RU2003115429A

RU2003115429A - DERIVATIVES OF IMIDES OF INDOLYLMALIC ACID AS PROTEINKINASE C INHIBITORS

Info

Publication number: RU2003115429A
Application number: RU2003115429/04A
Authority: RU
Inventors: Райнер Альберт; Найджел Грэм Кук; Сильвьяна КОТТЕН; Клаус Эрхард; Жан-Пьер ЭВЕН; Ришар Седрани; Петер ФОН-МАТТ; Юрген Вагнер; Герхард ЦЕНКЕ
Original assignee: Новартис Аг
Priority date: 2000-11-07
Filing date: 2001-11-05
Publication date: 2004-12-10

Claims

1. The compound of formula I

where R _a means H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyl, substituted by OH, NH ₂ , NH (C ₁ -C ₄ ) alkyl or N (di (C ₁ -C ₄ ) alkyl) ₂ ;

R _b means H or C ₁ -C ₄ alkyl;

R is a radical of formula (a), (b), (c), (d), (e) or (f), where

each of R ₁ , R ₄ , R ₇ , R ₈ , R ₁₁ and R ₁₄ is OH, SH, a heterocyclic radical, NR ₁₆ R ₁₇ , where each of R ₁₆ and R ₁₇ independently is H or C ₁ -C ₄ alkyl , or R ₁₆ and R _17, together with the nitrogen atom to which they are attached, form a heterocyclic residue, or a radical of the formula α

where X is a covalent bond. O, S or NR ₁₈ , where R ₁₈ is H or C ₁ -C ₄ alkyl;

R _c is C ₁ -C ₄ alkylene or C ₁ -C ₄ alkylene, in which one CH _{2 is} replaced by a group CR _x R _y , wherein one of R _x and R _y is H and the other is CH ₃ , each of R _x and R _y is CH ₃ or R _x and R _y together form a —CH ₂ —CH ₂ - group;

Y is bonded to the terminal carbon atom and is selected from the series consisting of OH, a heterocyclic residue, and —NR ₁₉ R ₂₀ , where each of R ₁₉ and R _{20 is} independently H, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl (C ₁ -C ₄ ) alkyl, aryl (C ₁ -C ₄ ) alkyl or C ₁ -C ₄ alkyl, optionally substituted at the terminal carbon atom by an OH group, or R ₁₉ and R ₂₀ together with the nitrogen atom to which they are attached form heterocyclic residue;

each of R _2, R _3, R _5, R _6, R _9, R _10, R _12, R _13, R ₁₅ and R _'15 independently represents H, halogen, C ₁ -C ₄ alkyl, CF _3, OH, SH, NH ₂ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, NH (C ₁ -C ₄ ) alkyl, N (di (C ₁ -C ₄ ) alkyl) ₂ or CN;

each E is —N = and G is —CH═ or E is —CH═ and G is —N =;

cycle A is optionally substituted,

or a salt of said compound.

2. The compound according to claim 1, where a heterocyclic residue such as R ₁ , R ₄ , R ₇ , R ₈ , R ₁₁ , R ₁₄ or Y, or formed, respectively, NR ₁₆ R ₁₇ or NR ₁₉ R ₂₀ , means A 3-8 membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, optionally substituted on one or more carbon atoms in the cycle and / or on the nitrogen atom in the cycle, if any.

3. The compound according to claim 2, where a heterocyclic residue such as R ₁ , R ₄ , R ₇ , R ₈ , R ₁₁ , R ₁₄ or Y, or formed, respectively, NR ₁₆ R ₁₇ or NR ₁₉ R ₂₀ , means the remainder of the formula (γ)

where the ring D means a 5, 6 or 7-membered saturated, unsaturated or aromatic cycle;

X _b is —N—, —C═ or —CH—;

X _c means —N =, —NR _f -, —CR _f ′ = or —CHR _f ′ -, where R _f is a nitrogen atom substituent in a ring selected from the group consisting of C ₁ -C ₆ alkyl, acyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl (C ₁ -C ₄ ) alkyl, phenyl, phenyl (C ₁ -C ₄ ) alkyl, a heterocyclic residue and a residue of formula β

where R ₂₁ is C ₁ -C ₄ alkylene or C ₂ -C ₄ alkylene interrupted by an O atom, and Y 'is OH, NH ₂ , NH (C ₁ -C ₄ ) alkyl or N (C ₁ -C ₄ alkyl) ₂ , and R _f ′ is a substituent on a carbon atom in a ring selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl optionally further substituted with a C ₁ -C ₄ alkyl group

where p is 1, 2 or 3, CF ₃ , halogen, OH, NH ₂ , —CH ₂ —NH ₂ , —CH ₂ —OH, piperidin-1-yl and pyrrolidinyl;

the bond between C ₁ and C ₂ is saturated or unsaturated, each of C ₁ and C ₂ independently means a carbon atom that is optionally substituted with one or two substituents selected from the substituents indicated above for the carbon atom in the ring, and lines between C ₃ and X _b and between C ₁ and X _b , respectively, mean several carbon atoms needed to build a 5, 6 or 7-membered ring D.

4. The compound according to claim 3, where D is a piperazinyl ring, optionally C- and / or N-substituted with the substituents indicated in claim 3.

5. The compound according to any one of the preceding paragraphs, where R is a radical of the formula (d), (e) or (f).

6. The compound according to claim 1, selected from the series containing

3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5-dione,

3- (1H-1-methylindol-3-yl) -4- [2- (4,7-diazaspiro [2.5] oct-7-yl) quinazolin-4-yl] pyrrole-2,5-dione,

3- (1H-indol-3-yl) -4- [2- (4-ethylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5-dione,

3- (1H-1-methylindol-3-yl) -4- [2- (4-ethylpiperazin-1-yl) -6-chloroquinazolin-4-yl] pyrrole-2,5-dione,

3- (1H-7-methylindol-3-yl) -4- [2- (4-methylpiperazin-1-yl) -6-chloroquinazolin-4-yl] pyrrole-2,5-dione,

3- (1H-1-methylindol-3-yl) -4- [2- (3 (S) -methylpiperazin-1-yl) -6-chloroquinazolin-4-yl] pyrrole-2,5-dione,

3- (1H-1-methylindol-3-yl) -4- [2- (3 (R) -methylpiperazin-1-yl) -6-chloroquinazolin-4-yl] pyrrole-2,5-dione and

3- (1H-indol-3-yl) -4- [3- (4-methylpiperazin-1-yl) isoquinazolin-1-yl] pyrrole-2,5-dione, or a salt thereof.

7. A method for producing a compound of formula I according to claim 1, comprising a) reacting a compound of formula II

where R _a , R _b and cycle A have the meanings indicated in claim 1, with a compound of formula III

where R has the meanings indicated in claim 1, b) the interaction of the compounds of formula IV

where R _a , R _b and cycle A have the meanings indicated in claim 1, with a compound of formula V

where R has the meanings indicated in claim 1, or c) the conversion of the substituent R ₁ , R ₄ , R ₇ , R ₈ , R ₁₁ or R ₁₄ in the compound of formula I to another substituent R ₁ , R ₄ , R ₇ , R ₈ , R ₁₁ or R ₁₄ and, if necessary, the conversion of the compounds of formula I, obtained in free form, into its salt or, conversely, vice versa.

8. The compound according to claim 1 for use as a pharmaceutical preparation.

9. A pharmaceutical composition comprising a compound of formula I according to claim 1 in free form or in the form of a pharmaceutically acceptable salt in admixture with a pharmaceutically acceptable diluent or carrier.

10. A combination comprising a) a protein kinase C inhibitor and T-cell activation and proliferation, and b) at least one other agent selected from drugs having immunosuppressive, immunomodulatory, anti-inflammatory, antiproliferative or antidiabetic effects.

11. A method for the prevention or treatment of disorders or diseases mediated by T lymphocytes and / or protein kinase C in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.