Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-01-29
2000-10-31
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
51421711, 514304, 514318, 514320, 514324, 514325, 514422, 544596, 546112, 546126, 546194, 546196, 546202, 546204, 548525, A61K 31453, A61K 314535, A61K 31439, C07D40512, C07D40912, C07D45114
Patent
active
061403385
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel compounds having antagonism against chemokines which are leukocytic migration factors, methods for producing them, and their use.
The compounds of the present invention have high affinity to chemokine receptors. By inhibiting the action of the chemokine receptors, they can be useful in the field of pharmaceuticals, to prevent or treat e.g. acute or chronic inflammatory diseases such as septicemia, pneumonia, arthritis or allergic diseases, acquired immune deficiency syndrome, cancer, ischemic reflow disorder, arteriosclerosis, or rejection symptoms after organ transplantation operation.
BACKGROUND ART
Chemokines are polypeptidic leukocytic migration factors having molecular weights of about 10,000, and at least 21 types of peptide families having similar structures have been found. Further, at least 7 types of the chemokine receptors to which chemokines bind exist on leukocyte, and the receptors are considered to play an important role by means of selective migration and activation of leukocyte in many inflammatory diseases [Trends in Pharmacological Sciences, 17, 209-213 (1996)].
Accordingly, substances which specifically inhibit binding of chemokines to the chemokine receptors are considered to suppress the selective migration and activation of leukocyte and thus be useful as pharmaceutical drugs for prevention or treatment of e.g. acute or chronic inflammatory diseases such as septicemia, pneumonia, arthritis or allergic diseases, cancer, ischemic reflow disorder, arteriosclerosis, or rejection symptoms after organ transplantation operation.
Further, in recent years, the chemokine receptors have been identified to be receptors on target cells, which are important for AIDS virus (HIV) to infect to the target cells [Nature, 381, 661-666 (1996); Nature, 381, 667-673 (1996); Cell, 85, 1149-1158 (1996)]. Further, it was clarified that chemokines and chemokines which lack an amino acid residue on the amino terminal inhibit infection of HIV to the target cells [Science, 270, 1811-1815 (1995); Nature, 383, 400 (1996)].
Accordingly, substances which specifically inhibit functions of the chemokine receptors are considered to inhibit infection of HIV to the target cells and thus be useful as pharmaceutical drugs for prevention or treatment of acquired immune deficiency syndrome.
DISCLOSURE OF THE INVENTION
The present invention provides a compound of the general formula: ##STR2## wherein each of R.sup.1 and R.sup.2 which may be the same or different, is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a formyl group, a carbamoyl group, a lower alkylaminocarbonyl group, a di-lower alkylaminocarbonyl group, a lower alkoxycarbonyl(lower)alkylaminocarbonyl group, an aralkyloxycarbonyl(lower)alkylaminocarbonyl group, an aralkylaminocarbonyl group, diaralkylaminocarbonyl group or a heteroaryl(lower)alkylaminocarbonyl group (wherein a heteroaryl group of the said heteroaryl(lower)alkylaminocarbonyl group contains one to three hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and when it contains at least one nitrogen atom, it may form a quaternary salt with a lower alkyl group or a lower alkenyl group), X is an oxygen atom, a sulfur atom or CH, Y is CH or a nitrogen atom, A is a group of the formula: ##STR3## wherein each of m and n is from 1 to 3, m+n is from 3 to 5, p is from 1 to 3, each of r, s and t which may be the same or different, is from 0 to 3, r+s+t is from 2 to 3, and Z is a group of the formula: ##STR4## wherein R.sup.3 is a C.sub.5-15 saturated or unsaturated aliphatic hydrocarbon group, R.sup.4 is a lower alkyl group or a lower alkenyl group, and Q.sup.- is an anion, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable anion- exchange product thereof or a hydrate thereof.
The compounds of the above formula [1] prov
REFERENCES:
Rico B et al. J. Heterocycl. Chem. 31(2), 313-18, 1994.
Hesselgesser J et al. J. Biol. Chem. 273(25), 15687-15692, Jun. 1998.
Cocchi et al. Science 270, pp. 1811-1815, 1995.
Dragic et al. Nature 381, pp. 667-673, Jun. 1996.
Iwasawa Yoshikazu
Naya Akira
Ohwaki Kenji
Owada Yufu
Saeki Toshihiko
Banyu Pharmaceutical Co. Ltd.
Huang Evelyn Mei
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