Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1993-12-16
1996-04-02
Schain, Howard E.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C07K 500, C07K 700, C07K 1700, A61K 3800
Patent
active
055041892
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel peptides, to their preparation and to their use in controlling diseases.
Various compounds have been isolated from tunicates of the species Trididemnum solidum and Trididemnum cyanophorum, and their structure has been elucidated (U.S. Pat. Nos. 4,493,796, 4,548,814, 4,782,135, EP 48 149, EP 393 883) and they have been found to have antiviral and antineoplastic effects.
We have now found that peptides of the formula I ##STR2## where
X.sup.1 is oxygen or NH, saturated or unsaturated aliphatic, aliphatic-aromatic or aromatic acyl radical which has 1-30 carbons and can be substituted by fluorine, nitro, oxo, hydroxyl, C.sub.1 -C.sub.4 -alkoxy or unprotected or protected amino, X.sup.2 are both oxygen, protected or free N--Me--D--Leu, and the salts thereof with physiologically tolerated acids, are easier to prepare and have an improved effect.
The N,O-dimethyltyrosyl radical can have the R or S configuration in the molecule.
Preferred compounds of the formula I are those where amino-protective group, a benzoyl radical which is unsubstituted or substituted by Cl or OH, a D-aminoacyl group which is free or N-terminally protected, or the sarcosyl radical,
Particularly suitable physiologically tolerated acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
The novel compounds can be prepared by conventional methods.
Thus, the compounds can be assembled sequentially from amino acid derivatives or by linkage of suitable small fragments. In the sequential assemblage, the peptide chain or peptolide chain is extended stepwise by one amino acid derivative each time. With fragment coupling it is possible to link together fragments of different length, it being possible in turn to obtain the fragments by sequential assemblage from amino acid derivatives or by fragment coupling. The cyclic compounds are obtained by a cyclization reaction after synthesis of the open-chain peptides or peptolides.
Both in sequential assemblage and in fragment coupling it is necessary to link the building blocks by forming an amide linkage or an ester linkage. Enzymatic and chemical methods are suitable for this.
Chemical methods for forming amide linkages are dealt with in detail by Muller, Methoden der Organischen Chemie Vol. XV/2, pp. 1-364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Synthesis, pp. 31-34, 71-82, Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, pp. 85-128, John Wiley & Sons, New York, 1976, and other standard works of peptide chemistry. The azide method, the symmetric and mixed anhydride method, active esters generated in situ or preformed (e.g. cyanothiopyridylesters) and the formation of amide linkages using coupling reagents (activators), especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-C1), diphenylphosphoryl azide (DPPA), Castro's reagent (BOP), O-benzotriazolyl-N,N,N'N'-tetramethyluronium salts (HBTU), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglichs Reagenz; HOTDO) and 1,1'-carbonyldiimidazole (CDI) are particularly preferred. The coupling reagents can be used alone or in combination with additives such as 4-dimethylaminopyridine (DMAP), N-hydroxybenzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
Chemical methods for the formation of ester linkages are dealt with in detail by Muller, Methoden der Organischen Chemie Vol. E5, pp. 656-773, Thieme Verlag Stuttgart, 1985. The reaction of carboxylic acid and alcohol with di
REFERENCES:
patent: 4493796 (1985-01-01), Rinehart, Jr.
patent: 4548814 (1985-10-01), Rinehart, Jr.
patent: 4782135 (1988-11-01), Rinehart, Jr.
patent: 4948791 (1990-08-01), Rinehart, Jr. et al.
Morrison and Boyd, Organic Chemistry, 3rd edition, p. 186, (1980).
ASM News vol. 56 p. 368 (1990).
Sandstrom et al. Drugs vol. 43 pp. 372-390 (1987).
Jaroff, Time May 23, 1988, pp. 56-64.
Johnson et al. Cancer Treatment Reviews vol. 2 pp. 1-31 (1975).
25th Ann. vol., Annual Reports In Medicinal Chemistry vol. 25, 1992 Total Synthesis of the Didemnins; . . . Synthesis, Schmidt et al., 294-300.
Anrineoplastic Activity of Didemnin Congeners: . . . , Jourin et al., Jr. of Med. Chem 1991, vol. 34, No. 2, 486-491.
Emling Franz
Griesser Helmut
Haas Gerhard
Haupt Andreas
Kluge Michael
BASF - Aktiengesellschaft
Huff Sheela J.
Schain Howard E.
LandOfFree
Peptides, their preparation and use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Peptides, their preparation and use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptides, their preparation and use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2017247