In the past, anti-inflammatory agents such as steroids have been used for inflammatory reactions arising from abnormal immune response in treatment of immune-related diseases such as rheumatoid arthritis and other autoimmune diseases. These are, however, a symptomatic therapy, but not a fundamental remedy.
Furthermore, it has been reported that immune system abnormalities are also involved in the development of diabetes and nephritis, but agents that improve these abnormalities have not yet been developed.
On the other hand, it is critical to develop an approach to suppress the immune response for avoiding rejection in transplanted tissues or cells, as well as for treating and preventing various autoimmune diseases.
However, immunosuppressants, such as cyclosporin A (CsA) and tacrolimus (TRL) that have been known in the past, are known to show toxicity against the kidney and liver. Although treatments that also use steroids are commonly used for the relief of such adverse reactions, it is presently the case that such agents have not necessarily led to producing a satisfactory immunosuppressive effect without showing any adverse reaction.
In light of this background, it has been attempted to find excellent compounds with immunosuppressive effects that are less toxic.
As to immunosuppressants, the following compounds are known.
(1) Compounds having the general formula (a) disclosed in WO 94/08943 (page 371)
{in the above compounds (a),
Rx, represents a straight or branched carbon chain which may optionally be substituted with one or more substituents [said chain may contain a double bond, a triple bond, an oxygen atom, a sulfur atom, a group of formula —N(Rx6)— (wherein Rx6 represents a hydrogen atom), an arylene group which may optionally be substituted with one or more substituents, or a heteroarylene group which may optionally be substituted with one or more substituents, and may contain, at the end of said chain, an aryl group which may optionally be substituted with one or more substituents, a cycloalkyl group which may optionally be substituted with one or more substituents, or an aromatic heterocyclic group which may optionally be substituted with one or more substituents], and
Rx2, Rx3, Rx4, and Rx5 are the same or different and each represents a hydrogen atom or an alkyl group] are known as immunosuppressants.
The above compounds (a) of the prior art contain two oxymethyl groups (—CH2ORx4 and —CH2ORx5) as essential groups substituted on the same carbon atom. The compounds of the present invention, however, contain one —CH2OR3 group and one lower alkyl group as essential groups substituted on the same carbon atom and are different from the compounds (a) in these substituents.
(2) Compounds having the general formula (b) disclosed in WO 96/06068 (page 271)
[in the above compounds (b),
Ry1, Ry2 and Ry3 each represent a hydrogen atom or the like, W represents a hydrogen atom, an alkyl group or the like, Zy represents a single bond or an alkylene group, Xy represents a hydrogen atom or an alkoxy group, and Yy represents a hydrogen atom, an alkyl, alkoxy, acyl, acyloxy, amino, acylamino group or the like] are known as immunosuppressants.
The above compounds (b) contain a phenyl group as an essential group in the basic skeleton. The compounds of the present invention contain a heterocyclic group such as a furyl group, a pyrrolyl group, or a pyrrolyl group having a substituent on the nitrogen atom instead of the phenyl group of compounds (b) and are different from the compounds (b).
However, compounds having a similar chemical structure to compounds (I) of the present invention have heretofore not been disclosed concretely in that publication.
(3) Compounds having the general formula (c) disclosed in WO 98/45249
[in the above compounds (c),
RZ1, RZ2, RZ3, and RZ4 are the same or different and each represents a hydrogen atom or an acyl group] are known as immunosuppressants.
The above compounds (c) contain two oxymethyl groups (—CH2ORZ3 and —CH2ORZ4) as essential groups substituted on the same carbon atom. The compounds of the present invention, however, contain one —CH2OR3 group and one lower alkyl group as essential groups substituted on the same carbon atom and are different from the compounds (c) in these substituents.
In addition, above compounds (c) contain a phenyl group between the —(CH2)2— group and the —CO—(CH2)4 group as an essential group in the basic skeleton. The compounds of the present invention contain a heterocyclic group such as a furyl group, a pyrrolyl group, or a pyrrolyl group having a substituent on the nitrogen atom instead of the phenyl group of compound (c) and are different from the compounds (c).
On the other hand, a compound having the general formula (II) of the present invention shown below wherein X represents a sulfur atom is disclosed in WO 02/06268 as a compound wherein the protecting group of the hydroxyl group is a residual group of an ester of phosphoric acid.
Furthermore, as to combinations of immunosuppressants, combinations of immunosuppressants such as FTY-720 and cyclosporin A or FTY-720 and tacrolimus are disclosed in Japanese Patent Publication (Kokai) Number Hei 11-80026.
In light of this background, it has been desired to find excellent pharmaceutical compositions with immunosuppressive effects that are less toxic.