Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-16
2001-02-27
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06194436
ABSTRACT:
The present invention relates to the use of certain NK-1 receptor antagonists, (including certain substance P receptor antagonists) to treat cancer patients afflicted with a small cell lung carcinoma, APUDoma, astrocytoma, neuroendocrine tumor or extrapulmonary small cell carcinoma.
Antal Orosz, et al.,
International Journal of Cancer
, 1995, 60, 82-87, describe the use of a variety of peptidic substance P antagonists to inhibit the proliferation of small cell lung carcinoma, e.g., in the cell line designated NCl-H69). Paul Bunn et al.,
Cancer Research
, 1994, 54, 3602-3610, describe another series of substance P antagonists which are also peptidic and which are capable of inhibiting in vitro growth of a number of small cell lung carcinoma cell lines (e.g., those designated NCl-H510, NCl-H345 and SHP-77).
SUMMARY OF THE INVENTION
The present invention relates to a method of treating cancer in a mammal, including a human, comprising administering to such mammal a therapeutically effective amount of an NK-1 receptor antagonist selected from the compounds described below.
“Treating cancer”, as used herein, means inhibiting or controlling the proliferation of a small cell lung carcinoma, APUDoma, neuroendocrine tumor, extrapulmonary small cell carcinoma or astrocytoma.
A “therapeutically effective amount”, as used herein, means an amount effective in treating cancer, as defined immediately above.
An “astrocytoma” is a tumor composed of astrocytes. Astrocytes are neuroglial cells of ectodermal origin, characterized by fibrous, protoplasmic or plasmatofibrous processes.
APUDomas are tumors composed of APUD (amine precursor uptake and decarboxylation) cells. APUD cells are found scattered throughout the body (e.g., in the chromaffin system, hypothalamus, hypophysis, thyroid, parathyroids, lungs, gastrointestinal tract and pancreas) and are apparently unrelated but for sharing certain cytochemical and ultrastructural characteristics. They synthesize structurally related peptides (usually biogenic amines) that function as hormones or neurotransmitters (e.g., epinephrine, norepinephrine, dopamine, serotonin, enkalphalin, somatostatin, neurotensin and substance P). ADUP cells concentrate the amino acid precursors of these amines and decarboxylate them to their respective amines.
More specifically, this invention relates to a method of treating cancer in a mammal, including a human, comprising administering to such mammal a therapeutically effective amount of an NK-1 receptor antagonist that is a compound of the formula
wherein A is a ring system selected from phenyl, naphthyl, thienyl, dihydroquinolinyl, quinolinyl and indolinyl, and wherein the sidechain containing NR
2
R
3
is attached to a carbon atom of ring system A;
AA is an aryl group selected from phenyl, naphthyl, thienyl, quinolinyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR
2
R
3
is attached to a carbon atom of AA;
AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl, quinolinyl and indolinyl, and wherein the —CH
2
PR
3
sidechain is attached to a carbon atom of ring AAA;
P is NR
2
, O, S, SO or SO
2
;
wherein the point of attachment of said
to ring AAA is the nitrogen atom and the point of attachment to X
5
is the sulfur atom;
W
1
and W
2
are selected, independently, from hydrogen, halo, (C
1
-C
6
) alkyl, S-(C
1
-C
3
)alkyl, and (C
1
-C
6
) alkoxy optionally substituted with from one to three fluorine atoms;
W is hydrogen, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, —S(O)
v
—(C
1
-C
6
) alkyl wherein v is zero, one or two, halo or (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
X
1
is hydrogen, (C
1
-C
10
) alkoxy optionally substituted with from one to three fluorine atoms or (C
1
-C
10
) alkyl optionally substituted with from one to three fluorine atoms;
X
2
and X
3
are independently selected from hydrogen, halo, nitro, (C
1
-C
10
) alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
10
) alkoxy optionally substituted with from one to three fluorine atoms, hydroxy, phenyl, cyano, amino, (C
1
-C
6
)-alkylamino, di-(C
1
-C
6
)alkylamino,
X
5
is a four to six membered heterocyclic ring containing from one to four heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms and halo;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C
1
-C
6
) alkyl optionally substituted with from one to three fluorine atoms and (C
1
-C
6
) alkoxy optionally substituted with from one to three fluorine atoms;
R
1
is selected from amino, (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino, —S(O)
v
-(C
1
-C
10
)-alkyl wherein v is zero, one or two, —S(O)
v
-phenyl wherein v is zero, one or two, —S(O)
v
-benzyl wherein v is zero, one or two, —O-phenyl, —O-benzyl, —SO
2
NR
4
R
5
wherein each of R
4
and R
5
is, independently, (C
1
-C
6
)alkyl, or R
4
and R
5
, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
(C
1
-C
10
)alkyl wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, —N(SO
2
-(C
1
-C
10
)alkyl)
2
,
and wherein any of the phenyl moieties in the foregoing R
1
groups may optionally be substituted with from one to three substituents independently selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy and halo;
or R
1
is phenyl substituted with a group having the formula
wherein a is 0, 1 or 2 and the asterisk represents a bond to a position meta to the R
2
R
3
NCH
2
side chain;
the dotted lines in formula Ib represent that one of the X—Y and Y—Z bonds may optionally be a double bond;
X is selected from ═CH—, —CH
2
—, —O—, —S—, —SO—, —SO
2
—, —N(R
4
)—, —NH—, ═N—, —CH [(C
1
-C
6
)alkyl]-, ═C[(C
1
-C
6
)alkyl]-, —CH(C
6
H
5
)— and ═C(C
6
H
5
)—;
Y is selected from C═O, C═NR
4
, C═S, ═CH—, —CH
2
—, ═C[(C
1
-C
6
)alkyl]-, —CH[(C
1
-C
6
)alkyl]-, ═C(C
6
H
5
)—, —CH(C
6
H
5
)—, ═N—, —NH—, —N(R
4
)—, ═C(halo)-, ═C(OR
4
)—, ═C(SR
4
)—, ═C(NR
4
)—, —O—, —S— and SO
2
, wherein the phenyl moieties of said ═C(C
6
H
5
)— and —CH(C
6
H
5
)— may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said ═[(C
1
-C
6
)alkyl]- and —CH[C
1
-C
6
)alkyl]- may optionally be substituted with from one to three fluorine atoms;
Z is selected from ═CH—, —CH
2
—, ═N—, —NH—, —S—, —N(R
4
)—, ═C(C
6
H
5
)—, —CH(C
6
H
5
)—, ═C[(C
1
-C
6
)alkyl]- and —CH[(C
1
-C
6
)alkyl]-;
or X, Y and Z, together with the two carbon atoms shared between the benzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;
R
4
is (C
1
-C
6
) alkyl or phenyl, and each occurrence of R
4
is independent of other occurrences of R
4
in the same molecule;
R
2
is hydrogen or —CO
2
(C
1
-C
10
)alkyl;
R
3
is selected from
wherein R
6
and R
10
are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein s
Appleman Jolene W.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Spivack Phyllis G.
LandOfFree
NK-1 receptor antagonists for the treatment of cancer does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with NK-1 receptor antagonists for the treatment of cancer, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and NK-1 receptor antagonists for the treatment of cancer will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2601766