Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-20
1999-11-09
Stockton, Laura L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514338, 514388, 546256, 5462734, 5483034, A61K 31415, A61K 3144, C07D23500, C07D40114
Patent
active
059815515
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein secreted by macrophages, fibroblasts, and endothelial cells originally identified by its ability to stimulate the survival, proliferation, and differentiation in vitro of predominantly neutrophilic granulocytes from bone marrow progenitors. Nicola, N. A., Annu. Rev. Biochem. (1989) 58:45. The capacity of G-CSF to regulate in vivo granulopoiesis is supported by animal and clinical studies, which demonstrated a reversible rise in circulating neutrophil levels in response to administered recombinant G-CSF. Gabrilove, J. L. et al., N. Engl. J. Med. (1988) 318:1414. G-CSF has pleiotropic effects on mature neutrophils, enhancing their survival and stimulating functional activation, including induction of neutrophil alkaline phosphatase (Sato. N. et al., J. Cell. Physiol. (1988) 37:272) and high affinity IgA F.sub.c receptors (Weisbart, R. H., et al., Nature (Lond.) (1988) 332:647), priming for respiratory burst (Nathan, C. F. Blood (1989) 73:301) and increased chemotaxis (Wang, J. M., Blood (1988) 72:1456). G-CSF effects have also been observed on hematopoietic cells that are not committed to the granulocyte lineage, for example, stimulation of the proliferation on monocytic differentiation in vitro of some myeloid leukemic cells (Geissler, K., J. Immunol. (1989) 143:140) and the proliferation in vitro of some multipotential hematopoietic precursors (Ferrero, D., Blood (1989) 73:402).
Administration of recombinant G-CSF to patients suffering from neutropenia due to various causes indicated that G-CSF is beneficial as an adjuvant in chemotherapy and in bone marrow transplantation (Morstyn, G., et al., Trends Phannacol. Sci. 10, (1989) 154-159). G-CSF activity is also associated with mobilization of hematopoietic stem cells from the marrow to the peripheral blood. (See review article, Good Review article Haylock et al., Blood 89:2233-2258, 1997).
It would be desirable to provide compounds which allow for the treatment of neutropenia to enhance leukocyte production by acting as a G-CSF mimetic.
As disclosed herein it has unexpectedly been discovered that certain non-peptide compounds are effective as G-CSF minmetics.
As disclosed herein it has unexpectedly been discovered that certain selected 2,5-Diimino-3a,6a-diaryl-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazol es are effective as G-CSF mimetics.
SUMMARY OF THE INVENTION
This invention relates to compounds of Formula (I): ##STR2## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently aryl, where aryl is cyclic or polycyclic aromatic C.sub.3 -C.sub.12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NR.sup.6 R.sup.7 and NR.sup.6 R.sup.7, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C.sub.6 -C.sub.12 aryl, alkoxy, acyloxy, substituted C.sub.6 -C.sub.12 aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, --C(O)OR.sup.6, --S(O).sub.n R.sup.5, protected --OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C.sub.6 -C.sub.12 aryl, substituted C.sub.6 -C.sub.12 aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, --C(O)OR.sup.6, --S(O).sub.n R.sup.7, aryloxy, nitro, cyano, halogen and protected --OH, where
R.sup.6 is hydrogen or alkyl,
n is 0-2,
R.sup.7 is hydrogen or alkyl and
R.sup.5 is hydrogen, cycloalkyl, C.sub.6 -C.sub.12 aryl, substituted cycloalkyl, substituted C.sub.6 -C.sub.12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, --C(O)OR.sup.6, --S(O).sub.n R.sup.7, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C.sub.6 -C.sub.12 aryl, substituted C.sub.6 -C.sub.12 aryl and protected --OH, where R.s
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Nishimura, et al., J. Org. Chem.; 1979, vol. 44, No. 5, pp. 818-824.
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Breen Ann L.
Chan James A.
Luengo Juan I.
Dustman Wayne J.
King William T.
Kinzig Charles M
SmithKline Beecham Corporation
Stockton Laura L.
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