Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/48—Nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
  • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings

Definitions

• the present invention relates to an ant i-Helicobacter pylori agent comprising an oxazolin-4-one derivative useful as a therapeutic agent for gastric and duodenal ulcer etc.
• antacids As therapeutic agents for ulcer, there have been developed antacids, anticholinergic agents, antigastrin agents, gastrointestinal hormones, antipepsine agents, histamine H 2 receptor antagonists, tissue repairing agents, mucosa-protecting agents, microcirculation-improving agents, proton pump inhibitors etc.
• histamine H 2 receptor antagonists and proton pump inhibitors both possessing potent acid secretion- suppressing activity, in particular, has facilitated ulcer treatment.
• Various diseases caused by Helicobacter pylori as such are treated by chemotherapies such as double chemotherapy with a bismuth preparation and an antibiotic, and triple chemotherapy with a bismuth preparation, metronidazole (US Patent No. 2,944,061) and either tetracycline ⁇ e.g., US Patent No. 2,712,517) or amoxicillin (US Patent No. 3,192,198).
• Metronidazole an imidazole derivative possessing ant i-Helicobacter pylori activity, is used in combination with antibiotics.
• These bismuth preparations, antibiotics, metronidazole etc. are administered orally. Also, clinical studies have shown that eradication of this microorganism results in healing and decreased recurrence rates in ulcer.
• Japanese Patent Unexamined Publication No. 117268/1993 discloses a pyridine derivative possessing ant i-Helicobacter pylori activity
• European Patent EPO 535528A1 discloses an imidazole derivative possessing ant i-Helicobacter pylori activity.
• the present invention relates to (1) an ant i-Helicobacter pylori composition comprising a compound of the formula:
• A represents an aromatic group which may be substituted
• R 1 and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3 and R 4 independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof, and a pharmacologically acceptable diluent, excipient or carrier
• the anti-Helicobacter pylori composition according to the description in (1) above wherein A is a group represented by the formula:
• ring B is a 6-membered aromatic ring which may be substituted
• X represents CH or N
• Y represents 0, S or -N- R 5 (R 5 represents a hydrogen atom or a hydrocarbon group which may be substituted)
• ring B is a 6-membered aromatic ring which may be substituted
• R 5 represents a hydrogen atom or a hydrocarbon group which may be substituted
• A represents an aromatic group which may be substituted
• R 1 and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3 and R 4 independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof for the preparation of an anti-Helicobacter pylori agent
• a method for prevention or treatment of a disease associated with Helicobacter pylori infection in a mammal which comprises administering to a subject in need an effective amount of a compound of the formula (I) :
• A represents an aromatic group which may be substituted
• R 1 and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3 and R 4 independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof
• ( 16 ) a method for producing an anti-Helicobacter pylori composition comprising mixing a compound of the formula ( I ) :
• A represents an aromatic group which may be substituted
• R 1 and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3 and R 4 independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof with a pharmacologically acceptable diluent, excipient or/and carrier, (17) a compound of the formula:
• A represents an aromatic group which may be substituted
• Ri and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3' and R 4 ' independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or a salt thereof, provided that (1) when A is 3-indolyl, Ri and R3' are hydrogen and R 2 is methyl, R 4 ' is neither C 3 - 6 cycloalkyl nor mono-substituted C 1 - 4 alkyl wherein said substituent is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl, aryl, or an unsaturated 2-4 carbon atoms side-chain and (2) when A is 3-indolyl, Ri and R3' are hydrogen and R 2 is C 1 - 3 alkyl, R 4 ' is not selected from hydrogen, phenyl, anisyl, toluidyl and C 1 - 4 alkyl, (18) a compound of the formula:
• A represents an aromatic group which may be substituted
• R 1 and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3' is a hydrogen atom or a hydrocarbon group which may be substituted
• R 4 " is an acyl group or a carbamoyl group which may be substituted, or a salt thereof, provided that when A is 3-indolyl, Rl is hydrogen and R2 and R3' are methyl
• R 4 " is neither a C 2 - 5 alkanoyl or an mono- substituted C 2 - 5 alkanoyl wherein said substituent is selected from amino, halogen, phenyl, p-hydroxyphenyl, or lower alkoxy, nor a carbamoyl group substituted by C ⁇ _ 4 alkyl, C 3 _ 6 cycloalkyl or phenyl, (19) a compound of the formula:
• A represents an aromatic group which may be substituted
• Ri and R 2 independently represent a hydrogen atom or a hydrocarbon group which may be substituted
• R3' is a hydrogen atom or a hydrocarbon group which may be substituted
• R 4 "' is a carboxyl group which may be esterified, or a salt thereof
• (21) a method of producing indolmycin by culturing the Streptomyces sp.
• HC-21 strain in a medium to produce and accumulate indolmycin in the culture broth, and harvesting the indolmycin, and (22) the Streptomyces sp. HC-21 strain which assimilates L- rhamnose and whose spores have a spiny surface.
• aromatic ring group which may be substituted represented by A in formula (I) is exemplified by monocyclic or condensed polycyclic aromatic hydrocarbon groups or aromatic heterocyclic groups.
• aromatic hydrocarbon groups include, for example, phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, with preference given to phenyl, 1-naphthyl, 2-naphthyl etc.
• the aromatic heterocyclic groups include, for example, aromatic monocyclic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensed heterocyclic groups such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindoly
• Substituents for the "aromatic ring group or aromatic heterocyclic group which may be substituted" represented by A in formula (I) include, for example, hydroxyl group, halogens (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, lower alkyls that may be substituted by 1 to 5 halogens (e.g., fluorine, chlorine, bromine, iodine), lower alkoxys that may be substituted by 1 to 5 halogens (e.g., fluorine, chlorine, bromine, iodine) benzyloxy and C ⁇ _ 4 alkoxy carbonyl (e.g.
• Such lower alkyls include, for example, alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, with preference given to methyl and ethyl.
• Such lower alkoxys include alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxy and ethoxy.
• Substituents for the "aromatic ring group or aromatic heterocyclic group which may be substituted" represented by A also include alkylene dioxo such as methylene dioxo and ethylene dioxo.
• the "hydrocarbon group which may be substituted" represented by R 1 or R 2 in formula (I) include aliphatic chain hydrocarbon groups, alicyclic hydrocarbon groups and aryl groups, with preference given to aliphatic chain hydrocarbon groups.
• Such aliphatic chain hydrocarbon groups include linear or branched aliphatic hydrocarbon groups such as alkyl groups, alkenyl groups and alkynyl groups. Particularly preferred are lower alkyl groups, lower alkenyl groups, lower alkynyl groups etc.
• Such lower alkyls include, for example, C 1 -7 alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and n- heptyl.
• C 1 -7 alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, 1-methyl
• C 1 - 3 alkyls such as methyl, ethyl and propyl, with greater preference given to C 1 - 2 alkyls such as methyl and ethyl.
• Such lower alkenyl groups include, for example, C 2 - 6 alkenyl groups such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1- propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4- methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl and 5-hexenyl, with preference given to C 2 - 5 alkenyls such as vinyl,
• Such lower alkynyl groups include, for example, C 2 - 6 alkynyls such as ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl and 5-hexynyl, with preference given to C 2 - 4 alkynyls such as ethynyl, 1-propynyl and 2-propynyl.
• Such alicyclic hydrocarbon groups include saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkyl groups, cycloalkenyl groups and cycloalkadienyl groups.
• Such cycloalkyl groups are preferably cycloalkyl groups having 3 to 9 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl, with greater preference given to C 3 - 6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Such cycloalkenyl groups include, for example, C3-6 cycloalkenyls such as 2- cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3- cyclohexen-1-yl, 1-cyclobuten-1-yl and 1-cyclopenten-1-yl.
• Such cycloalkadienyl groups include, for example, C 4 - 6 cycloalkadienyls such as 2,4-cyclopentadien-1-yl, 2,4- cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl.
• Tne aryl groups in the hydrocarbon groups include monocyclic or condensed polycyclic aromatic hydrocarbon groups such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, with preference given to phenyl, 1- naphthyl, 2-naphthyl etc.
• Substituents for the "hydrocarbon group which may be substituted" represented by R 1 or R 2 in formula (I) include aryl groups which may be substituted, cycloalkyl or cycloalkenyl groups which may be substituted, heterocyclic groups that may be substituted, amino group that may be substituted, hydroxyl group which may be substituted, thiol group which may be substituted, and halogens (e.g., fluorine, chlorine, bromine, iodine). One to five (preferably 1 to 3) of these optionally chosen substituents may be present.
• Such aryl groups which may be substituted include phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, with preference given to phenyl, 1- naphthyl and 2-naphthyl.
• Substituents for such aryl groups which may be substituted include alkoxy groups having 1 to 3 carbon atoms (e.g., methoxy, ethoxy, propoxy), halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); 1 to 2 of these optionally chosen substituents may be present.
• Such cycloalkyl groups which may be substituted include C3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• the kinds and number of substituents for such cycloalkyl groups which may be substituted are the same as those for the substituents the above-described aryl group that may be substituted.
• Such cycloalkenyl groups which may be substituted include C 3 - 6 cycloalkenyl groups such as cyclopropanyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
• Such heterocyclic groups which may be substituted for include aromatic heterocyclic groups having at least 1 hetero atom selected from oxygen, sulfur or nitrogen as a ring-constituting atom (ring atom), and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), with preference given to aromatic heterocyclic groups.
• aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and aromatic condensed heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo.b]thienyl, indolyl, iso
• Such non-aromatic heterocyclic groups include, for example, oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
• Substituents for such heterocyclic groups which may be substituted for include alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl).
• Substituents for such amino group which may be substituted for, hydroxyl group that may be substituted for, and thiol group that may be substituted for include, for example, lower (C 1 - 3 ) alkyl groups (e.g., methyl, ethyl, propyl).
• the "hydrocarbon group which may be a substituted" represented by R 1 or R 2 is an alicyclic hydrocarbon group or an aryl group
• the substituent may also be an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl) .
• R 1 and R 2 are hydrogen and R 2 is C ⁇ _ 3 alkyl which may be substituted by 1 to 5 halogens.
• hydrocarbon group and the substituent in the "hydrocarbon group which may be substituted" represented by R 3 or R 4 in formula (I) and represented by R3' or R 4 ' in formula (I 1 ) are exemplified by the same hydrocarbon groups and substituents mentioned to exemplify the hydrocarbon group and substituent for R 1 and R 2 above, respectively.
• R 3 and R 4 are that R3 is hydrogen and R 4 is C ⁇ - 3 alkyl.
• the acyl group represented by R 3 or R 4 in formula (I) is exemplified by aliphatic acyl groups such as alkanoyl groups, alkenoyl groups, cycloalkanecarbonyl groups and alkanesulfonyl groups; aromatic acyl groups such as aroyl groups, arylalkanoyl groups, arylalkenoyl groups and arenesulfonyl groups; heterocyclic aromatic acyl groups such as aromatic heterocyclic carbonyl groups and aromatic heterocyclic alkanoyl groups; and non-aromatic heterocyclic carbonyl groups (aliphatic heterocyclic carbonyl groups).
• Alkanoyl groups mean alkylcarbonyl groups, preferable examples thereof including lower alkanoyl groups having 1 to 8 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl.
• Alkenoyl groups mean alkenylcarbonyl groups, preferable examples thereof including C 3 - 6 alkenoyl groups such as acryloyl, methacryloyl, crotonoyl and isocrotonoyl.
• Cycloalkanecarbonyl groups mean cycloalkylcarbonyl groups, preferable examples thereof including those having 4 to 7 carbon atoms, such as cyclopropanecarbonyl groups, cyclobutanecarbonyl groups, cyclopentanecarbonyl groups and cyclohexanecarbonyl groups.
• Alkanesulfonyl groups mean alkylsulfonyl groups, preferable examples thereof including those having 1 to 4 carbon atoms, such as mesyl, ethanesulfonyl and propanesulfonyl.
• Aroyl groups mean arylcarbonyl groups, preferable examples thereof including those having 7 to 11 carbon atoms, such as benzoyl, p-toluoyl, 1-naphthoyl and 2- naphthoyl.
• Arylalkanoyl groups mean alkylcarbonyl groups substituted for by an aryl group, preferable examples thereof including C ⁇ - ⁇ aryl-C 2 -5 alkanoyl groups such as phenylacetyl, phenylpropionyl, hydroatropoyl and phenylbutyryl.
• Arylalkenoyl groups mean alkenylcarbonyl groups substituted for by an aryl group, preferable examples thereof including Ce- ⁇ aryl-C 3 -5 alkenoyl groups such as cinnamoyl and atropoyl.
• Arenesulfonyl groups mean arylsulfonyl groups, preferable examples thereof including those having 6 to 8 carbon atoms, such as benzenesulfonyl and p- toluenesulfonyl.
• aromatic heterocyclic carbonyl groups include furoyl, thenoyl, nicotinoyl, isonicotinoyl, pyrrolecarbonyl, oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl and pyrazolecarbonyl.
• Aromatic heterocyclic alkanoyl groups mean alkylcarbonyl groups substituted by an aromatic heterocyclic group, preferable examples thereof including aromatic heterocyclic ring-C 2 - 5 alkanoyl groups such as thienylacetyl, thienylpropanoyl, furylacetyl, thiazolylacetyl, 1,2,4-thiadiazolylacetyl and pyridylacetyl.
• non-aromatic heterocyclic carbonyl groups include aliphatic heterocyclic carbonyls such as azetidinylcarbonyl, pyrrolidinylcarbonyl and piperidinylcarbonyl.
• R 4 ' in formula ( I" ) is exemplified by "N- monosubstitutional carbamoyl groups” and “N,N- disubstitutional carbamoyl groups,” as well as non- substitutional carbamoyl.
• An "N-monosubstitutional carbamoyl group” means a carbamoyl group having one substituent on nitrogen.
• substituents examples include C ⁇ - 6 alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), C 3 - 6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl groups (e.g., phenyl, 1-naphthyl, 2- naphthyl), aralkyl groups (e.g., benzyl, phenethyl) and heterocyclic groups (e.g., the "heterocyclic groups" mentioned to exemplify the "substituent" for the
• hydrocarbon residue which may be substituted represented by R 1 or R 2 above).
• Such aryl groups, aralkyl groups and heterocyclic groups may be substituted.
• Said substituent is exemplified by hydroxyl group, amino group which may substituted by 1 or 2 lower alkyls (e.g., those having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl) or acyl groups (e.g., formyl, acetyl, propionyl, benzoyl), halogens (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, lower alkyls which may be substituted by 1 to 5 halogens (e.g., fluorine, chlorine, bromine, iodine) and lower alkoxys which may be substituted by 1 to 5 halogens (e.g., fluorine, chlorine, bromine, io
• Such lower alkyls include, for example, alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert- butyl, with preference given to methyl and ethyl.
• Such lower alkoxys include alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxy and ethoxy. It is preferable that 1 to 3 (preferably 1 to 2) of these substituents, whether identical or not, be present.
• N,N-disubstitutional carbamoyl group means a carbamoyl group having two substituents on a nitrogen atom.
• substituents include the same substituents as those mentioned to exemplify the substituent for the "N-monosubstitutional carbamoyl group” above;
• the other substituent include C ⁇ - 6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl, hexyl), C3-6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and C ⁇ -io aralkyl groups (e.g., benzyl, phenethyl).
• C ⁇ - 6 alkyl groups e.g., methyl, ethyl, propyl, isopropyl, butyl,
• the two substituents may form a cyclic amino group in cooperation with the nitrogen atom.
• cyclic aminocarbamoyl groups include 1-azetidinylcarbonyl, 1- pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl, and 1- piperazinylcarbonyl having a lower alkyl group such as C ⁇ _ 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl, hexyl), an aralkyl group such as benzyl and phenethyl, an aryl group such as phenyl, 1-naphthyl and 2- naphthyl, or the like, at the 4-position.
• C ⁇ _ 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, buty
• lower alkoxycarbonyl groups include those having 2 to 8 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and tert- pentyloxycarbonyl, with preference given to those having 2 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
• aryloxycarbonyl groups include those having 7 to 12 carbon atoms, such as phenoxycarbonyl, 1-naphthoxycarbonyl and 2- naphthoxycarbonyl.
• aralkyloxycarbonyl groups include those having 8 to 10 carbon atoms, such as benzyloxycarbonyl and phenethyloxycarbonyl. These aryloxycarbonyl groups and aralkyloxycarbonyl groups may be substituted; useful substituents are identical to those mentioned to exemplify the substituent for aryl groups and aralkyl groups in the case of N-monosubstitutional carbamoyl groups.
• the "6-membered aromatic ring which may be substituted" represented by ring B in formula (II) is exemplified by benzene ring which may be substituted, and 6-membered aromatic heterocyclic ring that may be substituted.
• formula (II) represents a group represented by the formula:
• ring D may be substituted; X and Y have the same definitions as those shown above.
• hydrocarbon group which may be substituted represented by R 5 in formula (II-l) is exemplified by the same hydrocarbon groups as those mentioned to exemplify the hydrocarbon group represented by R 1 or R 2 , which may be substituted.
• the preferable combination of A, Ri, R 2 , R3 and R 4 is that A is indolyl, Rl and R 3 are hydrogen, and R 2 and R 4 are C 1 - 3 alkyl.
• the specific examples of the above-described oxazolin-4-one derivative include indolmycin.
• acids that form an acid addition salt include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfamic acid and sulfonic acid.
• Compound (I) or a salt thereof, used for the present invention is effective as an antibacterial agent in the prevention or treatment of "duodenal ulcer, gastric ulcer, gastritis (including chronic gastritis), gastric cancer etc.” caused by Helicobacter pylori infection as described above, because it possesses antibacterial activity, especially potent antibacterial activity against the bacteria of the genus Helicobacter, represented by Helicobacter pylori.
• the preparation of the present invention containing compound (I) or a pharmacologically acceptable salt thereof, can be orally or non-orally administered as an antibacterial or antiulcer agent to mammals (e.g., humans, dogs, cats, monkeys, rats, mice, horses, bovines), oral administration being normally preferred.
• mammals e.g., humans, dogs, cats, monkeys, rats, mice, horses, bovines
• dosage forms for oral administration include tablets (including sugar-coated tablets and film- coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions and suspensions.
• dosage forms for non-oral administration include injectable preparations, infusions, drip infusions and suppositories.
• the content of compound (I) or a salt thereof in the preparation of the present invention is normally 2 to 85% by weight, preferably 5 to 70% by weight.
• compound (I) or a salt thereof in the above-mentioned dosage forms known production methods in common use in relevant fields are applicable.
• excipients, binders, disintegrants, lubricants, sweetening agents, surfactants, suspending agents, emulsifiers etc. in common use in the field of pharmaceutical making may be added in appropriate amounts as necessary.
• compound (I) or a salt thereof is prepared as tablets, for example, excipients, binders, disintegrants, lubricants etc. may be contained; when compound (I) or a salt thereof is prepared as pills or granules, excipients, binders, disintegrants etc. may be contained.
• excipients etc. When compound (I) or a salt thereof is prepared as powders or capsules, excipients etc. may be contained; when compound (I) or a salt thereof is prepared as syrups, sweetening agents etc. may be contained; when compound (I) or a salt thereof is prepared as emulsions or suspensions, suspending agents, surfactants, emulsifiers etc. may be contained.
• excipients include lactose, saccharose, glucose, starch, sucrose, microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen carbonate, calcium phosphate and calcium sulfate.
• binders include 5-10% by weight starch glue solutions, 10-20% by weight gum arabic solutions or gelatin solutions, 1-5% by weight tragacanth solutions, carboxymethyl cellulose solutions, sodium alginate solutions and glycerol.
• disintegrants include starch and calcium carbonate.
• lubricants include magnesium stearate, stearic acid, calcium stearate and purified talc.
• sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol and simple syrups.
• surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester and stearic acid polyoxyl 40.
• suspending agents include gum arabic, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose and bentonite.
• emulsifiers include gum arabic, tragacanth, gelatin and polysorbate 80.
• coloring agents, preservatives, flavoring agents, correctives, stabilizers, thickening agents etc. in common use in the field of pharmaceutical making may be added in appropriate amounts as desired.
• the preparation of the present invention which contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, is stable and of low toxicity, and can be safely used.
• the daily dose of the preparation of the present invention is normally 1 to 500 mg, preferably about 10 to 200 mg, based on active ingredient content (compound (I) or a salt thereof), per adult (weighing about 60 kg) for oral administration in patients with gastric ulcer caused by Helicobacter pylori infection.
• compound (I) or a salt thereof can be used in combination with other antibacterial agents and antiulcer agents.
• antibacterial agents that can be used in combination with compound (I) or a salt thereof include, for example, nitroimidazole antibiotics (e.g., tinidazole and metronidazole), tetracyclines (e.g., tetracycline, doxycycline and minocycline) , penicillins (e.g., amoxicillin, ampicillin and mezlocillin) , cephalosporins (e.g., cefaclor, cefadroxil, cefazolin, cefuroxime, cefuroxime axetil, cephalexin, cefpodoxime proxetil, ceftazidime and ceftriaxone) , carbapenems (e.g., imipenem and meropenem) , aminoglycosides (e.g., paromomycin) , macrolide antibiotics (e.g., erythromycin, clarithromycin and azithromycin
• Antiulcer agents that can be used in combination with compound (I) or a salt thereof include, for example, proton pump inhibitors (e.g. , omeprazole, ⁇ lansoprazole,* pantoprazole, rabeprazole) Histamine H 2 antagonists (e.g., ranitidine, cimetidine and famotidine), and mucosa-protecting antiulcer agents (e.g., sofalcone, plaunotol, teprenone, sucralfate).
• proton pump inhibitors e.g. , omeprazole, ⁇ lansoprazole,* pantoprazole, rabeprazole
• Histamine H 2 antagonists e.g., ranitidine, cimetidine and famotidine
• mucosa-protecting antiulcer agents e.g., sofalcone, plaunotol, teprenone, sucralfate
• the above-described other antibacterial agents and antiulcer agents may be used in combination of two or more kinds.
• the dose of antibacterial agent is normally 1 to 500 mg, preferably 5 to 200 mg, per adult per day in oral administration; the dose of antiulcer agent is normally 0.5 to 1,000 rag, preferably 1 to 500 mg, per adult per day in oral administration.
• the compound of formula (I) or a salt thereof can, for example, be produced by methods A through E below.
• Z represents a halogen atom or -O-SO 2 R 6 (R 6 represents a lower alkyl group or a substituted phenyl group) ; the other symbols have the same definitions as those shown above.
• the halogen atom represented by Z in formula (III) is exemplified by fluorine, chlorine, bromine and iodine.
• the lower alkyl group represented by R 6 is exemplified by alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl and 2-ethylbutyl, with preference given to those having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
• Useful substituents for the substituted phenyl group represented by R 6 include, for example, lower alkyl groups (same as those mentioned to exemplify the lower alkyl group represented by R 6 above), lower alkoxy groups (e.g., those having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and butoxy), halogen atoms (e.g., fluorine, chlorine, bromine, iodine), nitro groups, cyano groups and carboxyl groups.
• lower alkyl groups as those mentioned to exemplify the lower alkyl group represented by R 6 above
• lower alkoxy groups e.g., those having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and butoxy
• halogen atoms e.g., fluorine, chlorine, bromine, iodine
• nitro groups cyano groups and carboxyl groups.
• This method is conducted by reacting compound (III) or a salt thereof with compound (IV) in the presence of a base.
• the salt of compound (III) is exemplified by the acid addition salts mentioned to exemplify acids that form an acid addition salt with compound (I).
• This reaction is normally carried out in a solvent; a solvent that does not interfere with the reaction is chosen as appropriate.
• Such solvents include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane; hydrocarbons such as n- hexane, benzene and toluene; amides such as formamide, N,N- dimethylformamide and N,N-dimethylacetamide; ketones such as acetone, methyl ethyl ketone and methyl iso
• Useful bases include, for example, Ci- ⁇ alkyl or aryl lithiums such as methyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and phenyl lithium; lithium alkylamides having 2 to 6 carbon atoms, such as lithium dimethylamide, lithium diethylamide and lithium diisopropylamide; metal hydrides such as lithium hydride and sodium hydride; metal alkoxides having 1 to 6 carbon atoms, such as lithium ethoxide, lithium tert- butoxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide; amides such as lithium amide, potassium amide and sodium amide; inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and tertiary amines such as triethylamine, tri(n-propyl)amine, tri(n
• reaction temperature is normally about -80 to 100°C, preferably -50 to 60°C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 24 hours, depending on the kinds of compounds (III) and (IV), the kind of solvent, reaction temperature etc.
• R 7 represents hydrogen or a lower alkyl group
• R 8 represents hydrogen or a hydroxyl group-protecting group
• the lower alkyl group represented by R 7 is exemplified by the same lower alkyl groups as those mentioned to exemplify the lower alkyl group used for R 6 in method A.
• the hydroxyl group-protecting group represented by R 8 may be any one, as long as it does not interfere with the reaction; preferable examples thereof include ether-forming protecting groups such as methoxymethyl, benzyloxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, methylthiomethyl, 2- tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, 2- tetrahydrofranyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl and trityl; silyl ether-forming protecting groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert- butyldiphenylsilyl,
• R 8 in formula (V) is hydrogen, compound (V) or a salt thereof is reacted with compound (VI).
• the salt of compound (V) is exemplified by acid adduct salts with the acids mentioned to exemplify acids that form an acid adduct salt with compound (I).
• This reaction is normally carried out in a solvent and, if necessary, in the presence of a base.
• solvents and bases are identical to the solvents and bases mentioned for method A above.
• the reaction is carried out using 1 to 10 mol, preferably 1 to 5 mol, of compound (VI) per mol of compound (V) or salt thereof.
• Reaction temperature is normally about -30 to
• reaction time is normally 1 minute to 120 hours, preferably 15 minutes to 48 hours, depending on the kinds of compounds (V) and (VI), the kinds of solvent and base, reaction temperature etc.
• Compound (I) can also be produced by producing compound (VIII) from compounds (V) and (VII) and cyclizing compound (VIII). This method involves the acylation of compound (VII) or a salt thereof with compound (V), a salt thereof or a reactive derivative thereof.
• free acid (V), a salt thereof (inorganic salt, organic salt) or a reactive derivative thereof e.g., acid halide, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, active thioester etc.
• inorganic salts include alkali metal salts (e.g., sodium salt, potassium salt) and alkaline earth metal salts (e.g., calcium salt).
• Organic salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N,N- dimethylaniline salt, pyridine salt and quinoline salt.
• Acid halides include, for example, acid chloride and acid bromide.
• Mixed acid anhydrides include mono-C ⁇ _ 4 alkylcarbonic acid mixed acid anhydrides (e.g., mixed acid anhydrides of free acid (V) and monomethylcarbonic acid, monoethylcarbonic acid, monoisopropylcarbonic acid, monoisobutylcarbonic acid, mono-tert-butylcarbonic acid, monobenzylcarbonic acid, raono(p-nitrobenzyl)carbonic acid, monoallylcarbonic acid etc.), Ci- ⁇ aliphatic carboxylic acid mixed acid anhydrides (e.g., mixed acid anhydrides of free acid (V) and acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid etc.), C7- 11 aromatic carboxylic acid mixed acid anhydrides (e.g., mixed acid anhydrides of free
• Active amides include amides with nitrogen-containing heterocyclic compounds [e.g., acid amides of free acid (V) and pyrazole, imidazole, benzotriazole etc.; these nitrogen-containing heterocyclic compounds may be substituted for by C 1 - 4 alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), Cj.- ⁇ alkoxys (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy) , halogen atoms (e.g., fluorine, chlorine, bromine), oxo, thioxo, C 1 - 6 alkylthios (e.g., methylthio, ethylthio, propylthio, butylthio) etc.].
• nitrogen-containing heterocyclic compounds
• Active esters include, for example, organic phosphoric acid esters (e.g., diethoxyphosphoric acid esters, diphenoxyphosphoric acid esters), p-nitrophenyl ester, 2,4- dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1- hydroxybenzotriazole ester and l-hydroxy-lH-2-pyridone ester.
• organic phosphoric acid esters e.g., diethoxyphosphoric acid esters, diphenoxyphosphoric acid esters
• p-nitrophenyl ester 2,4- dinitrophenyl ester
• cyanomethyl ester pentachlorophenyl ester
• N-hydroxysuccinimide ester N-hydroxyphthalimide ester
• 1-hydroxybenzotriazole ester 6-chloro-1- hydroxybenzo
• Active thioesters include esters with aromatic heterocyclic thiol compounds [their heterocyclic rings may be substituted for by C 1 - 4 alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), C 1 - 6 alkoxys (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), halogen atoms (e.g., fluorine, chlorine, bromine), Ci- ⁇ alkylthios (e.g., methylthio, ethylthio, propylthio, butylthio) etc.] [e.g., 2- pyridylthiol ester, 2-benzothiazolylthiol ester].
• C 1 - 4 alkyls e.g., methyl, ethyl,
• the salt of compound (VII) is exemplified by salts with alkali metals (e.g., potassium, sodium, lithium), salts with alkaline earth metals (e.g., calcium, magnesium) and acid addition salts (acid adduct salts with the acids mentioned to exemplify acids that form an acid addition salt with compound (I)).
• alkali metals e.g., potassium, sodium, lithium
• alkaline earth metals e.g., calcium, magnesium
• acid addition salts acid adduct salts with the acids mentioned to exemplify acids that form an acid addition salt with compound (I)
• This reaction is normally carried in a solvent; a solvent that does not interfere with the reaction is chosen as appropriate.
• solvents include, for example, ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol- dimethyl ether; esters such as ethyl formate, ethyl acetate and butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane; hydrocarbons such as n- hexane, benzene and toluene; amides such as formamide, N,N- dimethylformamide and N,N-dimethylacetamide; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as
• the amount of compound (VII) used is normally 1 to 10 mol, preferably 1 to 5 mol, per mol of compound (V).
• the reaction is normally carried out in the temperature range from -80 to 200°C, preferably from -40 to 150°C, and most preferably from -30 to 100°C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 24 hours, depending on the kinds of compounds (V) and (VII), the kind of solvent (also mixing ratio in the case of a mixed solvent), reaction temperature etc.
• the reaction can be carried out in the presence of a deoxidizer to remove the released hydrogen halide from the reaction system.
• Such deoxidizers include, for example, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogen carbonate; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, y-collidine, N,N-dimethylaniline, N-methylpiperidine, N- methylpyrrolidine and N-methylmorpholine; and alkylene oxides such as propylene oxide and epichlorohydrin.
• inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogen carbonate
• tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, y-collidine, N,N-dimethylaniline, N-methylpiperidine, N- methylpyrrolidine and N-
• Compound (VIII) can be then cyclized to yield compound (I) after the hydroxyl group-protecting group R 8 is removed as necessary.
• this deprotection reaction can be carried out by a known method chosen as appropriate.
• deprotection can be achieved with an acid (e.g., formic acid, acetic acid, propionic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid) or by catalytic reduction [Raney nickel, platinum, palladium, rhodium, or the like, for example, used as a catalyst at normal pressure or increased pressure (2 to 100 atm) ] in the case of ether-forming protecting groups, with one of the above-mentioned acids or a Lewis acid (e.g., zinc chloride, zinc bromide, aluminum chloride, titanium chloride) or a fluoride
• a Lewis acid
• the amount of acid or Lewis acid used is normally 0.001 to 100 mol, preferably 0.01 to 50 mol, per mol of compound (V).
• Reaction temperature is normally -50 to 150 ⁇ C, preferably -20 to 100 ⁇ C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 48 hours.
• the amount of base used is normally 0.01 to 50 mol, preferably
• Reaction temperature is normally -20 to 150°C, preferably -10 to 100°C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 48 hours.
• reaction promoter there may be used, for example, 2-chloro-3- methylbenzoxazolium tetrafluoroborate, 2-chloro-3- ethylbenzoxazolium tetrafluoroborate, 2-chloro-3- methylbenzothiazolium tetrafluoroborate, 2-chloro-3- ethylbenzothiazolium fluoroborate, 2-chloro-1- methylpyridinium tetrafluoroborate and 2-chloro-1- ethylpyridinium tetrafluoroborate.
• the amount of reaction promoter used is normally 1 to 10 mol, preferably 1 to 3 mol, per mol of compound (VIII).
• a base is also used when a reaction promoter is used. Such bases are exemplified by the bases used for method A.
• Reaction temperature is normally -30 to 150°C, preferably -20 to 100°C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 48 hours.
• compound (I) When one of R3 and R* is an acyl group, an esterified carboxyl group or a carbamoyl group that may have a substituent, compound (I) can be produced by methods C, D and E below.
• compound (lb), which has an acyl group for or R 4 can be produced by method C.
• R 4a represents an acyl group
• R 4b represents a group resulting from removal of the carbonyl group or sulfonyl group from an acyl group
• the other symbols have the same definitions as those shown above.
• the acyl group represented by R 4a means an acyl group represented by R 4 ;
• the "acyl group” in the "group resulting from removal of the carbonyl group or sulfonyl group from an acyl group” represented by R 4b means an acyl group represented by R 4 .
• compound (la) or a salt thereof can be acylated with compound (IX) or (X) or a reactive derivative thereof to yield compound (lb).
• the salt of 5 compound (Ia) is exemplified by the same acid adduct salts as those mentioned to exemplify the salt of compound (I).
• the reactive derivative of compound (IX) is exemplified by the reactive derivatives mentioned for method B.
• the reactive derivative of compound (X) is exemplified by o sulfonic acid halides (e.g., sulfonyl bromide, sulfonyl chloride) and sulfonic anhydride; the reaction is carried out by the method described for method B or a modification thereof.
• o sulfonic acid halides e.g., sulfonyl bromide, sulfonyl chloride
• sulfonic anhydride e.g., sulfonic anhydride
• compound (Ic), which 5 has an esterified carboxyl group for R 4 can be produced by method D.
• R 4c represents an esterified carboxyl group; Q represents a halogen atom; the other symbols have the same definitions as those shown above.
• R 4c is any one of the carboxyl groups that may be
• the halogen represented by Q is exemplified by fluorine, chlorine, bromine and iodine. This reaction is carried out by reacting compound (Ia) or a salt thereof and
• compound (XI) The salt of compound (Ia) is exemplified by the acid adduct salts mentioned to exemplify the acid adduct salt of compound (Ia) for reaction D above.
• This reaction is normally carried out in a solvent; such solvents are exemplified by the solvents used for method B.
• a hydrogen halide is released.
• the reaction can be carried out in the presence of an acid scavenger.
• Such acid scavenger includes, for example, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogen carbonate; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, / -collidine, N,N-dimethylaniline, N-methylpiperidine, N- methylpyrrolidine and N-methylmorpholine; and alkylene oxides such as propylene oxide and epichlorohydrin.
• the amount of compound (XI) used is normally 1 to 20 mol, preferably 1 to 10 mol, per mol of compound (Ia).
• Reaction temperature is normally -30 to 120°C, preferably -20 to 80°C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 48 hours.
• compound (Id) which has a carbamoyl group which may be substituted, can be produced by method E.
• R 4d represents a carbamoyl group which may be substituted
• R 9 , R 10 and R 11 whether identical or not, represent hydrogen or one of the substituents mentioned to exemplify the substituent for the carbamoyl group represented by R 4 , which may be substituted; the other symbols have the same definitions as those shown above.
• compound (Ic) or a salt thereof can be reacted with compound (XII) to yield compound (Id).
• the salt of compound (Ic) is exemplified by the same acid addition salts as those mentioned to exemplify the salt of compound (I).
• This reaction is normally carried out in a solvent; such solvents are exemplified by the solvents used for method A.
• the amount of compound (XII) used is normally 1 to 100 mol, preferably 1 to 30 mol, per mol of compound (Ic).
• Reaction temperature is normally -30 to 200°C, preferably -10 to 100°C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 48 hours.
• Compound (Id) can also be produced by reacting compound (Ia) with isocyanate derivative (XIII).
• the reaction is normally carried out in a solvent.
• Said solvent may be any one, as long as it does not interfere with the reaction.
• ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl ether, diisopropyl ether and ethylene glycol-dimethyl ether
• esters such as ethyl formate, ethyl acetate and n-butyl acetate
• halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2- dichloroethane
• hydrocarbons such as n-hexane, benzene and toluene
• amides such as formamide, N,N-dimethylformamide and N,N-dimethylacetamide
• ketones
• the amount of compound (XIII) used is normally 1 to 30 mol, preferably 1 to 15 mol, per mol of compound (Ia).
• Reaction temperature is normally -20 to 150°C, preferably -10 to 100 ⁇ C.
• Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to 48 hours.
• R 12 represents hydrogen, a lower alkyl group, a cycloalkyl group, an aralkyl group or an acyl group
• R 13 and R 14 whether identical or not, represent hydrogen or a lower alkyl group
• R 15 represents hydrogen, a lower alkyl group or an aralkyl group
• R 16 represents a lower alkyl group or an aryl group
• the lower alkyl group represented by R 12 in formula (XIV) is exemplified by alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, with preference given to those having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
• alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, is
• the cycloalkyl group represented by R 12 is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl, with preference given to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the aralkyl group represented by R 12 is exemplified by benzyl, phenethyl and phenylpropyl.
• the acyl group represented by R 12 is exemplified by aliphatic acyl groups such as alkanoyl groups, alkenoyl groups, cycloalkanecarbonyl groups and alkanesulfonyl groups; aromatic acyl groups such as aroyl groups, arylalkanoyl groups, arylalkenoyl groups and arenesulfonyl groups; heterocyclic aromatic acyl groups such as aromatic heterocyclic carbonyl groups and aromatic heterocyclic alkanoyl groups; and non-aromatic heterocyclic carbonyl groups (aliphatic heterocyclic carbonyl groups).
• Alkanoyl groups mean alkylcarbonyl groups, preferable examples thereof including lower alkanoyl groups having 1 to 8 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl.
• Alkenoyl groups mean alkenylcarbonyl groups, preferable examples thereof including C 3 - 6 alkenoyl groups such as acryloyl, methacryloyl, crotonoyl and isocrotonoyl.
• “Cycloalkanecarbonyl groups” mean cycloalkylcarbonyl groups, preferable examples thereof including those having 4 to 7 carbon atoms, such as cyclopropanecarbonyl groups, cyclobutanecarbonyl groups, cyclopentanecarbonyl groups and cyclohexanecarbonyl groups.
• “Alkanesulfonyl groups” mean alkylsulfonyl groups, preferable examples thereof including those having 1 to 4 carbon atoms, such as mesyl, ethanesulfonyl and propanesulfonyl.
• Aroyl groups mean arylcarbonyl groups, preferable examples thereof including those having 7 to 11 carbon atoms, such as benzoyl, p-toluoyl, 1-naphthoyl and 2- naphthoyl.
• Arylalkanoyl groups mean alkylcarbonyl groups substituted for by an aryl group, preferable examples thereof including C ⁇ - ⁇ aryl-C 2 -5 alkanoyl groups such as phenylacetyl, phenylpropionyl, hydroatropoyl and phenylbutyryl.
• Arylalkenoyl groups mean alkenylcarbonyl groups substituted for by an aryl group, preferable examples thereof including C ⁇ - ⁇ aryl-C 3 _s alkenoyl groups such as cinnamoyl and atropoyl.
• Alkyl groups mean arylsulfonyl groups, preferable examples thereof including those having 6 to 8 carbon atoms, such as benzenesulfonyl and p- toluenesulfonyl.
• aromatic heterocyclic carbonyl groups include furoyl, thenoyl, nicotinoyl, isonicotinoyl, pyrrolecarbonyl, oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl and pyrazolecarbonyl.
• Aromatic heterocyclic alkanoyl groups mean alkylcarbonyl groups substituted for by an aromatic heterocyclic group, preferable examples thereof including aromatic heterocyclic ring-C 2 - 5 alkanoyl groups such as thienylacetyl, thienylpropanoyl, furylacetyl, thiazolylacetyl, 1,2,4-thiadiazolylacetyl and pyridylacetyl.
• non-aromatic heterocyclic carbonyl groups include aliphatic heterocyclic carbonyls such as azetidinylcarbonyl, pyrrolidinylcarbonyl and piperidinylcarbonyl.
• the lower alkyl group represented by R 13 , R 14 , R 15 or R 16 in formulas (XIV), (XV) and (XVI) is exemplified by lower alkyl groups represented by R 12 .
• the aralkyl group represented by R 15 is exemplified by aralkyl groups represented by R 12 .
• the aryl group represented by R 16 is exemplified by phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl groups, with preference given to phenyl and naphthyl. These aryl groups may have 1 to 5 substituents.
• substituents include alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), alkoxy groups having 1 to 3 carbon atoms (e.g., methoxy, ethoxy, propoxy) and halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
• alkyl groups having 1 to 3 carbon atoms e.g., methyl, ethyl, propyl
• alkoxy groups having 1 to 3 carbon atoms e.g., methoxy, ethoxy, propoxy
• halogen atoms e.g., fluorine, chlorine, bromine, iodine
• compounds (XIV) and (XV) are reacted in the presence of compound (XVI) to yield compound (XVII).
• This reaction is normally carried out in a solvent; a solvent that does not interfere with the reaction is chosen as appropriate.
• solvents include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2- dichloroethane; hydrocarbons such as n-hexane, benz
• Reaction temperature is normally -80 to 150°C, preferably -50 to 120°C.
• (XV) and (XVI) used is normally 1 to 5 mol, preferably 1 to 3 mol, per mol of compound (XIV).
• ester of compound (XVII) is then subjected to hydrolysis, hydrogenolysis, or the like, to yield compound (XVIII).
• This hydrogenolysis reaction is normally carried out in a solvent; a solvent that does not interfere with the reaction is chosen as appropriate.
• Such solvents include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2- dichloroethane; hydrocarbons such as n-hexane, benzene and toluene; amides such as formamide, N,N-dimethylformamide and N,N-dimethylacetamide; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; dimethyl sulfox
• bases include metal hydroxides such as lithium hydroxide, potassium hydroxide, sodium hydroxide and barium hydroxide, and metal carbonates such as potassium carbonate, sodium carbonate and barium carbonate.
• the amount of base used is normally 1 to 30 mol, preferably 1 to 10 mol, per mol of compound (XVII).
• Reaction temperature is normally -30 to 150 ⁇ C, preferably -10 to
• Reaction time is normally 15 minutes to 48 hours, preferably 30 minutes to 24 hours.
• This catalyst is preferably one for catalytic reduction reaction, exemplified by platinum catalysts (e.g., platinum oxide, platinum black, platinum-carbon), palladium catalysts (e.g., palladium chloride, palladium- carbon, palladium-calcium carbonate, palladium-barium sulfate), rhodium catalysts (e.g., rhodium-carbon, rhodium- alumina) and ruthenium catalysts (e.g., ruthenium oxide, ruthenium-carbon), with greater preference given to palladium catalysts.
• platinum catalysts e.g., platinum oxide, platinum black, platinum-carbon
• palladium catalysts e.g., palladium chloride, palladium- carbon, palladium-calcium carbonate, palladium-barium sulfate
• rhodium catalysts e.g., rhodium-carbon, rhodium- alumina
• the reaction is normally carried out in a solvent; a solvent that does not interfere with the reaction is chosen as appropriate.
• solvents include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n- butyl acetate; hydrocarbons such as n-hexane, benzene and toluene; amides such as formamide, N,N-dimethylformamide and N,N-dimethylacetamide; and water; these solvents are used as simple or mixed solvents.
• Reaction temperature is normally -10 to 120°C, preferably 0 to 100°C. Although this reaction is normally carried out at normal pressure, it may be carried out at increased pressure in some cases. Such pressure is preferably 1 to 200 atm.
• Compound (XVIII) can be decarbonized by heating to yield compound (I).
• This reaction is normally carried out in a solvent; a solvent that does not interfere with the reaction is chosen as appropriate.
• solvents include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n- butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane; hydrocarbons such as n- hexane, benzene and toluene; amide
• Reaction temperature is normally 0 to 180°C, preferably 10 to 150°C.
• Reaction time is normally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
• the group may incorporate a protecting group in common use in peptide chemistry and other fields; the desired compound can be obtained by removing the protecting group as necessary after reaction.
• Useful amino group-protecting groups include, for example, formyl group, C ⁇ _ 6 alkylcarbonyl groups (e.g., acetyl, ethylcarbonyl), benzyl group, tert-butyloxycarbonyl group, benzyloxycarbonyl group, 9- fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, phenylcarbonyl group, C ⁇ _ ⁇ alkyloxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), C 7 - 10 aralkylcarbonyl groups (e.g., benzylcarbonyl) , trityl group, phthaloyl group and N,N-dimethylaminomethylene group. These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine), nitro group etc.
• halogen atoms e.g., fluorine,
• carboxyl group-protecting groups include C ⁇ _ 6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl group, silyl group, benzyl group and allyl group. These groups may be substituted for by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine), nitro group etc.
• Useful hydroxyl group-protecting groups include methoxymethyl group, allyl group, tert-butyl group, C 7 -. 10 aralkyl groups (e.g., benzyl), formyl group, C ⁇ _ 6 alkylcarbonyl groups (e.g., acetyl, ethylcarbonyl), benzoyl group, C7-10 aralkylcarbonyl groups (e.g., benzylcarbonyl), pyranyl group, furanyl group and trialkylsilyl groups.
• aralkyl groups e.g., benzyl
• formyl group e.g., acetyl, ethylcarbonyl
• C ⁇ _ 6 alkylcarbonyl groups e.g., acetyl, ethylcarbonyl
• benzoyl group e.g., C7-10 aralkylcarbonyl groups (e.g., benzyl
• These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine), Ci- ⁇ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl), phenyl group, C7- 10 aralkyl groups (e.g., benzyl), nitro group etc.
• halogen atoms e.g., fluorine, chlorine, bromine
• Ci- ⁇ alkyl groups e.g., methyl, ethyl, propyl, isopropyl, butyl, tert- butyl
• phenyl group e.g., C7- 10 aralkyl groups (e.g., benzyl), nitro group etc.
• protecting groups can be removed by commonly known methods or modifications thereof, including those using acids, bases, reduction, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate etc.
• a compound When a compound is obtained in a free form by each of the above-described reactions of the present invention, it may be converted to a salt by a conventional method; when it is obtained as a salt, it may be converted to a free form or another salt by a conventional method.
• Compound (I) thus obtained can be isolated and purified from the reaction mixture by commonly known means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin-layer chromatography.
• a salt of compound (I) can be produced by, for example, adding one of the above-described inorganic acids or organic acids to compound (I) by a commonly known means.
• Compounds (III) and (IV), used as starting compounds in method A above, can be produced by, for example, the method described in US Patent No. 4,584,385 or a method based thereon.
• Compound (V) used as a starting compound in method B above, can be produced by, for example, the method described in the Journal of Medicinal Chemistry, 2JL, 82 (1978) or Chemistry Letters, 166 (1980) or a method based thereon; compound (VI) can be produced by, for example, the method described in the Journal of Organic Chemistry, 42, 3608 (1977) or a method based thereon; compound (VII) can be produced by the method described in the Journal of the Chemical Society, 9_5_, 132 (1909) or a method based thereon.
• compound (I) can also be produced by the method described in US Patent No. 4,584,385 or a method based thereon.
• compound (I) can be produced by chemical processes as described above, it can also be produced using microorganisms.
• o indolmycin can be produced by, for example, the methods described in the literature [K.V. Rao, Antibiotics and Chemotherapy (Washington, D.C.), 1_0, 312 (1960); W.S. Marsh et al., ibid., 10, 316 (1960); Schach von Wittenau, M. et al., J. Am. Chem. Soc. 83, 4678 (1961), ibid., 8_5, 3425 5 (1963)], using as producer strains Streptomyces griseus subsp.
• griseus ATCC 1264 American Type Culture Collection Catalogue of Bacteria & Bacteriophages, 18th edition, 1992
• Streptomyces sp. HC-21 a new strain, can also be used as a producer strain.
• the microorganism used for the method of indolmycin production of the present invention is the Streptomyces sp. HC-21 strain (hereinafter also referred to as "HC-21 strain") isolated from a soil sample from Tenninkyo, 5 Asahikawa-shi, Hokkaido, Japan.
• the HC-21 strain is characterized as follows: All findings on medium were obtained during 14 days of cultivation and Q observation at 28°C, unless otherwise stated.
• the aerial mycelia elongate in simple branches from well elongated and branched substrate mycelia, with gently 5 waved or key-shaped spore chains (normally 10 to 50 spores or more) on their tips. No whirls are noted. Spores are cylindrical (1.1 to 1.2 x 1.4 to 1.5 ⁇ m) and have a spiny surface.
• G Degree of growth
• AM aerial mycelia
• R back face color tone
• SP presence or absence and color tone of soluble pigment
• Streptomyces sp. HC-21 strain as such is characterized by the capability of L-rhamnose assimilation and spiny spore surfaces.
• Streptomyces sp. HC-21 strain as such has been deposited under accession number IFO-15984 at the Institute for Fermentation, Osaka (foundation), since June 12, 1996, and under accession number FERM BP-5571 at the National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology, Ministry of International Trade and Industry of the Japan (1-3, Higashi 1-chome, Yatabe, Tsukuba City, Ibaraki Prefecture), since June 25, 1996.
• the bacteria of the genus Streptomyces can undergo variation, naturally or by mutagens, as a general nature of microorganisms.
• the culture medium for the method of the present invention may be liquid or solid, as long as it contains nutrient sources usable by the strain used, a liquid medium is preferred for large-scale treatment.
• the medium is supplemented as appropriate with assimilable nutrient sources, digestible nitrogen sources, inorganic substances, and trace nutrients.
• Carbon sources include, for example, glucose, lactose, sucrose, maltose, dextrin, starch, glycerol, mannitol, sorbitol, oils and fats (e.g., soybean oil, olive oil, rice bran oil, sesame oil, lard oil, chicken oil); nitrogen sources include, for example, meat extract, yeast extract, dry yeasts, soybean flour, corn steep liquor, peptone, cottonseed flour, blackstrap molasses, urea, ammonium salts (e.g., ammonium sulfate, ammonium chloride, ammonium nitrate, ammonium acetate) and others.
• oils and fats e.g., soybean oil, olive oil, rice bran oil, sesame oil, lard oil, chicken oil
• nitrogen sources include, for example, meat extract, yeast extract, dry yeasts, soybean flour, corn steep liquor, peptone, cottonseed flour, blackstrap molasses, urea, am
• salts containing sodium, potassium, calcium, magnesium etc. metal salts such as those of iron, manganese, zinc, cobalt, nickel etc., salts of phosphoric acid, boric acid etc., and salts of organic acids such as acetic acid and propionic acid.
• amino acids e.g., glutamic acid, aspartic acid, alanine, lysine, valine, methionine, proline
• vitamins e.g., Bi, B 2 , nicotinic acid, Bi 2 r C
• nucleic acids e.g. purine, pyrimidine and derivatives thereof
• inorganic or organic acids alkalis, buffers etc. for regulation of the medium's pH, and appropriate amounts of oils and fats, surfactants etc. for defoaming.
• Cultivation may be achieved by standing culture, shaking culture, spinner culture, or the like.
• submerged spinner culture is of course desirable.
• culturing conditions vary depending on the condition and composition of the medium, the kind of strain, and the means of cultivation, it is normally recommended that temperature and initial pH be 15 to 26°C and about 5 to 9, respectively. It is desirable that temperature in the middle stage of cultivation and initial pH be 20 to 25°C and about 6 to 8, respectively.
• Duration of cultivation also varies depending on the above-mentioned conditions but it is recommended that cultivation be continued until the concentration of the desired bioactive substance reaches maximum. It normally takes about 1 to 10 days in the case of shaking culture or spinner culture using a liquid medium.
• the resulting bioactive substance indolmycin can be extracted and purified from the culture on the basis of its chemical nature.
• indolmycin is produced in the culture broth and cells, it can be purified by separating the culture broth and cells by filtration or centrifugation from the culture, extracting it from the resulting filtrate or centrifugal supernatant using an organic solvent, or extracting it from cells using an organic solvent, and isolating it from each extract or the combined extract.
• indolmycin is a weakly basic oil-soluble substance
• its collection from the culture broth permits the use of means of separation and purification in common use for collection of related microbial metabolites.
• methods based on solubility differences from impurity substances and chromatographies using various carriers such as activated charcoal nonionic high porous resin, silica gel, alumina and dextran gel can be used singly or in combination.
• the method of isolating and collecting indolmycin from the culture is hereinafter described specifically.
• cells are removed by filtration from the culture broth; the resulting supernatant is adjusted to appropriate pH; a solvent such as ethyl acetate is added, followed by vigorous stirring, to yield an ethyl acetate layer.
• the organic layer obtained is sequentially washed with alkali, acid and water, after which it is concentrated; the resulting concentrate is subjected to silica gel column chromatography.
• Useful developing solvents include, for example, chloroform-methanol or hexane-acetone mixed solvents. After the effective fractions are combined and concentrated, the concentrate is subjected to Sephadex LH- 20 chromatography.
• Useful developing solvents are methanol and mixed solvents such as hexane-toluene-methanol and hexane-methylene chloride-methanol. After concentration, the eluate containing the effective fractions is purified by preparative high performance liquid chromatography.
• the column packing used here is ODS-SH343 S-15 (produced by Yamamura Kagaku Kenkyujo); the solvent system used is a combination of 0.02 M phosphate buffer (pH 6.3) and 26% CH 3 CN.
• room temperature means about 15 to 30°C.
• a platinum loopful of Streptomyces sp. HC-21 strain previously sufficiently grown on a slant medium consisting of yeast extract-maltose extract-agar, was inoculated to a sterile 2 1 Sakaguchi flask containing 500 ml of a seed medium of pH 7.0 consisting of 2% glucose, 3% soluble starch, 1% corn steep liquor, 1% fresh soybean flour, 0.5% polypeptone, 0.3% sodium chloride and 0.5% precipitating calcium carbonate, and cultured at 24°C on a reciprocal shaker for 2 days.
• the 120 1 of the culture broth thus obtained was filtered using Hyflo Super Cel to yield 110 1 of a 0 filtrate.
• This filtrate was adjusted to pH 3.0 with dilute sulfuric acid; an equal amount of ethyl acetate was added, followed by vigorous stirring, to yield 80 1 of an ethyl acetate layer.
• This ethyl acetate layer was washed with 30 1 of a 2% NaHC ⁇ 3 solution, then with 30 1 of a 0.02 N-HC1 5 solution, and thoroughly washed with water, after which it was concentrated under reduced pressure to yield about 30 g of a concentrate.
• This concentrate was passed through a silica gel column (0.8 1) to adsorb the active ingredient, followed by sequential elution with 4 1 of hexane-acetone o (80:20), 4 1 of hexane-acetone (50:50) and 4 1 of hexane- acetone (20:80). The effective fractions were combined and concentrated under reduced pressure to yield 1.53 g of a concentrate.
• This concentrate was dissolved in methanol; the resulting solution was passed through a column (2 1) of 5 Sephadex LH-20 (produced by Pharmacia, Sweden), thoroughly washed previously; the effective eluted fractions from 1.3 1 to 1.7 1 were combined and concentrated under reduced pressure to yield 490 mg of a powder.
• This powder was further developed (20 ml/min, 20 ml fractions) with a 0 solvent system of 0.02 M phosphate buffer (pH 6.3) and 26% CH 3 CN, using preparative liquid chromatography (Hitachi model L-6250, detector L-4000, YMC-Pack, ODS SH343 S-15 120 A, 214 nm) , to yield effective fractions (fraction Nos. 30 through 39).
• CH 3 CN was removed, the effective 5 fractions were washed with water and again extracted with ethyl acetate; the ethyl acetate layer was concentrated under reduced pressure to yield 315 mg of crystalline indolmycin.
• Example 2 the following compounds were prepared.
• Example 6 the following compounds were prepared. (5S)-5-[ (lR)-1-(indol-3-yl)ethyl ⁇ -2-(N-(2- trifluoromethylbenzoyl)-N-methyl]amino-2-oxazolin-4-one, IR (KBr) cm -1 : 3287, 1748, 1717.
• Benzyl 2-dimethylamino-5-[l-(6-fluoroindol-3- yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate 500 mg was dissolved into 15 ml of a solution of ethanol and tetrahydrofuran in a ration of 5:1. 10% palladium-carbon (170 mg) was added. The whole was subjected to hydrogenation under normal temperature and normal pressure for 1.5 hours. The whole was stirred at 80°C under nitrogen atmosphere for 1 hour and then filtered to remove the catalyst. The filtrate was concentrated to give 2- dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl3-2-oxazolin-4- one (340 mg) .
• Example 24 Following the same procedure as described in Example 23, the following compounds were prepared. 2-methylamino-5-[ (2-methylindol-3-yl)methyl]-2- oxazolin-4-one,
• Helicobacter pylori was subjected to shaking culture at 37°C in a gas pack jar incorporating CampyPakTM (BBL R Beckton Dickinson Microbiology Systems) for 20 hours, using Brucella broth medium supplemented with 2.5% fetal bovine serum, to yield a seed inoculum.
• CampyPakTM BBL R Beckton Dickinson Microbiology Systems
• the other test microorganisms were each cultured at 37°C for 20 hours, using Brucella broth medium, to yield respective seed inocula.
• MIC was determined by agar dilution method using Brucella agar supplemented with 7% horse blood.
• compound (I) exhibits very selective antimicrobial activity against the bacteria of the genus Helicobacter, represented by Helicobacter pylori .
• HCS/Sea After mongolian gerbils (MGS/Sea, male, 6 weeks of age) were fasted for 24 hours, Helicobacter pylori TN2GF4 was inoculated to the stomach at 10 7,08 per mongolian gerbil. Starting at 11 days after infection, a 3, 10, 30, or 100 mg/kg suspension of the test compound in a 0.5% aqueous solution of methyl cellulose was orally administered twice daily (morning and evening) for 3 days.
• indolmycin at 10 mg/kg or higher reduced the mongolian gerbil gastric bacterial cell count with dose dependency, the clearance rates achieved being 25% at 30 mg/kg and 80% at 100 mg/kg.
• the preparation of the present invention which contains a compound represented by formula (I) or a salt thereof, can be produced with the following formulations: 1.
• Components (1), (2) and (3), a two-third portion of component (4) and a half portion of component (5) were mixed and granulated. To these granules, the remaining portions of components (4) and (5) were added, and the whole mixture was tableted by compressive tableting.
• Compound (I) or a salt thereof exhibits very specific potent antibacterial activity against the bacteria of the genus Helicobacter represented by Helicobacter pylori.
• the use of compound (I) of the present invention or a salt thereof therefore provides the desired effect for an anti- Helicobacter pylori agent at doses much lower than the effective doses of conventional antibacterial agents for the bacteria of the genus Helicobacter (especially Helicobacter pylori ) .
• Compound (I) or a salt thereof is effective in the prevention or treatment of various diseases caused by bacteria of the genus Helicobacter such as duodenal ulcer, gastric ulcer, chronic gastritis and gastric cancer, and, because Helicobacter pylori is a major cause of ulcer recurrence, compound (I) or a salt thereof is also effective in the prevention of ulcer recurrence.
• compound (I) or a salt thereof exhibits no antibacterial action against gram-positive bacteria such as those of the genera Staphylococcus and Bacillus and against gram-negative bacteria such as those of the genera Escherichia, Pseudomonas, Proteus , Klebsiella, Serratia, Salmonella, Citrobacter and Alcaligenes.
• Compound ( I ) or a salt thereof is therefore selectively effective in the prevention or treatment of diseases caused by bacteria of the genus Helicobacter, and can be used as a safe pharmaceutical without adverse effects having little influence on other bacteria and fungi .
• Compound ( I ) or a salt thereof is stable and of low toxicity. Accordingly, the present invention provides an excellent anti-Helicobacter pylori agent without adverse effects .

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