Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-20
2003-10-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S209000, C544S211000, C544S212000, C544S213000, C548S156000, C548S222000, C548S305400
Reexamination Certificate
active
06630470
ABSTRACT:
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
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 Pharmacol. 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 mimetics.
As disclosed herein it has unexpectedly been discovered that certain octacyclic compounds are effective as G-CSF mimetics.
SUMMARY OF THE INVENTION
This invention relates to compounds of Formula (1):
wherein R
1
and R
2
are independently aryl,
where aryl is cyclic or polycyclic aromatic C
3
-C
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
11
R
12
, NR
11
R
12
, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C
6
-C
12
aryl, alkoxy, acyloxy, substituted C
6
-C
12
aryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, —C(O)OR
11
, —S(O)
2
NR
11
R
12
, —S(O)
n
R
13
, protected —OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C
6
-C
12
aryl, substituted C
6
-C
12
aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR
11
, —S(O)
2
NR
11
R
13
, —S(O)
n
R
13
, aryloxy, nitro, cyano, halogen and protected —OH, where
R
11
and R
12
are independently hydrogen, cycloalkyl, C
6
-C
12
aryl, substituted cycloalkyl, substituted C
6
-C
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
13
, —S(O)
n
R
13
, C(O)N(R
13
)
2
, S(O)
2
N(R
13
)
2
, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C
6
-C
12
aryl. substituted C
6
-C
12
aryl and protected —OH,
n is 0-2,
R
13
is hydrogen, alkyl, cycloalkyl, C
6
-C
12
aryl, substituted alkyl, substituted cycloalkyl and substituted C
6
-C
12
aryl;
R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
are independently hydrogen, C(O)NRC
11
R
12
, NR
11
R
12
, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C
6
-C
12
aryl, alkoxy, acyloxy, substituted C
6
-C
12
aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, —C(O)OR
11
, —S(O)
2
NR
11
R
12
, —S(O)
n
R
13
, protected —OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C
6
-C
12
aryl, substituted C
6
-C
12
aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR
11
, —S(O)
2
NR
11
R
12
, —S(O)
n
R
13
, aryloxy, nitro, cyano, halogen and protected —OH, where R
11
, n, R
12
and R
13
are as described above;
X is O, S or NR
11
,
where R
11
is as described above; and
Y is O or S; and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
The present invention also relates to the discovery that the compounds of Formula (I) are active as G-CSF mimetics.
The invention also is a method for treating neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.
The invention is also a method for treating bacterial and fungal infections in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.
In a further aspect of the invention there is provided novel processes useful in preparing the presently invented G-CSF mimetics compounds.
Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.
Also included in the present invention are methods of co-administering the presently invented G-CSF mimetics compounds with further active ingredients.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention that act as G-CSF mimetics have the following Formula (1):
wherein R
1
and R
2
are independently aryl,
where aryl is cyclic or polycyclic aromatic C
3
-C
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
11
R
12
, NR
11
R
12
, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C
6
-C
12
aryl, alkoxy, acyloxy, substituted C
6
-C
12
aryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, —C(O)OR
11
, —S(O)
2
NR
11
R
12
, —S(O)
n
R
13
, protected —OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C
6
-C
12
aryl, substituted C
6
-C
12
aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR
11
, —S(O)
2
NR
11
R
12
, —S(O)
n
R
13
, aryloxy, nitro, cyano, halogen and protected —OH, where
R
11
and R
12
are independently hydrogen, cycloalkyl, C
6
-C
12
aryl, substituted cycloalkyl, substituted C
6
-C
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
13
, —S(O)
n
R
13
, C(O)N(R
13
)
2
, S(O)
2
N(R
13
)
2
, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C
6
-C
12
aryl, substituted C
6
-C
12
aryl and protected —OH,
n is 0-2,
R
13
is hydrogen, alkyl, cycloalkyl, C
6
-C
12
aryl, substituted alkyl, substituted cycloalkyl and substituted C
6
-C
12
aryl;
R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
are independently hydrogen, C(O)NR
11
R
12
, NR
11
R
12
, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C
6
-C
12
aryl, alkoxy, acyloxy, substituted C
6
-C
12
aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, —C(O)OR
11
, —S(O)
2
NR
11
R
12
, —S(O)
n
R
13
, protected —OH and alkyl substituted with one or more subst
Duffy Kevin J
Luengo Juan I
Balasubramanian Venkataraman
Dustman Wayne J.
Kinzig Charles M.
Raymond Richard L.
SmithKline Beecham Corporation
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