Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-01-05
2001-04-10
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S548000, C514S630000, C514S633000, C564S221000, C564S360000, C560S194000, C560S250000, C560S252000, C424S400000
Reexamination Certificate
active
06214873
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a 2-aminopropane-1,3-diol compound useful for pharmaceuticals, particularly immunosuppressants, a pharmaceutical use thereof and a synthetic intermediate therefor.
WO94/08943 discloses 2-aminopropane-1,3-diol compounds including 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride useful as a suppressant of rejection in organ or bone marrow transplantation, or as a therapeutic agent of various autoimmune diseases such as psoriasis, Behçet's disease and the like, and rheumatic diseases. WO96/06068 discloses a benzene compound useful as a suppressant of rejection in organ or bone marrow transplantation or as a therapeutic agent of various autoimmune diseases such as psoriasis, Behçet's disease and the like, and rheumatic diseases.
J. Org. Chem., vol. 25, p2057-2059 (1960) teaches 2-methylamino-2-(phenylmethyl or phenylmethyl substituted by 2-methyl, 3-methyl, 4-methyl, 4-methoxy or 4-hydroxy)propane-1,3-diol. In U.S. Pat. No. 3,660,488, 2amino-2-(p-chlorobenzyl)propane-1,3-diol as an anti-radiation drug is disclosed.
The object of the present invention is to provide a more effective and highly safe compound as a suppressant of rejection in organ or bone marrow transplantation or as a therapeutic agent of autoimmune diseases such as atopic dermatitis, psoriasis, articular rheumatism and Behçet's disease, a pharmaceutical comprising the said compound, and a synthetic key compound of the said compound.
The present inventors have made intensive studies in order to achieve the above-mentioned object, and found that, of the 2-aminopropane-1,3-diol compounds represented by the general formula disclosed in WO94/08943
a compound wherein, at the substituent R of this compound, a p-phenylene group in the carbon chain and a phenyl group at the end of the carbon chain are substituted and, in the carbon chain between the said p-phenylene group and the phenyl group, the carbon at the &bgr;-position of the p-phenylene group is substituted by a carbonyl group (these compounds are not disclosed concretely in the said official gazette) possesses less toxicity, high safety and superior immunosuppressive action, which resulted in the completion of the present invention.
SUMMARY OF THE INVENTION
Namely, the present invention relates to the following.
(1) A 2-aminopropane-1,3-diol compound of the general formula (hereinafter sometimes to be referred to as Compound (I))
wherein R
1
, R
2
, R
3
and R
4
are the same or different and each is a hydrogen or an acyl; a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(2) the 2-aminopropane-1,3-diol compound according to aforementioned (1), which is 2-amino-2-(2-(4-(1-oxo-5-phenylpentyl)phenyl)ethyl)propane-1,3diol (hereinafter sometimes to be referred to as Compound (I-a)), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(3) a pharmaceutical comprising the 2-aminopropane-1,3-diol compound according to the aforementioned (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(4) an immunosuppressant comprising, as an active ingredient, the 2aminopropane-1,3-diol compound according to the aforementioned (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(5) a suppressant of rejection comprising, as an active ingredient, the 2aminopropane-1,3-diol compound according to the aforementioned (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(6) an agent for the prevention or treatment of graft-versus-host diseases comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to the aforementioned (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(7) an agent for the prevention or treatment of autoimmune diseases or allergic diseases comprising, as an active ingredient, the 2-aminopropane-1,3-diol compound according to the aforementioned (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof,
(8) a pharmaceutical composition comprising the 2-aminopropane-1,3-diol compound according to the aforementioned (1) or (2), a pharmaceutically acceptable acid addition salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier,
(9) 2-amino-2-(2-(4-(1-hydroxy-5-phenylpentyl)phenyl)ethyl)propane-1,3-diol (hereinafter sometimes to be referred to as Compound (II)), a compound thereof wherein amino group and/or hydroxy group are(is) protected or a salt thereof,
(10) 2-amino-2-(2-(4-formylphenyl)ethyl)propane-1,3-diol (hereinafter sometimes to be referred to as Compound A), a compound thereof wherein amino group and/or hydroxy group are(is) protected or a salt thereof
The compound of the present invention (I) is represented by the formula
wherein each symbol is as defined above, and has structural characteristic that, in the carbon chain at the 2-position of the 2-aminopropane-1,3-diol skeleton, a p-phenylene group in the said carbon chain and a phenyl group at the end of the said carbon chain are substituted and, in the carbon chain between the said p-phenylene group and the phenyl group, the carbon at the &agr;-position of the p-phenylene group is substituted by a carbonyl group. Due to this structural characteristic, the compound of the present invention possesses less toxicity and high safety and shows superior immunosuppressive action.
Compound (II) of the present invention is represented by the formula
and Compound A of the present invention is represented by the formula
The groups represented by the respective symbols in the present specification are explained in the following.
The acyl at R
1
, R
2
, R
3
and R
4
is exemplified by a straight or branched chain alkanoyl having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl; a straight or branched chain alkanoyl having 2 to 6 carbon atoms which is substituted by phenyl, such as phenylacetyl and phenylpropionyl; an aroyl such as benzoyl; an alkoxycarbonyl wherein the alkoxy moiety is a straight or branched chain alkoxy having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, tert-pentyloxycarbonyl and hexyloxycarbonyl; and an aralkyloxycarbonyl such as benzyloxycarbonyl.
Examples of the pharmaceutically acceptable acid addition salts of the present compound (I) include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or salts with an organic acid such as acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 10-camphorsulfonic acid. The present compound can be converted to salts thereof with oxalic acid to obtain crystals. The salts of compound (II) and compound A also include the aforementioned acid addition salts.
Examples of the hydrate of the present compound (I) include monohydrate, ½ hydrate, ⅕ hydrate, 2 hydrate and {fraction (3/2)} hydrate. The present invention also encompasses solvates.
The amino-protecting group of the compound (II) and compound A useful as a synthetic intermediate for the compound of the present invention is exemplified by an aliphatic acyl such as formyl, acetyl, propionyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methanesulfonyl and ethanesulfonyl; an aromatic acyl such as phthaloyl, benzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, benzenesulfonyl and toluenesulfonyl; a carbonate such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, 2-cyanoethoxycarbony, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, diphenylmethoxycarbonyl, m
Adachi Kunitomo
Aoki Yoshiyuki
Fujita Tetsuro
Hanano Tokushi
Hoshino Yukio
Barts Samuel
Evenson, McKeown, Edwards & Lenahan P.L.L.C.
Welfide Corporation
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