Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-10
1997-03-04
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 514255, 544357, 544368, 544370, 544385, A61K 31495, C07D24102, C07D40302, C07D24104
Patent
active
056079346
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP94/01071, filed Jul. 1, 1994.
FIELD OF THE INDUSTRIAL UTILIZATION
The present invention relates to novel piperazine derivatives and salts thereof.
BACKGROUND ART
There have been known some piperazine derivatives having chemical structural formulae similar to those of the piperazine derivatives of the present invention, from the following prior art references, i.e. EP-A2-303250 and U.S. Pat. No. 5,021,419.
DISCLOSURE OF THE INVENTION
The present invention provides piperazine derivatives and salts thereof, which are novel and are not known in prior art references. Said piperazine derivatives are represented by the following general formulae (1) and (2): ##STR2## wherein R.sup.1 is a lower alkyl group; to 3 substituents selected from the group consisting of a hydroxyl group, a phenyl-lower alkoxy group, a lower alkyl group, a lower alkoxy group and a halogen atom, an imidazolyl-substituted lower alkyl group which may have phenyl-lower alkyl group(s) as the substituent(s) on the imidazolyl ring, or a group of the formula: ##STR3## (wherein R.sup.5 and R.sup.6 are the same or different and are each a hydrogen atom, a benzothiazolyl group, or a phenyl-lower alkyl group which may have, on the phenyl ring, 1 to 3 substituents selected from the group consisting of a lower alkoxy group, a phenyl-lower alkoxy group, a lower alkyl group and a hydroxyl group; further, said R.sup.5 and R.sup.6 and the adjacent nitrogen atom bonding thereto may form, together with or without other nitrogen atom or an oxygen atom, a 5- to 6-membered saturated heterocyclic group; said heterocyclic group may have, as the substituent(s), phenyl group(s) which may have lower alkoxy group(s) as the substituent(s) on the phenyl ring); group; and tetrahydropyranyloxy group; and ##STR4## wherein R.sup.7 is a lower alkyl group, a phenyl-lower alkyl group which may have, on the phenyl ring, substituent(s) selected from the group consisting of a hydroxyl group and a phenyl-lower alkoxy group, a lower alkylthio group-substituted lower alkyl group, a phenyl-lower alkoxy group-substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl group-substituted lower alkyl group or a hydroxyl group-substituted lower alkyl group; trimethylene group together; and
The piperazine derivatives represented by the above general formulae (1) and (2) and the salts thereof according to the present invention possess an inhibitory effect against superoxide radical (O.sub.2.sup.-) released from the macrophage cells of guinea pig by stimulation, and also possess an anti-albuminuria activity in Masugi nephritis. Thus, the piperazine derivatives represented by general formulae (1) and (2) and the salts thereof are useful agents for preventing and treating various diseases caused by the above-mentioned superoxide radical, for example, diseases of autoimmunity (e.g. rheumatoid arthritis), artheriosclerosis, ischemic heart disease, transient cerebral ischematic attack, hepatic insufficiency and renal insufficiency. They are also useful agents for preventing and treating the nephritis in various clinical fields.
In addition to the above, the piperazine derivatives of general formulae (1) and (2) and the salts thereof also possess an inhibitory effect against the proliferation of Mesangium cells which are closely related to the development of the nephritis; thus, they are useful agents for preventing and treating the proliferative nephritis.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the present specification, each of the substituents in general formulae (1) and (2) is specifically as follows.
The lower alkoxy group can be exemplified by straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups and the like.
The lower alkyl group can be exemplified by straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl
REFERENCES:
Synthesis of 2,5-dioxygenated pyrazine 4-oxides: total synthesis of a new inhibitor of superoxide anion generation, OPC-15161, Yasuyuki Kita et al., J. of the Chemical Society, Perkin Transactions 1, No. 7, Apr. 1994, pp. 875-884.
Pyrazine Chemistry, A. Kayhan Gokturk et al., Chem. Abstr., vol. 97, (1982) 38916u.
Stereochemical studies on the biosynthesis of the a.beta.-didehydro amino acid units of mycelianamide, cyclopenin, and cyclopenol, Gordon W. Kirby et al., Chem. Abstr., vol. 85, (1976) 173991g.
Isolation of some new 3,6-dialkyl-1,4-dihydroxy-piperazine-2,5-diones from Aspergillus terreus, Mary J. Garson et al., Chem. Abstr., vol. 105, (1986) 111582x.
Conversion of N-hydroxytryptophans into .alpha.,.beta.-dehydrotryptophan, Ralf Plate et al., Chem. Abstr., vol. 108 (1987) 222064m.
Conversion of N-hydroxytryptophan into .alpha.-functionalized tryptophans, Ralf Plate et al., Chem. Abstr., vol. 109 (1987) 23333u.
N-Hydroxy amides. Part 6. Synthesis and spectroscopic properties of 1-hydroxypiperazine-2,5-diones, Masayasu Akiyama et al., Chem. Abstr., vol. 111 (1989) 134729p.
Pulcherrimin: A synthesis of 1,4-dihydroxy-2,5-dioxopiperazines A. H. Cook et al., Chem. Abstr., vol. 51 (1957) 8763c.
Studies in relation to biosynthesis. XXIX. Terpenoid chain of mycelianamide, A. J. Birch et al., Chem. Abstr., vol. 57 (1962) 5958.
Biosynthetic incorporation of stereoselectively labeled tyrosine-.beta.H into mycelianamide, Gordon W. Kirby et al., Chem. Abstr., vol. 79 (1973) 15643s.
Total synthesis of (.+-.)-mycelianamide, Noboru Shinmon et al., Chem. Abstr., vol. 94 (1981) 121466f.
.alpha.-Functionalized amino acid derivatives. A synthetic approach of possible biogenetic importance, Jacobus D. M. Herscheid, Chem. Abstr., vol. 93 (1980) 8480x.
Biosynthesis of gliotoxin. Synthesis of sulfur-bridged dioxopiperazines from N-hydroxyamino acids, Jacobus D. M. Herscheid et al., Chem. Abstr., vol. 93 (1980) 26386a.
1,4-Dihydroxy-2,5-dioxopiperazines from activated N-hydroxyamino acids, Jacobus D. M. Herscheid et al., Chem. Abstr., vol. 95 (1981) 97729s.
N-Hydroxytryptophan in the synthesis of natural products containing oxidized dioxopiperazines. An approach to the neoechinulin and sporidesmin series, Harry C. J. Ottenheijm et al., Chem. Abstr., vol.97 (1982) 6749a.
Synthesis and reaction of .alpha..beta.-unsaturated .alpha.-nitro carboxylic esters, Chung Ch'i Shin et al., Chem. Abstr., vol. 74 (1971) 12570b.
The .alpha..beta.-unsaturated carboxylic acid derivatives. IX. Cyclization of .alpha.(N-acylhydroxyamino)acid esters with ammonia or hydroxylamine, Chung-Gi Shin et al., Chem. Abstr., vol. 84 (1976) 17694m.
.alpha..beta.-Unsaturated carboxylic acid derivatives. XIII. The synthesis and configuration of alkyl 2-acyl-amino-2-alkenoates and their cyclized 2,5-piperazinedione derivatives, Chung-Gi Shin, Chem. Abstr., vol. 88 (1978) 190747m.
Standardized one-and two-dimensional thin-layer chromatographic methods for the identification of secondary metabolites in Penicillium and other fungi, R. R. M. Paterson, Chem. Abstr., vol. 106 (1986), 29448v.
High-performance liquid chromatographic determination of profiles of mycotoxins and other secondary metabolites, Jens C. Frisvad, Chem. Abstr., vol. 107 (1987) 36247c.
Standardized high-performance liquid chromatography of 182 mycotoxins and other fungal metabolites based on alkylphenone retention indexes and UV-VIS spectra (diode array detection), Jens Frisvad et al., Chem. Abstr., vol. 107 (1987) 192376z.
Gradient high-performance liquid chromatography using alkylphenone retention indices of insecticidal extracts of Penicillium strains, R. Russell et al., Chem. Abstr., vol. 112 (1989) 115080z.
Neutral, alkaline and difference ultraviolet spectra of secondary metabolites from Penicillium and other fungi, and comparisons to published maxima from gradient high-performance liquid chromatography with diodearray detection, R. Russell et al., Chem. Abstr., vol. 113 (1990) 128844x.
Structure of cyclo(-N-hydroxyglycyl-L-ph
Miyazaki Toshiki
Morisue Masatoshi
Nakano Yoshimasa
Tamura Katsumi
Tone Hitoshi
Otsuka Pharmaceutical Co. Ltd.
Tsang Cecilia
LandOfFree
Piperazine derivatives and salts thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Piperazine derivatives and salts thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Piperazine derivatives and salts thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2146083