Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-24
2002-05-28
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S313000, C546S153000, C546S155000, C546S159000
Reexamination Certificate
active
06395750
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for the clinical treatment of a plurality of malignant tumours, especially in solid form, in mammals by the administering of quinoline derivatives. Furthermore, the present invention relates to structurally novel quinoline derivatives, to methods for their preparation and to compositions containing them. The types of cancer that are especially inhibited by the quinoline derivatives of the present invention include, for example, breast cancers, colon cancers, Kaposi's sarcoma, lung cancers, ovarian cancers, prostatic cancers, and skin cancers. More particularly, the present invention relates to quinoline derivatives suitable for treatment of and preventing the development of prostatic cancer, and for preventing and treatment of the metastases of prostatic cancer.
BACKGROUND OF THE INVENTION
Solid tumours, primary or metastases consist of several types of cells where the tumour cells are the pivotal cell type and the driving force. When microtumours reach a certain size, the requirement of nutrition cannot be satisfied by plain diffusion. New vessels penetrate the tumour establishing a microenvironment providing the tumour with optimal nutrition for further proliferation and growth. This tumour induced angiogenesis, inducing proliferation, migration and differentiation of normal endothelial cells from nearby small blood vessels, is a prerequisite for the growth of solid tumours. In concordance the inhibition of angiogenesis results in an effective inhibition of growth of solid tumours.
Solid tumours spread by penetrating tissue borders and give rise to daughter cell colonies or metastases. Single tumour cells or small cell aggregates spread by the blood or the lymph system to distant sites. In this process the tumour cells are vulnerable and can be extinguished by natural killer (NK) cells, a distinct type of cytotoxic lymphocytes. Enhanced activity or an increased number of NK cells reduce or inhibit the metastasising process in solid tumour disease.
Prostatic cancer is a malignant tumour disease that spreads to distant sites as tumour metastases and comprises tumours with great dependence of neovascularisation. Prostatic cancer has long been a major affliction of men, and it is becoming more common and dangerous as the population ages. It is an adenocarcinoma that is second only to lung cancer in mortality. Prostate cancer currently accounts for about 35,000 deaths each year in the United States alone. To the present time, there are no effective preventive or treatment methods for prostatic cancer. When the cancer is in its early, hormone-dependent stage, it is commonly treated by orchiectomy or chemical castration. In the later stages of prostatic cancer, the disease becomes hormone-independent and metastasises widely, usually first into the skeleton. Treatment for advanced disease initially involves hormonal manipulations and palliative radiotherapy or treatment with cytostatic agents. These strategies have proven to be of marked clinical benefit in terms of symptomatic relief but there are no effective methods, which can put prostatic cancer into remission in that stage. The use of cytotoxic agents in the management of hormone-resistant advanced prostate cancer remains poorly defined. A few single agents have become “standard therapy”, although demonstration of their efficacy, by contemporary standards, is lacking. Thus, prostatic cancer is not only relatively common, but is refractory to treatment once the disease crosses into the hormone-independent stage.
In U.S. Pat. No. 4,547,511 and in EP 59,698 some derivatives of N-aryl-1,2-dihydro-4-amino-1-alkyl-2-oxo-quinoline-3-carboxamide and N-aryl-1,2-dihydro-4-hydroxy-1-alkyl-2-oxo-quinoline-3-carboxamide are claimed as enhancers of cell-mediated immunity. Roquinimex (Merck Index 12
th
Ed., No. 8418; Linomide®, N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide) has been reported to have antitumour effects on Dunning R-3327 rat prostatic cancers (1).
Some 5-substituted N-aryl-1,2-dihydro-4-hydroxy-1-alkyl-2-oxo-quinoline-3-carboxamides effective in the treatment of diseases resulting from autoimmunity and pathologic inflammation are known from U.S. Pat. No. 6,077,851, U.S. Ser. Nos. 09/352,886 and 09/352,887.
Roquinimex, a compound with shown anti-angiogenic and pro NK lymphocyte activities also induce pro-inflammatory side effects in humans that was emphasised when treating patients with renal cell carcinoma (2). Roquinimex in this study was poorly tolerated, with 40% of the patients being withdrawn or having dose reductions due to adverse events, mostly influenza-like symptoms of myalgia, arthralgia and fatigue. Several cases of pericarditis and neuropathy were also observed.
Pro-inflammatory effects induced by roquinimex are efficiently monitored in the beagle dog. Roquinimex induces the beagle pain syndrome characterised by fever, myalgia, arthralgia as well as arteritis (3, 4).
DESCRIPTION OF THE INVENTION
A primary objective of the present invention is a method for the clinical treatment of a plurality of malignant tumours, especially in solid form, in mammals by the administration of quinoline derivatives. Another objective is to provide structurally novel quinoline derivatives, having a pharmacological profile that is distinguished by high potency in experimental models and low level of side effects. The types of cancer that are especially inhibited by these quinoline derivatives include, for example, breast cancers, colon cancers, Kaposi's sarcoma, lung cancers, ovarian cancers, prostatic cancers, and skin cancers. More particularly, the present invention relates to quinoline derivatives suitable for the prevention of the development of malignant tumours, in particular prostatic cancers, and prevention and treatment of the metastases of malignant tumours, particularly of prostatic cancers. To increase the cure rate of metastatic malignant tumours, in particular of prostatic cancers, an effective therapy for malignant tumour cells, particularly androgen-independent prostatic cancer cells, is needed. The approach we have chosen is to inhibit the tumour-induced angiogenesis and to stimulate the host immune system to evoke/enhance an antitumour response. In the present invention, the ability of quinoline compounds to elicit an antitumour effect against an androgen-independent Dunning R-3327 AT-1 rat prostatic cancer was tested.
It has now surprisingly been found that the compounds of general formula (I)
wherein
A is selected from OR
41
and NR
42
R
43
wherein
R
41
is selected from hydrogen and pharmaceutically acceptable inorganic cations, such as sodium, potassium and calcium, and organic cations such as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and the like, and COR
A
wherein
R
A
is selected from alkyl and aryl groups, such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl, neo-pentyl, phenyl, benzyl, phenethyl and the like;
R
42
and R
43
are the same and different and selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, cyclopropyl, cyclopentyl and cyclohexyl; or
R
42
is selected from benzyl and phenethyl, optionally mono- or disubstituted by a group selected from methyl, iso-propyl, methoxy, fluoro, chloro, bromo, dimethylamino, trifluoromethyl and nitro and R
43
is hydrogen; or
R
42
and R
43
together with the nitrogen to which they are bonded, form a 5- or 6′-membered ring; or
R
42
is COR
B
wherein
R
B
is selected from alkyl and aryl groups, such as C1-C4-alkyl, phenyl, benzyl and the like, or
from —CH
2
N(CH
3
)
2
and —CH
1
CH
2
CH
2
COOH; or
COR
B
is a 2-acyloxymethylbenzoyl group
wherein
R
C
is selected from methyl, ethyl, phenyl and benzyl and the like; or
R
42
is COOR
D
wherein
R
D
is selected from C1-C4-alkyl, phenyl and benzyl; or
R
42
is —CH
2
OCO-tert.-butyl; or
R
42
is CONR
F
R
G
wherein
R
F
and R
G
are the same and different and are C1-C4-alkyl; or
R
42
is CXNHR
E
wherein
X is selected from O or S and R
E
is selected from C
Björk Anders
Hedlund Gunnar
Jansson Karl
Jönsson Stig
Active Biotech AB
Browdy and Neimark , P.L.L.C.
Robinson Binta
Rotman Alan L.
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