JP2010515750A5

JP2010515750A5 -

Info

Publication number: JP2010515750A5
Application number: JP2009545669A
Authority: JP
Filing date: 2008-01-10
Publication date: 2011-03-03

Claims

A compound of formula I having a sphingosine-1-phosphate receptor agonist and / or antagonist biological activity, or a pharmaceutically acceptable salt of said compound:

Wherein R ¹ , R ² , R ³ and R ⁴ are independently hydrogen, a linear or branched alkyl group having 1 to 12 carbon atoms, a double bond with 2 to 6 carbon atoms Alkenyl groups having 1 or 2 carbon atoms, alkynyl groups having 2 to 6 carbon atoms and 1 or 2 triple bonds, carbocyclic hydrocarbon groups having 3 to 20 carbon atoms, up to 20 carbon atoms and in the ring oxygen, nitrogen and / or heterocyclic group having at least one sulfur, halo, C ₁ -C ₁₂ haloalkyl group, a hydroxyl group, C ₁ -C ₁₂ alkoxy group, C ₃ -C ₂₀ arylalkyloxy group, C ₁ -C ₁₂ alkylcarbonyl group, a formyl group, an oxycarbonyl group, a carboxy group, C ₁ -C ₁₂ alkyl carboxylate, C ₁ -C ₁₂ alkyl amide group, aminocarbonyl group, an amino group, a cyano group, a diazo group Nitro group, thio group, sulfoxyl group, and sulfonyl group Selected from the group;
X and X ¹ are independently selected from the group consisting of NR ⁵ , O and S;
R ⁵ is hydrogen, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 5 to 10 carbon atoms, phenyl or lower alkylphenyl;
Y is a carbocyclic aryl group or a heterocyclic aryl group, wherein the carbocyclic aryl comprises 6-20 atoms, and the heterocyclic aryl comprises 2-20 carbon atoms and nitrogen , Containing 1 to 5 heteroatoms selected from the group consisting of oxygen and sulfur, the aryl may be bonded to A at any position;
Z is O or S;
n is 0 or an integer from 1 to 5;
o is 0 or an integer from 1 to 3;
p is 0 or an integer from 1 to 3;
q is 0 or 1;
r is 0 or 1;
A, A ¹ and A ² are independently (CH ₂ ) _v (where v is 0 or an integer from 1 to 12), branched alkyl having 3 to 12 carbon atoms, carbon Selected from the group consisting of cycloalkyl having 3-12 atoms, alkenyl having 2-10 carbon atoms and 1-3 double bonds, and alkynyl having 2-10 carbon atoms and 1-3 triple bonds. ;
B is selected from the group consisting of hydrogen, OR ⁶ , COOR ⁷ , NR ⁸ R ⁹ , CONR ⁸ R ⁹ , COR ¹⁰ , CH = NOR ¹¹ , CH = NNR ¹² R ¹³ , where R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ are independently hydrogen, straight-chain or branched alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 6 carbon atoms and 1 or 2 double bonds, carbon atom Alkynyl having 2 to 6 and 1 or 2 triple bonds, carbocyclic hydrocarbon group having 3 to 20 carbon atoms, up to 20 carbon atoms and at least one of oxygen, nitrogen and / or sulfur in the ring R ⁸ , R ⁹ , R ¹² and R ¹³ are independently hydrogen, linear or branched alkyl having 1 to 12 carbon atoms, carbon atoms 2 -6 alkenyl having 1 or 2 double bonds, alkynyl having 2 to 6 carbon atoms and 1 or 2 triple bonds, carbocyclic hydrocarbon group having 3 to 20 carbon atoms, carbon atom 20 Individual And oxygen in the ring, selected from the group consisting of heterocyclic group having at least one nitrogen and / or sulfur, or R ⁸ and R ⁹ and / or R ¹² and R ¹³ are carbon atoms 2 together 5 divalent carbon groups can be formed to form a heterocycle with nitrogen, where R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² or R ¹³ Any of them may be substituted with one or more halogen groups, hydroxy groups, alkyloxy groups, cyano groups, nitro groups, mercapto groups, or thiol groups; provided that v is 0 and r is 0 , B is not hydrogen; or B is a carbocyclic hydrocarbon group having 3 to 20 carbon atoms, or a heterocyclic ring having 20 carbon atoms and at least one of oxygen, nitrogen and / or sulfur in the ring Wherein, when B is a carbocyclic group or a heterocyclic group, B may be bonded to A ² at any position).

2. The compound of claim 1, wherein Z is O.

The compound according to claim 2, wherein Y is a phenyl group or a pyridyl group.

A is CH _2, A compound according to claim 3.

5. A compound according to claim 4, wherein X is NH.

6. The compound according to claim 5, wherein n is 0 or an integer of 1 or 2, and R ⁴ is fluoro.

7. A compound according to claim 6, wherein R < ¹ > is i-propyl.

8. The compound according to claim 7, wherein R ³ is selected from the group consisting of phenyl optionally substituted with one or two fluoro groups, and pyridyl.

9. A compound according to claim 8, wherein p is 0.

A ¹ and A ² is absent The compound according to claim 9.

X ¹ is O, r is 1, A ¹ is absent, A ² is (CH ₂ ) _v (where v is 1 or 2), and B is it is oR ⁶ or NR ⁸ R ^9, compounds of claim 10.

B is a CR ¹⁰ = NOR ¹¹ R ^10, wherein, R ¹⁰ is H, R ¹¹ is methyl or i- butyl, compound of claim 10.

B is CONR ⁸ R ⁹ wherein R ⁸ and R ⁹ are selected from the group consisting of H, methyl, ethyl and propyl, or R ⁸ and R ⁹ together with N are 5 members 11. A compound according to claim 10, which forms a ring.

6-substituted indole-3-carboxylic acid-N-arylmethylamide having sphingosine-1-phosphate antagonist activity, wherein the 6-substituent is represented by the following formula: Acid-N-arylmethylamide
(X ¹ ) _r -A ² -B
Wherein X ¹ is O;
r is 0 or 1;
A ² is absent or is (CH ₂ ) _v , where v is 1 or 2;
B is OR ⁶ or NR ⁸ R ⁹ , where R ⁶ , R ⁸ and R ⁹ are methyl; or
B is CR ¹⁰ = NO R ¹¹ R ¹⁰ where R ¹⁰ is H and R ¹¹ is methyl or i-butyl; or
B is CONR ⁸ R ⁹ wherein R ⁸ and R ⁹ are selected from the group consisting of H, methyl, ethyl and propyl, or R ⁸ and R ⁹ together with N are a 5-membered ring Form; or
B is OR ⁶ where R ⁶ is H; or
B is COR ¹⁰ where R ¹⁰ is methyl).

A sphingosine-1- represented by the following general formula I for producing a composition for treating a disease or disorder selected from the group consisting of glaucoma, dry eye, angiogenesis, cardiovascular disease and disorder, and wound healing: Use of a compound having a phosphate receptor agonist and / or antagonist biological activity: