds may preferably be used as
medicaments for therapeutic treatment of gastritis, gastric ulcer
and duodenal ulcer; medicaments for preventive treatment of gastric
ulcer, duodenal ulcer, gastric malignant lymphoma, gastric cancer,
and duodenal carcinoma; and medicaments for preventive treatment of
recurrence of gastric ulcer and duodenal ulcer.
[0077] As an active ingredient of the medicament of the present
invention, one or more substances selected from the group
consisting of the compound represented by the above general formula
(I) and a pharmaceutically acceptable salt thereof, and a solvate
thereof and a hydrate thereof can be used. The medicament of the
present invention may preferably be provided in the form of a
pharmaceutical composition comprising the above substance as an
active ingredient and one or more pharmaceutically acceptable
additives for pharmaceutical preparations. In the pharmaceutical
compositions, a ratio of the active ingredient to the
pharmaceutical additive may be about 1% by weight to about 90% by
weight.
[0078] The medicament of the present invention may be administered
as a pharmaceutical composition for oral administration such as
granules, subtilized granules, powders, hard capsules, soft
capsules, syrups, emulsions, suspensions, and liquid drugs, or
administered as a pharmaceutical composition for parenteral
administration such as injections for intravenous, intramuscular or
subcutaneous administration, drip infusions, and suppositories. A
preparation prepared as a powdery pharmaceutical composition may be
dissolved before use and used as an injection or a drip
infusion.
[0079] Solid or liquid pharmaceutical additives may be used for
preparation of the pharmaceutical compositions. The pharmaceutical
additives may be either organic or inorganic materials. Examples of
excipients used for manufacturing solid preparations include, for
example, lactose, sucrose, starch, talc, cellulose, dextrin, china
clay, and calcium carbonate. For the manufacture of liquid
formulations for oral administration such as emulsions, syrups,
suspensions, and liquids, for example, ordinary inert diluents such
as water and vegetable oils may be used. In addition to the inert
diluents, auxiliaries such as, for example, moistening agents,
suspending aids, sweetening agents, aromatics, colorants,
preservatives and the like may be formulated. Liquid preparations
may be filled in capsules after their preparation that are made of
an absorbable material such as gelatin. Examples of solvents or
suspending mediums used for the manufacture of pharmaceutical
preparations for parenteral administration such as injections and
suppositories include, for example, water, propylene glycol,
polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the
like. Examples of base materials used for preparation of
suppositories include, for example, cacao butter, emulsified cacao
butter, lauric lipid, Witepsol and the like. Methods for
manufacturing the pharmaceutical preparations are not particularly
limited, and any methods ordinarily used in the art may be
employed.
[0080] A dose of the medicament of the present invention may
generally be from about 0.01 to 5,000 mg per day for an adult based
on the weight of the compounds of the present invention. However,
it is preferred to suitably increase or decreased depending on age,
conditions, symptoms or other of a patient. The daily dose may be
administered once a day or two to three times a day with suitable
intervals, or alternatively, intermittently administered with
intervals of several days. When used as an injection, a dose of the
medicaments of the present invention may be about 0.001 to 100 mg
per day for an adult based on the weight of the compounds of the
present invention.
EXAMPLES
[0081] The present invention will be explained more specifically by
referring to the following examples. However, the scope of the
present invention is not limited to these examples.
Example 1
Preparation of N-(3-methylcarbamoylphenyl)-3-chlorophenylacetamide
(Compound No. 17 in Table 1)
[0082] 3-Chlorophenylacetic acid (192 mg) was dissolved in
methylene chloride (8 ml), and oxalyl chloride (0.10 ml) and one
drop of dimethylformamide were added to the solution. After
stirring for 1 hour at room temperature, 3-aminobenzoylmethylamide
(167 mg) and pyridine (0.19 ml) were added to the reaction mixture,
and then stirred at room temperature overnight. After the solvent
was evaporated under reduced pressure, water (10 ml) and 2N aqueous
hydrochloric acid (l ml) were added to the residue, and the
deposited crystals were collected by filtration and washed with
water. These crystals were dried and added in ethyl acetate (6 ml),
and then the mixture was heated under reflux for ten minutes. The
mixture was cooled to room temperature, and the crystals were
collected by filtration and washed with ethyl acetate to obtain the
desired compound (233 mg, yield 68%).
[0083] Melting point: 165-166.degree. C.
[0084] IR (KBr, cm.sup.-1): 3324, 1642, 1593, 1555.
[0085] NMR DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.68 (s,
2H), 7.25-7.42 (m, 5H), 7.48 (d, J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz,
1H), 8.02 (dd, J=1.8 Hz, 1.8 Hz, 1H), 8.36 (d, J=4.5 Hz, 1H), 10.31
(s, 1H).
[0086] In similar manners to the method of Example 1, compounds of
Examples 2-50 were prepared. Their physicochemical properties are
set out below.
Example 2
Preparation of N-(3-methylcarbamoylphenyl)cyclohexylacetamide
(Compound No. 4 in Table 1)
[0087] Melting point: 183.degree. C.
[0088] IR (KBr, cm.sup.-1): 3293, 1657, 1640, 1588, 1535.
[0089] NMR (DMSO-d.sub.6, .delta.): 0.99 m, 2H), 1.03-1.38 (m, 3H),
1.55-1.90 (m, 6H), 2.19 (d, J=7.0 Hz, 2 H), 2.76 (d, J=4.5 Hz, 3H),
7.34 (dd, J=7.8 Hz, 7.8 Hz, 1H, 7.45 (d, J=7.8 Hz, 1H), 7.74 (d,
J=7.8 Hz, 1H), 8.01 (s, 1H), 8.34 (d, J=4.5 Hz, 1H), 9.95 (s,
1H).
Example 3
Preparation of N-(3-methylcarbamoylphenyl)phenylacetamide (Compound
No. 7 in Table 1)
[0090] Melting point: 140-142.degree. C.
[0091] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.5 Hz, 3H), 3.63
(s, 2H). 7.22-7.48 (m, 7H), 7.74 (m, 1H), 8.01 (s, 1H), 8.37 (d,
J=4.5 Hz, 1H), 10.30 (s, 1H).
Example 4
Preparation of
N-(3-methylcarbamoylphenyl)-1-phenylcyclopentanecarboxamide
(Compound No. 11 in Table 1)
[0092] Melting point: 147.degree. C.
[0093] IR (KBr, cm.sup.-1): 3339, 3275, 1638, 1586, 1557, 1528.
[0094] NMR (DMSO-d.sub.6, .delta.): 1.67 (m, 4H), 1.94 (m, 2H),
2.65 (m, 2H), 2.75 (d, J=4.5 Hz, 3H), 7.20-7.60 (m, 7H), 7.76 (d,
J=7.2 Hz, 1H), 7.98 (s, 1H), 8.33 (d, J=4.5 Hz, 1H), 9.32 (s,
1H).
Example 5
Preparation of N-(3-methylcarbamoylphenyl)-3-fluorophenylacetamide
(Compound No. 14 in Table 1)
[0095] Melting point: 147-148.degree. C.
[0096] IR (KBr, cm.sup.-1): 3314, 1661, 1636, 1587, 1530.
[0097] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.2 Hz, 3H), 3.69(s,
2H), 7.08 (dd, J=5.7 Hz, 5.7 Hz, 1H), 7.14 (d, J=7.5 Hz, 2H), 7.38
(m, 2H), 7.47 (d, J=8.1 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 8.02 (s,
1H), 8.35 (d, J=4.2 Hz, 1H), 10.30 (s, 1H).
Example 6
Preparation of N-(3-methylcarbamoylphenyl-4-fluorophenylacetamide
(Compound No. 15 in Table 1)
[0098] Melting point: 155-156.degree. C.
[0099] IR (KBr, cm.sup.-1): 3293, 1657, 1634, 1588, 1535, 1512.
[0100] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=3.9 Hz, 3H), 3.65
(s, 2H), 7.15 (dd, J=9.0 Hz, 9.0 Hz, 2H), 7.25-7.41 (m, 3H), 7.47
(d, J=7.5 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H). 8.02 (s, 1H), 8.35 (d,
J=3.9 Hz, 1H, 10.28 (s, 1H).
Example 7
Preparation of N-(3-methylcarbamoylphenyl)-2-chlorophenylacetamide
(Compound No. 16 in Table 1)
[0101] Melting point: 211-212.degree. C.
[0102] IR (KBr, cm.sup.-1): 3268, 1659, 1642, 1586, 1535.
[0103] NMR (DMSO-d.sub.6, .delta.): 2.77 (d, J=3.6 Hz, 3H), 3.85
(s, 2H), 7.25-7.55 (m, 6H), 7.74 (d, J=7.5 Hz, 1H), 8.04 (s, 1H),
8.36 (d, J=3.6 Hz, 1H), 10.34 (s, 1H).
Example 8
Preparation of N-(3-methylcarbamoylphenyl)-4-chlorophenylacetamide
(Compound No. 18 in Table 1)
[0104] Melting point: 163-164.degree. C.
[0105] IR (KBr, cm.sup.-1): 3279, 1663, 1640, 1588, 1535.
[0106] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=3.9 Hz, 3H), 3.66
(s, 2H), 7.35-7.42 (m, 5H), 7.47 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8
Hz, 1H), 8.02 (dd, J=1.5 Hz, 1.5 Hz, 1H), 8.36 (d, J=3.9 Hz, 1H),
10.30 (s, 1H.
Example 9
Preparation of N-(3-carbamoylphenyl)-3-bromophenylacetamide
(Compound No. 20 in Table 1)
[0107] Melting point: 202.degree. C.
[0108] IR (KBr, cm.sup.-1): 3378, 3295, 1659, 1624, 1586, 1534.
[0109] NMR (DMSO-d.sub.6, .delta.): 3.67 (s, 2H), 7.20-7.60 (m,
7H), 7.76 (d, J=9.3 Hz, 1H), 7.94 (s, 1H), 8.03(s, 1H, 10.33 (s,
1H).
Example 10
Preparation of N-(3-methylcarbamoylphenyl)-3-bromophenylacetamide
(Compound No. 22 in Table 1)
[0110] Melting point: 176-178.degree. C.
[0111] IR (KBr, cm.sup.-1): 3324, 3254, 1642, 1591, 1554.
[0112] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.68
(s, 2H), 7.27-7.41 (m, 3H), 7.45-7.50 (m, 2H), 7.56 (s, 1H), 7.75
(d, J=8.0 Hz, 1H), 8.03 (s, 1H), 8.42 (d, J=4.5 Hz, 1H), 10.35 (s,
1H).
Example 11
Preparation of N-(3-dimethylcarbamoylphenyl)-3-bromophenylacetamide
(Compound No. 23 in Table 1)
[0113] Melting point: 119-120.degree. C.
[0114] IR (KBr, cm.sup.-1): 1678, 1613, 1588, 1557.
[0115] NMR (DMSO-d.sub.6, .delta.): 2.90 (s, 3H), 2.96 (s, 8H),
3.68 (s, 2H), 7.06 (d, J=7.8 Hz, 1H), 725-7.41 (m, 3H), 7.47 (m,
1H), 7.53-7.60 (m, 2H), 7.68 (s, 1H), 10.30 (s, 1H).
Example 12
Preparation of N-(3-ethylcarbamoylphenyl)-3-bromophenylacetamide
(Compound No. 24 in Table 1)
[0116] Melting point: 155.degree. C.
[0117] IR (KBr, cm.sup.-1): 3329, 3268, 1665, 1640, 1549.
[0118] NMR (DMSO-d.sub.6, .delta.): 1.11 (t, J=6.9 Hz, 3H), 3.29 m,
2H), 3.67 (s, 2H), 7.20-7.40 (m, 3H), 7.47 (d, J=8.1 Hz, 1H), 7.49
(d, J=8.1 Hz, 1H), 7.56 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.00 (s,
1H), 8.41 (t, J=5.1 Hz, 1H), 10.32 (s, 1H).
Example 13
Preparation of
N-(3-(2hydroxyethyl)carbamoylphenyl)-3-bromophenylacetamide
(Compound No. 28 in Table 1)
[0119] Melting point: 202.degree. C.
[0120] IR (KBr, cm.sup.-1): 3407, 3358, 3279, 1671, 1640, 1589,
1539.
[0121] NMR (DMSO-d.sub.6, .delta.): 3.26 (m, 2H), 3.47 (m, 2H),
3.65 (s 2H), 4.67 (t, J=5.7 Hz, 1H), 7.20-7.60 (m, 6H), 7.73 (d,
J=7.2 Hz, 1H), 7.99 (s, 1H), 8.32 (m, 1H), 10.28 (s, 1H).
Example 14
Preparation of N-(3-hydroxycarbamoylphenyl)-3-bromophenylacetamide
(Compound No. 29 in Table 1)
[0122] Melting point: 184-186.degree. C. (decomposition)
[0123] IR (KBr, cm.sup.-1): 3314, 3231, 1663, 1632, 1582, 1535.
[0124] NMR (DMSO-d.sub.6, .delta.): 3.68 (s 2H:, 7.25-7.60 (m, 6H),
7.75 (d, J=6.9 Hz, 1H), 7.98 (s, 1H), 9.01 (s, 1H, 10.33 (s, 1H),
11.12 (s, 1H).
Example 15
Preparation of N-(methoxycarbamoylphenyl)-3-bromophenylacetamide
(Compound No. 30 in Table 1)
[0125] Melting point: 166.degree. C.
[0126] IR (KBr, cm.sup.-1): 3299, 3187, 1659, 1611, 1595, 1560.
[0127] NMR (DMSO-d.sub.6, .delta.): 3.69 (s, 5H), 7.22-7.60 (m,
6H), 7.77 (s, 1H, 8.00 (s, 1H), 10.37 (s, 1H), 11.69 (s, 1H).
Example 16
Preparation of N-(3-methylcarbamoylphenyl)-4-bromophenylacetamide
(Compound No. 33 in Table 1)
[0128] Melting point: 165-166.degree. C.
[0129] IR (KBr, cm.sup.-1): 3283, 1665, 1642, 1588, 1534.
[0130] NMR (DMSO-d.sub.6, .delta.): 2.77 (d, J=4.5 Hz, 3H), 3.64
(s, 2H), 7.23-7.40 (m, 3H), 7.40-7.58 (m, 3H), 7.75 (d, J=7.8 Hz,
1H), 8.01 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 10.30 (s, 1H).
Example 17
Preparation of N-(3-methylcarbamoylphenyl)-3-methylphenylacetamide
(Compound No. 42 in Table 1)
[0131] Melting point: 131.degree. C.
[0132] IR (KBr, cm.sup.-1): 3299, 1659, 1634, 1586, 1530.
[0133] NMR (DMSO-d.sub.6, .delta.): 2.29 (s, 3H), 2.76 (d, J=4.5
Hz, 3H), 3.60 (s, 2H), 7.06 (d, J=6.9 Hz, 1H, 7.09-7.22 (m, 3H),
7.36 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.75 (d,
J=7.8 Hz, 1H), 8.02 (s, 1H), 8.35 (d, J=4.5 Hz, 1H), 10.26 (s,
1H).
Example 18
Preparation of N-(3-methylcarbamoylphenyl)-4-methylphenylacetamide
(Compound No. 43 in Table 1)
[0134] Melting point: 174-175.degree. C.
[0135] IR (KBr, cm.sup.-1): 3339, 3296, 1659, 1639, 1586, 1528.
[0136] NMR (DMSO-d.sub.6, .delta.): 2.27 (s, 3H), 2.76 (d, J=4.5
Hz, 3H), 3.59 (s, 2H), 7.12 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.1 Hz,
2H), 7.36 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.75
(d, J=7.8 Hz, 1H), 8.01 (s, 1H), 8.35 (d, J=1.5 Hz, 1H), 10.24 (s,
1H).
Example 19
Preparation of N-(3-methylcarbamoylphenyl)-3-methoxyphenylacetamide
(Compound No. 59 in Table 1)
[0137] Melting point: 104-106.degree. C.
[0138] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.60
(s, 2H), 3.73 (s, 3H), 6.81 (m, 1H), 6.89-6.92 (m, 2H), 7.23 (m,
2H, 7.36 (m, 1H), 7.47 (m, 1H), 7.76 (m, 1H), 8.02 (s, 1H), 8.38
(m, 1H), 10.28 (s, 1H).
Example 20
Preparation of N-(3-methylcarbamoylphenyl)-4-methoxyphenylacetamide
(Compound No. 60 in Table 1)
[0139] Melting point: 155-157.degree. C.
[0140] NMR (DMSO-.sub.6, .delta.): 2.75 (d, J=4.5 Hz, 3H), 3.55 (s,
2H), 3.71 (s, 3H), 6.88 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H),
7.35 (m, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 8.00
(s, 1H), 8.37 (m, 1H), 10.24 (s, 1H).
Example 21
Preparation of
N-(3-methylcarbamoylphenyl)-3,4-dimethoxyphenylacetamide (Compound
No. 61 in Table 1)
[0141] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.5 Hz, 3H), 3.55
(s, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 6.82-6.94 (m, 3H), 7.35 (m,
1H), 7.46 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.00 (s, 1H),
8.37 (m, 1H), 10.22 (s, 1H).
Example 22
Preparation of
N-(3-methylcarbamoylphenyl)-3,5-dimethoxyphenylacetamide (Compound
No. 62 in Table 1)
[0142] Melting point: 146-147.degree. C.
[0143] IR (KBr, cm.sup.-1): 3341, 3246, 1667, 1638, 1589, 1547.
[0144] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.2 Hz, 3H), 3.56
(s, 2H), 3.73 (s, 6H), 6.39 (s, 1H), 6.51 (s, 2H), 7.36 (dd, J=7.8
Hz, 7.8 Hz, 1H), 7.47 (d, J=7.8 H), 7.75 (d, J=7.8 Hz, 1H), 8.01
(s, 1H), 8.35 (d, J=4.2 Hz, 1H), 10.23 (s, 1H).
Example 23
Preparation of
N-(3-methylcarbamoylphenyl)-3,4,5-trimethoxyphenylacetamide
(Compound No. 63 in Table 1)
[0145] Melting point; 81-82.degree. C.
[0146] IR (KBr, cm.sup.-1): 3304, 1642, 1589, 1554, 1508.
[0147] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.57
(s, 2H), 3.63 (s, 3H), 3.77 (s, 6H), 6.66 (s, 2H), 7.39 (dd, J=7.8
Hz, 7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H),
8.03 (s, 1H), 8.37 (d, J=4.5 Hz, 1H, 10.23 (s, 1H).
Example 24
Preparation of
N-(3-methylcarbamoylphenyl)-3-benzyloxyphenylacetamide (Compound
No. 68 in Table 1)
[0148] Melting point; 150.degree. C.
[0149] IR (KBr, cm.sup.-1): 3302, 1661, 1634, 1586, 1530.
[0150] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.61
(s, 2H), 5.09 (s, 2H), 6.91 (dd, J=7.81 Hz, 7.8 Hz, 2H), 7.01 (s,
1H), 7.27 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.25-7.52 (m, 7H), 7.74 (d,
J=7.8 Hz, 1H), 8.02 (s, 1H), 8.36 (d, J=4.5 Hz, 1H), 10.27 (s,
1H).
Example 25
Preparation of N-(3-carbamoylphenyl)-3-hydroxyphenylacetamide
(Compound No 71 in Table 1)
[0151] Melting point; 188-189.degree. C.
[0152] NMR (DMSO-d.sub.6, .delta.): 3.52 (s, 2H), 6.62 (m, 1H),
6.72-6.75 (m, 2H), 7.08 (m, 1H), 7.32-7.37 (m, 2H), 7.51 (d, J=6.9
Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.92 (1H), 8.02 (s, 1H), 9.34 (s,
1H), 10.25 (s, 1H).
Example 26
Preparation of N-(3-methylcarbamoylphenyl)-3-hydroxyphenylacetamide
(Compound No. 72 in Table 1)
[0153] Melting point; 163.degree. C.
[0154] IR (KBr, cm.sup.-1): 3333, 3293, 1676, 1640, 1588, 1562.
[0155] NMR (DMSO-d.sub.6, .delta.): 2.74 (d, J=4.2 Hz, 3H), 3.53
(s, 2H), 6.61 (d, J=7.2 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.74 (s,
1H), 7.08 (dd, J=7.2 Hz, 7.2 Hz, 1H), 7.34 (dd, J=7.8 Hz, 7.8 Hz,
1H), 7.45 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.81 Hz, 1H), 7.80 (s, 1H),
8.34 (d, J=4.2 Hz, 1H), 9.30 (s, 1H), 10.22 (s, 1H).
Example 27
Preparation of N-(3-methylcarbamoylphenyl)-4-hydroxyphenylacetamide
(Compound No. 73 in Table 1)
[0156] Melting point; 195-196.degree. C.
[0157] IR (KBr, cm.sup.-1): 3393, 3283, 1661, 1638, 1541, 1518.
[0158] NMR (DMSO-d.sub.6, .delta.): 2.73 (d, J=4.5 Hz, 3H), 3.48
(s, 2H), 6.68 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.33 (dd,
J=7.8 Hz, 7.8 Hz, 1H), 7.43 (d, J=8.71 Hz, 1H), 7.72 (d, J=7.8 Hz,
1H), 7.98 (s, 1H), 8.32 (d, J=4.5 Hz, 1H), 9.20 (s, 1H), 10.14 (s,
1H).
Example 28
Preparation of
N-(3-methylcarbamoylphenyl)-3-methylcarbamoylphenyl)-3-nitr-
ophenylacetamide (Compound No. 74 in Table 1)
[0159] Melting point 139.degree. C.
[0160] IR (KBr, cm.sup.-1): 3322, 3250, 1665, 1640, 1666, 1524.
[0161] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.86
(s, 2H, 7.37 (dd, J=7.8 Hz, 7.8, Hz, 1H), 7.49 (d, J=7.8 Hz, 1H),
7.64 (dd, J=8.1 Hz, 8.1 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.80 (d,
J=8.1 Hz, 1H), 8.03 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.24 (s, 1H),
8.37 (d, J=4.5 Hz, 1H), 10.39 (s, 1H).
Example 29
Preparation of N-(3-methylcarbamoylphenyl)-4-nitrophenylacetamide
(Compound No. 75 in Table 1)
[0162] Melting point: 148-151.degree. C.
[0163] IR (KBr, cm.sup.-1): 3277, 1663, 1640, 1588, 1522.
[0164] NMR (DMSO-d.sub.6, .delta.): 2.74 (d, J=4.2 Hz, 3H), 3.83
(2H), 7.35 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.45 (m, 1H), 7.60 (d, J=8.7
Hz, 2H), 7.72 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 8.19 (d, J=8.7 Hz,
2H, 8.33 (d, J=4.2 Hz, 1H, 10.36 (s, 1H).
Example 30
Preparation of N-(3-methylcarbamoylphenyl)-1-naphthylacetamide
(Compound No. 113 in Table 1)
[0165] Melting point; 201-202.degree. C.
[0166] IR (KBr, cm.sup.-1): 3274, 1657, 1640, 1588, 1532.
[0167] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.5 Hz, 3H), 4.16 (,
2H), 7.36 (dd, J=8.1 Hz, 8.1 Hz, 1H), 7.40-7.60 (m, 5H), 7.74 (d,
J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.03
(s, 1H), 8.35 (d, J=7.8 Hz, 1H), 8.37 (d, J=4.5 Hz, 1H), 10.44 (s,
1H).
Example 31
Preparation of N-(3-methylcarbamoylphenyl)-2-naphthylacetamide
(Compound No. 114 in Table 1)
[0168] Melting point: 175-176.degree. C.
[0169] IR (KBr, cm.sup.-1): 3393, 1655, 1634, 1588, 1530.
[0170] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.83
(s, 2H), 7.37 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.40-7.55 (m, 4H), 7.77
(d, J=8.4 Hz, 1H), 7.81-7.96 (m, 4H), 8.04 (s, 1H), 8.36 (d, J=4.1
Hz, 1H), 10.37 (s, 1H).
Example 32
Preparation of N-(3-methylcarbamoylphenyl)-3-indolylacetamide
(Compound No. 140 in Table 1)
[0171] Melting point: 168-169.degree. C.
[0172] IR (KBr, cm.sup.-1): 3382, 3287, 1655, 1636, 1588, 1555,
1528.
[0173] NMR (DMSO-d.sub.6, .delta.): 2.73 (d, J=4.5 Hz, 3H), 3.72
(s, 2H), 6.96 (dd, J=7.5 Hz, 7.5 Hz, 1H), 7.05 (dd, J=7.81 Hz, 7.8
Hz, 1H), 7.24 (s, 1H), 7.27-7.38 (m, 2H), 7.43 (d, J=7.8 Hz, 1H),
7.59 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 8.00 (s, 1H), 8.32
(d, J=4.5 Hz, 1H), 10.18 (s, 1H), 10.88 (s, 1H).
Example 33
Preparation of N-(3-methylcarbamoylphenyl)-3-benzothienylacetamide
(Compound No. 146 in Table 1)
[0174] Melting point; 194.degree. C.
[0175] IR (KBr, cm.sup.-1): 3285, 1663, 1636, 1588, 1532.
[0176] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.2 Hz, 3H), 3.94
(s, 2H), 7.32-7.53 (4H), 7.61 (s, 1H), 7.76 (d, J=6.9 Hz, 1H), 7.91
(d, J=7.2 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 8.04 (s, 1H), 8.35 (d,
J=4.2 Hz, 1H), 10.40 (s, 1H).
Example 34
Preparation of N-(3-methylcarbamoylphenyl)-4-benzothienylacetamide
(Compound No. 148 in Table 1)
[0177] Melting point: 192.degree. C.
[0178] IR (KBr, cm.sup.-1): 3295, 1676, 1632, 1595, 1559.
[0179] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.2 Hz, 3H), 4.03
(s, 2H), 7.30-7.41 (m, 3H), 7.47 (d, J=7.8 Hz, 1H), 7.65 (d, J=5.4
Hz, 1H), 7.75 (d, J=6.3 Hz, 1H), 7.77 (d, J=5.4 Hz, 1H), 7.91 (m,
1H), 8.02 (s, 1H), 8.35 (d, J=4.2 Hz, 1H), 10.39 (s, 1H).
Example 35
Preparation of
N-(3-methylcarbamoylphenyl)-2,2-dimethyl-2,3-dihydro-5-benz-
ofuranylacetamide (Compound No. 157 in Table 1)
[0180] Melting point; 92-93.degree. C.
[0181] IR (KBr, cm.sup.-1): 3289, 1665, 1611, 1589, 1555
[0182] NMR (DMSO-.sub.6, .delta.): 1.39 (s, 6H), 1.53 (s, 1H), 2.75
(d, J=4.5 Hz, 3H), 2.99 (s, 2H), 6.65 (d, J=8.4 Hz, 1H), 7.05 (d,
J=8.1 Hz, 1H), 7.18 (s, 1H), 7.34 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.45
(d, J=7.5 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.02 (s, 1H), 8.33 (d,
J=4.5 Hz, 1H, 9.18 (s, 1H).
Example 36
Preparation of
N-(3-methylcarbamoylphenyl)-3,4-methylenedioxyphenyl-acetam- ide
(Compound No. 159 in Table 1)
[0183] Melting point: 174-175.degree. C.
[0184] IR (KBr, cm.sup.-1): 3337, 3291, 1659, 1634, 1586, 1530,
1505.
[0185] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.55
(s, 2H), 5.98 (s, 2H), 6.74-6.93 (m, 3H), 7.36 (dd, J=7.8 Hz, 7.8
Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.01 (s,
1H), 8.35 (d, J=4.5 Hz, 1H), 10.20 (s, 1H).
Example 37
Preparation of N-(3-methylcarbamoylphenyl)phenoxyacetamide
(Compound No. 176 in Table 1)
[0186] Melting point: 131.degree. C.
[0187] IR (KBR, cm.sup.-1): 3378, 3283, 1669, 1640, 1588, 1535.
[0188] NMR DMSO-d.sub.6, .delta.): 2.75 (d, J=4.5 Hz, 3H), 4.69 (s,
2H), 6.63-7.01 (m, 3H), 7.22-7.40 (m, 3H), 7.60 (d, J=7.8 Hz, 1H),
7.77 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.36 (d, J=4.5 Hz, 1H), 10.18
(s, 1H.
Example 38
Preparation of N-(3-methylcarbamoylphenyl)-2-chlorophenoxyacetamide
(Compound No. 177 in Table 1)
[0189] Melting point: 172-173.degree. C.
[0190] IR KBr, cm.sup.-1): 3385, 3297, 1688, 1640, 1591, 1549.
[0191] NMR (DMSO-d.sub.6, .delta.): 2.77 (d, J=4.5 Hz, 3H), 4.85
(s, 2H), 6.99 (dd, J=7.5 Hz, 7.5 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H),
7.30 (dd, J=7.5 Hz, 7.5 Hz, 1H), 7.38-7.60 (m, 3H), 7.76 (d, J=8.4
Hz, 1H), 8.06 (s, 1H), 8.42 (d, J=4.5 Hz, 1H), 10.31 (s, 1H).
Example 39
Preparation of N-(3-methylcarbamoylphenyl)-2-methylphenoxyacetamide
(Compound No. 183 in Table 1)
[0192] Melting point: 148.degree. C.
[0193] IR (KBr, cm.sup.-1): 3399, 3285, 1696, 1640, 1547.
[0194] NMR (DMSO-d.sub.6, .delta.): 2.24 (s, 3H), 2.75 (d, J=4.5
Hz, 3H), 4.70 (s, 2H), 6.80-6.90 (m, 2H), 7.07-7.19 (m, 2H), 7.37
(dd, J=8.1 Hz, 7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.1
Hz, 1H), 8.05 (s, 1H), 8.35 (d, J=4.5 Hz, 1H), 10.14 (s, 1H).
Example 40
Preparation of
N-(3-methylcarbamoylphenyl)-2-methoxyphenoxyacetamide (Compound No.
187 in Table 1)
[0195] Melting point: 133.degree. C.
[0196] IR (KBr, cm.sup.-1): 3385, 3268, 1690, 1638, 1591, 1547.
[0197] NMR (DMSO-d.sub.6, .delta.): 2.76 (d, J=4.5 Hz, 3H), 3.79
(s, 3H), 4.66 (s, 2H), 6.82-7.02 (m, 4H), 7.38 (dd, J=7.8 Hz, 7.8
Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H, 8.05 (s,
1H), 8.38 (d, J=4.5 Hz, 1H), 10.18 (s, 1H).
Example 41
Preparation of N-(3-methylcarbamoylphenyl)-1-naphthyloxyacetamide
(Compound No. 191 in Table 1)
[0198] Melting point: 194.degree. C.
[0199] IR (KBr, cm.sup.-1): 3405, 3304, 1696, 1638, 1541.
[0200] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.2 Hz, 3H), 4.92
(s, 2H), 6.92 (d, J=7.8 Hz, 1H, 7.33-7.62 (m, 6H), 7.79 (d, J=8.1
Hz, 1H), 7.88 (m, 1H), 8.08 (s, 1H), 8.31 (m, 1H), 8.41 (d, J=4.2
Hz, 1H), 10.36 (s, 1H).
Example 42
Preparation of N-(3-methylcarbamoylphenyl)-2-naphthyloxyacetamide
(Compound No. 192 in Table 1)
[0201] Melting point: 174.degree. C.
[0202] IR (KBr, cm.sup.-1): 3382, 3275, 1672, 1638, 1588, 1557,
1534.
[0203] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.5 Hz, 3H), 4.82(s,
2H), 7.22-7.58 (m, 6H), 7.78-7.95 (m, 1H), 8.09 (s, 1H), 8.40 (d,
J=4.5 Hz, 1H), 10.28 (s, 1H).
Example 43
Preparation of
N-(3-methylcarbamoylphenyl)-2,3-dichlorophenoxyacetamide (Compound
No. 204 in Table 1)
[0204] Melting point: 192-193.degree. C.
[0205] IR (KBr, cm.sup.-1): 3385, 3291, 1692, 1644, 1547.
[0206] NMR (DMSO-d.sub.6, .delta.): 2.77 (d, J=4.5 Hz, 3H), 4.91
(s, 2H), 7.08 (d, J=8.1 Hz, 1H), 7.20-7.45 (m, 3H), 7.52 (d, J=7.8
Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 8.05 (s, 1H), 8.42 (d, J=4.5 Hz,
1H), 10.34 (s, 1H).
Example 44
Preparation of
N-(3-methylcarbamoylphenyl)-2-methyl-1-naphthylacetamide (Compound
No. 216 in Table 1)
[0207] Melting point: 230-231.degree. C.
[0208] IR (KBr, cm.sup.-1): 3299, 3071, 1684, 1638, 1589, 1560.
[0209] NMR (DMSO-d.sub.6, .delta.): 2.50 (s, 3H), 2.73 (d, J=4.5
Hz, 3H), 4.21 (s, 2H), 7.22-7.55 (m, 5H), 7.65-7.78 (m, 2H), 7.85
(d, J=7.8 Hz, 1H, 8.01-8.15 (m, 2H), 8.36 (d, J=4.5 Hz, 1H), 10.50
(s, 1H).
Example 45
Preparation of
N-(3-methylcarbamoylphenyl)-2-hydroxy-1-naphthylacetamide (Compound
No. 219 in Table 1)
[0210] Melting point: 229-230.degree. C.
[0211] IR (KBr, cm.sup.-1): 3310, 1686, 1613, 1582, 1561.
[0212] NMR (DMSO-d.sub.6, .delta.): 2.75 (d, J=4.2 Hz, 3H), 4.11
(s, 2H), 7.19 (d, J=9.0 Hz, 1H), 7.20-7.50 (m, 4H), 7.66-7.82 (m,
3H), 7.87 (d, J=8.4 Hz, 1H), 8.04 (s, 1H), 8.37 (d, J=4.5 Hz, 9.79
(s, 1H), 10.32 (s, 1H).
Example 46
Preparation of N-(3-methylcarbamoylphenyl)-3-phenylpropionamide
(Compound No. 233 in Table 1)
[0213] Melting point: 142-143.degree. C.
[0214] IR (KBr, cm.sup.-1): 3295, 1657, 1613, 1593, 1545.
[0215] NMR (DMSO-d.sub.6, .delta.): 2.62 (t, J=7.8 Hz, 2H), 2.75
(d, J=4.5 Hz, 3H), 2.90 (t, J=7.8 Hz, 2H), 7.10-7.40 (m, 6H), 7.44
(d, J=7.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.99 (s, 1H), 8.33 (d,
J=4.5 Hz, 1H), 10.00 (s, 1H).
Example 47
Preparation of
N-(3-methylcarbamoylphenyl)-3-(2-methylphenyl)propionamide
(Compound No. 240 in Table 1)
[0216] Melting point: 131.degree. C.
[0217] IR (KBr, cm.sup.-1): 3289, 1674, 1640, 1555.
[0218] NMR (DMSO-d.sub.6, .delta.): 2.29 (s, 3H), 2.57 (t, J=7.8
Hz, 2H, 2.75 (d, J=4.2 Hz, 3H), 2.88 (t, J=7.8 Hz, 2H), 7.02-7.18
(m, 4H), 7.34 (dd, J=7.8 Hz, 7.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H),
7.73 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 8.33 (d, J=4.2 Hz, 1H), 10.01
(s, 1H)
Example 48
Preparation of
N-(3-methylcarbamoylphenyl)-3-(4-hydroxyphenyl)propionamide
(Compound No. 245 in Table 1)
[0219] Melting point: 158.degree. C.
[0220] IR (KBr, cm.sup.-1): 3424, 3285, 1647, 1553.
[0221] NMR (DMSO-d.sub.6, .delta.): 2.54 (t, J=7.8 Hz, 2H), 2.74
(d, J=4.2 Hz, 3I), 2.78 (t, J=7.8 Hz, 2H), 6.64 (d, J=8.1 Hz, 2H),
7.01 (d, J=8.1 Hz, 2H), 7.33 (dd, J=8.1 Hz, 7.5 Hz, 1H), 7.43 (d,
J=7.5 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 8.32 (d, J=4.2
Hz, 1H), 9.10 (s, 1H), 9.97 (s, 1H).
Example 49
Preparation of
N-(3-methylcarbamoylphenyl)-3-(2-methoxyphenyl)propionamide
(Compound No. 246 in Table 1)
[0222] Melting point: 150.degree. C.
[0223] IR (KBr, cm.sup.-1): 3297, 1658, 1644, 1550.
[0224] NMR (DMSO-d.sub.6, .delta.): 2.56 (t, J=7.2 Hz, 2H), 275 (d,
J=3.9 Hz, 3H), 2.85 (t, J=7.2 Hz, 2H), 3.78 (s, 3H), 6.84 (dd,
J=7.5 Hz, 7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 7.05-7.20 (m, 2H),
7.26 (dd, J=8.1 Hz, 8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.72 (d,
J=8.1 Hz, 1H), 7.99 (s, 1H), 8.38 (d, J=3.9 Hz, 1H), 9.67 (s,
1H).
Example 50
Preparation of
N-(3-methylcarbamoylphenyl)-3-(4-methoxyphenyl)propionamide
(Compound No. 248 in Table 1)
[0225] Melting point: 151-152.degree. C.
[0226] IR (KBr, cm.sup.-1): 3289, 1669, 1634, 1613, 1557, 1514.
[0227] NMR (DMSO-d.sub.6, .delta.): 2.57 (t, J=7.5 Hz, 2H), 2.77
(d, J=4.2 Hz, 3H), 2.85 (t, J=7.5 Hz, 2H), 3.71 (s, 3H), 6.84 (d,
J=8.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.35 (dd, J=7.8 Hz, 7.8 Hz,
1H), 7.45 (d, J=7.8 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 8.01 (s, 1H),
8.34 (d, J=4.2 Hz, 1H), 10.00 (s, 1H).
Example 51
Preparation of
N'-methyl-3-(4-methylbenzyloxycarbonylamino)benzamide (Compound
No.51 in Table 2)
[0228] 4-Methylbenzylalcohol (307 mg) and
di(N-succinimidyl)carbonate (966 mg) were dissolved in methylene
chloride (20 ml), and triethylamine (0.70 ml) was added to the
solution. After stirring for 4 hours at room temperature, water was
added and an aqueous layer was extracted with methylene chloride.
The extracted aqueous layer was successively washed with an aqueous
saturated sodium chloride solution, an aqueous saturated sodium
bicarbonate solution, an aqueous saturated sodium chloride
solution, 2N hydrochloric acid, and an aqueous saturated sodium
chloride solution, and dried over magnesium sulfate. After removing
magnesium sulfate by filtration, the filtrate was concentrated to
obtain N-(4-methylbenzyloxycarbonyloxy)succinate imide (664 mg) as
an intermediate.
[0229] N-(4-methylbenzyloxycarbonyloxy)succinate imide (610 mg of
the above-obtained product) was dissolved in dimethylformamide (2
ml), and 3-aminobenzoylmethyamide (313 mg) and triethylamine (0.32
ml) were added thereto. After stirring overnight at room
temperature, the obtained insoluble material was added to water (15
ml) while the insoluble products are being filtered. The crystals
obtained from filtrate was filtered and washed with water to obtain
crude crystals. The crude crystals were dried and added to ethyl
acetate (8 ml), and was heated under reflux for 10 minutes. The
mixture was cooled to room temperature, and the crystals were
collected by filtration and washed with ethyl acetate to obtain the
desired compound (167 mg, yield 27%).
[0230] Melting Point: 167-168.degree. C.
[0231] IR(KBr,cm.sup.-1): 3322,1738,1622,1557.
[0232] NMR(DMSO-d.sub.6, .delta.): 2.28(s,3H), 2.74(d,J=4.6 Hz,3H),
5.09(s,2H), 7.17(d,J=7.9 Hz,2H), 7.23-7.42(m,4H), 7.54(d,J=6.5
Hz,1H), 7.91(s, 1H), 8.31(d,J=4.6 Hz, 1H), 9.82(s,1H).
[0233] In similar manners to the method of Example 51, compounds of
Example 52-68 and Example 72 were prepared. Their physicochemical
properties are set out below.
Example 52
Preparation of
N'-methyl-3-(2-fluorobenzyloxycarbonylamino)benzamide (Compound
No.17 in Table 2)
[0234] Melting Point: 189-190.degree. C.
[0235] IR(KBr,cm.sup.-1): 3341,3291,1730,1622,1557.
[0236] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=4.2 Hz,3H), 5.22(s,2H,
7.20-7.45(m,5H), 7.50-7.60(m,2H), 7.94(s,1H), 8.36(d,J=4.2 Hz,1H),
9.93(s,1H).
Example 53
Preparation of
N'-methyl-3-(4-fluorobenzyloxycarbonylamino)benzamide (Compound
No.21 in Table 2)
[0237] Melting Point; 153.degree. C.
[0238] IR(KBr,cm.sup.-1): 3304,1732,1626,1613,1559.
[0239] NMR(DMSO-d.sub.6, .delta.): 2.76(d, J=3.4 Hz,3H),
5.15(s,2H), 7.23(dd,J=8.6 Hz,8.6 Hz,2H), 7.35(dd,J=7.7 Hz,7.4 Hz,
1H), 7.42(d,J=7.4 Hz,1H), 7.49(dd,J=8.6 Hz,8.6 Hz,2H), 7.57(d,J=7.7
Hz, 1H), 7.94(s, 1H), 8.36(d,J=3.4 Hz, 1H), 9.90(s, 1H.
Example 54
Preparation of
N'-methyl-3-(2-chlorobenzyloxycarbonylamino)benzamide (Compound
No.23 in Table 2)
[0240] Melting Point: 168.degree. C.
[0241] IR(KBr,cm.sup.-1): 3329,3289,1728,1622,1559.
[0242] NMR(DMSO-d.sub.6, .delta.): 2.74(d,J=4.4 Hz,3H, 5.23(s,2),
7.27-7.43(m,4H), 7.43-7.60(m,3H), 7.93(s, 1H), 8.30(d,J=4.4 Hz,1H),
9.94(s,1H).
Example 55
Preparation of
N'-methyl-3-(4-chlorobenzyloxycarbonylamino)benzamide (Compound
No.27 in Table 2)
[0243] Melting Point: 155-156.degree. C.
[0244] IR(KBr,cm.sup.-1): 3351,3299,1734,1624,1557.
[0245] NMR(DMSO-d.sub.6, .delta.): 2.74(d,J=4.5 Hz,3H), 5.14(s,2H),
7.25-7.43(m,6H), 7.55(d,J=8.3 Hz,1H), 7.91(s,1H), 8.32(d,J=4.5
Hz,1H), 9.88(s,1H).
Example 56
Preparation of
N'-methyl-3-(2,3-dichlorobenzyloxycarbonylamino)benzamide (Compound
No.29 in Table 2)
[0246] Melting Point: 167-168.degree. C.
[0247] IR(KBr,cm.sup.-1): 3401,3258,1744,1711,1649,1561.
[0248] NMR(DMSO-d.sub.6, .delta.): 2.74(d,J=4.4 Hz,3H), 5.26(s,2H),
7.25-7.43(m,3H), 7.50-7.60(m,2H), 7.64(d,J=8.0 Hz,1H), 7.93(s, 1H),
8.32(d,J=4.4 Hz, 1H), 9.97(s,1H).
Example 57
Preparation of
N'-methyl-3-(2,6-dichlorobenzyloxycarbonylamino)benzamide (Compound
No.85 in Table 2)
[0249] Melting Point: 219-220.degree. C.
[0250] IR(KBr,cm.sup.-1): 3380,3241,1717,1651,1562.
[0251] NMR(DMSO-d.sub.6, .delta.): 2.74(d,J=4.3 Hz,3H), 5.35(s,2H),
7.25-7.60(m,6H), 7.92(s,1H), 8.35(d,J=4.3 Hz,1H), 9.92(s,1H).
Example 58
Preparation of N'-methyl-3-(2-bromobenzyloxycarbonylamino)benzamide
(Compound No.41 in Table 2)
[0252] Melting Point: 163-164.degree. C.
[0253] IR(KBr,cm.sup.-1): 3324,1728,1622,1559.
[0254] NMR(DMSO-d.sub.6, .delta.): 2.73(d,J=4.0 Hz,3H), 5.19(s,2H,
7.24-7.75(m,7H), 7.93(s,1H), 8.35(d,J=4.0 Hz,1H), 9.98(s,1H).
Example 59
Preparation of
N'-methyl-3-(2-methylbenzyloxycarbonylamino)benzamide (Compound
No.47 in Table 2)
[0255] Melting Point: 163.degree. C.
[0256] IR(KBr,cm.sup.-1): 3358,3312,1734,1622,1557.
[0257] NMR(DMSO-d.sub.6, .delta.): 2.35(s,3H), 2.76(d,J=4.4 Hz,3H),
5.17(s,2H), 7.18-7.35(m,3H), 7.35-7.45(m,3H), 7.57(d,J=7.7 Hz,1H),
7.94(s,1H), 8.37(d,J=4.4 Hz,1H), 9.89(s,1H).
Example 60
Preparation of N'-methyl-3-(3-methylbenyloxycarbonylamino)benzamide
(Compound No.49 in Table 2)
[0258] Melting Point: 155.degree. C.
[0259] IR(KBr,cm.sup.-1): 3343,3279,1736,1624,1559.
[0260] NMR(DMSO-d.sub.6, .delta.): 2.32(s,3H), 2.76(d,J=4.2 Hz,3H),
5.12(s,2H), 7.10-7.45(m,6H), 7.57(d,J=8.0 Hz,1H), 7.94(s,1H), 8.36
(d,J=4.2 Hz, 1H), 9.89(s,1H).
Example 61
Preparation of
N'-methyl-3-(4-isopropylbenzyloxycarbonylamino)benzamide (Compound
No.57 in Table 2)
[0261] Melting Point: 189-190.degree. C.
[0262] IR(KBr,cm.sup.-1); 3380,3235,1709,1647,1561.
[0263] NMR(DMSO-d.sub.6, .delta.): 1.19(d,J=6.8 Hz,6H),
2.76(d,J=3.9 Hz,3H), 2.88(m,1H), 5.12(s, 2H), 7.20-7.40(m,6H),
7.57(d,J=7.7 Hz,1H), 7.93(s,1H), 8.35(d,J=3.9 Hz,1H),
9.87(s,1H).
Example 62
Preparation of
N'-methyl-3-(2-methoxybenzyloxycarbonylamino)benzamide (Compound
No.61 in Table 2)
[0264] Melting Point: 173.degree. C.
[0265] IR(KBr,cm.sup.-1): 3341,3266,1726,1624,1561.
[0266] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=4.0 Hz,3H), 3.82(s,3H),
5.14(s, 2H), 6.99(dd,J=7.4 Hz,7.4 Hz, 1H), 7.04(d,J=8.2 Hz,1H),
7.28-7.42(m,4H), 7.56(d,J=8.2 Hz,1H), 7.94(s,1H), 8.36(d,J=4.0 Hz,
1H), 9.89(s,1H).
Example 63
Preparation of
N'-methyl-3-(4-methoxybenzyloxycarbonylamino)benzamide (Compound
No.65 in Table 2)
[0267] Melting Point: 158-159.degree. C.
[0268] IR(KBr,cm.sup.-1): 3331,3295,1730,1613,1555.
[0269] NMR(DMSO-d.sub.6, .delta.): 2.74(d,J=4.3 Hz,3H), 3.73(s,3H),
5.06(s,2H), 6.92(d,J=8.2 Hz,2H), 7.20-7.40(m,4H), 7.54(d,J=7.7 Hz,
1H), 7.90(s,1H), 8.30(d,J=4.3 Hz, 1H), 9.78(s,1H).
Example 64
Preparation of
N'-methyl-3-(4-chloro2-nitrobenzyloxycarbonylamino)benzamid- e
(Compound No.77 in Table 2)
[0270] Melting Point: 193.degree. C.
[0271] IR(KBr,cm.sup.-1): 3366,3248,1717,1624,1662,1537.
[0272] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=3.3 Hz, 3H), 5.48(s,
2H, 7.36(dd,J=7.8 Hz,7.8 Hz, 1H), 7.44(d, J=7.8 Hz,1H),
7.58(d,J=7.8 Hz,1H), 7.77(d,J=8.1 Hz,1H), 7.90-7.98(m,2H),
8.23(s,1H), 8.35(d,J=3.3 Hz, 1H), 10.04(1H).
Example 65
Preparation of
N'-methyl-3-(1-naphthylmethoxycarbonylamino)benzamide (Compound
No.81 in Table 2)
[0273] Melting Point: 228-229.degree. C.
[0274] IR(KBr,cm.sup.-1): 3353,3285,1730,1626,1555.
[0275] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=4.4 Hz,3H), 5.64(s,2H),
7.30-7.45(m,2H), 7.50-7.70(m,5H, 7.90-8.03(m,3H), 8.12(d,J=7.6
Hz,1H), 8.38(d,J=4.4 Hz, 1H), 9.87(s,1H).
Example 66
Preparation of
N'-methyl-3-(2-naphthylmethoxycarbonylamino)benzamide (Compound No.
89 in Table 2)
[0276] Melting Point: 157-158.degree. C.
[0277] IR(KBr,cm.sup.-1): 3314,1699,1642,1589,1539.
[0278] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=4.8 Hz,3H), 5.32(s,2H),
7.23-7.42(m,2H), 7.42-7.60(m,4H), 7.82-7.98(m,5H), 8.32(d,J=4.8 Hz,
1H), 9.90(s,1H).
Example 67
Preparation of
N'-methyl-3-(5-fluorenylmethoxycarbonylamino)benzamide (Compound
No.99 in Table 2)
[0279] Melting Point: 217.degree. C.
[0280] IR(KBr,cm.sup.-1): 3349,3289,1730,1624,1586,1557.
[0281] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=4.2 Hz,3H),
4.32(d,J=6.6 Hz,1H), 4.48(d,J=6.6 Hz,2H), 7.25-7.50(m, 6H),
7.59(m,1H), 7.76(d,J=7.2 Hz,2H), 7.92(d,J=7.2 Hz,2H), 7.93(s,1H,
8.37(d,J=4.2 Hz,1H), 9.87(s,1H).
Example 68
Preparation of N'-methyl-3-(phenoxycarbonylamino)benzamide(Compound
No.181 in Table 2)
[0282] Melting Point: 193.degree. C.
[0283] IR(KBr,cm.sup.-1): 3401,3268,1753,1624,1555.
[0284] NMR(DMSO-d.sub.6, .delta.): 2.77(d,J=3.6 Hz,3H),
7.20-7.35(m, 3H), 7.35-7.45(m, 4H), 7.49(d,J=7.8 Hz, 1H), 7.63(s,
1H), 7.99(s,1H), 10.38(s,1H).
Example 69
Preparation of 1-(3-methylcarbamoylphenyl)-3-phenylurea(Compound
No.182 in Table 2)
[0285] Phenylisocyanate (209 mg) and 3-aminobenzoylmethylamide (239
mg) were dissolved in dimethylformamide (2 ml. After starring for 6
hours at room temperature, dilute hydrochloric acid (15 ml) was
added. The obtained crystals were filtered and washed with water to
obtain crude crystals. The crude crystals were dried under reduced
pressure and added to ethyl acetate (8 ml), and the mixture was
heated under reflux for 10 minutes. The mixture was cooled to room
temperature, and the crystals were collected by filtration and
washed with ethyl acetate to obtain the desired compound (386 mg,
yield 90%).
[0286] Melting Point: 209-210.degree. C.
[0287] IR(KBr,cm.sup.-1): 3328,3279,1699,1626,1557.
[0288] NMR(DMSO-d.sub.6, .delta.): 2.75(d,J=4.1 Hz,3H),
6.95(dd,J=7.3 Hz,7.3 Hz), 7.20-7.45(m,6H), 7.57(d,J=7.7 Hz,1H,
7.86(s,1H), 8.37(d,J=4.1 Hz, 1H), 8.67(s,1H), 8.79(s, 1H).
[0289] In similar manners to the method of Example 69, compounds of
Example 70 and Example 71 were prepared Their physicochemical
properties are set out below.
Example 70
Preparation of 3-benzyl-1-(3-methylcarbamoylphenyl)urea(Compound
No.5 in Table 2)
[0290] Melting Point: 189-190.degree. C.
[0291] IR(KBr,cm.sup.-1): 3366,3333,1640,1559.
[0292] NMR(DMSO-d.sub.6, .delta.): 2.73(d,J=4.4 Hz,3H),
4.28(d,J=5.9 Hz,2H), 6.62(t,J=5.9 Hz,1H), 7.15-7.40(m,7H),
7.54(d,J=7.3 Hz, 1H), 7.79(s, 1H); 8.28(d,J=4.4 Hz, 1H), 8.66(s,
1H).
Example 71
Preparation of
3-benzyl-1-(3-methylcarbamoylphenyl)thiourea(Compound No.6 in Table
2)
[0293] Melting Point: 199.degree. C.
[0294] IR(KBr,cm.sup.-1): 3343,2246,3069,1630,1584,1528
[0295] NMR(DMSO-d.sub.6, .delta.): 2.76(d,J=4.5 Hz,3H),
4.72(d,J=5.4 Hz,2H), 7.20-7.40(m,6H), 7.45-7.60(m,2H), 7.81(s,1H),
8.20(s,1H), 8.36(d,J=4.5 Hz, 1H), 9.65(s,1H).
Example 72
Preparation of N'-methyl-3-(2-(2-methyl-5-nitro-1-imidazolyl)
ethoxycarbonylamino)benzamide (Compound No.233 in Table 2)
[0296] Melting Point: 207.degree. C.
[0297] IR(KBr,cm.sup.-1): 3362,1734,1636,1591,1533.
[0298] NMR(DMSO-d.sub.6, .delta.): 2.48(s,3H), 2.76(d,J=4.2 Hz,3H),
4.47(t,J=4.8 Hz,2H), 1.61(t,J=4.8 Hz,2H), 7.34(dd,J=7.7 Hz,7.5
Hz,1H), 7.43(d,J=7.5 Hz,1H), 7.55(d,J=7.7 Hz,1H), 7.85(s,1H),
8.05(s,1H), 8.34(d,J=4.4 Hz,1H), 9.76(s, 1H)
Test Example 1
Measurement of anti-Helicobacter pylori activity
[0299] Brain heart infusion culture medium containing 10% fetal
bovine serum (Difco) (5 ml) was taken in a test tube, and then the
medium was inoculated with Helicobacter pylori strain 31A isolated
from human (obtained from the Metropolitan Health Institute,
Microorganism Department, First Laboratory of Bacteria).
Cultivation was carried out under slightly aerobic condition (5%
oxygen, 10% carbon dioxide, 85% nitrogen) at 37.degree. C. for 48
hours with shaking.
[0300] The culture was then inoculated to brain heart infusion
medium containing 10% fetal bovine serum at a ratio of 5%, and
added with a test compound dissolved in 10% dimethyl sulfoxide.
Cultivation was carried out under slightly aerobic condition at
37.degree. C. for 48 hours with shaking, and then growth of
Helicobacter pylori was examined. Antibacterial activity was
recorded as the lowest concentration that exhibited growth
inhibition (minimum inhibitory concentration: MIC). The results are
shown in Tables 3 and 4. From the results shown in Tables 3 and 4,
it can be understood that the compounds of the present invention
have potent inhibitory activity against Helicobacter pylori.
3 TABLE 3 Example No. (Compound No. in Table 1) MIC (.mu.g/ml) 1
(No. 17) 0.39 3 (No. 7) 1.56 8 (No. 18) 0.78 10 (No. 22) 0.39 16
(No. 33) 0.78 17 (No. 42) 0.39 18 (No. 43) 0.39 19 (No. 59) 0.78 20
(No. 60) 0.78 22 (No. 62) 1.56 23 (No. 63) 0.78 24 (No. 68) 0.78 30
(No.113) 0.10 31 (No. 114) 0.05 32 (No. 140) 0.78 33 (No. 146) 0.10
34 (No. 148) 0.20 36 (No. 159) 0.78 38 (No. 177) 0.78 41 (No. 191)
0.10 42 (No. 192) 0.39 43 (No. 204) 0.39 44 (No. 216) 0.78 45 (No.
219) 0.78 49 (No. 246) 0.78
[0301]
4 TABLE 4 Example No. (Compound No. in Table 2) MIC (.mu.g/ml) 51
(No. 51) 0.10 52 (No. 17) 0.78 53 (No. 21) 0.78 54 (No. 23) 0.39 55
(No. 27) 0.20 56 (No. 29) 0.20 57 (No. 35) 0.20 58 (No. 41) 0.39 59
(No. 47) 0.39 60 (No. 49) 0.39 61 (No. 57) 0.78 62 (No. 61) 0.78 63
(No. 65) 0.78 65 (No. 81) 0.05 66 (No. 89) 0.10 70 (No. 5) 1.56
Test Example 2
Measurement of anti-Campylobacter jejuni activity
[0302] According to a similar method to that of Test Example 1,
inhibitory activity of the compound of the present invention
against Campylobacter jejuni was determined. As a result, MIC of
the compound of Example 31 was 0.008 .mu.g/ml. From the result, it
can be understood that the compound of the present invention has
potent inhibitory activity against Campylobacter jejuni.
Test Example 3
Acute toxicity test
[0303] The compound of the present invention, suspended in 0.5%
CMC-Na aqueous solution, was forcibly administered orally to SD
male and female rats, and symptoms of the rats were observed for
seven days. As a result, each of LD.sub.50 values of the compounds
of Examples 30 and 31 was not lower than 2,000 mg/kg.
Formulation Examples
[0304] (1) Tablet
[0305] The following ingredients were mixed according to a
conventional method, and compressed to obtain a tablet by using a
conventional apparatus.
5 Compound of Example 31 100 mg Crystalline cellulose 180 mg Corn
starch 300 mg Lactose 600 mg Magnesium stearate 15 mg
[0306] (2) Soft capsule
[0307] The following ingredients were mixed according to a
conventional method, and filled in a soft capsule.
6 Compound of Example 41 100 mg Olive oil 900 mg Lecithin 60 mg
[0308] Industrial Applicability
[0309] The amide derivatives of the present invention have potent
antibacterial activity against Helicobacter pylori, and therefore,
they are useful as an active ingredient of medicaments.
* * * * *