Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-03-12
1993-04-27
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514333, 514338, 514407, 546256, 546271, 546279, 5483591, 5483595, A61K 31415, C07D23154, C07D 49052, C07D49504
Patent
active
052062589
DESCRIPTION:
BRIEF SUMMARY
Suppression of myelopoiesis is a frequent and sometimes life-threatening side-effect of the chemo- and radio-therapy in cancer and of the drugs used to treat rheumatoid arthritis and other autoimmune diseases.
Suppression of myelopoiesis is common also in patients with severe burns and bone marrow disorders and in subjects that undergo organ transplantation, who are given immuosuppressant drugs to minimize the danger of rejection.
To find a drug which is effective in stimulating myelopoiesis in bone marrow suppressed patients still remains an important target for the today's Medicinal Chemistry, with large potential clinical application.
The present invention relates, in one aspect, to a method of stimulating myelopoiesis in bone marrow suppressed mammals, including humans, which comprises administering to said mammals, in need of such treatment, a therapeutically effective amount of an active heteroaryl-3-oxo-propanenitrile derivative of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof.
In another aspect this invention relates to the use of a heteroaryl-3-oxo-propanenitrile derivative of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the use in stimulating myelopoiesis in bone marrow suppressed mammals, including humans.
Examples of pathological ocnditions in which a suppressed myelopoiesis takes place, which can be treated by the compounds of formula (I) or by the pharmaceutical compositions containing them, according to the method of treatment of the present invention, are those which occur in the case of cancer chemotherapy and cancer radiation therapy; in immunosuppressant therapy used for organ or tissue transplantation; in immunosuppressant therapy in the case of an autoimmune disease; in the case of autologous and allogenic bone marrow transplants; in the case of severe burns; in the case of accidental exposure to radiation or to certain chemicals, e.g. benzene, and in the case of aplastic anemia, myelodysplastic syndrome and congenital or acquired bone marrow disorders.
The heteroaryl-3-oxo-propanenitrile derivatives which are effective in stimulating myelopoiesis in bone marrow suppressed mammals and are useful in the method of treatment, or in the preparation of the pharmaceutical compositions, according to the present invneiton, are described in our patent applications EP-A-0274443, WO 89/12630, WO 89/12638 and British patent applicaton No. 8902596.9, and can be represented by the following formula (I) ##STR2## wherein
X represents --C.sub.6 alkyl; ##STR3## group, wherein n and R.sub.4 are as defined above; d) a ##STR4## group, wherein n and R.sub.4 are as defined above; or e) a ##STR5## group, wherein R.sub.4 is as defined above; R.sub.1 represents C.sub.1 -C.sub.6 alkyl, pyridyl or phenyl, the phenyl being unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, nitro, amino, formylamino and C.sub.2 -C.sub.8 alkanoylamino; R.sub.2 represents: ##STR6## group wherein each of R' and R" independently is C.sub.1 -C.sub.6 alkyl or R' and R", taken together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selected from N-pyrrolidinyl, N-piperazinyl, hexahydroazepin-1-yl, thiomorpholino, morpholino and piperidino and which is unsubstituted or substituted by C.sub.1 -C.sub.6 alkyl: ##STR7## group wherein R.sub.d is hydrogen or C.sub.1 -C.sub.6 alkyl and R.sub.c is hydrogen, phenyl or the side-chain of an .alpha.-aminoacid; ##STR8## group, wherein R.sub.c is as defined above; ##STR9## a --CH.sub.2 OCO(CH.sub.2).sub.n COOR or a --NHCO(CH.sub.2).sub.n COOR group, wherein n is as defined above and R is hydrogen or C.sub.1 -C.sub.6 alkyl; --CH.sub.2 COOH group; --CH.sub.2 CH.sub.2 OH, C.sub.2 or C.sub.3 alkoxycarbonyl or a --(CH.sub.2).sub.p --R'.sub.3 group wherein p is 1 or 2 and R'.sub.3 is COOH or C.sub.2 -C.sub.7 alkoxycarbonyl; ##STR10## group wherein R' a
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Doria Gianfederico
Ferrari Mario
Ferreccio Rinaldo
Fornasiero Maria C.
Isetta Anna M.
Farmitalia Carlo Erba S.r.l.
Higel Floyd D.
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