US20030083523A1 - Amide derivatives - Google Patents

Amide derivatives Download PDF

Info

Publication number
US20030083523A1
US20030083523A1 US10/173,076 US17307602A US2003083523A1 US 20030083523 A1 US20030083523 A1 US 20030083523A1 US 17307602 A US17307602 A US 17307602A US 2003083523 A1 US2003083523 A1 US 2003083523A1
Authority
US
United States
Prior art keywords
ring
group
1h
ch
hz
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/173,076
Inventor
Ryoichi Ando
Makoto Kawamura
Noriko Chiba
Kazutoshi Watanabe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Chemical Corp
Original Assignee
Mitsubishi Chemical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP9-168484 priority Critical
Priority to JP16848497 priority
Priority to US10350098A priority
Priority to US09/469,354 priority patent/US6444849B1/en
Application filed by Mitsubishi Chemical Corp filed Critical Mitsubishi Chemical Corp
Priority to US10/173,076 priority patent/US20030083523A1/en
Publication of US20030083523A1 publication Critical patent/US20030083523A1/en
Application status is Abandoned legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D317/00Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes unsubstituted on the hetero ring
    • C07D317/50Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/06Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated

Abstract

A compound represented by the following general formula (I):
Figure US20030083523A1-20030501-C00001
wherein X represents R1(R2)R3)C- where R1 represents a C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic residue, an optionally substituted C6-C14 aryloxy group, or an optionally substituted C7-C15 arylmethyl group; R2 and R3 independently represent hydrogen atom or a C1-C5 alkyl group, or R2 and R3 may combine to represent a C2-C7 alkylene group; or
X represents R7-A- wherein R7 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-R8 where R8 represents hydrogen atom or a C1-C5 alkyl group.
Y represents an oxygen atom or a sulfur atom,
R4 and R5 independently represent hydrogen atom or a C1-C5 alkyl group; and R6 represents hydrogen atom, a C1-C5 alkyl group which may optionally be substituted with a hydroxyl group, a hydroxyl group or a C1-C5 alkoxy group,
provided that the compounds wherein R7 is a benzyl group, A and Y are an oxygen atom, R4 and R5 are hydrogen atom, and R6 is a propyl group are excluded, or a salt thereof, or a solvate thereof or a hydrate thereof.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • 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.[0001]
  • TECHNICAL FIELD
  • The present invention relates to novel amide derivatives having strong antibacterial activity against [0002] 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).
  • For the treatment of gastrointestinal ulcers, medicaments such as H[0004] 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.
  • The compound represented by the general formula (I) defined herein below wherein R[0005] 7 is a benzyl group, and A and Y are an oxygen atom, and R4 and R5 are a hydrogen atom, and R6 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
  • The inventors of the present invention conducted researches to provide a novel anti-[0006] 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.
  • The present invention thus provides amide derivatives represented by the following general formula (I) and salts thereof and solvates thereof and hydrates thereof: [0007]
    Figure US20030083523A1-20030501-C00002
  • wherein X represents R[0008] 1(R2)(R3)C- where R1 represents a C3-C8 cycloalkyl group, an optionally substituted C6-C14 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 C6-C14 aryloxy group, or an optionally substituted C7-C15 arylmethyl group; R2 and R3 independently represent hydrogen atom or a C1-C5 alkyl group, or R2 and R3 may combine to represent a C2-C7 alkylene group; or
  • X represents R[0009] 7A- wherein R7 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-R8 where R6 represents hydrogen atom or a C1-C5 alkyl group,
  • Y represents an oxygen atom or a sulfur atom, [0010]
  • R[0011] 4 and R5 independently represent hydrogen atom or a C1-C5 alkyl group; and R6 represents hydrogen atom, a C1-C5 alkyl group which may optionally be substituted with a hydroxyl group, a hydroxyl group or a C1-C5 alkoxy group,
  • provided that the compounds wherein R[0012] 7 is a benzyl group, A and Y are an oxygen atom, R4 and R5 are hydrogen atom, and R6 is a propyl group are excluded, or a salt thereof, or a solvate thereof or a hydrate thereof.
  • 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-[0013] 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.
  • According to further aspects of the present invention, there are provided a method for treating digestive diseases related to [0014] 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
  • In the general formula (I), examples of the C[0015] 3-C8 cycloalkyl group represented by R1 include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group. Examples of the C6-C14 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.
  • 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[0016] 5-C14 aryloxy group include, for example, phenyloxy group, naphthyloxy group, and anthryloxy group, and examples of the C7-C15 arylmethyl group include, for example, benzyl group, naphthylmethyl group, and anthrylmethyl group.
  • The C[0017] 1-C5 alkyl group independently represented by R2 and R3 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 C2-C7 alkylene group represented by R2 combined with R3 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.
  • As the C[0018] 1-C5 alkyl group represented by R4 and R5, those explained for R2 and R3 can be independently used. In the present invention, R4 and R5 are preferably hydrogen atom.
  • As the C[0019] 1-C5 alkyl group represented by R6, those explained for R2 and R3 can be used, and these alkyl groups may be substituted with at least one, preferably one hydroxy group. The C1-C5 alkoxy group represented by R6 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, R6 is preferably an alkyl group, more preferably a methyl group.
  • As the C[0020] 1-C10 alkyl group represented by R7 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 C6-C14 aryl group, a fluorenyl group or a heterocyclic group. The C6-C14 aryl group which can be a substituent on the alkyl group represented by R7 includes, for example, a C6-C14 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 R7 includes, for example, those described for R1.
  • As the C[0021] 6-C14 aryl group and the heterocyclic group represented by R7, those described for the substituent on the C1-C10 alkyl group can be used.
  • R[0022] 7 is preferably a C1-C10 alkyl group which may optionally be substituted with an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group, more preferably a C1-C5 alkyl group which may optionally be substituted with an optionally substituted C6-C14 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, R7 is particularly preferably a methyl group which is substituted with an optionally substituted C6-C14 aryl group or a methyl group which is substituted with an optionally substituted heterocyclic group.
  • A represents an oxygen atom or -N-R[0023] 8 wherein R8 represents hydrogen atom or a C1-C5 alkyl group. The C1-C5 alkyl group represented by R8 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.
  • Y represents an oxygen atom or a sulfur atom. Y is preferably an oxygen atom. [0024]
  • 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[0025] 1-C5 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 C7-C15 aralkyl group such as benzyl group, phenylethyl group, and naphthylmethyl group; trifluoromethyl group; a C7-C15 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 C7-C15 aralkyloxy group such as benzyloxy group, phenylethyloxy group, and naphthylmethyloxy group; a C1-C5 alkylenedioxy group such as methylenedioxy group, ethylenedioxy group, and propylenedioxy group; hydroxy group; nitro group; a C2-C6 alkylcarbonyloxy group such as acetoxy group, propionyloxy group, butyryloxy group, and valeryloxy group; carboxyl group; a C2-C6 alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tertbutoxycarbonyl group, and pentyloxycarbonyl group; a C7-C16 aralkyloxycarbonyl group such as benzyloxycarbonyl group, phenylethyloxycarbonyl group, and naphthylmethyloxycarbonyl group; oxo group; a C2-C6 alkylcarbonyl group such as acetyl group, propioxyl group, butyryl group, and valeryl group; amino group; a C1-C5 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 C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C6 alkylcarbonylamimno group such as acetylamino group, propionylamino group, isopropionylamino group, butyrylamino group, and valerylamino group; a C2-C6 alkoxycarbonylamino group such as methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, tert-butoxycarbonylamino group, and pentyloxycarbonylamino group; a C7-C15 aralkyloxycarbonylamino group such as benzyloxycarbonylamino group, phenylethyloxycarbonylamino group, and naphthylmethyloxycarbonylamino group; carbamoyl group; a C2-C6 alkylcarbamoyl group such as methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group, tert-butylcarbamoyl group, and pentylcarbamoyl group; a C6-C12 aryl group such as phenyl group, and naphthyl group and the like.
  • Among the compounds of the present invention represented by the above formula (I) wherein X is R[0026] 1(R2)(R3)C-, preferred compounds include those wherein R1 is a C6-C14 aryl group which may optionally be substituted, a residue of a heterocyclic compound which may optionally be substituted, a C6-C14 aryloxy group which may optionally be substituted, or a C7-C15 arylmethyl group which may optionally be substituted, R2, R3, R4 and R5 are hydrogen atoms, R6 is a C1-C6 alkyl group, and Y is an oxygen atom. More preferred compounds include those wherein R1 is a C6-C14 aryl group which may optionally be substituted, a residue of a heterocyclic compound which may optionally be substituted, a C6-C14 aryloxy group which may optionally be substituted, or a C7-C15 arylmethyl group which may optionally be substituted, R2, R3, R4 and R5 are hydrogen atoms, R6 is methyl group, and Y is an oxygen atom.
  • Examples of particularly preferred compounds include: [0027]
  • N-(3-methylcarbamoylphenyl)-3-chlorophenylacetamide; [0028]
  • N-(3-methylcarbamoylphenyl)-4-chlorophenylacetamide,; [0029]
  • N-(3-methylcarbamoylphenyl)-3-bromophenylacetamide; [0030]
  • N-(3-methylcarbamoylphenyl)-4-bromophenylacetamide; [0031]
  • N-(3-methylcarbamoylphenyl)-3-methylphenylacetamide; [0032]
  • N-(3-methylcarbamoylphenyl)-4-methylphenylacetamide; [0033]
  • N-(3-methylcarbamoylphenyl)-3-methoxyphenylacetamide; [0034]
  • N-(3-methylcarbamoylphenyl)-4-methoxyphenylacetamide; [0035]
  • N-(3-methylcarbamoylphenyl)-3,4,5-trimethoxyphenylacetamide; [0036]
  • N-(3-methylcarbamoylphenyl)-3-benzyloxyphenylacetamide; [0037]
  • N-(3-methylcarbamoylphenyl)-1-naphthylacetamide; [0038]
  • N-(3-methylcarbamoylphenyl)-2-naphthylacetamide; [0039]
  • N-(3-methylcarbamoylphenyl)-3-indoly)acetamide; [0040]
  • N-(3-methylcarbamoylphenyl)-3-benzothienylacetamide; [0041]
  • N-(3-methylcarbamoylphenyl)-4-benzothienylacetamide; [0042]
  • N-(3-methylcarbamoylphenyl)-3,4-methylenedioxyphenylacetamide; [0043]
  • N-(3-methylcarbamoylphenyl)-2-chlorophenoxyacetamide; [0044]
  • N-(3-methylcarbamoylphenyl)-2,3-dichlorophenoxyacetamide; [0045]
  • N-(3-methylcarbamoylphenyl)-1-naphthyloxyacetide; [0046]
  • N-(3-methylcarbamoylphenyl)-2-naphthyloxyacetamide; and [0047]
  • N-(3-methylcarbamoylphenyl-3-(2-methoxyphenyl)propionamide. [0048]
  • Among the compounds of the above formula (I) wherein X is R[0049] 7-A-, preferred compounds include those wherein R4 and R5 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 R7 is a methyl group which is substituted with an optionally substituted C6-C4 aryl group or heterocyclic group, R4 and R5 are hydrogen atom, R6 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.
  • Particularly preferred compounds include a compound selected from the group consisting of: [0050]
  • N′-methyl-3-(2-chlorobenzyloxycarbonylamino)benzamide; [0051]
  • N′-methyl-3-(4-chlorobenzyloxycarbonylamino)benzamide; [0052]
  • N′-methyl-3-(2,3-dichlorobenzyloxycarbonylamino)benzamide; [0053]
  • N′methyl-3-(2,6-dichlorobenzyloxycarbonylamino)benzamide; [0054]
  • N′-methyl-3-(2-bromobenzyloxycarbonylamino)benzamide; [0055]
  • N′-methyl-3(2-methylbenzyloxycarbonylamino)benzamide; [0056]
  • N′-methyl-3-(3-methylbenzyloxycarbonylamino)benzamide; [0057]
  • N-methyl-3-(4-methylbenzyloxycarbonylamino)benzamide; [0058]
  • N′-methyl-3-(1-naphthylmethoxycarbonylamino)benzamide; and [0059]
  • N′-methyl-3-(2-naphthylmethoxycarbonylmino)benzamide; [0060]
  • or a pharmaceutically acceptable salt thereof, or a solvate thereof or a hydrate thereof. [0061]
  • 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. [0062]
  • 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. [0063]
  • Examples of specific examples of the amide derivatives of the present invention represented by the above general formula (I) wherein X is R[0064] 1(R2)(R3)C-, and Y is an oxygen atom, include those listed in Table 1.
    TABLE 1
    Compd.
    No. R1 R2 R3 R4 R5 R6
    1
    Figure US20030083523A1-20030501-C00003
    H H H H CH3
    2
    Figure US20030083523A1-20030501-C00004
    H H H H CH3
    3
    Figure US20030083523A1-20030501-C00005
    H H H H CH3
    4
    Figure US20030083523A1-20030501-C00006
    H H H H CH3
    5
    Figure US20030083523A1-20030501-C00007
    H H H H CH3
    6
    Figure US20030083523A1-20030501-C00008
    H H H H CH3
    7
    Figure US20030083523A1-20030501-C00009
    H H H H CH3
    8
    Figure US20030083523A1-20030501-C00010
    CH3 H H H CH3
    9
    Figure US20030083523A1-20030501-C00011
    CH3 CH3 H H CH3
    10
    Figure US20030083523A1-20030501-C00012
    CH3 CH3 CH3 H CH3
    11
    Figure US20030083523A1-20030501-C00013
    —(CH2)4 H H CH3
    12
    Figure US20030083523A1-20030501-C00014
    —(CH2)5 H H CH3
    13
    Figure US20030083523A1-20030501-C00015
    H H H H CH3
    14
    Figure US20030083523A1-20030501-C00016
    H H H H CH3
    15
    Figure US20030083523A1-20030501-C00017
    H H H H CH3
    16
    Figure US20030083523A1-20030501-C00018
    H H H H CH3
    17
    Figure US20030083523A1-20030501-C00019
    H H H H CH3
    18
    Figure US20030083523A1-20030501-C00020
    H H H H CH3
    19
    Figure US20030083523A1-20030501-C00021
    H H H H CH3
    20
    Figure US20030083523A1-20030501-C00022
    H H H H H
    21
    Figure US20030083523A1-20030501-C00023
    H H CH3 H CH3
    22
    Figure US20030083523A1-20030501-C00024
    H H H H CH3
    23
    Figure US20030083523A1-20030501-C00025
    H H H CH3 CH3
    24
    Figure US20030083523A1-20030501-C00026
    H H H H CH2CH3
    25
    Figure US20030083523A1-20030501-C00027
    H H H H CH2CH2CH3
    26
    Figure US20030083523A1-20030501-C00028
    H H H H (CH2)3CH3
    27
    Figure US20030083523A1-20030501-C00029
    H H H H (CH2)4CH3
    28
    Figure US20030083523A1-20030501-C00030
    H H H H CH2CH2OH
    29
    Figure US20030083523A1-20030501-C00031
    H H H H OH
    30
    Figure US20030083523A1-20030501-C00032
    H H H H OCH3
    31
    Figure US20030083523A1-20030501-C00033
    H H H H OCH2CH3
    32
    Figure US20030083523A1-20030501-C00034
    H H H CH2CH3 CH2CH3
    33
    Figure US20030083523A1-20030501-C00035
    H H H H CH3
    34
    Figure US20030083523A1-20030501-C00036
    H H H H CH3
    35
    Figure US20030083523A1-20030501-C00037
    H H H H CH3
    36
    Figure US20030083523A1-20030501-C00038
    H H H H CH3
    37
    Figure US20030083523A1-20030501-C00039
    H H H H CH3
    38
    Figure US20030083523A1-20030501-C00040
    H H H H CH3
    39
    Figure US20030083523A1-20030501-C00041
    H H H H CH3
    40
    Figure US20030083523A1-20030501-C00042
    H H H H CH3
    41
    Figure US20030083523A1-20030501-C00043
    H H H H CH3
    42
    Figure US20030083523A1-20030501-C00044
    H H H H CH3
    43
    Figure US20030083523A1-20030501-C00045
    H H H H CH3
    44
    Figure US20030083523A1-20030501-C00046
    H H H H CH3
    45
    Figure US20030083523A1-20030501-C00047
    H H H H CH3
    46
    Figure US20030083523A1-20030501-C00048
    H H H H CH3
    47
    Figure US20030083523A1-20030501-C00049
    H H H H CH3
    48
    Figure US20030083523A1-20030501-C00050
    H H H H CH3
    49
    Figure US20030083523A1-20030501-C00051
    H H H H CH3
    50
    Figure US20030083523A1-20030501-C00052
    H H H H CH3
    51
    Figure US20030083523A1-20030501-C00053
    H H H H CH3
    52
    Figure US20030083523A1-20030501-C00054
    H H H H CH3
    53
    Figure US20030083523A1-20030501-C00055
    H H H H CH3
    54
    Figure US20030083523A1-20030501-C00056
    H H H H CH3
    55
    Figure US20030083523A1-20030501-C00057
    H H H H CH3
    56
    Figure US20030083523A1-20030501-C00058
    H H H H CH3
    57
    Figure US20030083523A1-20030501-C00059
    H H H H CH3
    58
    Figure US20030083523A1-20030501-C00060
    H H H H CH3
    59
    Figure US20030083523A1-20030501-C00061
    H H H H CH3
    60
    Figure US20030083523A1-20030501-C00062
    H H H H CH3
    61
    Figure US20030083523A1-20030501-C00063
    H H H H CH3
    62
    Figure US20030083523A1-20030501-C00064
    H H H H CH3
    63
    Figure US20030083523A1-20030501-C00065
    H H H H CH3
    64
    Figure US20030083523A1-20030501-C00066
    H H H H CH3
    65
    Figure US20030083523A1-20030501-C00067
    H H H H CH3
    66
    Figure US20030083523A1-20030501-C00068
    H H H H CH3
    67
    Figure US20030083523A1-20030501-C00069
    H H H H CH3
    68
    Figure US20030083523A1-20030501-C00070
    H H H H CH3
    69
    Figure US20030083523A1-20030501-C00071
    H H H H CH3
    70
    Figure US20030083523A1-20030501-C00072
    H H H H CH3
    71
    Figure US20030083523A1-20030501-C00073
    H H H H H
    72
    Figure US20030083523A1-20030501-C00074
    H H H H CH3
    73
    Figure US20030083523A1-20030501-C00075
    H H H H CH3
    74
    Figure US20030083523A1-20030501-C00076
    H H H H CH3
    75
    Figure US20030083523A1-20030501-C00077
    H H H H CH3
    76
    Figure US20030083523A1-20030501-C00078
    H H H H CH3
    77
    Figure US20030083523A1-20030501-C00079
    H H H H CH3
    78
    Figure US20030083523A1-20030501-C00080
    H H H H CH3
    79
    Figure US20030083523A1-20030501-C00081
    H H H H CH3
    80
    Figure US20030083523A1-20030501-C00082
    H H H H CH3
    81
    Figure US20030083523A1-20030501-C00083
    H H H H CH3
    82
    Figure US20030083523A1-20030501-C00084
    H H H H CH3
    83
    Figure US20030083523A1-20030501-C00085
    H H H H CH3
    84
    Figure US20030083523A1-20030501-C00086
    H H H H CH3
    85
    Figure US20030083523A1-20030501-C00087
    H H H H CH3
    86
    Figure US20030083523A1-20030501-C00088
    H H H H CH3
    87
    Figure US20030083523A1-20030501-C00089
    H H H H CH3
    88
    Figure US20030083523A1-20030501-C00090
    H H H H CH3
    89
    Figure US20030083523A1-20030501-C00091
    H H H H CH3
    90
    Figure US20030083523A1-20030501-C00092
    H H H H CH3
    91
    Figure US20030083523A1-20030501-C00093
    H H H H CH3
    92
    Figure US20030083523A1-20030501-C00094
    H H H H CH3
    93
    Figure US20030083523A1-20030501-C00095
    H H H H CH3
    94
    Figure US20030083523A1-20030501-C00096
    H H H H CH3
    95
    Figure US20030083523A1-20030501-C00097
    H H H H CH3
    96
    Figure US20030083523A1-20030501-C00098
    H H H H CH3
    97
    Figure US20030083523A1-20030501-C00099
    H H H H CH3
    98
    Figure US20030083523A1-20030501-C00100
    H H H H CH3
    99
    Figure US20030083523A1-20030501-C00101
    H H H H CH3
    100
    Figure US20030083523A1-20030501-C00102
    H H H H CH3
    101
    Figure US20030083523A1-20030501-C00103
    H H H H CH3
    102
    Figure US20030083523A1-20030501-C00104
    H H H H CH3
    103
    Figure US20030083523A1-20030501-C00105
    H H H H CH3
    104
    Figure US20030083523A1-20030501-C00106
    H H H H CH3
    105
    Figure US20030083523A1-20030501-C00107
    H H H H CH3
    106
    Figure US20030083523A1-20030501-C00108
    H H H H CH3
    107
    Figure US20030083523A1-20030501-C00109
    H H H H CH3
    108
    Figure US20030083523A1-20030501-C00110
    H H H H CH3
    109
    Figure US20030083523A1-20030501-C00111
    H H H H CH3
    110
    Figure US20030083523A1-20030501-C00112
    H H H H CH3
    111
    Figure US20030083523A1-20030501-C00113
    H H H H CH3
    112
    Figure US20030083523A1-20030501-C00114
    H H H H CH3
    113
    Figure US20030083523A1-20030501-C00115
    H H H H CH3
    114
    Figure US20030083523A1-20030501-C00116
    H H H H CH3
    115
    Figure US20030083523A1-20030501-C00117
    H H H H CH3
    116
    Figure US20030083523A1-20030501-C00118
    H H H H CH3
    117
    Figure US20030083523A1-20030501-C00119
    H H H H CH3
    118
    Figure US20030083523A1-20030501-C00120
    H H H H CH3
    119
    Figure US20030083523A1-20030501-C00121
    H H H H CH3
    120
    Figure US20030083523A1-20030501-C00122
    H H H H CH3
    121
    Figure US20030083523A1-20030501-C00123
    H H H H CH3
    122
    Figure US20030083523A1-20030501-C00124
    H H H H CH3
    123
    Figure US20030083523A1-20030501-C00125
    H H H H CH3
    124
    Figure US20030083523A1-20030501-C00126
    H H H H CH3
    125
    Figure US20030083523A1-20030501-C00127
    H H H H CH3
    126
    Figure US20030083523A1-20030501-C00128
    H H H H CH3
    127
    Figure US20030083523A1-20030501-C00129
    H H H H CH3
    128
    Figure US20030083523A1-20030501-C00130
    H H H H CH3
    129
    Figure US20030083523A1-20030501-C00131
    H H H H CH3
    130
    Figure US20030083523A1-20030501-C00132
    H H H H CH3
    131
    Figure US20030083523A1-20030501-C00133
    H H H H CH3
    132
    Figure US20030083523A1-20030501-C00134
    H H H H CH3
    133
    Figure US20030083523A1-20030501-C00135
    H H H H CH3
    134
    Figure US20030083523A1-20030501-C00136
    H H H H CH3
    135
    Figure US20030083523A1-20030501-C00137
    H H H H CH3
    136
    Figure US20030083523A1-20030501-C00138
    H H H H CH3
    137
    Figure US20030083523A1-20030501-C00139
    H H H H CH3
    138
    Figure US20030083523A1-20030501-C00140
    H H H H CH3
    139
    Figure US20030083523A1-20030501-C00141
    H H H H CH3
    140
    Figure US20030083523A1-20030501-C00142
    H H H H CH3
    141
    Figure US20030083523A1-20030501-C00143
    H H H H CH3
    142
    Figure US20030083523A1-20030501-C00144
    H H H H CH3
    143
    Figure US20030083523A1-20030501-C00145
    H H H H CH3
    144
    Figure US20030083523A1-20030501-C00146
    H H H H CH3
    145
    Figure US20030083523A1-20030501-C00147
    H H H H CH3
    146
    Figure US20030083523A1-20030501-C00148
    H H H H CH3
    147
    Figure US20030083523A1-20030501-C00149
    H H H H CH3
    148
    Figure US20030083523A1-20030501-C00150
    H H H H CH3
    149
    Figure US20030083523A1-20030501-C00151
    H H H H CH3
    150
    Figure US20030083523A1-20030501-C00152
    H H H H CH3
    151
    Figure US20030083523A1-20030501-C00153
    H H H H CH3
    152
    Figure US20030083523A1-20030501-C00154
    H H H H CH3
    153
    Figure US20030083523A1-20030501-C00155
    H H H H CH3
    154
    Figure US20030083523A1-20030501-C00156
    H H H H CH3
    155
    Figure US20030083523A1-20030501-C00157
    H H H H CH3
    156
    Figure US20030083523A1-20030501-C00158
    CH3 H H H CH3
    157
    Figure US20030083523A1-20030501-C00159
    CH3 CH3 H H CH3
    158
    Figure US20030083523A1-20030501-C00160
    H H H H CH3
    159
    Figure US20030083523A1-20030501-C00161
    H H H H CH3
    160
    Figure US20030083523A1-20030501-C00162
    H H H H CH3
    161
    Figure US20030083523A1-20030501-C00163
    H H H H CH3
    162
    Figure US20030083523A1-20030501-C00164
    H H H H CH3
    163
    Figure US20030083523A1-20030501-C00165
    H H H H CH3
    164
    Figure US20030083523A1-20030501-C00166
    H H H H CH3
    165
    Figure US20030083523A1-20030501-C00167
    H H H H CH3
    166
    Figure US20030083523A1-20030501-C00168
    H H H H CH3
    167
    Figure US20030083523A1-20030501-C00169
    H H H H CH3
    168
    Figure US20030083523A1-20030501-C00170
    H H H H CH3
    169
    Figure US20030083523A1-20030501-C00171
    H H H H CH3
    170
    Figure US20030083523A1-20030501-C00172
    H H H H CH3
    171
    Figure US20030083523A1-20030501-C00173
    H H H H CH3
    172
    Figure US20030083523A1-20030501-C00174
    H H H H CH3
    173
    Figure US20030083523A1-20030501-C00175
    H H H H CH3
    174
    Figure US20030083523A1-20030501-C00176
    H H H H CH3
    175
    Figure US20030083523A1-20030501-C00177
    H H H H CH3
    176
    Figure US20030083523A1-20030501-C00178
    H H H H CH3
    177
    Figure US20030083523A1-20030501-C00179
    H H H H CH3
    178
    Figure US20030083523A1-20030501-C00180
    H H H H CH3
    179
    Figure US20030083523A1-20030501-C00181
    H H H H CH3
    180
    Figure US20030083523A1-20030501-C00182
    H H H H CH3
    181
    Figure US20030083523A1-20030501-C00183
    H H H H CH3
    182
    Figure US20030083523A1-20030501-C00184
    H H H H CH3
    183
    Figure US20030083523A1-20030501-C00185
    H H H H CH3
    184
    Figure US20030083523A1-20030501-C00186
    H H H H CH3
    185
    Figure US20030083523A1-20030501-C00187
    H H H H CH3
    186
    Figure US20030083523A1-20030501-C00188
    H H H H CH3
    187
    Figure US20030083523A1-20030501-C00189
    H H H H CH3
    188
    Figure US20030083523A1-20030501-C00190
    H H H H CH3
    189
    Figure US20030083523A1-20030501-C00191
    H H H H CH3
    190
    Figure US20030083523A1-20030501-C00192
    H H H H CH3
    191
    Figure US20030083523A1-20030501-C00193
    H H H H CH3
    192
    Figure US20030083523A1-20030501-C00194
    H H H H CH3
    193
    Figure US20030083523A1-20030501-C00195
    H H H H CH3
    194
    Figure US20030083523A1-20030501-C00196
    H H H H CH3
    195
    Figure US20030083523A1-20030501-C00197
    H H H H CH3
    196
    Figure US20030083523A1-20030501-C00198
    H H H H CH3
    197
    Figure US20030083523A1-20030501-C00199
    H H H H CH3
    198
    Figure US20030083523A1-20030501-C00200
    H H H H CH3
    200
    Figure US20030083523A1-20030501-C00201
    H H H H CH3
    201
    Figure US20030083523A1-20030501-C00202
    H H H H CH3
    202
    Figure US20030083523A1-20030501-C00203
    H H H H CH3
    203
    Figure US20030083523A1-20030501-C00204
    H H H H CH3
    204
    Figure US20030083523A1-20030501-C00205
    H H H H CH3
    205
    Figure US20030083523A1-20030501-C00206
    H H H H CH3
    206
    Figure US20030083523A1-20030501-C00207
    H H H H CH3
    207
    Figure US20030083523A1-20030501-C00208
    H H H H CH3
    208
    Figure US20030083523A1-20030501-C00209
    H H H H CH3
    209
    Figure US20030083523A1-20030501-C00210
    H H H H CH3
    210
    Figure US20030083523A1-20030501-C00211
    H H H H CH3
    211
    Figure US20030083523A1-20030501-C00212
    H H H H CH3
    212
    Figure US20030083523A1-20030501-C00213
    H H H H CH3
    213
    Figure US20030083523A1-20030501-C00214
    H H H H CH3
    214
    Figure US20030083523A1-20030501-C00215
    H H H H CH3
    215
    Figure US20030083523A1-20030501-C00216
    H H H H CH3
    216
    Figure US20030083523A1-20030501-C00217
    H H H H CH3
    217
    Figure US20030083523A1-20030501-C00218
    H H H H CH3
    218
    Figure US20030083523A1-20030501-C00219
    H H H H CH3
    219
    Figure US20030083523A1-20030501-C00220
    H H H H CH3
    220
    Figure US20030083523A1-20030501-C00221
    H H H H CH3
    221
    Figure US20030083523A1-20030501-C00222
    H H H H CH3
    222
    Figure US20030083523A1-20030501-C00223
    H H H H CH3
    223
    Figure US20030083523A1-20030501-C00224
    H H H H CH3
    224
    Figure US20030083523A1-20030501-C00225
    H H H H CH3
    225
    Figure US20030083523A1-20030501-C00226
    H H H H CH3
    226
    Figure US20030083523A1-20030501-C00227
    H H H H CH3
    227
    Figure US20030083523A1-20030501-C00228
    H H H H CH3
    228
    Figure US20030083523A1-20030501-C00229
    H H H H CH3
    229
    Figure US20030083523A1-20030501-C00230
    H H H H CH3
    230
    Figure US20030083523A1-20030501-C00231
    H H H H CH3
    231
    Figure US20030083523A1-20030501-C00232
    H H H H CH3
    232
    Figure US20030083523A1-20030501-C00233
    H H H H CH3
    233
    Figure US20030083523A1-20030501-C00234
    H H H H CH3
    234
    Figure US20030083523A1-20030501-C00235
    H H H H CH3
    235
    Figure US20030083523A1-20030501-C00236
    H H H H CH3
    236
    Figure US20030083523A1-20030501-C00237
    H H H H CH3
    237
    Figure US20030083523A1-20030501-C00238
    H H H H CH3
    238
    Figure US20030083523A1-20030501-C00239
    H H H H CH3
    239
    Figure US20030083523A1-20030501-C00240
    H H H H CH3
    240
    Figure US20030083523A1-20030501-C00241
    H H H H CH3
    241
    Figure US20030083523A1-20030501-C00242
    H H H H CH3
    242
    Figure US20030083523A1-20030501-C00243
    H H H H CH3
    243
    Figure US20030083523A1-20030501-C00244
    H H H H CH3
    244
    Figure US20030083523A1-20030501-C00245
    H H H H CH3
    245
    Figure US20030083523A1-20030501-C00246
    H H H H CH3
    246
    Figure US20030083523A1-20030501-C00247
    H H H H CH3
    247
    Figure US20030083523A1-20030501-C00248
    H H H H CH3
    248
    Figure US20030083523A1-20030501-C00249
    H H H H CH3
    249
    Figure US20030083523A1-20030501-C00250
    H H H H CH3
    250
    Figure US20030083523A1-20030501-C00251
    H H H H CH3
    251
    Figure US20030083523A1-20030501-C00252
    H H H H CH3
    252
    Figure US20030083523A1-20030501-C00253
    H H H H CH3
  • Examples of specific examples of the amide derivatives of the present invention represented by the above general formula (I) wherein X is R[0065] 7A-, include those listed in Table 2.
    TABLE 2
    Compd.
    No. R7 A Y R4 R5 R6
     1 CH3 O O H H CH3
     2 NH O
     3  4  5  6
    Figure US20030083523A1-20030501-C00254
    O O NH NH O S O S H H CH3
     7  8
    Figure US20030083523A1-20030501-C00255
    O NH O O H H H
     9  10
    Figure US20030083523A1-20030501-C00256
    O NH O O H CH3 CH3
     11  12
    Figure US20030083523A1-20030501-C00257
    O NH O O H H CH2CH3
     13  14
    Figure US20030083523A1-20030501-C00258
    O NH O O H H CH2CH2CH3
     15  16
    Figure US20030083523A1-20030501-C00259
    O NH O O CH3 H CH3
     17  18
    Figure US20030083523A1-20030501-C00260
    O NH O O H H CH3
     19  20
    Figure US20030083523A1-20030501-C00261
    O NH O O H H CH3
     21  22
    Figure US20030083523A1-20030501-C00262
    O NH O O H H CH3
     23  24
    Figure US20030083523A1-20030501-C00263
    O NH O O H H CH3
     25  26
    Figure US20030083523A1-20030501-C00264
    O NH O O H H CH3
     27  28
    Figure US20030083523A1-20030501-C00265
    O NH O O H H CH3
     29  30
    Figure US20030083523A1-20030501-C00266
    O NH O O H H CH3
     31  32
    Figure US20030083523A1-20030501-C00267
    O NH O O H H CH3
     33  34
    Figure US20030083523A1-20030501-C00268
    O NH O O H H CH3
     35  36
    Figure US20030083523A1-20030501-C00269
    O NH O O H H CH3
     37  38
    Figure US20030083523A1-20030501-C00270
    O NH O O H H CH3
     39  40
    Figure US20030083523A1-20030501-C00271
    O NH O O H H CH3
     41  42
    Figure US20030083523A1-20030501-C00272
    O NH O O H H CH3
     43  44
    Figure US20030083523A1-20030501-C00273
    O NH O O H H CH3
     45  46
    Figure US20030083523A1-20030501-C00274
    O NH O O H H CH3
     47  48
    Figure US20030083523A1-20030501-C00275
    O NH O O H H CH3
     49  50
    Figure US20030083523A1-20030501-C00276
    O NH O O H H CH3
     51  52
    Figure US20030083523A1-20030501-C00277
    O NH O O H H CH3
     53  54
    Figure US20030083523A1-20030501-C00278
    O NH O O H H CH3
     55  56
    Figure US20030083523A1-20030501-C00279
    O NH O O H H CH3
     57  58
    Figure US20030083523A1-20030501-C00280
    O NH O O H H CH3
     59  60
    Figure US20030083523A1-20030501-C00281
    O NH O O H H CH3
     61  62
    Figure US20030083523A1-20030501-C00282
    O NH O O H H CH3
     63  64
    Figure US20030083523A1-20030501-C00283
    O NH O O H H CH3
     65  66
    Figure US20030083523A1-20030501-C00284
    O NH O O H H CH3
     67  68
    Figure US20030083523A1-20030501-C00285
    O NH O O H H CH3
     69  70
    Figure US20030083523A1-20030501-C00286
    O NH O O H H CH3
     71  72
    Figure US20030083523A1-20030501-C00287
    O NH O O H H CH3
     73  74
    Figure US20030083523A1-20030501-C00288
    O NH O O H H CH3
     75  76
    Figure US20030083523A1-20030501-C00289
    O NH O O H H CH3
     77  78
    Figure US20030083523A1-20030501-C00290
    O NH O O H H CH3
     79  80
    Figure US20030083523A1-20030501-C00291
    O NH O O H H CH3
     81  82
    Figure US20030083523A1-20030501-C00292
    O NH O O H H CH3
     83  84
    Figure US20030083523A1-20030501-C00293
    O NH O O H H CH3
     85  86
    Figure US20030083523A1-20030501-C00294
    O NH O O H H CH3
     87  88
    Figure US20030083523A1-20030501-C00295
    O NH O O H H CH3
     89  90
    Figure US20030083523A1-20030501-C00296
    O NH O O H H CH3
     91  92
    Figure US20030083523A1-20030501-C00297
    O NH O O H H CH3
     93  94
    Figure US20030083523A1-20030501-C00298
    O NH O O H H CH3
     95  96
    Figure US20030083523A1-20030501-C00299
    O NH O O H H CH3
     97  98
    Figure US20030083523A1-20030501-C00300
    O NH O O H H CH3
     99 100
    Figure US20030083523A1-20030501-C00301
    O NH O O H H CH3
    101 102
    Figure US20030083523A1-20030501-C00302
    O NH O O H H CH3
    103 104
    Figure US20030083523A1-20030501-C00303
    O NH O O H H CH3
    105 106
    Figure US20030083523A1-20030501-C00304
    O NH O O H H CH3
    107 108
    Figure US20030083523A1-20030501-C00305
    O NH O O H H CH3
    109 110
    Figure US20030083523A1-20030501-C00306
    O NH O O H H CH3
    111 112
    Figure US20030083523A1-20030501-C00307
    O NH O O H H CH3
    113 114
    Figure US20030083523A1-20030501-C00308
    O NH O O H H CH3
    115 116
    Figure US20030083523A1-20030501-C00309
    O NH O O H H CH3
    117 118
    Figure US20030083523A1-20030501-C00310
    O NH O O H H CH3
    119 120
    Figure US20030083523A1-20030501-C00311
    O NH O O H H CH3
    121 122
    Figure US20030083523A1-20030501-C00312
    O NH O O H H CH3
    123 124
    Figure US20030083523A1-20030501-C00313
    O NH O O H H CH3
    125 126
    Figure US20030083523A1-20030501-C00314
    O NH O O H H CH3
    127 128
    Figure US20030083523A1-20030501-C00315
    O NH O O H H CH3
    129 130
    Figure US20030083523A1-20030501-C00316
    O NH O O H H CH3
    131 132
    Figure US20030083523A1-20030501-C00317
    O NH O O H H CH3
    133 134
    Figure US20030083523A1-20030501-C00318
    O NH O O H H CH3
    135 136
    Figure US20030083523A1-20030501-C00319
    O NH O O H H CH3
    137 138
    Figure US20030083523A1-20030501-C00320
    O NH O O H H CH3
    139 140
    Figure US20030083523A1-20030501-C00321
    O NH O O H H CH3
    141 CH3CH2 O O H H CH3
    142 NH O
    143 144
    Figure US20030083523A1-20030501-C00322
    O NH O O H H CH3
    145 146
    Figure US20030083523A1-20030501-C00323
    O NH O O H H CH3
    147 148
    Figure US20030083523A1-20030501-C00324
    O NH O O H H CH3
    149 150
    Figure US20030083523A1-20030501-C00325
    O NH O O H H CH3
    151 152
    Figure US20030083523A1-20030501-C00326
    O NH O O H H CH3
    153 154
    Figure US20030083523A1-20030501-C00327
    O NH O O H H CH3
    155 156
    Figure US20030083523A1-20030501-C00328
    O NH O O H H CH3
    157 158
    Figure US20030083523A1-20030501-C00329
    O NH O O H H CH3
    159 160
    Figure US20030083523A1-20030501-C00330
    O NH O O H H CH3
    161 162
    Figure US20030083523A1-20030501-C00331
    O NH O O H H CH3
    163 164
    Figure US20030083523A1-20030501-C00332
    O NH O O H H CH3
    165 166
    Figure US20030083523A1-20030501-C00333
    O NH O O H H CH3
    167 168
    Figure US20030083523A1-20030501-C00334
    O NH O O H H CH3
    169 170
    Figure US20030083523A1-20030501-C00335
    O NH O O H H CH3
    171 172
    Figure US20030083523A1-20030501-C00336
    O NH O O H H CH3
    173 174
    Figure US20030083523A1-20030501-C00337
    O NH O O H H CH3
    175 176
    Figure US20030083523A1-20030501-C00338
    O NH O O H H CH3
    177 178
    Figure US20030083523A1-20030501-C00339
    O NH O O H H CH3
    179 180
    Figure US20030083523A1-20030501-C00340
    O NH O O H H CH3
    181 182 183 184 185 186
    Figure US20030083523A1-20030501-C00341
    O NH NCH3O NH NCH3 O O O S S S H H CH3
    187 188
    Figure US20030083523A1-20030501-C00342
    O NH O O H H H
    189 190
    Figure US20030083523A1-20030501-C00343
    O NH O O H CH3 CH3
    191 192
    Figure US20030083523A1-20030501-C00344
    O NH O O H H CH2CH3
    193 194
    Figure US20030083523A1-20030501-C00345
    O NH O O H H CH2CH2CH3
    195 196
    Figure US20030083523A1-20030501-C00346
    O NH O O CH3 H CH3
    197 198
    Figure US20030083523A1-20030501-C00347
    O NH O O H H CH3
    199 200
    Figure US20030083523A1-20030501-C00348
    O NH O O H H CH3
    201 202
    Figure US20030083523A1-20030501-C00349
    O NH O O H H CH3
    203 204
    Figure US20030083523A1-20030501-C00350
    O NH O O H H CH3
    205 206
    Figure US20030083523A1-20030501-C00351
    O NH O O H H CH3
    207 208
    Figure US20030083523A1-20030501-C00352
    O NH O O H H CH3
    209 210
    Figure US20030083523A1-20030501-C00353
    O NH O O H H CH3
    211 212
    Figure US20030083523A1-20030501-C00354
    O NH O O H H CH3
    213 214
    Figure US20030083523A1-20030501-C00355
    O NH O O H H CH3
    215 216
    Figure US20030083523A1-20030501-C00356
    O NH O O H H CH3
    217 218
    Figure US20030083523A1-20030501-C00357
    O NH O O H H CH3
    219 220
    Figure US20030083523A1-20030501-C00358
    O NH O O H H CH3
    221 222
    Figure US20030083523A1-20030501-C00359
    O NH O O H H CH3
    223 224
    Figure US20030083523A1-20030501-C00360
    O NH O O H H CH3
    225 226
    Figure US20030083523A1-20030501-C00361
    O NH O O H H CH3
    227 228
    Figure US20030083523A1-20030501-C00362
    O NH O O H H CH3
    229 230
    Figure US20030083523A1-20030501-C00363
    O NH O O H H CH3
    231 232
    Figure US20030083523A1-20030501-C00364
    O NH O O H H CH3
    233 234
    Figure US20030083523A1-20030501-C00365
    O NH O O H H CH3
    235 236
    Figure US20030083523A1-20030501-C00366
    O NH O O H H CH3
    237 238
    Figure US20030083523A1-20030501-C00367
    O NH O O H H CH3
    239 240
    Figure US20030083523A1-20030501-C00368
    O NH O O H H CH3
  • The amide derivatives of the present invention represented by the above general formula (I) wherein X is R[0066] 1(R2)(R3)C-, and Y is an oxygen atom, can be prepared by, for example, the method explained below.
    Figure US20030083523A1-20030501-C00369
  • wherein R[0067] 1, R2, R3, R4, R5 and R6 are the same as those defined above.
  • 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. [0068]
  • 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. [0069]
  • The amide derivatives of the present invention represented by the above general formula (I) wherein X is R[0070] 7-A-, can be prepared by, for example, the method explained below.
    Figure US20030083523A1-20030501-C00370
  • wherein R[0071] 7, R4, R5, and R6 are the same as those defined above.
  • 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. [0072]
    Figure US20030083523A1-20030501-C00371
  • wherein R[0073] 7, R4, R5, R6 and Y are the same as those defined above.
  • 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. [0074]
  • 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. [0075]
  • The compounds of the present invention represented by the above general formula (I) have excellent antibacterial activity against [0076] 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.
  • 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. [0077]
  • 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. [0078]
  • 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. [0079]
  • 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.[0080]
  • EXAMPLES
  • 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. [0081]
  • Example 1 Preparation of N-(3-methylcarbamoylphenyl)-3-chlorophenylacetamide (Compound No. 17 in Table 1)
  • 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%). [0082]
  • Melting point: 165-166° C. [0083]
  • IR (KBr, cm[0084] −1): 3324, 1642, 1593, 1555.
  • NMR DMSO-d[0085] 6, δ): 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).
  • In similar manners to the method of Example 1, compounds of Examples 2-50 were prepared. Their physicochemical properties are set out below. [0086]
  • Example 2 Preparation of N-(3-methylcarbamoylphenyl)cyclohexylacetamide (Compound No. 4 in Table 1)
  • Melting point: 183° C. [0087]
  • IR (KBr, cm[0088] −1): 3293, 1657, 1640, 1588, 1535.
  • NMR (DMSO-d[0089] 6, δ): 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)
  • Melting point: 140-142° C. [0090]
  • NMR (DMSO-d[0091] 6, δ): 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)
  • Melting point: 147° C. [0092]
  • IR (KBr, cm[0093] −1): 3339, 3275, 1638, 1586, 1557, 1528.
  • NMR (DMSO-d[0094] 6, δ): 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)
  • Melting point: 147-148° C. [0095]
  • IR (KBr, cm[0096] −1): 3314, 1661, 1636, 1587, 1530.
  • NMR (DMSO-d[0097] 6, δ): 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)
  • Melting point: 155-156° C. [0098]
  • IR (KBr, cm[0099] −1): 3293, 1657, 1634, 1588, 1535, 1512.
  • NMR (DMSO-d[0100] 6, δ): 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)
  • Melting point: 211-212° C. [0101]
  • IR (KBr, cm[0102] −1): 3268, 1659, 1642, 1586, 1535.
  • NMR (DMSO-d[0103] 6, δ): 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)
  • Melting point: 163-164° C. [0104]
  • IR (KBr, cm[0105] −1): 3279, 1663, 1640, 1588, 1535.
  • NMR (DMSO-d[0106] 6, δ): 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)
  • Melting point: 202° C. [0107]
  • IR (KBr, cm[0108] −1): 3378, 3295, 1659, 1624, 1586, 1534.
  • NMR (DMSO-d[0109] 6, δ): 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)
  • Melting point: 176-178° C. [0110]
  • IR (KBr, cm[0111] −1): 3324, 3254, 1642, 1591, 1554.
  • NMR (DMSO-d[0112] 6, δ): 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)
  • Melting point: 119-120° C. [0113]
  • IR (KBr, cm[0114] −1): 1678, 1613, 1588, 1557.
  • NMR (DMSO-d[0115] 6, δ): 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)
  • Melting point: 155° C. [0116]
  • IR (KBr, cm[0117] −1): 3329, 3268, 1665, 1640, 1549.
  • NMR (DMSO-d[0118] 6, δ): 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)
  • Melting point: 202° C. [0119]
  • IR (KBr, cm[0120] −1): 3407, 3358, 3279, 1671, 1640, 1589, 1539.
  • NMR (DMSO-d[0121] 6, δ): 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)
  • Melting point: 184-186° C. (decomposition) [0122]
  • IR (KBr, cm[0123] −1): 3314, 3231, 1663, 1632, 1582, 1535.
  • NMR (DMSO-d[0124] 6, δ): 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)
  • Melting point: 166° C. [0125]
  • IR (KBr, cm[0126] −1): 3299, 3187, 1659, 1611, 1595, 1560.
  • NMR (DMSO-d[0127] 6, δ): 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)
  • Melting point: 165-166° C. [0128]
  • IR (KBr, cm[0129] −1): 3283, 1665, 1642, 1588, 1534.
  • NMR (DMSO-d[0130] 6, δ): 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)
  • Melting point: 131° C. [0131]
  • IR (KBr, cm[0132] −1): 3299, 1659, 1634, 1586, 1530.
  • NMR (DMSO-d[0133] 6, δ): 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)
  • Melting point: 174-175° C. [0134]
  • IR (KBr, cm[0135] −1): 3339, 3296, 1659, 1639, 1586, 1528.
  • NMR (DMSO-d[0136] 6, δ): 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)
  • Melting point: 104-106° C. [0137]
  • NMR (DMSO-d[0138] 6, δ): 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)
  • Melting point: 155-157° C. [0139]
  • NMR (DMSO-[0140] 6, δ): 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)
  • NMR (DMSO-d[0141] 6, δ): 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)
  • Melting point: 146-147° C. [0142]
  • IR (KBr, cm[0143] −1): 3341, 3246, 1667, 1638, 1589, 1547.
  • NMR (DMSO-d[0144] 6, δ): 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)
  • Melting point; 81-82° C. [0145]
  • IR (KBr, cm[0146] −1): 3304, 1642, 1589, 1554, 1508.
  • NMR (DMSO-d[0147] 6, δ): 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)
  • Melting point; 150° C. [0148]
  • IR (KBr, cm[0149] −1): 3302, 1661, 1634, 1586, 1530.
  • NMR (DMSO-d[0150] 6, δ): 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)
  • Melting point; 188-189° C. [0151]
  • NMR (DMSO-d[0152] 6, δ): 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)
  • Melting point; 163° C. [0153]
  • IR (KBr, cm[0154] −1): 3333, 3293, 1676, 1640, 1588, 1562.
  • NMR (DMSO-d[0155] 6, δ): 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)
  • Melting point; 195-196° C. [0156]
  • IR (KBr, cm[0157] −1): 3393, 3283, 1661, 1638, 1541, 1518.
  • NMR (DMSO-d[0158] 6, δ): 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-nitrophenylacetamide (Compound No. 74 in Table 1)
  • Melting point 139° C. [0159]
  • IR (KBr, cm[0160] −1): 3322, 3250, 1665, 1640, 1666, 1524.
  • NMR (DMSO-d[0161] 6, δ): 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)
  • Melting point: 148-151° C. [0162]
  • IR (KBr, cm[0163] −1): 3277, 1663, 1640, 1588, 1522.
  • NMR (DMSO-d[0164] 6, δ): 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)
  • Melting point; 201-202° C. [0165]
  • IR (KBr, cm[0166] −1): 3274, 1657, 1640, 1588, 1532.
  • NMR (DMSO-d[0167] 6, δ): 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)
  • Melting point: 175-176° C. [0168]
  • IR (KBr, cm[0169] −1): 3393, 1655, 1634, 1588, 1530.
  • NMR (DMSO-d[0170] 6, δ): 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)
  • Melting point: 168-169° C. [0171]
  • IR (KBr, cm[0172] −1): 3382, 3287, 1655, 1636, 1588, 1555, 1528.
  • NMR (DMSO-d[0173] 6, δ): 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)
  • Melting point; 194° C. [0174]
  • IR (KBr, cm[0175] −1): 3285, 1663, 1636, 1588, 1532.
  • NMR (DMSO-d[0176] 6, δ): 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)
  • Melting point: 192° C. [0177]
  • IR (KBr, cm[0178] −1): 3295, 1676, 1632, 1595, 1559.
  • NMR (DMSO-d[0179] 6, δ): 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-benzofuranylacetamide (Compound No. 157 in Table 1)
  • Melting point; 92-93° C. [0180]
  • IR (KBr, cm[0181] −1): 3289, 1665, 1611, 1589, 1555
  • NMR (DMSO-[0182] 6, δ): 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-acetamide (Compound No. 159 in Table 1)
  • Melting point: 174-175° C. [0183]
  • IR (KBr, cm[0184] −1): 3337, 3291, 1659, 1634, 1586, 1530, 1505.
  • NMR (DMSO-d[0185] 6, δ): 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)
  • Melting point: 131° C. [0186]
  • IR (KBR, cm[0187] −1): 3378, 3283, 1669, 1640, 1588, 1535.
  • NMR DMSO-d[0188] 6, δ): 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)
  • Melting point: 172-173° C. [0189]
  • IR KBr, cm[0190] −1): 3385, 3297, 1688, 1640, 1591, 1549.
  • NMR (DMSO-d[0191] 6, δ): 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)
  • Melting point: 148° C. [0192]
  • IR (KBr, cm[0193] −1): 3399, 3285, 1696, 1640, 1547.
  • NMR (DMSO-d[0194] 6, δ): 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)
  • Melting point: 133° C. [0195]
  • IR (KBr, cm[0196] −1): 3385, 3268, 1690, 1638, 1591, 1547.
  • NMR (DMSO-d[0197] 6, δ): 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)
  • Melting point: 194° C. [0198]
  • IR (KBr, cm[0199] −1): 3405, 3304, 1696, 1638, 1541.
  • NMR (DMSO-d[0200] 6, δ): 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)
  • Melting point: 174° C. [0201]
  • IR (KBr, cm[0202] −1): 3382, 3275, 1672, 1638, 1588, 1557, 1534.
  • NMR (DMSO-d[0203] 6, δ): 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)
  • Melting point: 192-193° C. [0204]
  • IR (KBr, cm[0205] −1): 3385, 3291, 1692, 1644, 1547.
  • NMR (DMSO-d[0206] 6, δ): 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)
  • Melting point: 230-231° C. [0207]
  • IR (KBr, cm[0208] −1): 3299, 3071, 1684, 1638, 1589, 1560.
  • NMR (DMSO-d[0209] 6, δ): 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)
  • Melting point: 229-230° C. [0210]
  • IR (KBr, cm[0211] −1): 3310, 1686, 1613, 1582, 1561.
  • NMR (DMSO-d[0212] 6, δ): 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)
  • Melting point: 142-143° C. [0213]
  • IR (KBr, cm[0214] −1): 3295, 1657, 1613, 1593, 1545.
  • NMR (DMSO-d[0215] 6, δ): 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)
  • Melting point: 131° C. [0216]
  • IR (KBr, cm[0217] −1): 3289, 1674, 1640, 1555.
  • NMR (DMSO-d[0218] 6, δ): 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)
  • Melting point: 158° C. [0219]
  • IR (KBr, cm[0220] −1): 3424, 3285, 1647, 1553.
  • NMR (DMSO-d[0221] 6, δ): 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)
  • Melting point: 150° C. [0222]
  • IR (KBr, cm[0223] −1): 3297, 1658, 1644, 1550.
  • NMR (DMSO-d[0224] 6, δ): 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)
  • Melting point: 151-152° C. [0225]
  • IR (KBr, cm[0226] −1): 3289, 1669, 1634, 1613, 1557, 1514.
  • NMR (DMSO-d[0227] 6, δ): 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)
  • 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. [0228]
  • 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%). [0229]
  • Melting Point: 167-168° C. [0230]
  • IR(KBr,cm[0231] −1): 3322,1738,1622,1557.
  • NMR(DMSO-d[0232] 6, δ): 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).
  • 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. [0233]
  • Example 52 Preparation of N′-methyl-3-(2-fluorobenzyloxycarbonylamino)benzamide (Compound No.17 in Table 2)
  • Melting Point: 189-190° C. [0234]
  • IR(KBr,cm[0235] −1): 3341,3291,1730,1622,1557.
  • NMR(DMSO-d[0236] 6, δ): 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)
  • Melting Point; 153° C. [0237]
  • IR(KBr,cm[0238] −1): 3304,1732,1626,1613,1559.
  • NMR(DMSO-d[0239] 6, δ): 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)
  • Melting Point: 168° C. [0240]
  • IR(KBr,cm[0241] −1): 3329,3289,1728,1622,1559.
  • NMR(DMSO-d[0242] 6, δ): 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)
  • Melting Point: 155-156° C. [0243]
  • IR(KBr,cm[0244] −1): 3351,3299,1734,1624,1557.
  • NMR(DMSO-d[0245] 6, δ): 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)
  • Melting Point: 167-168° C. [0246]
  • IR(KBr,cm[0247] −1): 3401,3258,1744,1711,1649,1561.
  • NMR(DMSO-d[0248] 6, δ): 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)
  • Melting Point: 219-220° C. [0249]
  • IR(KBr,cm[0250] −1): 3380,3241,1717,1651,1562.
  • NMR(DMSO-d[0251] 6, δ): 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)
  • Melting Point: 163-164° C. [0252]
  • IR(KBr,cm[0253] −1): 3324,1728,1622,1559.
  • NMR(DMSO-d[0254] 6, δ): 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)
  • Melting Point: 163° C. [0255]
  • IR(KBr,cm[0256] −1): 3358,3312,1734,1622,1557.
  • NMR(DMSO-d[0257] 6, δ): 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)
  • Melting Point: 155° C. [0258]
  • IR(KBr,cm[0259] −1): 3343,3279,1736,1624,1559.
  • NMR(DMSO-d[0260] 6, δ): 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)
  • Melting Point: 189-190° C. [0261]
  • IR(KBr,cm[0262] −1); 3380,3235,1709,1647,1561.
  • NMR(DMSO-d[0263] 6, δ): 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)
  • Melting Point: 173° C. [0264]
  • IR(KBr,cm[0265] −1): 3341,3266,1726,1624,1561.
  • NMR(DMSO-d[0266] 6, δ): 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)
  • Melting Point: 158-159° C. [0267]
  • IR(KBr,cm[0268] −1): 3331,3295,1730,1613,1555.
  • NMR(DMSO-d[0269] 6, δ): 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)benzamide (Compound No.77 in Table 2)
  • Melting Point: 193° C. [0270]
  • IR(KBr,cm[0271] −1): 3366,3248,1717,1624,1662,1537.
  • NMR(DMSO-d[0272] 6, δ): 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)
  • Melting Point: 228-229° C. [0273]
  • IR(KBr,cm[0274] −1): 3353,3285,1730,1626,1555.
  • NMR(DMSO-d[0275] 6, δ): 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)
  • Melting Point: 157-158° C. [0276]
  • IR(KBr,cm[0277] −1): 3314,1699,1642,1589,1539.
  • NMR(DMSO-d[0278] 6, δ): 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)
  • Melting Point: 217° C. [0279]
  • IR(KBr,cm[0280] −1): 3349,3289,1730,1624,1586,1557.
  • NMR(DMSO-d[0281] 6, δ): 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)
  • Melting Point: 193° C. [0282]
  • IR(KBr,cm[0283] −1): 3401,3268,1753,1624,1555.
  • NMR(DMSO-d[0284] 6, δ): 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)
  • 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%). [0285]
  • Melting Point: 209-210° C. [0286]
  • IR(KBr,cm[0287] −1): 3328,3279,1699,1626,1557.
  • NMR(DMSO-d[0288] 6, δ): 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).
  • 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. [0289]
  • Example 70 Preparation of 3-benzyl-1-(3-methylcarbamoylphenyl)urea(Compound No.5 in Table 2)
  • Melting Point: 189-190° C. [0290]
  • IR(KBr,cm[0291] −1): 3366,3333,1640,1559.
  • NMR(DMSO-d[0292] 6, δ): 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)
  • Melting Point: 199° C. [0293]
  • IR(KBr,cm[0294] −1): 3343,2246,3069,1630,1584,1528
  • NMR(DMSO-d[0295] 6, δ): 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)
  • Melting Point: 207° C. [0296]
  • IR(KBr,cm[0297] −1): 3362,1734,1636,1591,1533.
  • NMR(DMSO-d[0298] 6, δ): 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
  • 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 [0299] 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° C. for 48 hours with shaking.
  • 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° C. for 48 hours with shaking, and then growth of [0300] 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.
    TABLE 3
    Example No.
    (Compound No. in Table 1) MIC (μg/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]
    TABLE 4
    Example No.
    (Compound No. in Table 2) MIC (μg/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
  • According to a similar method to that of Test Example 1, inhibitory activity of the compound of the present invention against [0302] Campylobacter jejuni was determined. As a result, MIC of the compound of Example 31 was 0.008 μg/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
  • 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[0303] 50 values of the compounds of Examples 30 and 31 was not lower than 2,000 mg/kg.
  • Formulation Examples
  • (1) Tablet [0304]
  • The following ingredients were mixed according to a conventional method, and compressed to obtain a tablet by using a conventional apparatus. [0305]
    Compound of Example 31 100 mg
    Crystalline cellulose 180 mg
    Corn starch 300 mg
    Lactose 600 mg
    Magnesium stearate  15 mg
  • (2) Soft capsule [0306]
  • The following ingredients were mixed according to a conventional method, and filled in a soft capsule. [0307]
    Compound of Example 41 100 mg
    Olive oil 900 mg
    Lecithin  60 mg
  • Industrial Applicability [0308]
  • The amide derivatives of the present invention have potent antibacterial activity against [0309] Helicobacter pylori, and therefore, they are useful as an active ingredient of medicaments.

Claims (35)

What is claimed is:
1. A compound represented by the following general formula (I):
Figure US20030083523A1-20030501-C00372
wherein X represents R1(R2)(R3)C- where R1 represents a C3-C8 cycloakyl group, an optionally substituted C5-C14 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 C6-C14 aryloxy group, or an optionally substituted C7-C15 arylmethyl group; R2 and R3 independently represent hydrogen atom or a C1-C5 alkyl group, or R2 and R3 may combine to represent a C2-C7 alkylene group; or
X represents R7-A- wherein R7 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-R8 where R8 represents hydrogen atom or a C1-C5 alkyl group,
Y represents an oxygen atom or a sulfur atom,
R4 and R5 independently represent hydrogen atom or a C1-C5 alkyl group; and R6 represents hydrogen atom, a C1-C5 alkyl group which may optionally be substituted with a hydroxyl group, a hydroxyl group or a C1-C5 alkoxy group,
provided that the compounds wherein R7 is a benzyl group, A and Y are an oxygen atom, R4 and R6 are hydrogen atom, and R6 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 R4 is hydrogen atom.
3. The compound according to claim 1 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R5 is hydrogen atom.
4. The compound according to claim 3 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R6 is a C1-C5 alkyl group.
5. The compound according to claim 4 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R6 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 R1(R2)(R3)C-.
8. The compound according to claim 7 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R2 and R3 are hydrogen atoms.
9. The compound according to claim 7 or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R1 is a C6-C14 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 R1 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 R1 is a C6-C14 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 R1 is a C7-C15 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 R7-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 R7 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 R7 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 R7 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 R7 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 R7 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-methylcarbamoylphenyl)-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.
US10/173,076 1997-06-25 2002-06-18 Amide derivatives Abandoned US20030083523A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP9-168484 1997-06-25
JP16848497 1997-06-25
US10350098A true 1998-06-24 1998-06-24
US09/469,354 US6444849B1 (en) 1997-06-25 1999-12-22 Amide derivatives
US10/173,076 US20030083523A1 (en) 1997-06-25 2002-06-18 Amide derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10/173,076 US20030083523A1 (en) 1997-06-25 2002-06-18 Amide derivatives

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/469,354 Division US6444849B1 (en) 1997-06-25 1999-12-22 Amide derivatives

Publications (1)

Publication Number Publication Date
US20030083523A1 true US20030083523A1 (en) 2003-05-01

Family

ID=26492175

Family Applications (2)

Application Number Title Priority Date Filing Date
US09/469,354 Expired - Fee Related US6444849B1 (en) 1997-06-25 1999-12-22 Amide derivatives
US10/173,076 Abandoned US20030083523A1 (en) 1997-06-25 2002-06-18 Amide derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09/469,354 Expired - Fee Related US6444849B1 (en) 1997-06-25 1999-12-22 Amide derivatives

Country Status (1)

Country Link
US (2) US6444849B1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9334425B2 (en) 2009-03-30 2016-05-10 Avery Dennison Corporation Removable adhesive label containing high tensile modulus polymeric film layer
US9387652B2 (en) 2005-01-10 2016-07-12 Avery Dennison Corporation Removable curl labels
US9422465B2 (en) 2006-11-02 2016-08-23 Avery Dennison Corporation Emulsion adhesive for washable film
US10002549B2 (en) 2009-03-30 2018-06-19 Avery Dennison Corporation Removable adhesive label containing polymeric film layer having water affinity
US10157554B2 (en) 2009-03-30 2018-12-18 Avery Dennison Corporation Removable adhesive label containing inherently shrinkable polymeric film

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060264672A1 (en) * 2005-02-23 2006-11-23 Andrews Mark A Processes using alpha, omega-difunctional aldaramides as monomers and crosslinkers
CA2856037C (en) * 2005-12-28 2017-03-07 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US7671221B2 (en) * 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
KR100787131B1 (en) * 2006-07-04 2007-12-21 한국생명공학연구원 Compounds that inhibit hif-1 activity the method for preparation thereof and the pharmaceutical composition containing them as an effective component
KR100786336B1 (en) * 2007-10-30 2007-12-14 한국생명공학연구원 Compounds that inhibit hif-1 activity the method for preparation thereof and the pharmaceutical composition containing them as an effective component
WO2011048004A1 (en) * 2009-10-23 2011-04-28 Boehringer Ingelheim International Gmbh Inhibitors of the microsomal prostaglandin e2 synthase-1
TW201740943A (en) 2016-05-11 2017-12-01 Huya Bioscience International Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS577455A (en) 1980-06-13 1982-01-14 Kyoto Yakuhin Kogyo Kk Novel benzamide derivative and analgesic containing the same
DE3373810D1 (en) 1982-07-27 1987-10-29 Sumitomo Chemical Co fungicidal anilides
JPS6152140B2 (en) 1982-12-24 1986-11-12 Kanesho Kk
JPS61140556A (en) * 1984-12-11 1986-06-27 Sumitomo Seiyaku Kk Novel arylacetanilide derivative
US5280014A (en) * 1988-01-11 1994-01-18 Amylin Pharmaceuticals, Inc. Treatment of obesity and essential hypertension and related disorders
US5039805A (en) 1988-12-08 1991-08-13 Hoffmann-La Roche Inc. Novel benzoic and phenylacetic acid derivatives
IE62559B1 (en) 1989-02-02 1995-02-08 Ici Plc Fungicides
CZ267695A3 (en) 1993-04-15 1996-04-17 Glaxo Wellcome Inc 1,5-benzodiazepine derivatives, process of their preparation, their use and pharmaceutical preparations containing thereof
JP3490146B2 (en) 1994-06-27 2004-01-26 ユーシービージャパン株式会社 Anti-Helicobacter pylori agent
WO1997004770A1 (en) 1995-07-31 1997-02-13 Merck & Co., Inc. 2-(fluorenonyl)-carbapenems, compositions and methods of use
GB9519077D0 (en) 1995-09-18 1995-11-15 Fujisawa Pharmaceutical Co New heterocyclic compounds
KR19990082330A (en) 1996-02-06 1999-11-25 미즈노 마사루 Novel compounds and uses thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9387652B2 (en) 2005-01-10 2016-07-12 Avery Dennison Corporation Removable curl labels
US9422465B2 (en) 2006-11-02 2016-08-23 Avery Dennison Corporation Emulsion adhesive for washable film
US9334425B2 (en) 2009-03-30 2016-05-10 Avery Dennison Corporation Removable adhesive label containing high tensile modulus polymeric film layer
US10002549B2 (en) 2009-03-30 2018-06-19 Avery Dennison Corporation Removable adhesive label containing polymeric film layer having water affinity
US10157554B2 (en) 2009-03-30 2018-12-18 Avery Dennison Corporation Removable adhesive label containing inherently shrinkable polymeric film

Also Published As

Publication number Publication date
US6444849B1 (en) 2002-09-03

Similar Documents

Publication Publication Date Title
EP0432040B1 (en) Heterocyclic derivatives of acylaminothiazole, their preparation and pharmaceutical compositions containing them
USRE33024E (en) Bronchodilating 8-hydroxy-5-(1R)-1-hydroxy-2-(N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino)ethyl) carbostyril and intermediates thereof
USRE30577E (en) Ether of n-propanol amine
JP3507494B2 (en) Tachykinin antagonists
US6242432B1 (en) Antithrombotic organic nitrates
EP0512570B1 (en) Urea derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same
US5773475A (en) Anticonvulsant enantiomeric amino acid derivatives
JP3199451B2 (en) 2-acylamino-5-thiazole derivatives, preparation and compositions
RU2126382C1 (en) Compounds with sulfamoyl and amidine group, process for preparation thereof, and pharmaceutical compositions comprising said compounds
ES2266227T3 (en) New compounds (thio) urea and pharmaceutical compositions containing them.
SU1426451A3 (en) Method of producing 3-(substituted phenyl)-5-acylamido-methyloxazolidinons-2 in the form of l- or mixture of d- and l-stereoisomers
EP0354583B1 (en) DC-88A derivatives
US20020151586A1 (en) Acylphenylurea derivatives, a process for their preparation and their use as pharmaceuticals
EP0445206B1 (en) Hydroxamic acid based collagenase inhibitors
SU1424730A3 (en) Method of producing methylsulfonamidophenylalkyl amines and their pharmaceutically acceptable salts
US4374990A (en) Cyclic diamine derivatives
EP0603873B1 (en) Aminoketone derivatives
ES2249572T3 (en) Alquilhidroxamatos tricyclic, their preparation and their use as inhibitors of cell proliferation.
EP1633735B1 (en) Derivatives of piperidinyl- and piperazinyl-alkyl carbamates, preparation methods thereof and application of same in therapeutics
US5602179A (en) Optically-active derivatives of (R) 5-pentylamino-5-oxopentanoic acid with antagonistic activity towards cholecystokinin and a method for their preparation
US5100904A (en) Prolinal compounds which are useful in treating amnesia
US4407814A (en) Imidazolidine derivatives
KR100370888B1 (en) Inhibition of Leukotriene Biosynthesis with Urea Derivatives
JP3348725B2 (en) Hydroxamic acid-based collagenase and cytokine inhibitor
DE60216952T2 (en) Beta-carboline derivatives as inhibitors ptp

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION