EP1007038A2 - Entzündungshemmendes mittel - Google Patents
Entzündungshemmendes mittelInfo
- Publication number
- EP1007038A2 EP1007038A2 EP98938913A EP98938913A EP1007038A2 EP 1007038 A2 EP1007038 A2 EP 1007038A2 EP 98938913 A EP98938913 A EP 98938913A EP 98938913 A EP98938913 A EP 98938913A EP 1007038 A2 EP1007038 A2 EP 1007038A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- inflammatory agent
- groups
- compound
- tnf
- 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.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
Definitions
- the present invention relates to an anti-inflammatory agent which is useful as an agent for prophylaxis and treatment of a TNF (Tumor Necrosis Factor) - a mediated inflammatory disease.
- TNF Tumor Necrosis Factor
- JP-A H7 (1995) -285864 describes that a thiazolidine derivative inhibits production and response reaction of
- WO 96/34943 describes a method for treating a cytokine mediated autoimmune, inflammatory or atherosclerotic disorder with a human 12-lipoxygenase inhibitor.
- the human 12-lipoxygenase inhibitor is exemplified by pioglitazone, namely 5- [4- [2- (5-ethyl-2- pyridyl ) ethoxy]benzyl ] -2 , 4-thiazolidinedione .
- a thiazolidine derivative is useful as an agent for prophylaxis and treatment of a TNF- a mediated inflammatory disease.
- An inflammatory reaction includes various acute and chronic reactions which occur when stimulation was added to the living body. Such reactions include unfavorable reactions which cause destruction of the living tissues as well as favorable reactions to the living body with the purpose of excluding the alien substance. So far, inflammatory diseases are treated with steroid or a nonsteroidal anti-inflammatory agent, an immunosuppressive agent, and the like. However, such agents have problems that they inhibit favorable reactions as well as unfavorable reactions at the time of inflammation. Therefore, agents which inhibit only unfavorable reactions to the living body are desired. It is thought that various cytokines are produced to regulate inflammation reactions at the time of inflammation. TNF- a which is one of such cytokines is thought to play an important role in expansion and delay of inflammation. For instance, it is thought that production of TNF- ⁇ increased to cause destruction of articular tissues in rheumatoid arthritis which belongs to an inflammatory disease.
- agents which specifically inhibit TNF- a mediated inflammation reactions are expected to be an anti-inflammatory agent with reduced side effects, therefore development of such agents are desired.
- the present invention relates to (1) An anti-inflammatory agent which affects by way of a TNF- a inhibitory action and comprises a compound of the formula :
- R represents a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted
- Y represents a group of the formula -CO-, -CH(OH)-, or -NR 3 - where R 3 represents an alkyl group that may be substituted
- m is 0 or 1
- n is 0 , 1 or 2
- X represents CH or N
- A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms
- Q represents oxygen or sulfur
- R 1 represents hydrogen or an alkyl group
- ring E may have further 1 to 4 substituents, which may form a ring in combination with R 1 ;
- L and M respectively represent hydrogen or may be combined with each other to form a chemical bond; or a salt thereof (hereinafter referred to simply as Compound (I));
- heterocyclic group represented by R is a 5- to 7-membered monocyclic and heterocyclic group containing 1 to 4 hetero-atoms selected from oxygen, sulfur and nitrogen in addition to carbon as ring members or a condensed heterocyclic group;
- An anti-inflammatory agent according to the above (1) wherein L and M respectively represent hydrogen; (9) An anti-inflammatory agent according to the above (1) , wherein the compound is 5- [4- [ 2- ( 5-ethyl-2- pyridyl)ethoxy]benzyl] -2 , 4-thiazolidinedione;
- Method for treating or preventing a TNF- a mediated inflammatory disease in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound as defined in the above (1) or a pharmacologically acceptable salt thereof; and
- the hydrocarbon group includes aliphatic , alicyclic, alicyclic-aliphatic, aromatic-aliphatic, and aromatic hydrocarbon groups.
- the number of carbon atoms constituting such hydrocarbon groups is preferably 1 to 14.
- the aliphatic hydrocarbon group is preferably a aliphatic hydrocarbon group.
- the aliphatic hydrocarbon group includes saturated C x _ 8 aliphatic hydrocarbon groups (e.g.
- alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, -butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, heptyl, and octyl; and unsaturated C 2 . 8 aliphatic hydrocarbon groups (e.g.
- the alicyclic hydrocarbon group is preferably a C 3 . 7 alicyclic hydrocarbon group.
- the alicyclic hydrocarbon group includes saturated C 3 . 7 alicyclic hydrocarbon groups (e.g. cycloalkyl groups) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. and unsaturated C 5 . 7 alicyclic hydrocarbon groups (e.g.
- cycloalkenyl groups and cycloalkadienyl groups such as 1-cyclopentenyl, 2- cyclopentenyl , 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl , 3-cyclohexenyl, 1-cycloheptenyl, 2- cycloheptenyl , 3-cycloheptenyl, and 2, 4-cycloheptadienyl.
- the alicyclic-aliphatic hydrocarbon group is a group consisting of the above-described alicyclic hydrocarbon group and aliphatic hydrocarbon group (e.g. cycloalkyl- alkyl and cycloalkenyl-alkyl groups) and is preferably a C 4 . 9 alicyclic-aliphatic hydrocarbon group.
- the alicyclic-aliphatic hydrocarbon group includes cyclopropylmethyl , cyclopropylethyl , cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclopentenylmethyl , cyclohexylmethyl , 2- cyclohexenylmethyl, 3-cyclohexenylmethyl , ⁇ yclohexylethyl , cyclohexylpropyl, cycloheptylmethyl, ⁇ ycloheptylethyl, etc.
- the aromatic-aliphatic hydrocarbon group is preferably a C 7 . 13 aromatic-aliphatic hydrocarbon group (e.g. aralkyl and aryl-alkenyl groups) .
- the aromatic-aliphatic hydrocarbon group includes C 7 . 9 phenylalkyl such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; C u . 13 naphthylalkyl such as - naphthylmethyl, a -naphthylethyl, j3 -naphthylmethyl, and (5 -naphthylethyl; C 8 .
- phenylalkenyl such as styryl and 4-phenyl-l,3-butadienyl; and C 12 .
- naphthylalkenyl such as 2- ( 2-naphthy1)vinyl .
- the aromatic hydrocarbon group is preferably a C 6 . 14 aromatic hydrocarbon group (e.g. aryl groups).
- the aromatic hydrocarbon group includes phenyl and naphthyl ( a -naphthyl, ⁇ -naphthyl) .
- the heterocyclic group in a heterocyclic group that may be substituted for R is a 5- to 7-membered monocyclic and heterocyclic group containing 1 to 4 hetero-atoms selected from oxygen, sulfur, and nitrogen in addition to carbon as ring members or a condensed heterocyclic group.
- the condensed heterocyclic group may for example be one consisting of such a 5- to 7-membered monocyclic and heterocyclic group and a 6- membered ring containing 1 or 2 nitrogen atoms , a benzene ring, or a 5-membered ring containing one sulfur atom.
- heterocyclic group includes 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4- pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, 1 , 2 , 4-oxadiazol-5-yl, 1 , 2 , 4-triazol-3-yl, l,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazol-2-yl.
- the preferred heterocyclic group is pyridyl, oxazolyl, or thiazolyl.
- the hydrocarbon group and heterocyclic group for R may respectively have 1 to 5 , preferably 1 to 3 substituents at substitutable positions .
- substituents include for example aliphatic hydrocarbon groups , alicyclic hydrocarbon groups , aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, halogen, nitro, amino group that may be substituted, acyl groups that may be substituted, hydroxy group that may be substituted, thiol that may be substituted, and carboxyl group that may be esterified.
- the aliphatic hydrocarbon group includes straight- chain or branched aliphatic hydrocarbon groups having 1 to 15 carbon atoms, such as alkyl groups, alkenyl groups, and alkynyl groups.
- the preferred alkyl group is a C ⁇ _ 10 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethyIbutyl, 2,2- dimethyIbutyl, 3,3- imethyIbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, and decyl.
- C ⁇ _ 10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl,
- the preferred alkenyl group is a C 2 . 10 alkenyl group, such as vinyl, allyl, isopropenyl, 1-propenyl, 2- methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- ethyl-1-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.
- the preferred alkynyl group is a C 2 .
- alkynyl group 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.
- the alicyclic hydrocarbon group includes saturated and unsaturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms, such as cycloalkyl groups , cycloalkenyl groups, and cycloalkadienyl groups.
- the preferred cycloalkyl group is a C 3 . 10 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1]heptyl , bicyclo [2.2.2] octyl , bicyclo [3.2.1]octyl, bicyclo [ 3.2.2 ]nonyl, bicyclo [3.3. l]nonyl, bicyclo [ 4.2.1 ]nonyl, and bicyclo [4.3.1] decyl .
- cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1]heptyl , bicyclo [2.2.2] octyl , bi
- the preferred cycloalkenyl group is a C 3 . 10 cycloalkenyl group, such as 2-cyclopenten-l-yl, 3- cyclopenten-1-yl, 2-cyclohexen-l-yl, and 3-cyclohexen- 1-yl.
- the preferred cycloalkadienyl group is a C 4 . 10 cycloalkadienyl group, such as 2 , 4-cyclopentadien-l-yl, 2, 4-cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl.
- aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group.
- C 6 . 14 aryl groups such as phenyl , naphthyl , anthryl , phenanthryl, acenaphthylenyl can be mentioned. Particularly preferred are phenyl, 1-naphthyl, and 2- naphthyl .
- the preferred aromatic heterocyclic group includes 5- to 7-membered monocyclic aromatic heterocyclic groups containing 1 to 4 hetero-atoms selected from oxygen, sulfur, and nitrogen in addition to carbon as ring members , 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 bicyclic or tricyclic condensed aromatic heterocyclic groups containing 1 to 5
- the preferred non-aromatic heterocyclic group includes oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl , thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl , thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, and morpholino.
- the halogen includes fluorine , chlorine, bromine , and iodine, and is preferably fluorine or chlorine.
- the amino group that may be substituted includes amino (-NH 2 ) that may be mono- or di-substituted by, for example, C 1 . 10 alkyl groups , C 3 . 10 cycloalkyl groups , C 2 . 10 alkenyl groups, C 3 . 10 cycloalkenyl groups, C 1 . 13 acyl groups (e.g. C 2 . 10 alkanoyl groups , C 7 . 13 arylcarbonyl groups ) , or C 6 . 12 aryl groups.
- the substituted amino group there can be mentioned methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino , diallylamino, cyclohexylamino, acetylamino , propionylamino, benzoylamino, phenylamino, and N-methyl-N-phenylamino.
- the acyl group in the acyl groups that may be substituted includes C x . 13 acyl groups. For example, formyl and groups formed between carbonyl and C 1-10 alkyl groups , C 3 - ⁇ o cycloalkyl groups , C 2 _ 10 alkenyl groups , C 3 .
- the preferred acyl group includes acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl , crotonyl, 2-cyclohexenecarbonyl, benzoyl, and nicotinoyl.
- the substitutent in the substituted acyl groups includes C ⁇ alkyl, C ⁇ alkoxy groups, halogen (e.g. chlorine, fluorine, bromine, etc.), nitro, hydroxy, and amino.
- the substituted hydroxy includes alkoxy, alkenyloxy, aralkyloxy, acyloxy, and aryloxy groups .
- the preferred alkoxy group includes C 1-10 alkoxy groups , such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
- C 1-10 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
- the preferred alkenyloxy group includes C 2 . 10 alkenyloxy groups, such as allyloxy, crotyloxy, 2- pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy.
- the preferred aralkyloxy group includes C 7 _ 10 aralkyloxy groups, such as phenyl-C ⁇ ,, alkyloxy (e.g. benzyloxy, phenethyloxy, etc.).
- the preferred acyloxy group includes C 2 . 13 acyloxy groups, more preferably C 2 . 4 alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.).
- the preferred aryloxy group includes C 6 . 14 aryloxy groups, such as phenoxy, and naphthyloxy. This aryloxy group may have 1 or 2 substituents such as halogen (e.g. chlorine, fluorine, bromine, etc.).
- the substituted aryloxy group includes 4-chlorophenoxy. Referring to the thiol group that may be substituted, the substituted thiol group includes alkylthio, cycloalkylthio , aralkylthio, and acylthio groups.
- the preferred alkylthio group includes C ⁇ alkylthio groups, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, and nonylthio.
- the preferred cycloalkylthio group includes C 3 . 10 cycloalkylthio groups such as cyclobutylthio , cyclopentylthio , and cyclohexylthio.
- the preferred aralkylthio group includes C 7 . 10 aralkylthio groups, such as phenyl-C x _ 4 alkylthio (e.g. benzylthio, phenethylthio , etc.).
- the acylthio group is preferably a C 2 _ 13 acylthio group, more preferably a C 2 . 4 alkanoylthio group (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
- the carboxyl group that may be esterified includes alkoxycarbonyl, aralkyloxycarbonyl, and aryloxycarbonyl groups.
- the preferred alkoxycarbonyl group includes C 2 . 5 alkoxycarbonyl groups , such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl, and butoxycarbonyl .
- the preferred aralkyloxycarbonyl group includes C 8 . 10 aralkyloxycarbonyl groups, such as benzyloxycarbonyl .
- the preferred aryloxycarbonyl group includes C 7 . 15 aryloxycarbonyl groups, such as phenoxycarbonyl, and p- tolyloxycarbonyl.
- the preferred substituent on the hydrocarbon or heterocyclic group for R includes C ⁇ ,, alkyl groups, aromatic heterocyclic groups , and C 6 . 14 aryl groups . Particularly preferred is Ci. 3 alkyl, furyl, thienyl, phenyl, or naphthyl.
- substituent on the hydrocarbon or heterocyclic group for R is an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group
- this substituent may be further substituted by one or more, preferably 1 to 3 suitable substituents.
- substituents there can be mentioned C 1 . 6 alkyl groups , C 2 . 6 alkenyl groups, C 2 . 6 alkynyl groups, C 3 . 7 cycloalkyl groups, C 6 . 14 aryl groups (e.g. phenyl, naphthyl, etc.), aromatic heterocyclic groups (e.g.
- thienyl furyl, pyridyl, oxazolyl, thiazolyl, etc.
- non-aromatic heterocyclic groups e.g. tetrahydrofuryl , morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.
- C 7 . 9 aralkyl groups amino, N-mono(C 1 . 4 )alkylamino groups, N,N-di(C 1 . 4 ) alkylamino groups , C 2 . 8 acylamino groups (e.g.
- acetylamino e.g. C 2 . 8 alkanoyl groups, etc.
- carbamoyl e.g. C 2 . 8 alkanoyl groups, etc.
- N- mono ( C ⁇ ,, ) alkylcarbamoyl groups N,N-di(C 1 _
- alkylcarbamoyl groups sulfamoyl, N-mono(C 1 . 4 )alkylsulfamoyl groups , N,N-di( C ⁇ ,, ) alkylsulfamoyl groups , carboxyl, C 2 . 8 alkoxycarbonyl groups, hydroxy, C ⁇ ,, alkoxy groups , C 2 . 5 alkenyloxy groups , C 3 . 7 cycloalkyloxy groups , C 7 . 9 aralkyloxy groups, C 6 . 14 aryloxy groups (e.g. phenyloxy, naphthyloxy, etc.), mercapto, C x .
- aryloxy groups e.g. phenyloxy, naphthyloxy, etc.
- R is preferably a heterocyclic group that may be substituted.
- R is pyridyl, oxazolyl, or thiazolyl group, which may have 1 to 3 substituents selected from C 1-3 alkyl, furyl, thienyl, phenyl, and naphthyl.
- Y represents -CO-, - CH(OH) - or -NR 3 - .
- Y is preferably -CH(OH) - or -NR 3 - and more preferably -CH(OH)-.
- the alkyl group includes C ⁇ alkyl groups , such as methyl , ethyl , propyl , isopropyl , butyl , isobutyl, sec-butyl, and t-butyl.
- the substituent includes halogen (e.g. fluorine, chlorine, bromine. iodine), C x _ 4 alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy), hydroxy, nitro, and C 1 . i acyl groups (e.g. formyl, acetyl, propionyl, etc. ) .
- the symbol m represents 0 or 1 and is preferably 0.
- the symbol n represents 0, 1 or 2 and is preferably 0 or 1.
- the symbol X represents CH or N and is preferably CH.
- the symbol A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms.
- This aliphatic hydrocarbon group may be straight-chain or branched and may further be saturated or unsaturated.
- A preferably represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 4 carbon atoms , which is preferably a saturated group. More preferably, A represents a chemical bond, -CH 2 - or - (CH 2 ) 2 - . Still more preferably, A represents a chemical bond or -(CH 2 ) 2 -.
- the alkyl group for R 1 includes C x . 4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl.
- R 1 represents hydrogen .
- ring E may optionally have 1 to 4 substituents at substitutable positions.
- substituents include an alkyl group, a hydroxy group that may be substituted, halogen, an acyl group that may be substituted, nitro, and an amino group that may be substituted. These substituents may be the same as the substituents mentioned for the hydrocarbon or heterocyclic group for R.
- R 2 represents hydrogen, an alkyl group, a hydroxy group that may be substituted, halogen, an acyl group that may be substituted, nitro, or an amino group that may be substituted.
- the alkyl group, hydroxy group that may be substituted, halogen, acyl group that may be substituted, and amino group that may be substituted, for R 2 may each be the same as the substituents mentioned for the hydrocarbon or heterocyclic group for R.
- R 2 is hydrogen, hydroxy group that may be substituted, or halogen. More preferably, R 2 is hydrogen or hydroxy group that may be substituted. Particularly preferred is hydrogen or a C ⁇ ,, alkoxy group.
- L and M respectively represent hydrogen or may be combined with each other to form a chemical bond, and preferably they are hydrogen.
- each symbols has the same meanings as defined above , may exist as (E)- and (Z)- isomers, owing to the double bond at 5-position of the azolidinedione ring.
- each symbols may exist as optical isomers, i.e. (R)- and (S) -forms, with respect to the asymmetric carbon at 5-position of the azolidinedione ring.
- This compound includes those optically active compounds, i.e. (R)- and (S) -forms, as well as the racemic form.
- the preferred compound of the formula ( I ) is the compound in which R represents pyridyl, oxazolyl, or thiazolyl group, optionally having 1 to 3 substituents selected from the group consisting of C ⁇ alkyl, furyl, thienyl, phenyl, and naphthyl; Y represents -CH(OH)- or -NR 3 - wherein R 3 is methyl; n is 0 or 1 ; X represents CH; A represents a chemical bond or -(CH 2 ) 2 -; R 1 represents hydrogen; ring E, namely the partial structural formula:
- R ,2 is hydrogen or a C 1 _ i alkoxy group; and L and M respectively represent hydrogen.
- the salt of compound ( I ) of the present invention is preferably a pharmacologically acceptable salt, which includes salts with inorganic bases, salts with organic bases , salts with inorganic acids , salts with organic acids , and salts with basic or acidic amino acids.
- the preferred salt with an inorganic base includes alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; aluminum salt, and ammonium salts.
- the preferred salt with an organic base includes salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine , diethanolamine , triethanolamine , dicyclohexylamine , N,N' -dibenzylethylenediamine, etc.
- the preferred salt with an inorganic acid includes salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
- the preferred salt with an organic acid includes salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
- the preferred salt with a basic amino acid includes salts with arginine, lysine, ornithine, etc.
- the preferred salt with an acidic amino acid includes salts with aspartic acid, glutamic acid, etc.
- the most preferred of all the above-mentioned salts is hydrochloride , sodium salt or potassium salt.
- Compound ( I ) or a salt thereof of the present invention can be produced in accordance with methods described in JP-A S55(1980)-22636 (EP-A-8203), JP-A S60 ( 1985 ) -208980 (EP- A-155845), JP-A S61 ( 1986 ) -286376 (EP-A-208420 ) , JP-A S61(1986)-085372 (EP-A-177353 ) , JP-A S61 ( 1986 ) -267580
- Compound ( I ) or a salt thereof of the present invention is useful as an anti-inflammatory agent which affects by way of a TNF- a inhibitory action.
- the toxic potential of the compound of the present invention is low.
- the TNF- a inhibitory action means reduction in the production amount of TNF- a in the living tissues (e.g. , skeletal muscles , monocytes , macrophages , neutrophils , fibroblasts, epithelial cells, astrocytes, etc.) and reduction in the activity of TNF- .
- the anti-inflammatory agent of the present invention can be used as an agent for prophylaxis and treatment of TNF- a mediated inflammatory diseases in mammals (e.g. , man, mouse, rat, rabbit, dog, cat, bovine, equine, swine, monkey, etc.).
- TNF- a mediated inflammatory diseases mean inflammatory diseases which occur in the presence of TNF- a and can be treated by way of a TNF- a inhibitory action.
- inflammatory diseases include diabetic complications (e.g., retinopathy, nephropathy, neutropathy, disorders in the great arteries, etc.), rheumatoid arthritis, osteoarthritis of the spine, osteoarthritis, low back pain, gout, postoperative or traumatic inflammation, remission of swelling, neuralgia, laryngopharyngitis , cystitis, hepatitis, pneumonia, etc.
- diabetic complications e.g., retinopathy, nephropathy, neutropathy, disorders in the great arteries, etc.
- rheumatoid arthritis e.g., osteoarthritis of the spine
- osteoarthritis e.g., low back pain, gout, postoperative or traumatic inflammation, remission of swelling, neuralgia, laryngopharyngitis , cystitis, hepatitis, pneumonia, etc.
- the compound of the present invention as such can be used.
- the anti-inflammatory agent is used in the form of a pharmaceutical composition obtained by formulating the compound of the invention with per se known pharmaceutically acceptable carriers .
- the pharmaceutically acceptable carrier a variety of organic and inorganic carriers in common use as raw materials for pharmaceutical preparations are employed.
- the carrier is formulated in the form of the excipient, lubricant, binder, and disintegrator for a solid dosage form; and the solvent, solubilizer, suspending agent, isotonizing agent , buffering agent and local analgesic for a liquid dosage form.
- pharmaceutical additives such as the preservative, antioxidant, coloring agent, sweetener, etc. can also be used.
- the preferred excipient includes lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silicic anhydride, etc.
- the preferred lubricant includes magnesium stearate, calcium stearate, talc, colloidal silica, etc.
- the preferred binder includes crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose , polyvinylpyrrolidone, etc.
- the preferred disintegrator includes starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, etc.
- the preferred solvent includes water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, tricaprylin, etc.
- the preferred solubilizer includes polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane , cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
- the preferred suspending agent includes surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc. and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose , hydroxypropylcellulose, etc .
- the preferred isotonizing agent includes sodium chloride, glycerin, D-mannitol, etc.
- the preferred buffering agent includes buffer solutions such as phosphate, acetate, carbonate, citrate, etc.
- the preferred local anesthetic includes benzyl alcohol, etc.
- the preferred antiseptic includes p-hydroxybenzoic esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
- the preferred antioxidant includes salts of sulfurous acid, ascorbic acid, etc.
- the above pharmaceutical composition can be manufactured by conventional methods in the pharmaceutical preparation techniques , for example methods described in the Japanese Pharmacopoeia .
- dosage forms of the pharmaceutical composition include oral dosage forms such as tablets, capsules (inclusive of soft capsules and microcapsules) , powders , granules , and syrups ; and non-oral dosage forms such as injections, suppositories, pellets, and drip infusions. These dosage forms can be safely administered either orally or non-orally.
- the dosage of the anti-inflammatory agent of the present invention differs depending on the subject, route of administration, clinical condition, etc.
- the usual unit dose is about 0.1 mg/kg to about 30 mg/kg, preferably about 2 mg/kg to about 20 mg/kg, as the compound of the invention which is an active ingredient, which dose is preferably administered once to 3 times a day.
- Example 1 A fluidized-bed granulating and drying machine
- Test Example 1 Reduction of plasma TNF- a level in mice
- the plasma TNF- level was determined by using KKA y mice which are genetically obese, diabetic models, and a TNF- a inhibitory action of the compound of the present invention was evaluated.
- mice eighteen male KKA y mice (10 week old), genetically obese, diabetic models, were divided into two groups each of which consists of nine mice.
- a powdered commercial diet CE-2, produced by Japan Clea
- the above powdered diet also containing 0.001 %(w/w) of hydrochloride of Compound No. 1 was given to the other group (drug administration group) ad libitum.
- Mice in these groups were bred for 4 days. The average dosage of drug per mouse was 16 mg/kg body weight/day. On the fourth day, mice were sacrificed and blood was collected in tubes containing heparin.
- the collected blood was centrifuged and the plasma TNF- a level was determined by the enzyme immunoassay based on the biotin-streptavidin method. Namely, 5 l of a solution of an anti-TNF- a antibody IgG [produced by Genzyme, USA] (100 Mg/ml) diluted with 0.05 M Tris-HCl buffer (pH 8.0) was added to each wells of a 96-well polystyrene microtiter plate [produced by Falcon, USA], followed by standing at the room temperature for 2 hours to adhere the anti-TNF- a antibody IgG to the plate.
- each wells was washed with 0.1 M Tris-HCl buffer (pH 7.6) containing 0.4 M NaCl, 0.1 %(w/w) bovine serum albumin, 0.1 %(w/w) NaN 3 and 1 mM MgCl 2 (hereafter referred to as a washing buffer) .
- each wells was washed with a washing buffer, and ⁇ -D-galactosidase activity of an immune complex fixed at a solid phase was assayed.
- 30 Ml of a substrate [60 mM of 4-methylumbelliferyl- ⁇ -D-galactoside, produced by Sigma, USA] was added to each wells to start an enzyme reaction. After the reaction was conducted at the room temperature for 4 hours, the enzyme reaction was stopped by addition of 0.13 ml of 0.1 M glycine-NaOH buffer (pH 10.3) .
- the fluorescence intensity of the produced 4- methylumbelliferone was determined using a fluorescence spectrometer [Cyto Fluor II, PerSeptive Biosystems, USA] at the wavelengths of 350 and 460 nm for excitation and emission, respectively.
- the amount of TNF- a was calculated from the obtained fluorescence intensity using a separately prepared dose-response curve.
- Control Drug administration group group (Present invention)
- Test Example 2 (Reduction of plasma TNF- a level in rats)
- the plasma TNF- a level was determined by using Wistar fatty rats which are genetically obese, diabetic models, and a TNF- a inhibitory action of the compound of the present invention was evaluated. Namely, hydrochloride of Compound No. 1 was orally administered to sixteen male Wistar fatty rats ( 16 week old) , genetically obese, diabetic models, via gastric tube at a dose of 3 mg/kg body weight/day. Ten rats were sacrificed before drug administration, and the first, second, third and fourth day after drug administration, respectively. Then, blood was collected.
- Test Example 3 Reduction of TNF- a content in skeletal muscle of rats
- the TNF- a content in skeletal muscle was determined by using Wistar fatty rats which are genetically obese, diabetic models, and a TNF- a inhibitory action of the compound of the present invention was evaluated. Namely, hydrochloride of Compound No. 1 was administered to male Wistar fatty rats (16 week old), genetically obese, diabetic models in substantially the same manner as in Test Example 2. Ten rats were sacrificed before drug administration, and the first, second, third and fourth day after drug administration, respectively. Then, skeletal muscle was collected.
- Tris-HCl buffer pH 7.6 containing 1 M NaCl, 2 %(w/w) bovine serum albumin, 2 mM ethylenediaminetetraacetic acid disodium salt (EDTA) , aprotinin (80 tripsin-inhibitory units/liter) and 0.02 %(w/w) NaN 3 was added in an amount of 20 weight times of the weight of the wet skeletal muscle. After ultrasonic disintegration, the mixture was centrifuged at 15000 rpm for 30 minutes to obtain a supernatant. The amount of TNF- a in the obtained supernatant was determined in substantially the same manner as in Test Example 1.
- the in vitro effect of the compound of the present invention on suppression of the active oxygen production in neutrophils was evaluated by determining the amount of peroxides in cells .
- venous blood was collected from male Wistar rats (6 week old) while adding heparin.
- an aqueous solution of 3 %(w/w) dextran was added for separation of blood cells .
- precipitates obtained by centrifugation was suspended with saline.
- the suspension was piled on Ficoll-Hypaque solution (Sigma, USA), followed by centrifugation.
- erythrocytes were removed by hemolysis to separate neutrophils.
- the hemolysis was conducted in the following manner. Namely, 4 ml of an ice-cooled 0.2 %(w/w) aqueous solution of NaCl was added to the above precipitates, which was suspended quickly, followed by standing for 20 to 30 seconds to puncture the erythrocytes. Then, 4 ml of an ice-cooled 1.6 %(w/w) aqueous solution of NaCl was added to the obtained suspension, which was mixed to yield a mixed solution having the same osmotic pressure with the erythrocytes before puncture. The mixed solution was centrifuged at 4 °C at 150 g for 5 minutes. After the supernatants were removed, the precipitates were washed with PBS (phosphate buffer saline).
- PBS phosphate buffer saline
- the thus obtained erythrocytes were washed with saline , followed by addition of a minimum essential medium to prepare a neutrophils floating solution.
- the obtained neutrophils floating solution was fractionated into tubes so that the number of neutrophiles per tube is 106.
- hydrochloride of Compound No . 1 or Compound No . 8 was added to the obtained tubes at the concentration of 1 MM. After incubation for one hour, a fluorescent pigment [DCFH-DA (2,7-dichlorofluoresceine diacetic acid)] was added, which was subjected to determination of the fluorescence intensity by FACScan (Beeton Dickinton, USA) . As the control group, the fluorescence intensity in the case of adding no drug was determined.
- DCFH-DA 2,7-dichlorofluoresceine diacetic acid
- the relative values of the fluorescence intensity in the drug addition group when the fluorescence intensity in the control group was 100 were calculated. These values were defined as the amount of peroxides caused by active oxygen derived from neutrophils .
- TNF- a is produced by various cells such as monocytes , macrophages, neutrophils, fibroblasts, epithelial cells, astrocytes, and etc. TNF- increases production of active oxygen in neutrophils, which are suggested to have a close relation with occurrence of rheumatoid arthritis [Clinical and Experimental Rheumatology, vol. 15, pp.233-237 (1997); Inflammation, vol. 20, pp.427-438 (1996)].
- the compound of the present invention exhibited suppressive effects on the active oxygen production by reducing TNF- a production or TNF- a sensitivity in neutrophils based on the results of Test Example 4.
- the anti-inflammatory agent of the present invention is used as an agent for prophylaxis and treatment of TNF- a mediated inflammatory diseases such as diabetic complications (e.g. , retinopathy, nephropathy, neutropathy, disorders in the great arteries, etc.), rheumatoid arthritis, osteoarthritis of the spine, osteoarthritis, low back pain, gout, postoperative or traumatic inflammation, remission of swelling, neuralgia, sore throat, cystitis, hepatitis, pneumonia, and etc.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22530297 | 1997-08-21 | ||
JP22530297 | 1997-08-21 | ||
PCT/JP1998/003692 WO1999009965A2 (en) | 1997-08-21 | 1998-08-20 | Anti-inflammatory agent |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1007038A2 true EP1007038A2 (de) | 2000-06-14 |
Family
ID=16827222
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98938913A Withdrawn EP1007038A2 (de) | 1997-08-21 | 1998-08-20 | Entzündungshemmendes mittel |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1007038A2 (de) |
AU (1) | AU8747998A (de) |
CA (1) | CA2300813A1 (de) |
WO (1) | WO1999009965A2 (de) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUP0203367A3 (en) * | 1999-08-31 | 2004-12-28 | Maxia Pharmaceuticals Inc San | Benzylidine-thiazolidinediones and analogues and their use in the treatment of diabetes |
US6808902B1 (en) | 1999-11-12 | 2004-10-26 | Amgen Inc. | Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules |
CA2399463A1 (en) * | 2000-02-10 | 2001-08-16 | Takeda Chemical Industries, Ltd. | Combination drug |
WO2001062238A2 (en) * | 2000-02-24 | 2001-08-30 | San Diego State University | Ppar gamma agonists for the treatment of liver inflammatory disorders |
EP1385465A4 (de) | 2001-03-07 | 2005-09-07 | Incyte San Diego Inc | Heterozyklische derivative zur behandlung von krebs und anderer proliferativer erkrankungen |
EP1377559A4 (de) | 2001-03-08 | 2005-09-28 | Incyte San Diego Inc | Rxr-aktivierende moleküle |
CN1547486A (zh) | 2001-06-26 | 2004-11-17 | 抗opgl抗体 | |
EP1456187A4 (de) | 2001-11-15 | 2005-02-09 | Incyte San Diego Inc | N-substituierte heterocyclen zur behandlung von hypercholesterinämie, dyslipidämie und anderen metabolischen störungen, krebs und anderen krankheiten |
GB0128138D0 (en) * | 2001-11-23 | 2002-01-16 | King S College London | Pharmaceutical use |
US7196108B2 (en) | 2002-03-08 | 2007-03-27 | Incyte San Diego Inc. | Bicyclic heterocycles for the treatment of diabetes and other diseases |
US7102000B2 (en) | 2002-03-08 | 2006-09-05 | Incyte San Diego Inc. | Heterocyclic amide derivatives for the treatment of diabetes and other diseases |
US8915253B2 (en) | 2005-07-18 | 2014-12-23 | Tearscience, Inc. | Method and apparatus for treating gland dysfunction employing heated medium |
US8950405B2 (en) | 2006-05-15 | 2015-02-10 | Tearscience, Inc. | Treatment of obstructive disorders of the eye or eyelid |
US9314369B2 (en) | 2006-05-15 | 2016-04-19 | Tearscience, Inc. | System for inner eyelid treatment of meibomian gland dysfunction |
WO2008027069A1 (en) | 2006-08-21 | 2008-03-06 | Tearscience, Inc. | Method and apparatus for treating meibomian gland dysfunction employing fluid |
US10092449B2 (en) | 2013-04-30 | 2018-10-09 | Tear Film Innovations, Inc. | Systems and methods for the treatment of eye conditions |
US9763827B2 (en) | 2013-04-30 | 2017-09-19 | Tear Film Innovations, Inc. | Systems and methods for the treatment of eye conditions |
US10974063B2 (en) | 2016-06-30 | 2021-04-13 | Alcon Inc. | Light therapy for eyelash growth |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996034943A1 (en) * | 1995-05-04 | 1996-11-07 | City Of Hope | Human leukocyte 12-lipoxygenase and its role in the pathogenesis of disease states |
US5594015A (en) * | 1994-06-22 | 1997-01-14 | Regents Of The University Of California | Thiazolidine derivatives for the treatment of psoriasis |
WO1996024350A1 (de) * | 1995-02-10 | 1996-08-15 | Schering Aktiengesellschaft | Pharmazeutische präparate zur tnf-inhibition |
DE19540475A1 (de) * | 1995-10-20 | 1997-04-24 | Schering Ag | Chirale Methylphenyloxazolidinone |
CA2577233C (en) * | 1996-04-05 | 2009-08-18 | Takeda Pharmaceutical Company Limited | Pharmaceutical composition containing angiotensin ii antagonist |
HUP9903292A3 (en) * | 1996-05-31 | 2000-08-28 | Sankyo Co | Use of substances improving insulin resistance for production of remedies for autoimmune diseases |
-
1998
- 1998-08-20 AU AU87479/98A patent/AU8747998A/en not_active Abandoned
- 1998-08-20 EP EP98938913A patent/EP1007038A2/de not_active Withdrawn
- 1998-08-20 CA CA002300813A patent/CA2300813A1/en not_active Abandoned
- 1998-08-20 WO PCT/JP1998/003692 patent/WO1999009965A2/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9909965A3 * |
Also Published As
Publication number | Publication date |
---|---|
AU8747998A (en) | 1999-03-16 |
CA2300813A1 (en) | 1999-03-04 |
WO1999009965A3 (en) | 1999-05-20 |
WO1999009965A2 (en) | 1999-03-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6087384A (en) | Apoptosis inhibitor | |
JP3148973B2 (ja) | 医 薬 | |
EP1093370B1 (de) | Pharmazeutisches mittel zur behandlung von diabetes | |
EP1007038A2 (de) | Entzündungshemmendes mittel | |
EP0893995B1 (de) | Antikachektische zusammensetzung | |
CA2247946C (en) | Anticachectic composition | |
JP4473355B2 (ja) | アポトーシス抑制剤 | |
JPH11124331A (ja) | 抗炎症剤 | |
KR20020063555A (ko) | 약학 조성물 | |
JP2000080047A (ja) | 医 薬 | |
JP2008201800A (ja) | 悪液質の予防・治療剤 | |
JP2001294537A (ja) | 併用医薬 | |
MXPA00010582A (en) | Pharmaceutical composition for the treatment of diabetes | |
JP2003012551A (ja) | Abc発現促進剤 | |
JP2001342135A (ja) | 血管新生阻害剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19991122 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
17Q | First examination report despatched |
Effective date: 20020411 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20031215 |