JP2006509743A5

JP2006509743A5 -

Info

Publication number: JP2006509743A5
Application number: JP2004550274A
Authority: JP
Filing date: 2003-10-31
Publication date: 2006-07-20

Description

式中、
ｎは１、２または３の値を有し；
R⁵は、未置換であるかそれぞれがニトロ、シアノ、トリフルオロメチル、カルボエトキシ、カルボメトキシ、カルボプロポキシ、アセチル、カルバモイル、アセトキシ、カルボキシ、ヒドロキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、炭素原子数１〜10のアルキル、炭素原子数１〜10のアルコキシおよびハロからなる群から独立に選択される１〜４個の置換基で置換されたo-フェニレンであり；
R⁷は、(i)フェニルあるいはそれぞれニトロ、シアノ、トリフルオロメチル、カルボエトキシ、カルボメトキシ、カルボプロポキシ、アセチル、カルバモイル、アセトキシ、カルボキシ、ヒドロキシ、アミノ、炭素原子数１〜10のアルキル、炭素原子数１〜10のアルコキシおよびハロからなる群から他とは独立に選択される１以上の置換基で置換されたフェニル、(ii)未置換であるかニトロ、シアノ、トリフルオロメチル、カルボエトキシ、カルボメトキシ、カルボプロポキシ、アセチル、カルバモイル、アセトキシ、カルボキシ、ヒドロキシ、アミノ、炭素原子数１〜10のアルキル、炭素原子数１〜10のアルコキシおよびハロからなる群から選択される１〜３個の置換基で置換されたベンジル、(iii)ナフチルおよび(iv)ベンジルオキシであり；
R¹²は、-OH、炭素原子数１〜12のアルコキシ、あるいは
Where
n has a value of 1, 2 or 3;
R ⁵ is unsubstituted or each is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, carbon atom O-phenylene substituted with 1 to 4 substituents independently selected from the group consisting of alkyl having 1 to 10 carbons, alkoxy having 1 to 10 carbon atoms and halo;
R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, carbon atom Phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy and halo of the number 1-10, (ii) unsubstituted or nitro, cyano, trifluoromethyl, carboethoxy, 1-3 substitutions selected from the group consisting of carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms and halo Benzyl substituted with a group, (iii) naphthyl and (iv) benzyloxy;
R ¹² is —OH, alkoxy having 1 to 12 carbon atoms, or

式中、
*で示した炭素原子は、キラリティの中心を構成し；
ＹはC=O、CH₂、SO₂またはCH₂C=Oであり；
R¹、R²、R³およびR⁴はそれぞれ他とは独立に、水素、ハロ、炭素原子１〜４個のアルキル、炭素原子１〜４個のアルコキシ、ニトロ、シアノ、ヒドロキシまたは-NR⁸R⁹であり；あるいは隣接する炭素原子上のR¹、R²、R³およびR⁴のうちのいずれか２個が描かれているフェニレン環と一体となってナフチリデンであり；
R⁵およびR⁶はそれぞれ他方とは独立に、水素、炭素原子１〜４個のアルキル、炭素原子１〜４個のアルコキシ、シアノまたは炭素原子数18個以下のシクロアルコキシであり；
R⁷は、ヒドロキシ、炭素原子１〜８個のアルキル、フェニル、ベンジルまたはNR^8′R^9′であり；
R⁸およびR⁹はそれぞれ他方と独立の場合は、水素、炭素原子１〜８個のアルキル、フェニルまたはベンジルであり、あるいはR⁸およびR⁹のうちの一方が水素であって他方が-COR¹⁰または-SO₂R¹⁰であり、あるいはR⁸およびR⁹が一体となっている場合はテトラメチレン、ペンタメチレン、ヘキサメチレンまたは-CH₂CH₂X¹CH₂CH₂-であり、X¹は-O-、-S-または-NH-であり；
R^8′およびR^9′は他方と独立の場合は、水素、炭素原子１〜８個のアルキル、フェニルまたはベンジルであり、あるいはR^8′およびR^9′のうちの一方が水素であって他方が-COR^10′または-SO₂R^10′であり、あるいはR^8′およびR^9′が一体となっている場合はテトラメチレン、ペンタメチレン、ヘキサメチレンまたは-CH₂CH₂X²CH₂CH₂-であり、X²は-O-、-S-または-NH-であり；
R ¹⁰ は水素、炭素原子１〜８個のアルキルまたはフェニルであり；
R ^10′ は水素、炭素原子１〜８個のアルキルまたはフェニルである。 Where
The carbon atom marked with * constitutes the center of chirality;
Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;
R ¹ , R ² , R ³ and R ⁴ are each independently of the other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy or —NR ⁸ R ⁹ ; or naphthylidene together with a phenylene ring on which any ^two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms are depicted;
R ⁵ and R ⁶ are each independently of the other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano or cycloalkoxy having 18 or less carbon atoms;
R ⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR ^{8 ′} R ^{9 ′} ;
R ⁸ and R ⁹ are each independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R ⁸ and R ⁹ is hydrogen and the other is —COR ¹⁰ or -SO ₂ R ¹⁰ or, when R ⁸ and R ⁹ are combined, tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , X ¹ Is —O—, —S— or —NH—;
R ^{8 '} and R ^9' are independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R ^{8 '} and R ^9' is hydrogen and the other Is —COR ^{10 ′} or —SO ₂ R ^{10 ′} , or when R ^{8 ′} and R ^{9 ′} are combined, tetramethylene, pentamethylene, hexamethylene or —CH ₂ CH ₂ X ² CH ₂ CH _2- and X ² is -O-, -S- or -NH-;
R ¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl ;
R ^{10 '} is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl.

Claims

Treating macular degeneration, a pharmaceutical composition for the prevention or management, a pharmaceutically acceptable salt of a selective cytokine inhibitory drug, or the inhibitors, solvate or stereoisomer thereof, wherein the pharmaceutical composition.

The pharmaceutical composition of claim 1 further comprising a second active agent.

The pharmaceutical composition according to claim 1, further comprising a second active agent capable of reducing or avoiding the symptoms of macular degeneration.

Said second active agent is a steroid, photosensitizer, integrin, antioxidant, interferon, xanthine derivative, growth hormone, neurotrophic factor, neovascularization regulator, anti-VEGF antibody, prostaglandin, antibiotic, phyto The pharmaceutical composition according to claim 2 or 3 , which is an estrogen, an anti-inflammatory compound or an angiogenesis-inhibiting compound.

The second active agent is thalidomide, verteporfin, pullritin, angiogenesis-inhibiting steroid, rhuFab, interferon-2α or pentoxyphylline; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Item 4. The pharmaceutical composition according to Item 2 or 3 .

6. The pharmaceutical composition according to claim 5 , wherein the angiogenesis inhibiting compound is thalidomide.

The macular degeneration is wet macular degeneration, dry macular degeneration, age-related macular degeneration, age-related macular degeneration, choroidal neovascularization, retinal pigment epithelial detachment, retinal pigment epithelial atrophy, best disease, yolk-like degeneration, Stargardt disease The medicinal composition according to claim 1, which is juvenile macular dystrophy, ocular fundus jaundice, Beer's disease, Solsby's disease, Doin's disease, honeycomb dystrophy, or macular damage state.

The pharmaceutical composition according to claim 1, wherein the selective cytokine inhibitor is stereoisomerically pure.

A pharmaceutical composition for treating, preventing or managing macular degeneration comprising 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) Said pharmaceutical composition comprising propionamide or a pharmaceutically acceptable salt, solvate or stereoisomer of said compound .

The 3- (3,4-dimethoxy - phenyl) -3- (1-oxo-1,3-dihydro - isoindol-2-yl) - Claim 9 propionamide those enantiomerically pure Pharmaceutical composition .

Treating macular degeneration, a pharmaceutical composition for preventing or managing, cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy - phenyl) -2-methanesulfonyl - ethyl] -3- Said pharmaceutical composition comprising oxo-2,3-dihydro-1H-isoindol-4-yl-amide or a pharmaceutically acceptable salt, solvate or stereoisomer of said compound .

Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} The pharmaceutical composition according to claim 11 , wherein the amide is enantiomerically pure.

The pharmaceutical composition according to claim 1, wherein the selective cytokine inhibitor is of the following formula (I).

[Where:
n has a value of 1, 2 or 3;
R ⁵ is unsubstituted or each is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, carbon atom O-phenylene substituted with 1 to 4 substituents independently selected from the group consisting of alkyl having 1 to 10 carbons, alkoxy having 1 to 10 carbon atoms and halo;
R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, carbon atom Phenyl substituted with one or more substituents independently selected from the group consisting of alkoxy and halo of the number 1-10, (ii) unsubstituted or nitro, cyano, trifluoromethyl, carboethoxy, 1-3 substitutions selected from the group consisting of carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms and halo Benzyl substituted with a group, (iii) naphthyl and (iv) benzyloxy;
R ¹² is —OH, alkoxy having 1 to 12 carbon atoms, or

Is;
R ⁸ is hydrogen or alkyl having 1 to 10 carbon atoms;
R ⁹ is hydrogen, alkyl having 1 to 10 carbon atoms, —COR ¹⁰ or —SO ₂ R ¹⁰ ; R ¹⁰ is hydrogen, alkyl having 1 to 10 carbon atoms or phenyl. ]

14. The pharmaceutical composition according to claim 13 , wherein the selective cytokine inhibitor is enantiomerically pure.

The pharmaceutical composition according to claim 1, wherein the selective cytokine inhibitor is of the following formula (II).

[Where:
R ¹ and R ² are each hydrogen, lower alkyl, when taken independently of each other; alternatively, R ¹ and R ² are combined with the depicted carbon atom to which each is attached. O-phenylene, o-naphthylene or cyclohexene-1,2-diyl, which are unsubstituted or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, 1-4 independently selected from the group consisting of carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms and halo Substituted with a substituent of
R ³ is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms , Alkylthio having 1 to 10 carbon atoms, benzyloxy, cycloalkoxy having 3 to 6 carbon atoms, C _{4 to} C ₆ -cycloalkylidenemethyl, C _{3 to} C ₁₀ -alkylidenemethyl, indanyloxy and halo Phenyl substituted with 1 to 4 substituents selected from:
R ⁴ is hydrogen, alkyl having 1 to 6 carbon atoms, phenyl or benzyl;
R ^{4 ′} is hydrogen or alkyl of 1 to 6 carbon atoms;
R ⁵ _{_{is, -CH 2 -, - CH 2}} -CO -, - SO 2 -, - an S- or -NHCO-;
n has a value of 0, 1 or 2. ]

16. The pharmaceutical composition according to claim 15 , wherein the selective cytokine inhibitor is enantiomerically pure.

The pharmaceutical composition according to claim 1, wherein the selective cytokine inhibitor is of the following formula (III).

[Where:
The carbon atom indicated by * constitutes the center of chirality; Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O
R ¹ , R ² , R ³ and R ⁴ are each independently of the other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy or —NR ⁸ R ⁹ ; or naphthylidene together with a phenylene ring on which any ^two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms are depicted;
R ⁵ and R ⁶ are each independently of the other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano or cycloalkoxy having 18 or less carbon atoms;
R ⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR ^{8 ′} R ^{9 ′} ;
R ⁸ and R ⁹ are each independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R ⁸ and R ⁹ is hydrogen and the other is —COR ¹⁰ or -SO ₂ R ¹⁰ or, when R ⁸ and R ⁹ are combined, tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , X ¹ Is —O—, —S— or —NH—;
R ^{8 '} and R ^9' are independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R ^{8 '} and R ^9' is hydrogen and the other Is —COR ^{10 ′} or —SO ₂ R ^{10 ′} , or when R ^{8 ′} and R ^{9 ′} are combined, tetramethylene, pentamethylene, hexamethylene or —CH ₂ CH ₂ X ² CH ₂ CH _2- and X ² is -O-, -S- or -NH-;
R ¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl ;
R ^{10 '} is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl . ]

18. The pharmaceutical composition according to claim 17 , wherein the selective cytokine inhibitor is enantiomerically pure.

Treatment of macular degeneration, in the prevention or management methods, such treatment, prior to surgical intervention to reduce or prevent the symptoms of macular degeneration in a patient in need of prevention or management, a medicament for use during or after in the manufacture, a pharmaceutically acceptable salt of a selective cytokine inhibitory drug, or the inhibitors, the use of solvate or stereoisomer thereof.

20. Use according to claim 19 , wherein the surgical intervention is phototherapy, laser therapy, radiation therapy, retinal pigment epithelial transplantation or foveal movement .