EP0593761A1 - Nouveaux derives de thiophene - Google Patents
Nouveaux derives de thiopheneInfo
- Publication number
- EP0593761A1 EP0593761A1 EP91910169A EP91910169A EP0593761A1 EP 0593761 A1 EP0593761 A1 EP 0593761A1 EP 91910169 A EP91910169 A EP 91910169A EP 91910169 A EP91910169 A EP 91910169A EP 0593761 A1 EP0593761 A1 EP 0593761A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- salt
- optionally substituted
- amino
- 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.)
- Ceased
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- This invention relates to new thiophene derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
- the present invention relates to new thiophene derivatives and pharmaceutically acceptable salts thereof.
- inflammation and pain in joint and muscle e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc.
- inflammatory skin condition e.g. sunburn, eczema, etc.
- inflammatory eye condition e.g. conjunctivitis, etc.
- lung disorder in which inflammation is involved e.g. asthma, bronchitis. pigeon fancier's disease, farmer's lung, etc.
- condition of the gastrointestinal tract associated with inflammation e.g.
- aphthous ulcer Chrohn's disease, atropic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.
- gingivitis inflammation, pain and tumescence after operation or injury, pyresis, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, periarteritis nodosa, rheumatic fever, Sjögren's syndrome, Behcet disease, thyroiditis, type I diabetes, naphrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,
- One object of this invention is to provide new and useful thiophene derivatives and pharmaceutically
- Another object of this invention is to provide processes for the preparation of said thiophene
- a further object of this invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, said thiophene derivatives and
- Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of inflammatory conditions, various pains, and the other diseases mentioned above, using said thiophene derivatives and pharmaceutically acceptable salts thereof.
- R 1 is hydrogen; halogen; cyano; lower alkyl
- substituent( s) selected from the group consisting of halogen, hydroxy, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl
- substituent(s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfo; sulfamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxy, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy) lower alkyl; N-containing heterocyclicsulfonyl; hydroxy; or a heterocyclic group optionally
- R 2 is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower akylsulfonyl, nitro, amino, sulfamoyl and lower alkylsulfonylamino; and
- R 3 is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino, lower
- alkylamino alkylamino, acylamino, lower alkyl(acyl)amino, lower alkylsulfonylamino and sulfamoyl;
- R 3 is aryl substituted with substituent(s) selected from the group consisting of amino, mono(lower)alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl when R 1 is hydrogen, halogen or cyano, and pharmaceutically acceptable salts thereof.
- the object compound [I] or its salt can be prepared by the following processes .
- R 1 , R 2 and R 3 are each as defined above;
- R 1 a is cyano or acyl
- X is halogen
- R 1 b is halo(lower)alkyl
- R 1 c is lower alkanoyl optionally substituted with halogen; or aroyl optionally substituted with hydroxy;
- n is an integer of 0 to 6;
- R 4 is lower alkyl
- R 1 d is lower alkyl substituted with esterified
- A is -(CH 2 ) CO- or -SO 2 -;
- R 5 is amino optionally substituted with
- halo(lower)alkyl aryl, hydroxy, lower alkylamino( lower)alkyl, a heterocyclic group and (esterified carboxy) lower alkyl; or
- R 2 a is lower alkylthio-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino,sulfamoyl and lower alkylsulfonylamino;
- R 3 a is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfinyl , lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl) amino and sulfamoyl;
- R 2 b is lower alkylsulfinyl- or lower alkylsulfonyl- substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower
- R 2 c is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower
- R 3 b is lower alkylthio-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl;
- R 3 c is lower alkylsulfinyl- or lower alkylsulfonyl- substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl;
- R 2 d is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfonyl, nitro, amino, sulfamoyl and lower alkylsulfonylamino;
- R 1 d is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfonyl, nitro, amino, lower
- alkyl(acyl)amino and sulfamoyl alkyl(acyl)amino and sulfamoyl
- R 1 f is carboxy; esterified carboxy; lower alkyl substituted with carboxy or esterified carboxy; or lower alkanoyl optionally substituted with halogen;
- R 1 g is hydroxy(lower)alkyl optionally substituted with halogen
- R 1 h is lower alkoxyimino(lower)alkyl optionally substituted with halogen; or lower alkyl substituted with hydroxyimino and aryl optionally substituted with hydroxy;
- R 6 is hydrogen or lower alkyl
- R 1 i is nitro or sulfo
- R 2 e is nitro-substituted aryl optionally
- R 2 f is amino-substituted aryl optionally
- R 2 g is aryl optionally substituted with
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, sulfamoyl and lower alkylsulfonylamino;
- R 1 j is amino substituted with substituent(s)
- acyl and lower alkylsulfonyl selected from the group consisting of acyl and lower alkylsulfonyl
- R 1 k is hydrogen, halogen; cyano;
- heterocyclicsulfonyl or a heterocyclic group optionally substituted with oxo;
- R 2 h is lower alkylsulfonylamino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl;
- R 1 l is N-containing heterocycliccarbonyl; carbamoyl optionally substituted with lower alkyl; or lower alkyl substituted with carbamoyl optionally substituted with lower alkyl; R 1 m is lower alkyl substituted with N-containing heterocyclic group, amino or lower
- R 3 e is aryl optionally substituted with
- alkylsulfonyl nitro, acylamino, lower
- R 1 n is sulfamoyl optionally substituted with
- R 1o is thiazolyl substituted with amino or lower
- R 1 p is lower alkanoyl
- R 1 q is lower alkenyl optionally substituted with cyano
- B is di-esterified phosphono or substituted
- R 7 is lloowweerr alkyl optionally substituted with
- R 3 f is nitro-substituted aryl optionally
- alkylsulfinyl lower alkylsulfonyl, lower alkylamino, acylamino, lower
- alkyl(acyl)amino and sulfamoyl alkyl(acyl)amino and sulfamoyl
- R 3 g is amino-substituted aryl optionally
- alkylsulfinyl lower alkylsulfonyl, lower alkylamino, acylamino, lower alkyl( acyl)ammo and sulfamoyl;
- R 3 h is acylamino-substituted aryl optionally
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl( acyl)amino and sulfamoyl;
- R 3 i is lower alkyl(acyl)amino-substituted aryl
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl; and
- R 3 j is mono(lower)alkylamino-substituted aryl
- substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl.
- lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
- lower alkenyl is intended to mean a group having 2 to 6 carbon atoms .
- lower alkyl and lower alkyl moiety in the terms “lower alkylamino” , “lower alkyl(acyl)amino”, “lower alkylsulfonyl”, “lower alkylthio", “lower alkylsulfinyl” and “lower alkylsulfonylamino” may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is methyl or ethyl
- the lower alkyl group for R 1 may be substituted with substituent(s) as mentioned above, wherein the preferable number of the substituent(s) is 1 or 2.
- Suitable "aryl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di( tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl.
- the aryl group for R 2 may be substituted with 1 to 5 substituent(s) as mentioned above and the aryl group for R 3 may be substituted with 1 to 5 substituent(s) as stated above, wherein the preferable number of the substituent(s) is 1 or 2.
- Suitable “heterocyclic group” may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and
- preferable heterocyclic group may be N-containing
- heterocyclic group such as unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H-tetrazolyl,
- nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
- nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
- unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl,
- indolizinyl benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[l,5-b]pyridazinyl, etc.], etc.;
- an oxygen atom for example, pyranyl, furyl, etc.
- unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,
- unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzoxazolyl, benzoxadiazolyl, etc.
- Said "heterocyclic group” may have 1 to 3 substituents such as lower alkyl as exemplified above, hydroxy, oxo, amino and lower alkylamino.
- Preferable one is lower alkyl substituted with a heterocyclic group for R is pyrrolidinylmethyl.
- one in a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of hydroxy, oxo, amino and lower alkylamino for R is 4-hydroxy-2,5-dioxo-3-pyrrolin-3-yl,
- Suitable "halogen” may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine or
- acyl and acyl moiety in the terms “acylamino” and “lower alkyl(acyl) amino” may be carboxy; esterified carboxy; carbamoyl optionally substituted with substituent( s) selected from the group consisting of lower alkyl, halo(lower) alkyl, aryl, hydroxy, lower
- alkylamino(lower) alkyl, a heterocyclic group, (esterified carboxy) lower alkyl and carboxy(lower)alkyl e.g. lower alkyl-carbamoyl; aryl-carbamoyl; carbamoyl substituted with a heterocyclic group, (esterified carboxy) lower alkyl or carboxy(lower) alkyl; lower alkylcarbamoyl substituted with hydroxy, lower alkylamino, (esterified carboxy) lower alkyl or carboxy(lower) alkyl; etc.]; lower alkanoyl;
- the esterified carboxy may be substituted or
- unsubstituted lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
- the lower alkyl-carbamoyl may be substituted with halogen or unsubstituted one such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,
- the aryl-carbamoyl may be phenylcarbamoyl
- the carbamoyl substituted with a heterocyclic group may be one substituted with a heterocyclic group as mentioned above, in which preferable, one is
- carboxy lower alkyl may be methoxycarbonylmethylcarbamoyl, methoxycarbonylethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, ethoxycarbonylethylcarbamoyl,
- the carbamoyl substituted with carboxy(lower) alkyl may be carboxymethylcarbamoyl, carboxyethylcarbamoyl and the like.
- the lower alkylcarbamoyl substituted with hydroxy may be N-hydroxy-N-methylcarbamoyl
- N-ethyl-N-hydroxycarbamoyl N-hydroxy-N-propylcarbamoyl, N-hydroxy-N-isopropylcarbamoyl and the like, in which preferable one is N-hydroxy-N-meth ⁇ lcarbamoyl.
- the lower alkylcarbamoyl substituted with lower alkylamino may be methylaminomethylcarbamoyl
- dimethylaminomethylcarbamoyl dimethylaminoethylcarbamoyl, diethylaminoethylcarbamoyl, isopropylaminomethylcarbamoyl, isopropylaminoisobutylcarbamoyl and the like, in which preferable one is dimethylaminoethylcarbamoyl.
- the lower alkylcarbamoyl substituted with (esterified carboxy) lower alkyl may be (methoxycarbonylmethyl)-ethycarbamoyl, (ethoxycarbonylmethyl)methylcarbamoyl, (benzyloxycarbonylmethyl)methylcarbamoyl,
- carboxy(lower)alkyl may be (carboxymethyl)ethylcarbamoyl, (carboxymethyl)methylcarbamoyl,
- preferable one is (carboxymethyl)methylcarbamoyl.
- the lower alkanoyl may be substituted or
- unsubstituted one such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which preferable one is formyl, acetyl, propionyl or trifluoroacetyl.
- the aroyl may be benzoyl, naphthoyl, toluoyl,
- di(tert-butyl)benzoyl and the like and the aryl in said aroyl may be substituted with hydroxy.
- a heterocycliccarbonyl may be one mentioned above as a heterocyclic group and preferable one in said
- heterocycliccarbonyl is morpholinocarbonyl
- Suitable "lower alkoxy” and lower alkoxy moiety in term “lower alkoxyimino” may be methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, in which preferable one is methoxy.
- lower alkyl substituted with halogen is trifluoromethyl or pentafluoroethyl.
- Suitable "lower alkenyl” may be a straight or
- branched one such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl or the like, in which preferable one is isopropenyl.
- Said lower alkenyl may be substituted with cyano.
- Suitable “lower alkylamino” may be mono or di( lower alkyl)amino such as methylamino, ethylamina,
- Suitable "sulfamoyl substituted with lower alkyl” may be methylsulfamoyl, ethyIsulfamoyl, isopropylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like, in which preferable one is methylsulfamoyl or dimethylsulfamoyl.
- ester moiety in the term "di-esterified phosphono" can be referred to the ester moiety as
- ester group of the di-esterified phosphono may be the same or different.
- Suitable "substituted phosphonium salt” can be referred to the phosphonium salt conventionally used in the Wittig reaction [e.g. triphenylphosphonium bromide, tri(n-butyl)phosphonium chloride, etc.].
- Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g.
- a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
- a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt
- the compound [I-1] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its salt.
- Suitable salt of the compound [II] may be acid addition salt as exemplified for the compound [I].
- Suitable salts of the compound [III] may be base salt as exemplified for the compound [I].
- Suitable salt of the compound [I-1] may be the same as those exemplified for the compound [I].
- This reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g.
- alkaline earth metal hydride e.g. calcium hydride, etc.
- alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
- alkaline earth metal alkoxide e.g. magnesium methoxide, magnesium ethoxide, etc.
- trialkylamine e.g. trimethylamine, triethylamine, etc.
- the reaction is usually carried out in a conventional solvent such as dioxane, tetrahydrofuran, pyridine or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as dioxane, tetrahydrofuran, pyridine or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the compound [I-2] or its salt can be prepared by reacting a compound [IV] or its salt with a haloalkylating agent.
- Suitable salts of the compounds [IV] and [I-2] may be acid addition salts as exemplified for the compound [I].
- Suitable haloalkylating agent may be a metal salt of halo(lower)alkanoic acid [e.g. sodium trifluoroacetate, sodium pentafluoropropionate, etc.] and the like.
- halo(lower)alkanoic acid e.g. sodium trifluoroacetate, sodium pentafluoropropionate, etc.
- the present reaction is preferably carried out in the presence of a copper salt [e.g. cuprous iodide, etc.] and the like.
- a copper salt e.g. cuprous iodide, etc.
- the reaction is usually carried out in a solvent
- reaction temperature is not critical, and the reaction is usually carried out under warming or heating.
- the compound [I-3] or its salt can be prepared by reacting a compound [V] or its salt with an acylating agent.
- Suitable salts of the compounds [V] and [I-3] may be acid addition salts as exemplified for the compound [I].
- Suitable acylating agent may be a conventional one used in the Friedel-Crafts acylation reaction such as an acid halide [e.g. acid chloride, acid bromide, etc.], an acid anhydride or the like.
- an acid halide e.g. acid chloride, acid bromide, etc.
- an acid anhydride e.g. anhydride or the like.
- This reaction is preferably carried out in the presence of a Lewis acid such as aluminum halide [e.g. aluminum chloride, aluminum bromide, etc.], titanium halide [e.g. titanium tetrachloride, etc.] or the like.
- a Lewis acid such as aluminum halide [e.g. aluminum chloride, aluminum bromide, etc.], titanium halide [e.g. titanium tetrachloride, etc.] or the like.
- the reaction is usually carried out in a conventional solvent such as carbon disulfide, dichloroethane, benzene or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as carbon disulfide, dichloroethane, benzene or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the compound [I-5] or its salt can be prepared by reacting a compound [I-4] or its salt with a compound
- Suitable salts of the compounds [I-4] and [I-5] may be acid addition salts as exemplified for the compound
- the present reaction is preferably carried out in the presence of a thallium(III) salt [e.g. thallium(III) nitrate, etc.], an acid [e.g. perchloric acid, etc.] and the like.
- a thallium(III) salt e.g. thallium(III) nitrate, etc.
- an acid e.g. perchloric acid, etc.
- the reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
- a solvent such as dioxane, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under warming to heating.
- the compound [I-7] or its salt can be prepared by subjecting a compound [I-6] or its salt to
- Suitable salt of the compound [I-6] may be acid addition salt as exemplified for the compound [I].
- Suitable salt of the compound [I-7] may be the same as those exemplified for the compound [I].
- the reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
- the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
- Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4,3,0]non-5-ene,
- an alkali metal e.g. sodium, potassium, etc.
- an alkaline earth metal e.g. magnesium, calcium, etc.
- trialkylamine e.g. trimethylamine, triethylamine, etc.
- picoline 1,5-diazabicyclo[4,3,0]non-5-ene
- Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.].
- organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
- an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
- the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
- a liquid base or acid can be also used as the solvent.
- the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- the reduction can be applied preferably for
- ester moiety such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or the like.
- the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
- Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid,
- Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g.
- platinum plate spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
- palladium catalyst e.g. spongy palladium, palladium black
- palladium oxide palladium on carbon
- colloidal palladium palladium on barium sulfate
- nickel catalyst e.g. reduced nickel, nickel oxide, Raney nickel, etc.
- cobalt catalyst e.g. reduced cobalt, Raney cobalt, etc.
- iron catalyst e.g. reduced iron, Raney iron, etc.
- copper catalyst e.g.
- the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol,
- N,N-dimethylformamide or a mixture thereof.
- a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether. dioxane, tetrahydrofuran, etc., or a mixture thereof.
- reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
- the compound [I-9] or its salt can be prepared by reacting a compound [I-8] or its reactive derivative at the carboxy or sulfo group or a salt thereof with an amine, or formamide and alkali metal alkoxide.
- Suitable salts of the compound [I-8] and its reactive derivative at the carboxy or sulfo group may be acid addition salts as exemplified for the compound [I].
- Suitable “amine” may be ammonia, lower alkylamine, halo(lower)alkylamine, arylamine, lower
- alkylhydroxylamine lower alkylamino(lower)alkylamine, amine substituted with a heterocyclic group, an amino acid ester, N-containing heterocyclic compound and the like.
- the lower alkylamine may be mono or di(lower)-alkylamine such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, pentylamine, hexylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, di-isopropylamine, dipentylamine,
- the halo(lower)alkylamine may be fluoromethylamine, chloroethylamine, difluoroethylamine, dichloroethylamine, trichloroethylamme, trifluoroethylamine and the like, in which preferable one is trifluoroethylamme.
- the arylamine may be aniline, naphthylamine and the like, in which preferable one is aniline.
- the lower alkylhydroxylamine may be any organic compound having the lower alkylhydroxylamine.
- the lower alkylamino( lower)alkylamine may be any lower alkylamino( lower)alkylamine.
- dimethylaminomethylamine diethylaminomethylamine, dimethylaminoethylamine, diethylaminoethylamine and the like, in which preferable one is dimethylaminoethylamine.
- the amine substituted with a heterocyclic group may be aminothiazole, aminothiadiazole, aminotriazole, aminotetrazole and the like, in which preferable one is aminotetrazole.
- the amino acid ester may be amino acid lower alkyl ester [e.g. glycine methyl ester, N-methylglycine ethyl ester, ⁇ -alanine methyl ester, isoleucine ethyl ester, etc.], amino acid ar( lower)alkyl ester [e.g. glycine benzyl ester,N-methylglycine benzyl ester, ⁇ -alanine benzyl ester, etc. ] and the like, in which preferable one is N-methylglycine ethyl ester.
- amino acid lower alkyl ester e.g. glycine methyl ester, N-methylglycine ethyl ester, ⁇ -alanine methyl ester, isoleucine ethyl ester, etc.
- amino acid ar( lower)alkyl ester e.g. glycine benzyl ester,N-methylglycine benzyl
- the N-containing heterocyclic compound may be any organic compound.
- N-, or N- and S-, or N- and O- containing heterocyclic compound such as pyrrolidine, imidazolidine, piperidine, piperazine,
- N-(lower)alkylpiperazine e.g. N-methylpiperazine
- Suitable "alkali metal alkoxide” may be sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
- Suitable reactive derivative at the carboxy or sulfo group of the compound [I-8] may include an ester, an acid halide, an acid anhydride and the like.
- the suitable examples of the reactive derivatives may be an acid halide
- a symmetrical acid anhydride a mixed acid anhydride with 1,1'-carbonyl diimidazole or an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.], substituted phosphoric acid
- ester such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, etc.], substituted or unsubstituted ar( lower) alkyl ester [e.g. benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted or unsubstituted aryl ester [e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine,
- lower alkyl ester e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, etc.
- substituted or unsubstituted ar( lower) alkyl ester e.g
- the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
- hydrophilic solvents may be used in a mixture with water.
- the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide,
- the reaction is also preferably carried out in the presence of a conventional base such as triethylamine, pyridine, sodium hydroxide or the like.
- the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
- the compound [I-11] or its salt can be prepared by reacting a compound [I-10] or its salt with a compound [VII].
- Suitable salt of the compound [I-10] may be acid addition salt as exemplified for the compound [I].
- Suitable salt of the compound [I-11] may be the same as those exemplified for the compound [I].
- This reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], alkaline earth metal [e.g.
- alkali metal hydride e.g. sodium, magnesium, etc.
- alkaline earth metal hydride e.g. calcium hydride, etc.
- alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
- alkaline earth metal alkoxide e.g. magnesium methoxide, magnesium ethoxide, etc.
- the reaction is usually carried out in a conventional solvent such as an alcohol [e.g. methanol, ethanol, etc.], dioxane, tetrahydrofuran, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as an alcohol [e.g. methanol, ethanol, etc.], dioxane, tetrahydrofuran, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the compound [I-13] or its salt can be prepared by reacting a compound [I-12] or its salt with an oxidizing agent.
- Suitable salts of the compounds [I-12] and [I-13] may be the same as those exemplified for the compound [I].
- Suitable oxidizing agent may be hydrogen peroxide, Jones reagent, peracid [e.g. pera ⁇ etic acid, perbenzoic acid, m-chloroperbenzoic acid, etc.], chromic acid, potassium permanganate, alkali metal periodate [e.g.
- This reaction is usually carried out in a solvent which does not adversely influence the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, an alcohol [e.g. methanol, ethanol, etc.], a mixture thereof or the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
- alkylamino( lower)alkyl for R 1 may be obtained respectively according to reaction conditions. These cases are
- the compound [I-15] or its salt can be prepared by reacting a compound [I-14] or its salt with an oxidizing agent.
- Suitable salts of the compounds [I-14] and [I-15] may be the same as those exemplified for the compound [I].
- Suitable oxidizing agent may be the same as those exemplified in Process 8.
- reaction can be carried out in substantially the same manner as Process 8, and therefore the reaction mode and reaction condition [e.g. solvent, reaction
- the compound [I-16] or its salt can be prepared by reacting a compound [I-3] or its salt with an oxidizing agent.
- Suitable salts of the compounds [I-3] and [I-16] may be the same as those exemplified for the compound [I].
- Suitable oxidizing agent may be the same as those exemplified in Process 8.
- reaction can be carried out in substantially the same manner as Process 8, and therefore the reaction mode and reaction condition [e.g. solvent, reaction
- the compound [I-18] or its salt can be prepared by reacting a compound [I-17] or its salt with a reducing agent.
- Suitable salts of the compounds [I-17] and [I-18] may be the same as those exemplified for the compound [I].
- Suitable reducing agent may be aluminum hydride compound [e.g. lithium aluminum hydride, lithium
- tri-t-butoxyaluminum hydride, etc. tri-t-butoxyaluminum hydride, etc.]
- borohydride compound e.g. sodium borohydride, etc.
- aluminum alkoxide e.g. aluminum isopropoxide, etc.
- the reaction is usually carried out in a conventional solvent, such as water, an alcohol [e.g. methanol,
- the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
- the compound [I-19] or its salt can be prepared by reacting a compound [I-3] or its salt with a compound
- [VIII] may be acid addition salts as exemplified for the compound [I].
- the reaction is usually carried out in a conventional solvent such as water, an alcohol [e.g methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
- a conventional solvent such as water, an alcohol [e.g methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform,
- the reaction is preferably carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate [e.g. sodium bicarbonate, potassium
- alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
- tri( lower)alkylamine e.g. triethylamine, etc.
- pyridine e.g. pyridine, or the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the compound [I-20] or its salt can be prepared by reacting a compound [V] or its salt with a nitrating agent or a sulfonating agent.
- Suitable salts of the compounds [I-20] and [V] may be acid addition salts as exemplified for the compound [I].
- Suitable nitrating agent may be nitric acid, fuming nitric acid, potassium nitrate, nitronium
- Suitable sulfonating agent may be sulfuric acid, fuming sulfuric acid and the like.
- the reaction is usually carried out in an acid or an acid anhydride such as sulfuric acid, acetic acid,
- reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the compound [I-22] or its salt can be prepared by subjecting a compound [I-21] or its salt to reduction.
- Suitable salts of the compounds [I-21] and [I-22] may be acid addition salts as exemplified for the compound
- the present reduction is carried out by chemical reduction, catalytic reduction, or the like.
- Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid,
- Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g.
- platinum plate spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
- palladium catalyst e.g. spongy palladium, palladium black
- palladium oxide palladium on carbon
- colloidal palladium palladium on barium sulfate
- nickel catalyst e.g. reduced nickel, nickel oxide, Raney nickel, etc.
- cobalt catalyst e.g. reduced cobalt, Raney cobalt, etc.
- iron catalyst e.g. reduced iron, Raney iron, etc.
- copper catalyst e.g.
- the reduction is usually carried out in a
- a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, methylene chloride, dioxane, tetrahydrofuran, etc., or a mixture thereof.
- reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
- the compound [I-24] or its salt can be prepared by subjecting a compound [I-23] or its salt to reduction.
- Suitable salts of the compounds [I-23] and [I-24] may be the same as those exemplified for the compound [I].
- This reaction can be carried out in substantially the same manner as Process 14, and therefore the reducing agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 14.
- the reducing agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 14.
- the compound [I-26] can be prepared by reacting a compound [I-25] or its salt with an acylating or
- Suitable salt of the compound [I-25] may be acid addition salt as exemplified for the compound [I].
- the acylating or sulfonylating agent may include an organic acid represented by the formula : R 8 -OH, in which R 8 is acyl or lower alkylsulfonyl as illustrated above, or a reactive derivative thereof, a compound of the formula :
- Suitable reactive derivative of the organic acid may be a conventional one such as an acid halide [e.g. acid chloride, acid bromide, etc.], an acid azide, an acid anhydride, an activated amide, an activated ester, etc.
- an acid halide e.g. acid chloride, acid bromide, etc.
- an acid azide e.g. an acid anhydride
- an activated amide e.g., an activated ester, etc.
- the present reaction may preferably be carried out in the presence of conventional condensing agent such as N,N'-dicyclohexylcarbodiiraide, acetic
- This reaction is usually carried out in a conventional solvent such as dioxane, chloroform, methylene chloride, tetrahydrofuran, pyridine or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as dioxane, chloroform, methylene chloride, tetrahydrofuran, pyridine or any other organic solvent which does not adversely influence the reaction.
- the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium
- tri( lower)alkylamine e.g. triethylamine, etc.
- triethylamine e.g. triethylamine, etc.
- the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
- acylamino or lower alkylsulfonylamino for R 3 may be obtained according to reaction conditions. This case is included within the scope of the present reaction.
- the compound [I-28] can be prepared by reacting a compound [I-27] or its salt with a sulfonylating agent.
- Suitable salt of the compound [I-27] may be acid addition salt as exemplified for the compound [I].
- This reaction can be carried out in substantially the same manner as Process 16, and therefore the sulfonylating agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 16.
- the sulfonylating agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 16.
- the compound [I-30] or its salt can be prepared by reacting a compound [I-29] or its salt with a reducing agent.
- Suitable salts of the compounds [I-29] and [I-30] may be acid addition salts as exemplified for the compound
- Suitable reducing agent may be diborane, a metal hydride [e.g. lithium aluminum hydride, etc.] and the like.
- the reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
- the compound [I-31] or its salt can be prepared by reacting a compound [V] or its salt with a formylating agent.
- Suitable salts of the compounds [V] and [I-31] may be acid addition salts as exemplified for the compound [I].
- Suitable formylating agent may be
- N,N-dimethylformamide N,N-dimethylformamide
- Vilsmeir reagent prepared by the reaction of N,N-dimethylformamide with phosphorus oxychloride, phosgene, etc.; and the like.
- a formylating agent is N,N-dimethylformamide
- the reaction is preferably carried out in the presence of a base such as lower alkyl alkali metal [e.g. n-butyl lithium, etc.], or the like.
- the reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform, or any other organic solvent which does not adversely influence the reaction.
- a solvent such as dioxane, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform, or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the compound [I-32] can be prepared by the following methods. Namely, 1) the compound [Va] is firstly reacted with a chlorosulfonylatmg agent, and then 2) reacting the resultant product with an amine.
- Suitable "amine” may be the same as those exemplified in Process 6.
- suitable chlorosulfonylatmg agent may be chlorosulfonic acid, and the like.
- the chlorosulfonylating agent is usually used as a solvent.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the reaction is carried out in a solvent such as water, ethyl acetate, tetrahydrofuran or any other solvent which does not adversely influence the reaction.
- a solvent such as water, ethyl acetate, tetrahydrofuran or any other solvent which does not adversely influence the reaction.
- This reaction temperature is not critical, and the reaction is usually carried out under cooling.
- the compound [I-34] or its salt can be prepared by reacting a compound [I-33] or its salt with thiourea or lower(alkyl)thiourea.
- Suitable salts of the compounds [I-33] and [I-34] may be acid addition salts as exemplified for the compound [I].
- the reaction is usually carried out in a solvent such as an alcohol [e.g. methanol ethanol, etc.], chloroform, methylene chloride, tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction.
- a solvent such as an alcohol [e.g. methanol ethanol, etc.], chloroform, methylene chloride, tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
- the compound [I-36] or its salt can be prepared by reacting a compound [I-35] or its salt with a compound
- Suitable salts of the compounds [I-35] and [I-36] may be acid addition salts as exemplified for the compound
- This reaction is preferably carried out in the
- an inorganic or organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate thereof, alkali metal hydride [e.g. sodium hydride, etc.], alkali metal amide [e.g. sodium amide, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], alkaline earth metal alkoxide [e.g.
- an inorganic or organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate thereof, alkali metal hydride [e.g. sodium hydride, etc.], alkali metal amide [e.g. sodium amide,
- magnesium methoxide, magnesium ethoxide, etc.] lower alkyl alkali metal [e.g. n-butyl lithium, etc.], trialkylamine [e.g. trimethylamine, triethylamine, etc.], pyridine, piperidine, picoline, 1, 5-diazabicyclo[4,3,0]non-5-ene,
- lower alkyl alkali metal e.g. n-butyl lithium, etc.
- trialkylamine e.g. trimethylamine, triethylamine, etc.
- pyridine piperidine, picoline, 1, 5-diazabicyclo[4,3,0]non-5-ene
- the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], chloroform, methylene chloride, nitromethane, benzene, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adversely influence the reaction.
- a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], chloroform, methylene chloride, nitromethane, benzene, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adversely influence the reaction.
- the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
- the phosphorane compound may be used instead of the compound [IX]. This case is also included within the scope of the present reaction.
- the compound [I-38] or its salt can be prepared by subjecting a compound [I-37] or its salt to reduction.
- Suitable salts of the compounds [I-37] and [I-38] may be the same as those exemplified for the compound [I].
- This reaction can be carried out . in substantially the same manner as Process 14, and therefore the reducing agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 14.
- the reducing agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 14.
- the compound [I-38] having amino for R 1 and/or aryl substituted with amino for R 2 may be obtained according to reaction conditions. This case is included within the scope of the present reaction.
- the compound [I-40] can be prepared by reacting a compound [I-39] or its salt with an acylating agent.
- Suitable salt of the compound [I-39] may be acid addition salt as exemplified for the compound [I].
- the compound [I-41] can be prepared by reacting a compound [I-40] with an alkylating agent.
- Suitable alkylating agent may be lower alkyl halide [e.g. methyl iodide, ethyl bromide, etc.] and the like.
- the reaction is preferably carried out in the presence of a base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydride thereof or the like.
- a base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydride thereof or the like.
- the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dioxane, tetrahydrofuran, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned alkylating agent are in liquid, they can also be used as a solvent.
- the reaction temperature is not critical and the reaction can be carried out under cooling to heating.
- the compound [I-43] or its salt can be prepared by reacting a compound [I-42] or its salt with a dehydrating agent.
- Suitable salts of the compounds [I-42] and [I-43] may be acid addition salts as exemplified for the compound
- Suitable dehydrating agent may be phosphorus compound [e.g. phosphorus pentoxide, phosphorus pentachloride, phosphorus oxychloride, etc.], thionyl chloride, acid anhydride [e.g. acetic anhydride, etc.], phosgene, arylsulfonyl chloride [e.g. benzenesulfonyl chloride, p-toluenesulfonyl chloride, etc.], methanesulfonyl
- the reaction is usually carried out in a conventional solvent such as acetonitrile, methylene chloride, ethylene chloride, benzene, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
- a conventional solvent such as acetonitrile, methylene chloride, ethylene chloride, benzene, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
- dehydrating agents are in liquid, they can also be used as a solvent.
- the reaction temperature is not critical and the reaction is preferably carried out under warming or heating.
- the compound [I-44] or its salt can be prepared by subjecting a compound [I-41] to deacylation reaction.
- Suitable salt of the compound [I-44] may be acid addition salt as exemplified for the compound [I].
- This reaction may preferably be conducted in the presence of an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, etc.] and an organic acid [e.g.
- the reaction is usually carried out in a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.
- a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.
- the reaction temperature is not critical, and the reaction can be carried out cooling to heating.
- the compound [I-45] or its salt can be prepared by reacting a compound [I-43] or its salt with an azide compound.
- Suitable salts of the compounds [I-43] and [I-45] may be the same as those exemplified for the compound [I].
- Suitable azide compound may be alkali metal azide
- alkaline earth metal azide e.g. calcium azide, etc.
- hydrogen azide and the like e.g. sodium azide, potassium azide, etc.
- alkaline earth metal azide e.g. calcium azide, etc.
- hydrogen azide and the like e.g. sodium azide, potassium azide, etc.
- alkaline earth metal azide e.g. calcium azide, etc.
- hydrogen azide and the like e.g. sodium azide, potassium azide, etc.
- reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane,
- the reaction temperature is not critical, and the reaction can be carried out warming to heating.
- the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like. It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
- acceptable salts thereof possess strong antiinflammatory and analgesic activities, and are useful for the treatment and/or prevention of inflammatory conditions and various pains, collagen diseases, autoimmune diseases and various immunity diseases in human beingsor animals, and more particularly to methods for the treatment and/or
- rheumatoid arthritis rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc.
- inflammatory skin condition e.g. sunburn, eczema, etc.
- inflammatory eye condition e.g. conjunctivitis, etc.
- lung disorder in which inflammation is involved e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.] condition of the gastrointensinal tract associated with inflammation [e.g.
- aphthous ulcer Chrohn's disease, atropic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.
- gingivitis inflammation, pain and tumescence after operation or injury, pyresis, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lups erythematosus, scleroderma, polymyositis, periarteritis nodosa, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,
- methylcellulose was injected into the right hind paw.
- the pain threshold was determined 3 hours after yeast
- the drugs were given orally 2 hours after yeast injection.
- the pain threshold in the treated animals was compared with that in the control animals.
- Type II bovine collagen was solublized in 0.1 M acetic acid and emulsified in complete Freund's adjuvant (CFA). Mice were primed with 0.2 mg of Type II collagen in CFA
- mice were inspected weekly for visual signs of arthritis.
- An arthritis index was used to grade limb 0-3, representing joint swelling and erythema (Grade 1), visible joint disorder (Grade 2) and detectable joint ankylosis (Grade 3).
- a 0.04 ml challenge dose of 2.5 mg/ml type II collagen in phosphate buffered saline (PBS) was injected into the plantar region of the right hind foot and 0.04 ml PBS into the left hind foot to act as a control. Twenty four hours after challenge, the volume of both hind feet were measured with a volume meter (Muromachi MK-550). The drug was administered orally on consecutive days except holidays starting from the sensitization.
- PBS phosphate buffered saline
- the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical
- compositions may be capsules, tablets, dragees, granules, suppositories, solution, suspension, emulsion, or the like. If desired, there may be included in these
- the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
- the following Preparations and Examples are given for the purpose of illustrating this invention.
- Example 5 The following compounds (Examples 5-1) and 5-2)) were obtained according to a similar manner to that of Example 4 .
- Example 5 The following compounds (Examples 5-1) and 5-2)) were obtained according to a similar manner to that of Example 4 .
- Example 5
- Titanium (IV) chloride (2.7 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4- (methylsulfonyl)phenyl]thiophene (5 g) and acetyl chloride (2.2 ml) in benzene (50 ml) at 5 to 10°C. The mixture was stirred at ambient temperature for 4 hours, poured into ice-water, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated.
- the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was
- Example 18-1) to 18-9 were obtained according to a similar manner to that of Example 17.
- Example 22 The following compounds (Examples 22-1) to 22-19)) were obtained according to a similar manner to that of Example 21.
- Example 22 The following compounds (Examples 22-1) to 22-19)) were obtained according to a similar manner to that of Example 21.
- Example 22
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Abstract
L'invention concerne de nouveaux dérivés de thiophène possédant une activité anti-inflammatoire et analgésique et représentés par la formule (I) dans laquelle R1 est hydrogène, halogène, cyano, alkyle inférieur substitué, alcényle inférieur substitué ou non substitué, acyle, nitro, amino substitué ou non substitué, sulfo, sulfamoyle substitué ou non substitué, sulfonyle hétérocyclique renfermant de l'azote, hydroxy, groupe hétérocyclique substitué ou non substitué, R2 est aryle substitué ou non substitué, et R3 est aryle substitué ou non substitué, à condition que R3 soit aryle substitué avec un ou des substituants choisis dans le groupe composé d'amino, mono-alkylamino (inférieur), acylamino, (acyle)amino alkyle inférieur et sulfamoyle lorsque R1 est hydrogène, halogène ou cyano, ainsi que leurs sels pharmaceutiquement acceptables, des procédés pour leur préparation et une composition pharmaceutique les renfermant.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909012936A GB9012936D0 (en) | 1990-06-11 | 1990-06-11 | Thiophene derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
GB9012936 | 1990-06-11 | ||
PCT/JP1991/000744 WO1991019708A1 (fr) | 1990-06-11 | 1991-05-31 | Nouveaux derives de thiophene |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0593761A1 true EP0593761A1 (fr) | 1994-04-27 |
Family
ID=10677388
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91910169A Ceased EP0593761A1 (fr) | 1990-06-11 | 1991-05-31 | Nouveaux derives de thiophene |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0593761A1 (fr) |
JP (1) | JPH06501919A (fr) |
CN (1) | CN1059142A (fr) |
AU (1) | AU7973191A (fr) |
GB (1) | GB9012936D0 (fr) |
IE (1) | IE911942A1 (fr) |
IL (1) | IL98393A0 (fr) |
PT (1) | PT97906B (fr) |
WO (1) | WO1991019708A1 (fr) |
ZA (1) | ZA914241B (fr) |
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JPH06135961A (ja) * | 1992-10-23 | 1994-05-17 | Nippon Iyakuhin Kogyo Kk | 新規ジフェニルピロリルフラン誘導体 |
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GB9420616D0 (en) * | 1994-10-12 | 1994-11-30 | Merck Sharp & Dohme | Method, compositions and use |
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
CA2180651A1 (fr) * | 1994-01-10 | 1995-07-13 | Yves Ducharme | Heterocycles phenyliques utilises comme inhibiteurs de cox-2 |
JP2636819B2 (ja) | 1994-12-20 | 1997-07-30 | 日本たばこ産業株式会社 | オキサゾール系複素環式芳香族化合物 |
FR2730996B1 (fr) * | 1995-02-23 | 1997-06-20 | Adir | Nouveaux composes du thiophene, leur procede de preparation et les compositions pharmaceutiques les renfermant |
CA2213537A1 (fr) * | 1995-02-24 | 1996-08-29 | Kiyomi Tanaka | Derives de phenylamidinothiophene et agent antiphlogistique les contenant |
CA2223154A1 (fr) * | 1995-06-02 | 1996-12-05 | G.D. Searle & Co. | Derives heterocyclo-substitues d'acide hydroxamique utilises comme inhibiteurs de la cyclo-oxygenase-2 et de la 5-lipoxygenase |
US6515014B2 (en) | 1995-06-02 | 2003-02-04 | G. D. Searle & Co. | Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
JPH11507670A (ja) * | 1995-06-12 | 1999-07-06 | ジー.ディー.サール アンド カンパニー | シクロオキシゲナーゼ−2インヒビターと5−リポキシゲナーゼインヒビターの組合せによる炎症と炎症関連疾患の治療 |
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FR2752576B1 (fr) * | 1996-08-22 | 1999-02-26 | Adir | Nouveaux composes du thiophene, leur procede de preparation et les compositions pharmaceutiques les renfermant |
US6034089A (en) * | 1997-10-03 | 2000-03-07 | Merck & Co., Inc. | Aryl thiophene derivatives as PDE IV inhibitors |
JP3409029B2 (ja) * | 1997-10-03 | 2003-05-19 | メルク フロスト カナダ アンド カンパニー | Pdeiv阻害剤としてのアリールチオフェン誘導体 |
JP2003531202A (ja) | 2000-04-25 | 2003-10-21 | ファルマシア・コーポレーション | 3,4−ジ(カルボシクリルまたはヘテロシクリル)チオフェンの位置選択的合成 |
JP2002037784A (ja) * | 2000-05-17 | 2002-02-06 | Nikken Chem Co Ltd | 新規チオフェンアミド化合物 |
AUPR283801A0 (en) * | 2001-02-01 | 2001-03-01 | Australian National University, The | Chemical compounds and methods |
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
US7202257B2 (en) | 2003-12-24 | 2007-04-10 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
US7279576B2 (en) | 2002-12-31 | 2007-10-09 | Deciphera Pharmaceuticals, Llc | Anti-cancer medicaments |
CN1309717C (zh) * | 2003-06-03 | 2007-04-11 | 李小虎 | 4-芳基-5h-噻吩-2-酮衍生物、其制法和用途 |
FR2860792B1 (fr) * | 2003-10-10 | 2006-02-24 | Sanofi Synthelabo | Derives de thiophene-2-carboxamide, leur preparation et leur application en therapeutique |
FR2880023B1 (fr) | 2004-12-23 | 2007-02-23 | Sanofi Aventis Sa | Derives de n-[(4,5-diphenyl-3-alkyl-2-thienyl) methyl] amine leur preparation et leur application en therapeutique |
AU2005321946B2 (en) | 2004-12-23 | 2012-08-16 | Deciphera Pharmaceuticals, Llc | Enzyme modulators and treatments |
FR2880890B1 (fr) * | 2005-01-19 | 2007-03-30 | Sanofi Aventis Sa | Derives de n-[(4,5-diphenyl-2-thienyl)methyl]sulfonamide, leur preparation et leur application en therapeutique |
FR2881744B1 (fr) | 2005-02-09 | 2007-04-27 | Sanofi Aventis Sa | Derives de n-[(4,5-diphenyl-2-thienyl)methyl]amine, leur preparation et leur application en therapeutique |
GB0603041D0 (en) | 2006-02-15 | 2006-03-29 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
US20090324581A1 (en) | 2006-05-09 | 2009-12-31 | Daiichi Sankyo Company Limited | Heteroarylamide lower carboxylic acid derivative |
US8188113B2 (en) | 2006-09-14 | 2012-05-29 | Deciphera Pharmaceuticals, Inc. | Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
US7790756B2 (en) | 2006-10-11 | 2010-09-07 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases |
AU2008242697A1 (en) | 2007-04-20 | 2008-10-30 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases |
DE102008015032A1 (de) | 2008-03-17 | 2009-09-24 | Aicuris Gmbh & Co. Kg | Substituierte Pyrazolamide und ihre Verwendung |
DE102008015033A1 (de) | 2008-03-17 | 2009-09-24 | Aicuris Gmbh & Co. Kg | Substituierte (Pyrazolyl-carbonyl)imidazolidinone und ihre Verwendung |
FR2934594B1 (fr) * | 2008-08-01 | 2010-09-10 | Sanofi Aventis | Derives de thiophene-2-carboxamide, leur preparation et leur application en therapeutique. |
CA2742007C (fr) | 2008-10-29 | 2014-07-08 | Deciphera Pharmaceuticals, Llc | Amides de cyclopropane et analogues presentant des activites anticancereuses et antiproliferatives |
DE102008062863A1 (de) | 2008-12-17 | 2010-06-24 | Aicuris Gmbh & Co. Kg | Substituierte (Thiophenyl-carbonyl)imidazolidinone und ihre Verwendung |
DE102008062878A1 (de) | 2008-12-17 | 2010-06-24 | Aicuris Gmbh & Co. Kg | Substituierte Furancarboxamide und ihre Verwendung |
ES2583093T3 (es) * | 2011-03-03 | 2016-09-19 | Denovamed Inc. | Compuestos antimicrobianos/adyuvantes |
WO2013146754A1 (fr) * | 2012-03-27 | 2013-10-03 | 塩野義製薬株式会社 | Dérivé à noyau à cinq chaînons hétérocyclique aromatique ayant une activité inhibitrice de trpv4 |
MX2014014614A (es) * | 2012-05-31 | 2015-02-12 | Phenex Pharmaceuticals Ag | Tiazoles sustituidos por carboxamida o sulfonamida y derivados relacionados como moduladores para el receptor nuclear huerfano ror [gamma). |
US8461179B1 (en) | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
JO3215B1 (ar) | 2012-08-09 | 2018-03-08 | Phenex Pharmaceuticals Ag | حلقات غير متجانسة بها 5 ذرات تحتوي على النيتروجين بها استبدال بكربوكساميد أو سلفوناميد كمعدلات لمستقبل نووي غير محمي RORy |
US20170266173A1 (en) | 2014-08-25 | 2017-09-21 | Bing Hui Wang | Mapk inhibitors |
CA3089566A1 (fr) | 2018-01-31 | 2019-08-08 | Deciphera Pharmaceuticals, Llc | Polytherapie pour le traitement de tumeurs stromales gastro-intestinales |
WO2019169479A1 (fr) | 2018-03-05 | 2019-09-12 | Denovamed Inc. | Dérivés de thiophène-2-amide à substitution diphényle et compositions pharmaceutiques de ceux-ci utiles en tant qu'agent antimicrobien |
JP2022544234A (ja) | 2019-08-12 | 2022-10-17 | デシフェラ・ファーマシューティカルズ,エルエルシー | 胃腸間質腫瘍を治療するためのリプレチニブ |
WO2021030405A1 (fr) | 2019-08-12 | 2021-02-18 | Deciphera Pharmaceuticals, Llc | Ripretinib pour le traitement de tumeurs stromales gastro-intestinales |
KR20220123058A (ko) | 2019-12-30 | 2022-09-05 | 데시페라 파마슈티칼스, 엘엘씨. | 1-(4-브로모-5-(1-에틸-7-(메틸아미노)-2-옥소-1,2-디히드로-1,6-나프티리딘-3-일)-2-플루오로페닐)-3-페닐우레아의 조성물 |
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US4302461A (en) * | 1979-08-09 | 1981-11-24 | E. I. Du Pont De Nemours And Company | Antiinflammatory 5-substituted-2,3-diarylthiophenes |
EP0055471A1 (fr) * | 1980-12-29 | 1982-07-07 | E.I. Du Pont De Nemours And Company | 4,5-Diaryl-alpha,alpha-bis-(polyhalométhyl)-2-thiophène-méthan-amines anti-inflammatoires |
US4381311A (en) * | 1980-12-29 | 1983-04-26 | E. I. Du Pont De Nemours And Company | Antiinflammatory 4,5-diaryl-α-(polyhalomethyl)-2-thiophenemethanols |
EP0087629B1 (fr) * | 1982-03-03 | 1986-01-15 | E.I. Du Pont De Nemours And Company | 2,3-Diaryl-5-halo-thiophènes, anti-inflammatoires et/ou analgésiques |
US4432974A (en) * | 1982-03-04 | 1984-02-21 | E. I. Du Pont De Nemours And Company | Antiinflammatory and/or analgesic 2,3-diaryl-5-silyl thiophenes |
US4749712A (en) * | 1983-03-01 | 1988-06-07 | E. I. Du Pont De Nemours And Company | Antiinflammatory and/or analgesic 5-alkylthiophenes |
-
1990
- 1990-06-11 GB GB909012936A patent/GB9012936D0/en active Pending
-
1991
- 1991-05-31 EP EP91910169A patent/EP0593761A1/fr not_active Ceased
- 1991-05-31 AU AU79731/91A patent/AU7973191A/en not_active Abandoned
- 1991-05-31 JP JP3509612A patent/JPH06501919A/ja active Pending
- 1991-05-31 WO PCT/JP1991/000744 patent/WO1991019708A1/fr not_active Application Discontinuation
- 1991-06-04 ZA ZA914241A patent/ZA914241B/xx unknown
- 1991-06-06 IL IL98393A patent/IL98393A0/xx unknown
- 1991-06-06 IE IE194291A patent/IE911942A1/en unknown
- 1991-06-07 PT PT97906A patent/PT97906B/pt not_active IP Right Cessation
- 1991-06-10 CN CN91104746A patent/CN1059142A/zh active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO9119708A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1991019708A1 (fr) | 1991-12-26 |
JPH06501919A (ja) | 1994-03-03 |
PT97906B (pt) | 1998-10-30 |
CN1059142A (zh) | 1992-03-04 |
IE911942A1 (en) | 1991-12-18 |
GB9012936D0 (en) | 1990-08-01 |
AU7973191A (en) | 1992-01-07 |
ZA914241B (en) | 1992-03-25 |
PT97906A (pt) | 1992-03-31 |
IL98393A0 (en) | 1992-07-15 |
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