Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-07
2004-04-20
Lambkin, Deborah (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S075000
Reexamination Certificate
active
06723745
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to amino alcohol derivatives having excellent immune suppression activity, pharmacologically acceptable salts thereof, esters thereof or other derivatives thereof; to pharmacological compositions containing said compound as an active ingredient; to the use of said compounds in the preparation of said pharmaceutical compositions; and to methods for prevention or treatment of autoimmune diseases which comprise administering a pharmacologically effective amount of said compound to warm blooded animals in need of such prevention of treatment.
In another aspect, the present invention relates to optically active novel amino alcohol derivatives (particularly, optically active 4,4-disubstiuted oxazolidin-2-one derivatives), which are useful synthetic intermediates for the preparation of said amino alcohol derivatives or other medicaments.
In yet another aspect the present invention relates to a novel processes for the excellent selective preparation of oily active 2-substituted 2-amino-1,3-propanediol mono-ester derivatives, which are useful synthetic intermediates for the preparation of said amino alcohol derivatives in optically active form.
Steroids or antiinflammatory drugs have been used as therapeutic agents for inflammatory responses caused by normal immunological responses in diseases related to the immune system such as rheumatoid arthritis and other autoimmune diseases. However, these agents are agents that improve the symptoms, but they do not provide treatment of the causes.
Although abnormal immunological responses have also been reported to contribute to the pathogenesis of diabetes mellits and nephritis [Kidney International, 51, 94 (1997); Journal of Immunology, 157, 4691 (1996)], no agents have ever been developed to improve the abnormal immunological responses.
On the other had, development of immune suppressors is important for prevention of immunological rejection occurring in organ transplantation or for the prevention or therapy of autoimmune diseases. Nevertheless, well known immunosuppressors such as cyclosporin A (CsA) and tacrolimus (TRL) are known to cause renal toxicity or hepatotoxicity. Although steroids have been administered together with immunosuppressors in order to decrease such adverse effects of the immunosuppressors, the immunosuppressing effects could not be satisfactorily elicited without the adverse events.
From these backgrounds, many attempts have been made to find compounds exerting excellent immunosuppressing effects with low toxicity.
The following compounds are known as immunosuppressive agents:
(1) In the specification of WO94/08943 (EP627406) compounds of formula (a) are disclosed as immunosuppressive agents,
wherein R is a straight or branched carbon chain which may have, in the chain, a group selected from the group consisting of a double bond, a triple bond, oxygen atom, sulfur atom —N(R
6
)— (wherein R
6
is a hydrogen atom), optionally substituted akylene, optionally substituted heteroarylene or the like, and which may be substituted, at the chain end thereof, by optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl or the like; and R
2
, R
3
, R
4
, R
5
are the same or different and each represent a hydrogen atom, an alkyl group or the like.
The compounds of formula (a) have two oxymethyl groups (—CH
2
OR
4
and —CH
2
OR
5
) as essential groups. The compounds of the present invention, however, have a —CH
2
OR
3
group and a lower alkyl group and are different from the compounds of formula (a) in these substituents.
In said specification no typical compounds similar to the compounds of formula (I) in the present invention are disclosed at all. Only the following two compounds of the compounds of formula (a) are highly similar in chemical structure to the compounds of formula (I) in the present invention:
Example 29 (FTY720)
Example 293
(2) In the specification of WO96/06068 compounds of formula (b) are disclosed as immunosuppressive agents,
wherein R
1
, R
2
and R
3
each are a hydrogen atom or the like; W is a hydrogen atom, an alkyl group or the like; Z is a single bond or an alkylene group; X is a hydrogen atom or an alkoxy group; Y is a hydrogen atom, an alkyl, alkoxy, acyl, acyloxy, amino, acylamino group or the like.
The compounds of formula (b) essentially have a phenyl group as a basic skeleton. The compounds of formula (I) in the present invention have a thiophene group instead of the phenyl group of compounds of formula (b) and are different from the compounds of formula (b) in the basic skeleton.
In said specification no typical compounds similar to the compounds of formula (I) in the present invention are disclosed at all. Only the following three compounds of the compounds of formula (b) are highly similar in chemical structure to the compounds of formula (I) in the present invention:
Example 26
Example 57
Example 87
(3) In the specification of WO98/45249 compounds of formula (c) are disclosed as immunosuppressive agents,
wherein R
1
, R
2
, R
3
, R
4
are the same or different and each represent a hydrogen atom or an acyl group. The compounds of formula (c) have two oxymethyl groups (—CH
2
OR
3
and —CH
2
OR
4
) as essential substituent groups. The compounds of the present invention have a CH
2
OR
3
group and a lower alkyl group and are different from the compounds of formula (a) in these substituents. The compounds of formula (c) have a phenyl group between —(CH
2
)
2
— and —CO(CH
2
)
4
— as a basic skeleton. The compounds of formula (I) in the present invention have a thiophene group instead of the phenyl group of the compounds of formula (c). The present compounds of formula (I) are also different from the compounds of formula (c) in the basic skeleton. The compounds of formula (c) have only a phenyl group at the end of —CO—(CH
2
)
4
— group. The compounds of formula (I) in the present invention may have a phenyl group, a cycloalkyl group or a heterocyclic group at the end of the molecule.
In said specification no typical compounds similar in chemical structure to the compounds of formula (I) in the present invention are disclosed at all. Only the following three compounds of the compounds of formula (c) are highly similar in chemical structure to the compounds of formula (I) in the present invention:
Example 1
Example 3
On the other hand, various optically active substituted amino acid and substituted amino alcohol derivatives (particularly &agr;-substituted amino acid and &agr;-substituted amino alcohol derivatives) exhibit biological activity, are partial components of natural products and pharmaceutical agents; and are important synthetic intermediates. For example, &agr;-methyl-&agr;-vinyl amino acids are useful as an amino acid decarboxylase inhibitor, &agr;-ethynyl-&agr;-methyl amino acids are useful as a glutamic acid decarboxylase inhibitor, ISP-1 (Myriocin), which is isolated from metabolites of
Isalia sinclairii
, has immune suppression activity; and Conagenine and the like participate in the regulation of immune response through T-cells. From these results, &agr;-substituted amino acid and amino alcohol derivatives are very interesting compounds as a partial component of natural products having biological activity, in the field of biochemistry and in the field of organic synthesis.
These &agr;-substituted amino acid and amino alcohol derivatives have an asymmetric center(s) and an efficient process for the preparation of one enantiomer thereof has been expected.
There are a few reports of processes for the preparation of optically active substituted amino acid and amino alcohol derivatives and a few reports of synthetic examples of optically active amino alcohol derivatives such as optically active 4,4-disubstituted oxazolizin-2-one derivatives, which are useful synthetic intermediates of optically active substituted amino acid and amino alcohol derivatives described hereinbefore. For example, there are reports by C. Cativiela et al., Tetrahedron: Asymmetry, 9, 3517 (1998) and Synthes
Nara Futoshi
Nishi Takahide
Shimozato Takaichi
Takemoto Toshiyasu
Frishauf Holtz Goodman & Chick P.C.
Lambkin Deborah
Sankyo Company Limited
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