RU97102700A

RU97102700A - ORGANIC COMPOUNDS

Info

Publication number: RU97102700A
Application number: RU97102700/04A
Authority: RU
Inventors: Михель Моррис Дрейфусс; Кэролин Энн Фостер; Ханс-Ульрих Наэгели; Берндт Оберхаузер
Original assignee: Новартис Аг
Priority date: 1994-07-27
Filing date: 1995-07-26
Publication date: 1999-04-27

Claims

1. Cyclopeptolide formula I

where a is a residue of butyric acid, substituted by α-hydroxyl group, which may be additionally substituted at the γ-position by the residue R ₆ , representing CN, COOR ₂ , CONR ₃ R ₄ , COR ₅ , CSNH ₂ or alkyl, which may be substituted by an azido group, a halogen atom, an alkoxy group, an optionally protected hydroxyl or amino group, vinyl, which may be substituted by an alkyl, a halogen atom or a CN group, cycloalkyl, tetrazolyl or a group —C≡CH; where R ₂ represents a hydrogen atom or an alkyl which may be further substituted by aryl, R ₃ and R ₄ are the same or different and represent a hydrogen atom or an alkyl or form together with the nitrogen atom a ring consisting of from 3 to 6 atoms, which may contain a second heteroatom, and R ₅ represents a hydrogen atom or lower alkyl;
B is a residue of α-amino-γ-methyl-substituted octanoic acid;
R ₁ is a hydrogen atom or methyl;
C represents a residue of tryptophan or N-methyltryptophan of formula VI

where R ₈ is a hydrogen atom, alkoxygroup, alkyl or benzyl, R ₉ is a hydrogen atom or halogen, R ₁₀ is a hydrogen atom or methyl, and

are single or double bond;
X is an α-amino-substituted (C ₂ -C ₁₄ ) carboxylic acid residue;
Y is an α-amino or N-methyl-α-amino-substituted (C ₂ -C ₁₀ ) carboxylic acid residue.

2. Cyclopeptolide according to claim 1, in which A is an α-hydroxybutyric acid residue that is a γ-substituted cyano group; a COOR ₂ ′ group, where R ₂ ′ is hydrogen, lower alkyl with 1 to 4 carbon atoms or diphenylmethyl; CONR ₃ 'R ₄ ', where R ₃ 'represents a hydrogen atom or methyl, and R ₄ ' is a hydrogen atom or alkyl, or R ₃ 'and R ₄ ' together with the nitrogen atom form a ring containing from 3 to 6 atoms, or morpholinyl ring; CH ₂ OH; COR ₅ ', where R ₅ ' represents a hydrogen atom or lower alkyl containing from 1 to 4 carbon atoms; vinyl, which may be further substituted by a group of CN, Br or lower alkyl containing from 1 to 4 carbon atoms; alkyl, which may be further substituted azido -. amino, hydroxy, chloro or alkoxy; tetrazolyl, cyclopropyl, CSNH ₂ or -C≡CH.
3. Cyclopeptolide according to claim 1 or 2, in which C is a residue of an N-methyltryptophan of formula VI, where R ₈ is a hydrogen atom, (C ₁ -C ₄ ) alkoxy, mainly methoxy, or alkyl, and R ₉ is an atom hydrogen or halogen.

4. Cyclopeptolide according to claim 1, 2 or 3, in which X is a residue of an α-amino-substituted (C ₄ -C ₈ ) carboxylic acid, which may be further substituted with a β- or γ- (C ₁ -C ₄ ) alkyl substituent.

5. Cyclopeptolide on PP. 1 to 4, in which X is α-amino-β- or γ- (C ₁ -C ₄ ) alkyl-, mainly methyl-, substituted octanoic or butyric acid residue.

6. Cyclopeptolide on PP. 1-5, in which Y is a residue of an N-methyl-α-amino-substituted (C ₂ -C ₄ ) carboxylic acid, which may be further substituted with a β- or γ- (C ₁ -C ₄ ) alkyl substituent.

7. Cyclopeptolide on PP. 1 to 5, in which Y is a residue of N-methylalanine or N-methylvaline.

8. Cyclopeptolide formula II

9. Cyclopeptolide formula III

10. Peptide or peptolide with an open chain, corresponding to cyclopeptolide according to any one of paragraphs. nineteen.

11. Peptide or peptolide with an open chain of formula IV
H - C - X - Y - A - B - R ₁ Leu - Leu • OR ₇ IV,
where the substituents are the same as in paragraph 1, and R ₇ represents a hydrogen atom or alkyl.

12. Peptide or peptolide with an open chain of the formula V
HA - B - R ₁ Leu - Leu - C - X - Y • OR ₇ V,
where the substituents are the same as in paragraph 1, and R ₇ represents a hydrogen atom or alkyl.

13. Cyclopeptolide formula Ip

where A _p represents the residue of α-hydroxy-substituted butyric acid, which can be substituted at the γ-position by the group R _6p , which is a CN group, possibly protected groups CH ₂ OH, COOR _2p , CONR _3p R _4p , COR _5p or -CH ═CH ₂ , where R _2p is a hydrogen atom or an alkyl which may be further substituted by aryl, R _3p and R _4p are the same or different and represent a polingoride or alkyl or form together with the nitrogen atom a 5 or 6 membered ring, which can contain a second heteroatom, and R _5p represents a hydrogen atom or a bottom s alkyl;
B _p is a residue of α-amino-γ-methyl-substituted octanoic acid;
R _1p is a hydrogen atom or methyl;
C _p is a tryptophan or N-methyltryptophan residue, which may be N ′ - (C ₁ -C ₄ ) alkoxy substituted;
X _p is an α-amino-substituted (C ₂ -C ₁₄ ) carboxylic acid residue;
Y ₂ is an α-amino or N-methyl-α-amino-substituted (C ₂ -C ₁₀ ) carboxylic acid residue.

14. Cyclopeptolide Formula I'p

where A ′ _p is the residue of α-hydroxy-substituted butyric acid, which may be substituted at the γ-position by the group R ′ _6p , which is CN, COOR ′ _2p , CONR ′ _3p R ’ _4p , COR’ _5p , alkyl, which may be substituted by an azido group, a halogen atom, an alkoxy group, an optionally protected hydroxyl or amino group, vinyl (may be substituted with an alkyl, a halogen atom or a CN group), cycloalkyl, tetrazolyl or a group —C≡CH; where R ' _2p represents a hydrogen atom or an alkyl which may be substituted by aryl, R' _3p and R ' _4p are the same or different and represent a hydrogen atom or an alkyl or form together with the nitrogen atom a ring consisting of from 3 to 6 atoms which may contain a second heteroatom, and R ' _5p represents a hydrogen atom or lower alkyl;
B ' _p is a residue of α-amino-γ-methyl-substituted octanoic acid;
R ' _1p is a hydrogen atom or methyl;
C ' _p is a tryptophan or N-methyltryptophan residue of formula VI'p

where R ' _8p is a hydrogen atom, alkoxy, alkyl or benzyl, R' _9p is a hydrogen or halogen atom, R ' _10p is a hydrogen atom or methyl, and

represents a single or double bond;
X ′ _p is an α-amino-substituted (C ₂ -C ₁₄ ) carboxylic acid residue;
Y ′ _p is an α-amino or N-methyl-α-amino-substituted (C ₂ -C ₁₀ ) carboxylic acid residue.

15. The compound according to any one of paragraphs. 1-14 in the form of a salt or ether.

16. A compound having properties 2, 3, and 5 to 8 of compound A, shown in Table 1.

17. A compound possessing properties 2, 3 and 5 - 8 of compound B, presented in Table 1.

18. Fungal strain F92-4471 / 08, deposited as NRRL 21123, or its mutants or derivatives.

19. New cyclopeptolides produced by strain F92-4471 / 08 deposited as NRRL 21123.

20. The method of producing the compound according to claim 1 by culturing strain F92-4471 / 08 / (NRRL 21123), or its mutant or derivative, or strains of similar fungal species in a nutrient medium and extracting the compound from them.

21. A method for producing a compound according to claim 1 by modifying a compound of formula II or III, comprising:
a) to obtain compounds of formula I, in which R ₆ is a group COOR ₂ ', where R ₂ ' is alkyl, which can be substituted by aryl, the interaction of compounds of formula I, where R ₆ is represented by a CN group, with nucleophiles, preferably with alcohols, with an appropriate basic or acid catalyst, preferably hydrochloric acid, in organic solvents, preferably ether, or
b) to obtain compounds of formula I, in which R ₆ is SOAlkyl, the interaction of compounds of formula 1, where R ₆ is a CN group, using organo-metallic compounds as nucleophiles, preferably Grignard compounds or lithioalkyls that interact in aprotic organic solvents, preferably ethers, with or without a catalyst, or
c) to obtain compounds of formula 1 in which R ₆ is a COOH group, hydrolysis of compounds of formula I, where R ₆ is represented by COOAlkyl, with the help of a mineral acid, preferably hydrochloric, in an aqueous alcohol solution, or a base, or
d) for the preparation of compounds of the formula I, in which R ₆ is a COOR ₂ group, the esterification of compounds of formula I, where R ₆ is represented by the COOH group, by standard methods, preferably by converting an acid chloride with an acid using, for example, thionyl chloride and treating with a suitable alcohol in the presence or absence of an acid binder, or
d) to obtain compounds of formula I, in which R ₆ is a group CH ₂ OH, reduction of compounds of formula I, where R ₆ is represented by COOR ₂ group, with the help of metal hydrides or boron hydrides, preferably borane dimethylsulfide complex, in organic solvents, or
e) to obtain compounds of formula I, in which R ₆ is a group CONR ₃ R ₄ , the conversion of compounds of formula I, where R ₆ is represented by the group COOR ₂ , in the reaction with amines, preferably by converting the free acid to the acid chloride and the reaction with the amine Formula HNR ₃ R ₄ or
g) to obtain compounds of formula I, in which R ₆ is a CHO group, oxidation of compounds of formula I, where R ₆ is represented by the group CH ₂ OH, or
h) to obtain compounds of formula I, in which R ₆ is a possibly substituted vinyl, reacting compounds of formula I, where R ₆ is a CHO group, with a Witting reagent in methyl form, or
i) to obtain compounds of the formula I, in which R ₆ is a possibly substituted alkyl, the interaction of the compounds of the formula I, where R ₆ is represented by the group CH ₂ OH, or
K) to obtain compounds of the formula I, in which R ₆ is a group CH ₂ NH ₂ , the reduction of compounds of the formula I, where R ₆ is represented by the group CH ₂ N ₃ , or
l) to obtain compounds of formula I, in which R ₆ is a group -C -CH, the interaction of compounds of formula I, where R ₆ is represented by the group CH = CBr ₂ , or
m) to obtain compounds of formula I, in which R ₆ is cyclopropyl, the interaction of the compounds of formula I, where R ₆ is represented by vinyl, with diazomethane, or
n) to obtain compounds of formula I, in which R ₆ is tetrazolyl, reacting compounds of formula I, where R ₆ is represented by the CN group, with an azide-containing compound, or
o) to obtain compounds of formula I, in which R ₈ represents a hydrogen atom, removing the methoxy group from compounds of formula I, where R ₈ is represented by a group of OCH ₃ , or
p) to obtain compounds of the formula I, in which the symbol

denotes a single bond, the reduction of compounds of the formula I, where the symbol.

denotes a double bond, or
p) to obtain compounds of formula I, in which R ₈ is alkyl or benzyl, the introduction of these groups into compounds of formula I, where R ₈ is represented by a hydrogen atom, or
c) to obtain compounds of the formula I, in which R ₆ represents a halogen atom, halogenation of compounds of the formula I, where R ₉ is represented by a hydrogen atom, or
t) to obtain compounds of the formula I, in which R ₈ is an alkoxy group and the symbol

denotes a double bond, the interaction of compounds of the formula I, where R ₈ is represented by a hydrogen atom and the symbol

denotes a single bond, with alkaline tungstate and hydrogen peroxide and alkylation of the N-hydroxyindole intermediate, or
y) to obtain compounds of formula I, in which R ₆ is a group of CSNH ₂ , the interaction of compounds of formula I with derivatives of sulfur, preferably with diphenylphosphinodithioic acid.

22. The method of producing a compound according to claim 1, comprising cyclizing a linear peptide or peptolide containing the acid residues A, B, R ₁ Leu, Leu, C, X and Y combined with each other in the appropriate order.

23. The therapeutic use of a compound according to claim 1.

24. The therapeutic use of a compound according to claim 1 for inhibiting the expression of adhesion molecules.

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

26. A therapeutic composition comprising a therapeutically effective amount of a compound according to claim 1.

27. The therapeutic composition of claim 24 in the form of a cream, or lotion, or the like for topical use.

28. The therapeutic composition of claim 24, in the form of an aerosol for use with an inhaler.

29. The use of a compound according to claim 1 for the preparation of a drug for therapeutic use in the treatment or prevention of diseases characterized by an increased level of expression of adhesion molecules.