Cyclic hexapeptide compounds

Details Cyclic hexapeptide compounds Cyclic hexapeptide compounds

1998-05-05

1999-07-13

Tsang, Cecilia J.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

530329, 530345, 514 10, 514 6, A61K 3812, C07K 750

Patent

active

059228385

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a cyclic hexapeptide compound having a distinguished antitumor effect and its salts.


BACKGROUND ART

Cancer now ranks at the top of causes of death and this tendency seems to last much longer. Thus, many attempts have been made to develop medicaments for curing the cancer and many researchers have engaged in studies to extract anti-tumor components from plants for a long time. For analogs of cyclic hexapeptide compounds including N-methyltyrosine and alanine of the present invention, RA-VII (TPC-B; JP-A-58-21655), RA-V (Chem. Pharm. Bull., 32, 284-290, 1984), etc., which are extracts from Rubiaceae herbs, a kind of medicinal plants, are known, among which RA-VII has been regarded as promising, but has been found not fully effective yet.
An object of the present invention is to provide a cyclic hexapeptide compound having a superior pharmaceutical effect than RA-VII.


DISCLOSURE OF THE INVENTION

The present invention provides a cyclic hexapeptide compound represented by the following formula: ##STR4## where R is a group represented by the following formula: ##STR5## (where R.sup.1 and R.sup.2 are each an alkyl group, a phenyl group or a benzyl group), or a group represented by the following formula: ##STR6## (where n is an integer of 4 to 6).
In the present invention, the alkyl group is straight or branched alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, t-butyl, etc.
The present compound can be produced in the following manner: the hydroxyl group of the compound of formula (I) wherein R is a hydrogen atom (which will be hereinafter referred to as "RA-V") is allowed to react with a nitrogen atom-containing halide, represented by the following formula: produce the present compound.
For a reaction solvent, N,N-dimethylformamide can give a good result, but dimethyl sulfoxide, 1,4-dioxane, acetone, methylethylketone, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, etc. can be also used.
The reaction is carried out preferably in the presence of a base, such as potassium carbonate, sodium carbonate, potassium hydride and sodium hydride. The reaction temperature is usually in a range of 5.degree. to 80.degree. C., though depending upon the boiling point of a solvent.


BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be further explained below, referring to Examples. Structures and abbreviations of compounds produced in Examples are shown in Table 1.


TABLE 1 ______________________________________ 1 #STR7## Example No. Abbreviation Substituent R ______________________________________ 1 TI-351 2 #STR8## 2 TI-356 3 #STR9## 3 TI-355 4 #STR10## 3 TI-357 5 #STR11## 3 TI-358 6 #STR12## 3 TI-359 7 #STR13## 3 TI-360 8 #STR14## 3 TI-361 9 #STR15## ______________________________________


EXAMPLE 1 (TI-351)

372 mg (0.49 mmole) of RA-V and 106 mg (0.74 mmole) of 2-chloroethyldimethylamine hydrochloride are dissolved into 3 ml of N,N-dimethylformamide and then admixed with 271 mg (2.0 mmoles) of potassium carbonate with stirring at room temperature for 60 hours. Then, 1 ml of 28% aqueous ammonia is added to the reaction solution, followed by stirring at room temperature for 12 hours. Then, the reaction mixture is diluted with 20 ml of chloroform, followed by drying over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure and the resulting residues are subjected to an alumina column chromatography. The chloroform/methanol (20:1) eluted fraction is recrystallized from methanol, whereby 198 mg of TI-351 is obtained.


EXAMPLE 2 (TI-356)

379 mg (0.50 mmole) of RA-V and 150 mg (0.75 mmole) of 2-chloroethyldiisopropylamine hydrochloride are dissolved into 3 ml of N,N-dimethylformamide and then admixed with 276 mg (2.0 mmoles) of potassium carbonate with stirring at room temperature for 60 hours. Then, 1 ml of 28% aqueous ammonia is added to the reaction solution, followed by stirring at room temperature for 12 hours. Then, the reaction mixture is

REFERENCES:
patent: 4476299 (1984-10-01), Hokawa
Chem Pharm. Bull, vol. 32 (1984) pp. 284-290.
Itakawa, et al. "Isolation and Anti-tumor Activity of Cyclic Hexapeptides Isolated from Rubiae Radix" Chem. Pharm. Bull., 1984, 284-290.

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