Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1997-12-29
1999-01-05
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
514 9, 514 11, A61K 3812, C07K 700, C07K 1600, C07K 1700
Patent
active
058564365
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/01748, filed Jun. 24, 1996.
TECHNICAL FIELD
This invention relates to an alternative production technology for depsipeptide derivatives having anthelmintic activity and to novel intermediates for synthesis of such depsipeptides.
BACKGROUND ART
The following objective compound (I) is an anthelmintic compound known to have high parasiticidal activity and be suitable for human and animal use, and for its production there is known a process using the following route of total synthesis (WO 93/19053). The prior art route is: ##STR2##
However, this process is not altogether suitable for industrial-scale production, for each of the intermediates in the route from compound (B) to objective compound (I) has the basic group morpholino which restricts handling and prevents recrystallization for purification, with the consequence that resort must be had to column chromatography or the like for purification.
Having been developed to overcome the above disadvantages, this invention provides a novel industrial process for producing the objective compound (I) in good yield by way of synthesis via novel intermediates.
DISCLOSURE OF INVENTION
The objective depsipeptide derivative of this invention is a known compound which may be represented by the following general formula (I). ##STR3##
In accordance with this invention, the objective compound (I) or salt thereof can be produced by a process comprising the following series of steps. ##STR4##
(In the above reaction schema, R.sub.1 represents hydrogen or an amino-protecting group; R.sub.2 represents carboxy or protected carboxy; R.sub.3 and R.sub.4 independently represent hydrogen, lower alkyl, or an amino-protecting group, provided that at least either R.sub.3 or R.sub.4 represents an amino-protecting group; X represents a leaving group).
In the above reaction schema, compounds (Ia) and compound (IV) are novel substances.
Throughout this specification, amino acids, peptides, protective groups, condensing agents, etc. are indicated by the abbreviations adopted by IUPAC-IUB (the Commission on the Nomenclature of Organic Chemistry), which are conventionally used in the art.
Moreover, the amino acids and their residues as represented by such abbreviations are L-configured unless otherwise specified, and any D-configured compound or residue is indicated by the prefix D-.
The abbreviations used in connection with this invention are as follows.
Boc: t-butoxycarbonyl
Bzl: benzyl
Lac: 2-hydroxypropionic acid (lactic acid)
MeLeu: methylleucine
p-CbmNHPhLac: 2-hydroxy-3-(4-methoxycarbonylaminophenyl)propionic acid
p-MorPhLac: 2-hydroxy-3-(4-morpholinophenyl)propionic acid
P-NH.sub.2 PhLac: 3-(4-aminophenyl)-2-hydroxypropionic acid
Ms: methanesulfonic acid
The preferred salt of any of compounds (I), (Ia), (Ib), (II), (III), (IV), (V), and (VI) includes nontoxic salts of the common kinds, namely salts with bases and acid addition salts. To be more specific, there can be mentioned alkali metal salts (e.g. sodium salt, potassium salt, cesium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), salts with inorganic bases such as ammonium salt, salts with organic bases such as organic amines (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic carboxylic acid addition salts or organic sulfonic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), and salts with basic or acidic amino acids (e.g. arginate, aspartate, glutamate, etc.).
The preferred examples as well as paraphrases of various terms defining this invention as used hereinbefore and after in this specification are now presented.
The term "lower" means that the number of constituent carbon atoms is within the range of 1-6, inclusive, preferably 1-4, unless otherw
REFERENCES:
patent: 5514773 (1996-05-01), Nishiyama et al.
patent: 5646244 (1997-07-01), Nishiyama et al.
Nishiyama Hitoshi
Ohgaki Masaru
Yamanishi Ryo
Fujisawa Pharmaceutical Co. Ltd.
Marshall S. G.
Tsang Cecilia J.
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