WO1993024442A1 - Medicament renfermant un derive d'acide benzoique, et nouveau derive d'acide benzoique - Google Patents

Medicament renfermant un derive d'acide benzoique, et nouveau derive d'acide benzoique Download PDF

Info

Publication number
WO1993024442A1
WO1993024442A1 PCT/JP1993/000710 JP9300710W WO9324442A1 WO 1993024442 A1 WO1993024442 A1 WO 1993024442A1 JP 9300710 W JP9300710 W JP 9300710W WO 9324442 A1 WO9324442 A1 WO 9324442A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
nmr
benzoic acid
reference example
Prior art date
Application number
PCT/JP1993/000710
Other languages
English (en)
Japanese (ja)
Inventor
Hiromu Hara
Susumu Igarashi
Takenori Kimura
Masahiko Isaka
Ryo Naito
Hitoshi Nagaoka
Hiroshi Koutoku
Ken-Ichi Tomioka
Toshiyasu Mase
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP16414492A external-priority patent/JPH05331104A/ja
Priority claimed from JP16842492A external-priority patent/JPH05331059A/ja
Priority claimed from JP35594892A external-priority patent/JPH06183961A/ja
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Publication of WO1993024442A1 publication Critical patent/WO1993024442A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/33—Polycyclic acids
    • C07C63/331—Polycyclic acids with all carboxyl groups bound to non-condensed rings

Definitions

  • the present invention relates to a testosterone 5 ⁇ -reductase inhibitor and a novel benzoic acid derivative having a testosterone 5 ⁇ -reductase inhibitory activity, which contain a benzoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to a pharmaceutically acceptable salt.
  • Testosterone (TS) secreted by the testis and adrenal gland is taken up by androsidun target cells, and then reduced to dihydrotestosterone (DHT) by the action of intracellular 5 ⁇ -reductase.
  • DHT generated in this way is thought to be closely related to the development of prostatic hyperplasia and prostate cancer.
  • the onset and exacerbation of androgenetic alopecia and acne seborrhea are also considered to be one of the causes of excess DHT and T S.
  • Steroid type compounds include, for example, Japanese Patent Publication No. 63-65080
  • the compounds described in the publications are also known as non-steroid type compounds, for example, benzoylaminophenoxybutanoic acid derivatives of the following formula described in JP-A-11-156950.
  • ONO-3805 contained in this claim had the most potent 5 ⁇ -reductase inhibitory activity among conventional non-steroidal compounds. ing.
  • this compound is not only completely different in structure from the compound of the present invention, but its activity is more than 50 times weaker than that of the compound of steroid type.
  • ⁇ ⁇ -3805 is a compound that selectively acts on rat-derived enzymes, and has strong activity against rats, but has insufficient activity against human-derived enzymes.
  • the compound differs from the compound of the present invention in that the compound must have a specific substituted amide at the 0-position of carboxyphenoxyphenyl.
  • the compound selectively acts on a rat-derived enzyme as in the case of ON 0-3805.
  • JP-A-60-142936 discloses a general formula
  • a compound represented by is disclosed. Specifically,
  • the present inventors have proposed a benzoic acid derivative embraced by the following general formula (I) or a pharmaceutically acceptable derivative thereof having a different structure from a compound having a 5 ⁇ -reductase inhibitory activity.
  • the present inventors have recognized that the salt has a human testosterone 5 ⁇ -reductase inhibitory action several times to several hundred times stronger than a conventionally known non-steroid type compound, and have completed the present invention.
  • the compound of the present invention Most of the compounds of the present invention have an activity comparable to that of the conventionally known steroid-type 5 ⁇ -reductase inhibitory compound, and some of the compounds of the present invention have even better activity than the steroid-type 5 ⁇ -reductase inhibitor. It was confirmed that active compounds were also included.
  • the present invention is based on the action of a 5a-reductase inhibitor containing a benzoic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, or an androgen:
  • a 5a-reductase inhibitor containing a benzoic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, or an androgen The use of the compound (I) or a pharmaceutically acceptable salt thereof for preventing and / or treating a disease, or a method for preventing and / or treating the disease using the compound is provided.
  • the compounds represented by the following general formulas ((), (I) and (IV) are all novel, and the present invention provides compounds ( ⁇ ), (! ) Or (IV) or the invention of a pharmaceutically acceptable salt, and the purpose is to provide these compounds.
  • R 1 , R 2 , R s , R 4 , R 5 , R e , R 7 and R 8 identical or different, a hydrogen atom or an organic residue;
  • X 1 a group represented by the formula —0—, one S—, one N—, or one (0) one A 1 — (0) m —; R: a hydrogen atom; an organic residue; or a compound of the formula: R 1D , A 2 — R ie ,
  • a 2 -X 3 A group represented by R 10 ;
  • n 0, 1 or 2;
  • R 9 a hydrogen atom or a lower alkyl group
  • a 1 an alkylene group having 1 to 20 carbon atoms or a lower alkenylene group
  • R 10 an aromatic carbocyclic group which may have a substituent; or a cycloalkyl group which may have a substituent and may be cross-linked;
  • a 2 and A 3 same or different, lower alkylene group, lower alkenylene group, or lower alkynylene group;
  • X 2 and X 3 same or different, formula — 0—, one S—, one N—,
  • R 11 a hydrogen atom, a lower alkyl group, an aromatic carbocyclic group, or an aralkyl group.
  • R is a group other than a hydrogen atom, it is bonded at the m-position or the p-position to X 1 , and R is integrated with R 8 and a benzene ring; Or
  • X 4 is a group represented by the formula 1 C 1 or ——C——
  • R 1S is the same or different and represents a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxy group.
  • R 21 , R 22 , R ", R", R 25 , R 2 R 27 and R 28 same or different, hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, trihalogeno Methyl group, carboxyl lower alkyl group, hydroxy group, lower alkoxy group, carboxy lower alkoxy group, phenoxy group, benzyloxy group, hydroxyl group, lower alkoxycarbonyl group, cyano group, nitro group, amino group, or mono- or G lower alkylamino group (0) r I
  • X 21 a group represented by the formula — 0—, one S—, one N—, — CH 2 —, _CH 2 CH 2 _, —CH 2 — 0—, or one 0—CH 2 —;
  • R wherein - R 30, one A 22 - R 30, one X 22 - R 30, _A 22 - X 22 - R 30 - - X 22 - A 23 - R 3. , — A 22 — X 22 — A 23 — R 3 . Or — a group represented by C0CH 2 — R 3D ;
  • R 29 a hydrogen atom or a lower alkyl group
  • R 30 a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a trihalogenomethyl group, a hydroxy group, a lower alkoxy group, an acyl group, a cyano group, a nitro group, an amino group, a mono-lower alkylamino group and An aromatic carbocyclic group which may be substituted with one or more substituents selected from the group consisting of di-lower alkylamino groups; which may be substituted with a lower alkyl group or which may be bridged Cycloalkyl group;
  • a 22 and A 23 the same or different, a lower alkylene group, a lower alkenylene group, or a lower alkynylene group;
  • X 22 a group represented by formula 1 0-, -S—, or —N—;
  • R 31 is a hydrogen atom, a lower alkyl group, an aralkyl group, or an aromatic carbon, provided that (a) X 1 is a group represented by the formula 10— or —S 0 2 — and R ′ is a p-phenyl group Where (b) X 21 is a group represented by the formula —0—, and Ra is a p-phenoxy group, a p— (p-hydroxyphenoxy) group, and a p— (p-methoxyphenoxy) Group, or p- (p-acetyl A phenoxy) group, or (c) at least one of R 21 to R 28 when X 21 is a group represented by the formula 10- and Ra is a p- (p-chlorophenylsulfonyl) group One means a group other than a hydrogen atom. )
  • X 23 a group represented by the formula—0—, 1 S—, or 1 NH—;
  • R 32 and R 33 both are united with a benzene ring
  • R 21 , R 22 , R 23 and R 24 have the above-mentioned meanings, and other symbols have the following meanings.
  • X 24 a group represented by the formula: 1—, —S—, or —NH—;
  • R 34 , R 35 and R 36 are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group,
  • At least two are halogen atoms
  • R 21 to R 24 represents a halogen atom.
  • Compound (I) which is an active ingredient of the medicament of the present invention, has its R 1 to R 8 , R and X 1 substituted or converted with various monovalent or divalent groups, as is clear from the pharmacological experiment results described below. However, all of them show strong testosterone 5 ⁇ -reductase inhibitory activity, so that benzene is substituted (m or p) or unsubstituted benzene at the m-position or p-position, especially the p-position of benzoic acid via a linking group.
  • the point at which the rings are linked is considered to have chemical structural characteristics that provide strong pharmacological activity, and this structure is considered to be the basic structure.
  • the organic residue represented by R 1 to R 8 or R and the substituent of R 1 are an organic group capable of bonding to an aromatic carbocyclic ring. Any residue may be used as long as it is a residue. Specific examples include a hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group; a halogen atom; a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, and an acyloxyalkyl group.
  • Substituted hydrocarbon groups such as carboxyalkyl, alkoxycarbonylalkyl, aminoalkyl, mono or dialkylaminoalkyl, hydroxycycloalkyl; hydroxy, alkoxy, phenoxy Hydroxyl-based substitution such as a group, a phenylalkoxy group, a mercapto group, an alkylthio group, a phenylthio group, a phenylalkylthio group, a carboxyalkoxy group, a carboxyalkylthio group, an alkoxycarbonylalkoxy group, or an alkoxyl-proponylalkylthio group Group groups; carboxy group, alkoxycarbonyl group, alkanoyl group, arylcarbonyl group, arylalkanoyl group, sulfonic acid group, oxamoyl group, alkoxamoyl group, and other acyl-based substituent groups; oxo group
  • the substituent of R 1 to R 8 is preferably an electron-withdrawing group such as a halogen atom, a trihalogenomethyl group, a hydroxy group, a lower alkoxy group, a cyano group or a nitro group.
  • R 1 to R 4 it is preferable in particular to replace the position of R 1 and / or R 4.
  • substituents which may be substituted on the “optionally crosslinked cycloalkyl group” include all of the substituents usually used as a substituent of the cycloalkyl, such as a lower alkyl group.
  • "lower” means that the number of carbon atoms is not specified unless otherwise specified. It means 1 to 6 straight or branched carbon chains.
  • the “lower alkyl group” specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, etc., of which methyl, ethyl, propyl , an isopropyl group, C t one C 4 alkyl group such as butyl group, taking divided methyl and Echiru group mentioned as suitable groups.
  • the “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propyl group, an isopropyl group, a 1-butenyl group.
  • the “lower alkynyl group” is a linear or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, Petinyl group, 3-petinyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentinyl Group, 3-pentynyl group, 4-pentynyl group, a 1-hexynyl group, 2-to hexynyl group, a 3-hexynyl group, hexynyl group to 4, 5 - to hexynyl group and the like, preferably a C 2 — A C 4 alkynyl group, optimally an ethynyl group is exemplified.
  • the “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentyl Examples thereof include a xy group and a hexyloxy group, and among them, —C and an alkoxy group are preferable.
  • lower alkylene group examples include a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, a propylene group, a dimethylmethylene group, a tetramethylene group, a 1-methyltrimethylene group, and a 2-methyltrimethylene group.
  • 3-methyltrimethylene group, tetramethyl alkylene group, a pentamethylene group, d such Kisamechiren group to - C e ⁇ alkylene group, and preferably d - as c "lower alkenylene group" is a C 5 alkylene group Specifically, for example, a vinylene group, a propenylene group, a 2-propenylene group, a methylvinylene group, a butenylene group, a 2-butenylene group, a 3-butenylene group, a 1-methylpropenylene group, Mechirupuro Bae ylene group, pent two alkylene groups, 1 Mechi Rubute two alkylene groups, to such Kiseniren group C 2 - C e alkenylene group ani Among them, a C 2 -C 3 alkenylene group is preferable.
  • “Lower alkynylene group” includes ethynylene group, propynylene group, 2-propynylene group, petynylene group, 2-pentynylene group, 3-pentynylene group, 3-methylpropynylene group, pentynylene group, Examples thereof include a 4-methylbutynylene group and a hexynylene group, and preferred are an ethylenylene group, a propynylene group, and a 2-propynylene group.
  • the “carboxy lower alkyl group” is a group in which an arbitrary hydrogen atom of the lower alkyl group is substituted with a carboxy group, specifically, for example, a carboxymethyl group, a 2-carboxyethyl group, a 1-carboxyethyl group, Examples include 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 3-carboxy-2-methylpropyl, 5-carboxypentyl, and 6-carboxyhexyl. Carboxy d-C 4 alkyl groups, especially carboxy-C 3 alkyl groups, are preferred.
  • the “carboxy lower alkoxy group” is a group in which any hydrogen atom of the lower alkoxy group is substituted with a carboxy group, and specifically, for example, a carboxymethoxy group, a 2-carboxyethoxy group, a 1-carboxyethoxy group , 3-carboxypropoxy, 2-carboxy 1-1 -methylethyloxy, 4-carboxybutoxy, 3-force ruboxy-2 -methylpropyloxy, 5-carboxypentyloxy, 6-carboxy Xyloxy groups and the like are exemplified, and among them, a carboxy d-C 4 alkoxy group, particularly carboxy C i -C 3 alkoxy, is preferred.
  • the “lower alkoxycarbonyl group” includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, Examples thereof include an amyloxycarbonyl group, an isoamyloxycarbonyl group, and a hexyloxycarbonyl group. Among them, a C 1, 1C 3 alkoxycarbonyl group is preferable.
  • “Mono- or di-lower alkylamino group”, c is also one of the Amino group means a group in which two hydrogen atoms are substituted with the lower alkyl group Specifically, monoamino such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, and isohexylamino group.
  • monoamino such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, and isohexylamino group.
  • Disubstituted symmetric dialkylamino groups such as alkylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, and ethylmethylamino
  • Asymmetric dialkylamino groups such as methyl, aminopropyl, methylpropylamino, ethylpropylamino, butylmethylamino, butylethylamino, and butylpropylamino, among which methylamino, ethylamino, Propylamino group, dimethylamine Group, Jechirua amino group, such as Jipuropiruamino groups are preferred.
  • Examples of the alkylene group having 1 to 2 0 carbon A 1 is shown, in addition to examples of the low-grade alkylene group, heptamethylene group, Okutamechiren group, nonamethylene group, decamethylene group, Undekamechiren group, de de Kamechiren group, trideca Examples include a methylene group, a tetradecamethylene group, a pentacamethylene group, a hexadecamethylene group, a heptadecamethylene group, an octadecamethylene group, a nonadecamethylene group, an eicosamethylene group, and among them, d. Alkylene group, especially d - C 7 alkylene groups are preferred.
  • acyl group refers to a monocyclic or polycyclic carbocyclic arylcarbonyl group such as a formyl group, an acetyl group, a propionyl group or the like, a -C e alkanol group; a benzoyl group; Polycyclic carbocyclic arylalkanoyl groups; lower alkoxamoyl groups such as methoxamoyl; and the like. Among them, alkanoyl, arylcarbonyl and the like are preferable.
  • the “halogen atom” is not particularly limited, and includes all halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • trihalogenomethyl group a trifluoromethyl group, a trichloromethyl group, etc., and a trifluoromethyl group are particularly preferable.
  • the "cycloalkyl group” preferably has 3 to 8 carbon atoms, and specifically includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Preferably, it is a C 5 -C 7 cycloalkyl group, most preferably cyclohexyl. .
  • cross-linked cycloalkyl group examples include an adamantyl group, a bicyclo [2.2.2] octyl group, a bicyclo [3.2.1] octyl group, and a bicyclo [3.3.1] nonyl group. Among them, a madmantyl group is preferable.
  • R 1 D, RH, R 3 D or R 3 1 represents "aromatic carbocyclic group", Fuweni group, a naphthyl group, Bifuweniru group, monocyclic anthracenyl group, Fuenanto Reniru group, bicyclic, A tricyclic aryl group is mentioned, and among them, a phenyl group, a naphthyl group and a biphenyl group are preferable.
  • an “aralkyl group” is a group in which any one to three hydrogen atoms of the lower alkyl group are substituted with the above aryl group.
  • the compounds (I), ( ⁇ ), ( ⁇ ) and (IV) of the present invention form salts with bases. Further, depending on the type of the substituent, a salt with an acid may be formed.
  • the present invention includes pharmaceutically acceptable salts of these compounds. Specific examples of such salts include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, methylamine, and ethylamine.
  • Salts with bases such as organic bases such as ethanol, ethanolamine, and cyclohexylamine; bases such as basic amino acids such as lysine and orditin; hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid Mineral acids, formic acid, carboxylic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, etc. And acid salts such as acidic amino acids such as organic acids, aspartic acid and glutamic acid, and ammonium salts.
  • bases such as organic bases such as ethanol, ethanolamine, and cyclohexylamine
  • bases such as basic amino acids such as lysine and orditin
  • the compounds (i), (n), (m), (n and pharmaceutically acceptable salts thereof may be, depending on the type of the substituent, an optical isomer based on the presence of an asymmetric carbon atom, There are various isomers, such as geometric isomers based on the presence of double bonds, keto-enol tautomers, etc.
  • the present invention also includes isolated isomers of these isomers and mixtures thereof.
  • the compound of the present invention may be isolated as a solvate such as a hydrate or ethanol or a polymorph, and the present invention provides a compound of these hydrate, solvate or polymorph. Is also included.
  • R in the compounds, particularly preferred compounds, R (hence R a as well) has the formula one R 10, - A 1 - R ' ⁇ - A 2 -X 2 -R' ⁇ -X 2 one A 3 - R 10 , -A 2 -X 2- A 3 — R 1 . Or —CO—CH 2 —R 1 .
  • R 111 is a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a trihalogenomethyl group, a hydroxy group, a lower alkoxy group, an acyl group, a cyano group, a nitro group, an amino group, It may be substituted with a phenyl or naphthyl group which may be substituted with one or more substituents selected from the group consisting of a mono-lower alkylamino group and a di-lower alkylamino group, and may be substituted with a lower alkyl group. And a compound which is a cycloalkyl group which may be crosslinked. More preferably,
  • R is the formula — R 10 -0 10 10
  • -CH CH-R 10, one CH 2 0- R 10, - CH 2 S- R 1C, - CH 2 NH- R 10,
  • R 1D is Ru said specific group Der are preferred.
  • R (therefore also for Ra ) is the aforementioned group.
  • X 1 is a group represented by the formula: —0—, —S—, —N— (R 9 has the above-mentioned meaning), —CH 2 — or one CH 2 CH 2 —, and more preferably a group represented by the formula: Compounds having 0- or 1S-, optimally -0-, are more preferred.
  • the compounds (I) to (W) of the present invention can be produced by applying various synthetic methods by utilizing the characteristics based on the basic skeleton or the type of the substituent.
  • the representative production method is described below.
  • the pharmaceutical compound (I) of the present invention and the compounds ( ⁇ ), ( ⁇ ) and (W) of the present invention contained in the compound (I) can be produced by hydrolyzing the corresponding nitrile compound (V).
  • the reaction can be carried out by a conventional method, in a concentrated alkali such as sodium hydroxide or potassium hydroxide, or in a solution such as hydrochloric acid, sulfuric acid or phosphoric acid. In a strong acid, it is preferred to heat, preferably to reflux.
  • a solvent an organic solvent such as ethanol, methanol, isopropanol or the like, which is miscible with water such as alcohol, is usually used.
  • R 14 means an ester-forming group
  • the compounds (I), ( ⁇ ), (! And (IV) of the present invention can also be produced by subjecting the corresponding ester compound (VI) to ester hydrolysis or hydrogenolysis.
  • ester-forming group examples include carboxylic acids such as lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group, and aralkyl groups such as benzyl group.
  • carboxylic acids such as lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group
  • aralkyl groups such as benzyl group.
  • the compounds (1), ( ⁇ ), ( ⁇ ) and (IV) of the present invention can also be produced by reacting the corresponding aldehyde compound (W) with an oxidizing agent.
  • organic peracids such as silver nitrate, silver oxide, potassium permanganate, chromic acid, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid and peracetic acid are preferable.
  • the reaction varies depending on the type of oxidizing agent. For example, when silver nitrate is used, an aqueous alkali solution such as sodium hydroxide or potassium hydroxide is used. Medium, heating, preferably by heating to reflux
  • an organic solvent that can be mixed with water such as ethanol, methanol, or isopropanol, is usually used.
  • the reaction is usually performed in an organic solvent such as alcohol, ether such as chloroform, toluene, methanol, and ethanol with VF.
  • the reaction is carried out by reacting with an alcohol or ether such as methanol or ethanol and, if necessary, heating.
  • a metal catalyst such as vanadium or molybdenum.
  • the compound of the present invention is characterized by its conversion reaction in consideration of the characteristics of monovalent groups such as R 1 to R 8 and R and divalent groups such as X 1 , X 2 , X 3 , A 1 , A 2 and A 3 . It can also be manufactured. That is, the target compound (I) can be produced by a conventional method in this field, for example, the methods described in Examples and Reference Examples, or according to these methods. Specifically, for example,
  • the compound of the present invention can be obtained by applying a conventional method such as this.
  • the reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt thereof, or various solvates.
  • the salt can be produced by subjecting the salt to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Industrial applicability such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compounds of the present invention have testosterone 5 ⁇ -reductase inhibitory activity, and are used for various diseases caused by prostatic hypertrophy and other androgen actions, such as prostate cancer, seborrhea, acne, and male pattern. It is useful for treating alopecia.
  • the testosterone 5 ⁇ -reductase inhibitory activity of the compound of the present invention can be clarified by a test of 5 ⁇ -reductase inhibitory activity (in vitro) using prostate tissue obtained from a patient with benign prostatic hypertrophy as shown below.
  • Human prostate tissue obtained from a patient with benign prostatic hyperplasia was added to 10 mM tris-monohydrochloride buffer (pH 7.0) containing 0.33% sucrose, 1 mM dithiothreitol, and 50% M NADPH, and then poly- After homogenization with Tron and Sonifir, it was centrifuged at 140,000 ⁇ g. The resulting precipitate was suspended in 10 mM Tris-hydrochloric acid buffer (pH 7.0) to obtain an enzyme solution.
  • the testosterone 5 ⁇ -reductase inhibitory activity of the compound of the present invention measured using human prostate is shown in relation to the difference in various groups.
  • C A known non-steroid type control compound ON 0-3805 (Japanese Unexamined Patent Publication No. Table 1 shows the inhibitory activity values of the compounds described in JP-A-156950.
  • R ! C1
  • the compound of the present invention shows extremely high activity in the test of testosterone 5 ⁇ -reductase inhibitory activity using human prostate and is highly clinically useful.
  • the non-steroid type control compound similar to the compound of the present invention is a compound described in JP-A-11-569950, and is being developed as a drug as a clinical trial noisyONO-3805.
  • the compound of the present invention is several times to several hundred times more effective than this compound.
  • the compounds of the present invention have strong and almost uniform testosterone 5 ⁇ even when the substitution positions of R 1 to R 8 , R, X 1 , X 2 , R 10 and R 1 () are different. -These groups show reductase inhibitory activity, confirming that these groups are variable with a wide variety of groups.
  • the carriers and excipients for pharmaceutical preparations prepared using the above additives include solid or liquid non-toxic pharmaceutical substances. These include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa batata, ethylene glycol and the like and other commonly used ones.
  • Administration may be in the form of tablets, pills, capsules, granules, liquids, or the like, oral administration, intravenous injection, intramuscular injection, or the like, parenteral administration in the form of suppositories, transdermals, etc. .
  • the dose is determined as appropriate depending on the individual case in consideration of the symptoms, age of the administration subject, sex, and the like.
  • 3 g of the compound (I) of the present invention and 456 g of lactose are uniformly mixed.
  • This mixture is mixed and pulverized by a sample mill.
  • 450 g of the mixed ground material and 120 g of starch are uniformly mixed with a fluidized-granulation coating device (to this, 180 g of a 10% hydroxypropylcellulose solution is sprayed and granulated).
  • the mixture is sieved, mixed with 3 g of magnesium stearate, and mixed with a rotary tableting machine using a 6.5 mni X 7.8 R mortar to make 10 Omg tablets.
  • This tablet is chilled with a coating device.
  • composition 0.5 m Kassel
  • Methyl 4 (4-benzylaminophenoxy) 13-clo mouth benzoate 350 mg in a solution of formic acid (99%) 3 ml, formaldehyde aqueous solution (35%) 3 ml was added and stirred at 100 ° C. for 1 hour. Allow to cool to room temperature, add water, neutralize with potassium carbonate, and extract with ethyl acetate Issued. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Acetyl chloride (7.85 g) was added dropwise to 50 ml of a dichloromethane suspension of 13.33 g of aluminum chloride at room temperature, and the mixture was stirred at room temperature for 20 minutes. Under ice cooling, 25 ml of a methylene chloride solution of 8.4 1 g of 4-methylbiphenyl was added dropwise, and the mixture was stirred for 2 hours under ice cooling. The reaction solution was poured into ice water, and the organic layer was washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. (4) Acetofenone 6.30 g was obtained.
  • the extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • To the obtained residue were added 3,4-dichlorobenzene aldehyde (3.16 g, 10.Ommo 1), potassium carbonate (2.76 g, 20.0 mm 01) and dimethyl sulfoxide (40 ml).
  • the mixture was stirred at 100 ° C. for 15 hours.
  • the reaction mixture The mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate.
  • the extract was washed successively with water, a 1N aqueous sodium hydroxide solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the compound of Reference Example 119 was obtained in the same manner as in Reference Example 29, and the compound of Reference Example 120 was obtained in the same manner as in Reference Example 114.
  • Reference example 1 4 4 Methyl 4 _ (5-benzoate Melting point 59-60 ° C

Abstract

Médicament renfermant un dérivé d'acide benzoïque représenté par la formule générale (I), ou bien un sel pharmaceutiquement acceptable de celui-ci, et l'un quelconque des nouveaux dérivés d'acide benzoïque représentés par les formules générales (II), (III) et (IV), toutes incluses dans la formule générale (I), ou bien un sel pharmaceutiquement acceptable de ceux-ci. Ces composés présentent une activité inhibitrice de la testostérone 5α-réductase et sont utiles pour prévenir et/ou traiter la prostatomégalie, le cancer de la prostate et d'autres maladies analogues.
PCT/JP1993/000710 1992-05-29 1993-05-27 Medicament renfermant un derive d'acide benzoique, et nouveau derive d'acide benzoique WO1993024442A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP4/164144 1992-05-29
JP16414492A JPH05331104A (ja) 1992-05-29 1992-05-29 新規な安息香酸誘導体またはその塩
JP4/168424 1992-06-02
JP16842492A JPH05331059A (ja) 1992-06-02 1992-06-02 テストステロン ５α−リダクタ−ゼ阻害剤
JP4/355948 1992-12-18
JP35594892A JPH06183961A (ja) 1992-12-18 1992-12-18 安息香酸誘導体を含有する医薬及び新規な安息香酸誘導体

Publications (1)

Publication Number Publication Date
WO1993024442A1 true WO1993024442A1 (fr) 1993-12-09

Family

ID=27322278

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/000710 WO1993024442A1 (fr) 1992-05-29 1993-05-27 Medicament renfermant un derive d'acide benzoique, et nouveau derive d'acide benzoique

Country Status (2)

Country Link
AU (1) AU4090093A (fr)
WO (1) WO1993024442A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
EP0757982A1 (fr) 1995-08-08 1997-02-12 Roussel Uclaf Composés biphényles, leur procédé de préparation et les intermédiaires de ce procédé, leur application en tant qu'inhibiteur de la 5-alpha-réductase et les compositions pharmaceutiques les contenant
US5736576A (en) * 1996-06-04 1998-04-07 Octamer, Inc. Method of treating malignant tumors with thyroxine analogues having no significant hormonal activity
WO1998042328A1 (fr) * 1997-03-26 1998-10-01 Biosource Technologies, Inc. Ethers di-aryle et leurs derives utilises comme agents anticancereux
US5872280A (en) * 1995-11-23 1999-02-16 Bayer Aktiengesellschaft Leukotriene antagonistic benzoic acid derivatives
US6017958A (en) * 1996-06-04 2000-01-25 Octamer, Inc. Method of treating malignant tumors with thyroxine analogues having no significant hormonal activity
WO2001036351A2 (fr) * 1999-11-19 2001-05-25 Corvas International, Inc. Antagonistes de l'inhibiteur des activateurs du plasminogène
US6291442B1 (en) 1998-02-03 2001-09-18 The General Hospital Corporation Pharmacological modulators of voltage-gated potassium ion channels
US6506798B1 (en) 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
US6770778B2 (en) 2002-01-23 2004-08-03 Pfizer Inc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6891066B2 (en) 2002-01-23 2005-05-10 Warner-Lambert Company N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6936638B2 (en) 2002-12-20 2005-08-30 Migenix Corp. Ligands of adenine nucleotide translocase (ANT) and compositions and methods related thereto
US7001905B2 (en) 2000-03-15 2006-02-21 Warner-Lambert Company Substituted diarylamines as MEK inhibitors
US7012100B1 (en) 2002-06-04 2006-03-14 Avolix Pharmaceuticals, Inc. Cell migration inhibiting compositions and methods and compositions for treating cancer
WO2006058648A2 (fr) * 2004-12-03 2006-06-08 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
WO2009080835A1 (fr) * 2007-12-24 2009-07-02 Karo Bio Ab Composés thyromimétiques utilisés dans le traitement d'une maladie associée à la voie de signalisation sonic hedgehog
US7700632B2 (en) 2003-06-24 2010-04-20 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
US8012988B2 (en) 2005-04-11 2011-09-06 Novartis Ag N-(2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,4-dihydro-2H-quinazolin-3-yl)methanesulfonamide
US8212045B2 (en) 2007-09-21 2012-07-03 Array Biopharma, Inc. Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US8299085B2 (en) 2004-07-27 2012-10-30 Novartis Ag Quinazoline derivatives
WO2017158190A1 (fr) 2016-03-17 2017-09-21 Ecole polytechnique fédérale de Lausanne (EPFL) Activateurs de signalisation notch et leur utilisation dans le traitement de cancers et de malignités guérissables par régulation à la hausse de notch
WO2018154118A3 (fr) * 2017-02-24 2018-12-06 Xeniopro GmbH Nouveaux composés aromatiques
JP2020511427A (ja) * 2017-02-24 2020-04-16 ゼニオプロ ゲーエムベーハー 新規の芳香族化合物

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3692828A (en) * 1970-05-01 1972-09-19 Gulf Research Development Co Process for preparing phenyl sulfone carboxylic acids
US3886162A (en) * 1972-07-19 1975-05-27 Syntex Inc Acridone carboxylic acids and derivatives
US3965146A (en) * 1973-06-04 1976-06-22 Raychem Corporation Biphenylyloxy benzoic acid and esters thereof
GB1543965A (en) * 1977-04-05 1979-04-11 Ici Ltd Substituted phenoxybenzoic acids and their esters and salts and herbicidal compositions containing them
JPS61165313A (ja) * 1985-01-14 1986-07-26 ヘンケル・コマンデイトゲゼルシヤフト・アウフ・アクテイーン アルコキシ‐又はアルキルベンジルオキシ‐安息香酸又はその塩を含有する脂漏抑制化粧料
JPS62103057A (ja) * 1985-07-23 1987-05-13 Asahi Glass Co Ltd ジフルオロシアノ化合物及びそれを含有する液晶組成物
JPS6399036A (ja) * 1986-10-15 1988-04-30 Asahi Chem Ind Co Ltd 芳香族ヒドロキシカルボン酸の製造方法
EP0291245A2 (fr) * 1987-05-11 1988-11-17 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide benzoylaminophénoxybutanoique
EP0294035A2 (fr) * 1987-06-04 1988-12-07 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide benzoylaminophénoxybutyrique
JPH02108656A (ja) * 1988-10-18 1990-04-20 Seimi Chem Kk ハロゲノシアノベンゼン誘導体化合物及びそれを含有する液晶組成物
JPH02270835A (ja) * 1989-02-10 1990-11-05 Basf Ag ジフエニルヘテロアルキル誘導体

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3692828A (en) * 1970-05-01 1972-09-19 Gulf Research Development Co Process for preparing phenyl sulfone carboxylic acids
US3886162A (en) * 1972-07-19 1975-05-27 Syntex Inc Acridone carboxylic acids and derivatives
US3965146A (en) * 1973-06-04 1976-06-22 Raychem Corporation Biphenylyloxy benzoic acid and esters thereof
GB1543965A (en) * 1977-04-05 1979-04-11 Ici Ltd Substituted phenoxybenzoic acids and their esters and salts and herbicidal compositions containing them
JPS61165313A (ja) * 1985-01-14 1986-07-26 ヘンケル・コマンデイトゲゼルシヤフト・アウフ・アクテイーン アルコキシ‐又はアルキルベンジルオキシ‐安息香酸又はその塩を含有する脂漏抑制化粧料
JPS62103057A (ja) * 1985-07-23 1987-05-13 Asahi Glass Co Ltd ジフルオロシアノ化合物及びそれを含有する液晶組成物
JPS6399036A (ja) * 1986-10-15 1988-04-30 Asahi Chem Ind Co Ltd 芳香族ヒドロキシカルボン酸の製造方法
EP0291245A2 (fr) * 1987-05-11 1988-11-17 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide benzoylaminophénoxybutanoique
EP0294035A2 (fr) * 1987-06-04 1988-12-07 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide benzoylaminophénoxybutyrique
JPH02108656A (ja) * 1988-10-18 1990-04-20 Seimi Chem Kk ハロゲノシアノベンゼン誘導体化合物及びそれを含有する液晶組成物
JPH02270835A (ja) * 1989-02-10 1990-11-05 Basf Ag ジフエニルヘテロアルキル誘導体

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
EP0757982A1 (fr) 1995-08-08 1997-02-12 Roussel Uclaf Composés biphényles, leur procédé de préparation et les intermédiaires de ce procédé, leur application en tant qu'inhibiteur de la 5-alpha-réductase et les compositions pharmaceutiques les contenant
FR2737721A1 (fr) * 1995-08-08 1997-02-14 Roussel Uclaf Nouveaux composes biphenyles, leur procede de preparation et les intermediaires de ce procede, leur application a titre de medicament et les compositions pharmaceutiques les contenant
US5827887A (en) * 1995-08-08 1998-10-27 Roussel Uclaf Biphenyl compounds
US5872280A (en) * 1995-11-23 1999-02-16 Bayer Aktiengesellschaft Leukotriene antagonistic benzoic acid derivatives
US6017958A (en) * 1996-06-04 2000-01-25 Octamer, Inc. Method of treating malignant tumors with thyroxine analogues having no significant hormonal activity
US5736576A (en) * 1996-06-04 1998-04-07 Octamer, Inc. Method of treating malignant tumors with thyroxine analogues having no significant hormonal activity
US6169104B1 (en) 1997-03-26 2001-01-02 Large Scale Biology Corporation Di-aryl ethers and their derivatives as anti-cancer agents
AU741382B2 (en) * 1997-03-26 2001-11-29 Large Scale Biology Corporation Di-aryl ethers and their derivatives as anti-cancer agents
WO1998042328A1 (fr) * 1997-03-26 1998-10-01 Biosource Technologies, Inc. Ethers di-aryle et leurs derives utilises comme agents anticancereux
US6506798B1 (en) 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
US6291442B1 (en) 1998-02-03 2001-09-18 The General Hospital Corporation Pharmacological modulators of voltage-gated potassium ion channels
WO2001036351A2 (fr) * 1999-11-19 2001-05-25 Corvas International, Inc. Antagonistes de l'inhibiteur des activateurs du plasminogène
WO2001036351A3 (fr) * 1999-11-19 2002-07-11 Corvas Int Inc Antagonistes de l'inhibiteur des activateurs du plasminogène
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
US6677473B1 (en) 1999-11-19 2004-01-13 Corvas International Inc Plasminogen activator inhibitor antagonists
US7001905B2 (en) 2000-03-15 2006-02-21 Warner-Lambert Company Substituted diarylamines as MEK inhibitors
US7078438B2 (en) 2002-01-23 2006-07-18 Warner-Lambert Company N-(4 substituted phenyl)-anthranilic acid hydroxamate esters
US6891066B2 (en) 2002-01-23 2005-05-10 Warner-Lambert Company N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6770778B2 (en) 2002-01-23 2004-08-03 Pfizer Inc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US7012100B1 (en) 2002-06-04 2006-03-14 Avolix Pharmaceuticals, Inc. Cell migration inhibiting compositions and methods and compositions for treating cancer
US7700615B2 (en) 2002-06-04 2010-04-20 Avolix Pharmaceuticals, Inc. Cell migration inhibiting compositions and methods and compositions for treating cancer
US6936638B2 (en) 2002-12-20 2005-08-30 Migenix Corp. Ligands of adenine nucleotide translocase (ANT) and compositions and methods related thereto
US7700632B2 (en) 2003-06-24 2010-04-20 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
US7842825B2 (en) 2003-06-24 2010-11-30 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
US8299085B2 (en) 2004-07-27 2012-10-30 Novartis Ag Quinazoline derivatives
WO2006058648A2 (fr) * 2004-12-03 2006-06-08 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
US7524870B2 (en) 2004-12-03 2009-04-28 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activators
WO2006058648A3 (fr) * 2004-12-03 2006-12-28 Hoffmann La Roche Acides biaryloxymethylarenecarboxyliques
US8513268B2 (en) 2005-04-11 2013-08-20 Novartis Ag 1H-quinazoline-2,4-diones processes for their production, pharmaceutical compositions, and treatment for epilepsy
US8012988B2 (en) 2005-04-11 2011-09-06 Novartis Ag N-(2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,4-dihydro-2H-quinazolin-3-yl)methanesulfonamide
US8212045B2 (en) 2007-09-21 2012-07-03 Array Biopharma, Inc. Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US8853409B2 (en) 2007-09-21 2014-10-07 Array Biopharma Inc. Pyridin-2yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US9079890B2 (en) 2007-09-21 2015-07-14 Array Biopharma Inc. Intermediates for the preparation of pyridin-2-yl-amino-1,2,4-thiadiazole derivatives
WO2009080835A1 (fr) * 2007-12-24 2009-07-02 Karo Bio Ab Composés thyromimétiques utilisés dans le traitement d'une maladie associée à la voie de signalisation sonic hedgehog
AU2017232391C1 (en) * 2016-03-17 2022-12-22 Xeniopro GmbH Enhancers of notch signaling and their use in the treatment of cancers and malignancies medicable by upregulation of notch
JP2019513703A (ja) * 2016-03-17 2019-05-30 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
US10772876B2 (en) 2016-03-17 2020-09-15 Xeniopro GmbH Enhancers of Notch signaling and the use thereof in the treatment of cancers and malignancies medicable by upregulation of Notch
AU2017232391B2 (en) * 2016-03-17 2022-07-14 Xeniopro GmbH Enhancers of notch signaling and their use in the treatment of cancers and malignancies medicable by upregulation of notch
WO2017158190A1 (fr) 2016-03-17 2017-09-21 Ecole polytechnique fédérale de Lausanne (EPFL) Activateurs de signalisation notch et leur utilisation dans le traitement de cancers et de malignités guérissables par régulation à la hausse de notch
JP7402300B2 (ja) 2016-03-17 2023-12-20 ゼニオプロ ゲーエムベーハー ＮｏｔｃｈシグナリングのエンハンサーならびにＮｏｔｃｈのアップレギュレーションにより治療可能ながんおよび悪性腫瘍の治療におけるその使用
WO2018154118A3 (fr) * 2017-02-24 2018-12-06 Xeniopro GmbH Nouveaux composés aromatiques
JP2020511427A (ja) * 2017-02-24 2020-04-16 ゼニオプロ ゲーエムベーハー 新規の芳香族化合物
US11591289B2 (en) 2017-02-24 2023-02-28 Xeniopro GmbH Aromatic compounds
JP7282036B2 (ja) 2017-02-24 2023-05-26 ゼニオプロ ゲーエムベーハー 新規の芳香族化合物

Also Published As

Publication number Publication date
AU4090093A (en) 1993-12-30

Similar Documents

Publication Publication Date Title
WO1993024442A1 (fr) Medicament renfermant un derive d'acide benzoique, et nouveau derive d'acide benzoique
AU762735B2 (en) Nonsteroidal antiinflammatories
US7166592B2 (en) Nonsteroidal antiinflammatory agents
JP3157882B2 (ja) 新規なベンゾチオフエン誘導体
US7151196B2 (en) Estrogen receptor modulators
US20080319078A1 (en) Triphenylethylene Compounds Useful as Selective Estrogen Receptor Modulators
US20080255089A1 (en) Triphenylethylene Compounds Useful as Selective Estrogen Receptor Modulators
JP2007509116A (ja) アンドロゲン受容体モジュレーター
US20080306036A1 (en) Triphenylethylene Compounds Useful as Selective Estrogen Modulators
EP1827421A2 (fr) Modulateurs du recepteur de l'oestrogene
BRPI0618589B1 (pt) composto de oxazol, composição farmacêutica compreendendo o referido composto, processos de fabricação e usos dos mesmos
ES2218853T3 (es) Nuevos compuestos de dihidronaftaleno y procesos para la obtencion de los mismos.
JP2009542803A (ja) 鎮痛剤としての３−オキソイソインドリン−１−カルボキサミド誘導体
JP2808460B2 (ja) イミダゾール誘導体
Sharma et al. A study of anti‐inflammatory activity of some novel α‐amino naphthalene and β‐amino naphthalene derivatives
WO2001042181A1 (fr) Benzyl-tetralines, formulations et utilisations associees
JPWO2008001959A1 (ja) 新規６−５系二環式複素環誘導体及びその医薬用途
JP7142406B2 (ja) インドリジン誘導体及びその医学的応用
EP0424929A1 (fr) Dérivés de l'isoquinoléine, leurs préparation et application
JP5443348B2 (ja) 新規な気管支拡張性α，β−不飽和イソキノリンアミド
JP5054882B2 (ja) テトラヒドロベンズフルオレン誘導体
JPH07145147A (ja) 安息香酸誘導体又はその塩
US6071943A (en) Imidazole derivative and medicine comprising the same as active ingredient
WO2010060277A1 (fr) Dérivés d'hydrazide de type acétyle substitué, leur synthèse et leurs applications
JPH06312976A (ja) 安息香酸誘導体又はその塩

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CZ FI HU JP KR KZ LK MG MN MW NO NZ PL PT RO RU SD SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA