Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1996-12-26
2001-09-04
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S650000, C514S648000, C514S252120, C514S239200
Reexamination Certificate
active
06284799
ABSTRACT:
The present invention is concerned with the identification of compounds which increase the therapeutic index of chemotherapy drugs and which stimulate the growth of cancers, their use in the treatment of cancer and with certain novel compounds useful in such treatment.
BACKGROUND OF THE INVENTION
Over the last 50 years the treatment of a variety of human illnesses has vastly improved with the identification of active drugs and their introduction into clinical use. While perhaps not as dramatic as penicillin or insulin, various clauses of agents, nonetheless, have improved the therapy and/or prognosis of common disorders, including (1) mental illness, especially schizophrenia (e.g. phenothiazines) and major depressive disease (e.g. tricyclic antidepressants and newer, non-tricyclic agents such as fluoxetine); (2) hayfever, asthma, urticaria and other acute allergic disorders (e.g. H
1
-antagonists); (3) peptic ulcer disease (e.g. H
2
-antagonists); (4) fungal diseases (imidazoles e.g. clotrimazole, ketoconazole); (5) breast cancer (e.g. tamoxifen); and (6) hypertension, arrythmia and angina (&bgr;-adrenergic antagonist). While these seemingly disparate classes of drugs have differing chemical structures, interactions, and indicated uses, in most cases the mechanisms by which they produce their effects are incompletely understood.
For example, although the phenothiazines are known to be antagonists of dopamine (D
2
) receptors, interactions at many other intracellular sites, including calmodulin, protein kinase C and calcium channels may be important to their activity. Similarly, while antidepressants are known to decrease the uptake of biogenic amine neurotransmitters into nerve endings (especially aerotonin and norepinephrine) thereby increasing their concentration in synapses, a good correlation between potency to inhibit the uptake of any specific amine and potency as antidepressant agents has not been shown.
As another example, while histamine antagonists appear to produce their antiallergic and antiacid effects through binding H
1
and H
2
receptors, respectively, P450 microsomal enzymes, important in the metabolism of lipids and eicosanoids, have been identified as a major site of binding of the former, as well as of imidazoles. In addition, antidepressant drugs, such as doxepin, do not bind H
2
receptors, yet are potent to inhibit acid secretion. As a final example, the antiestrogeni tamoxifen is thought to inhibit breast cancer proliferation through binding estrogen receptors. Yet, it has been reported that tamoxifen is effective in 10% of breast cancers negative for estrogens receptors, suggesting additional mechanisms of action.
Recently, there has been described the existence of unique intracellular histamine receptors, designated H
IC
, in brain membranes and liver microsomes. The paradiphenyl-methane derivative, N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]-ethanamine.HCl (DPPE) is a potent antagonist of H
IC
. Surprisingly, the other classes of drugs mentioned above, including phenothiazines, H
1
antagonists, serotonin (5HT
1
, and 5HT
3
) antagonists, triphenylethylene antiestrogens and &bgr;-adrenergic antagonists also compete, with varying degrees of affinity, for both DPPE and H
IC
binding. While H
2
antagonists and other imidazoles do not compete for DPPE binding, they do compete for H
IC
, but with lower affinity than for compounds which bind both AEBS and H
IC
.
Through binding H
IC
, histamine functions as Man intracellular messenger to mediate aggregation in blood platelets and is implicated in the proliferation of normal and malignant cells. A second messenger role for histamine at H
IC
also has been postulated in estrogen action and in brain function. Thus, it is possible that H
IC
binding may be common to the action of many classes of drugs, including phenothiazines, antidepressants, antiestrogens, histamine (H
1
, H
2
, H
3
) antagonists, serotonin (5HT
1
, 5HT
3
) antagonists, &bgr;-adrenergic antagonists and antifungal agents.
Recently, in published International patent application WO 92/11035, U.S. Ser. No. 711,957 filed Jun. 7, 1991), there is described a novel method of treatment for cancer, combining DPPE or its analogues with chemotherapy drugs, such as doxorubicin (Adriamycin™). In animals and humans, this method of treatment results in the protection of normal stem cells, including bone marrows and mucosal epithelium, while enhancing the anticancer effects of chemotherapy on malignant cells. Although the mechanism of this differential action is not fully understood, in vitro studies indicate that DPPE inhibits normal cell proliferation, in the absence of toxicity, but stimulates malignant cell proliferation and cytotoxicity. Increased response to chemotherapy has been demonstrated in tumor-bearing animals treated concurrently with DPPE. In addition, DPPE also directly cytoprotects normal gut mucosa in vitro, an effect related to DPPE-induced increases in endogenous levels of the protective prggtaglandin, PGI
2
, and reversed by indomethicin.
SUMMARY OF INVENTION
New data, provided herein, indicate that (1) DPPE alone at low doses directly stimulates tumor cell growth in vivo and (2) increases the inflammatory response in skin elicited by the tumor-promoting phorbol ester, PMA (phorbol myristate acetate). Several other classes of compounds, such as antidepressants, phenothiazines, triphenylethylenes, histamine (H
1
, H
2
, H
3
) antagonists, serotonin (5HT
1
, 5HT
3
) antagonists, &bgr;-adrenergic antagonists and imidazole analogs, also have been identified as producing the same results as those obtained for DPPE.
It now also has been found that tricyclic antidepressant drugs and the non-tricyclic agent, fluoxetine (Prozac™), as well as H
1
-antihistamines and &bgr;-adrenergic antagonists, also compete for the binding of
3
H-DPPE and
3
H-histamine to H
IC
in rat liver microsomes or brain membranes and, likewise, promote tumor growth.
Accordingly, in one aspect of the present invention, there is provided a method for the treatment of cancer cells in an animal, which comprises:
(a) administering to the animal a compound which inhibits normal cell proliferation while promoting malignant cell proliferation in an amount sufficient to inhibit the binding of intracellular histamine in normal cells, and
(b) subsequently administering to the animal at least one chemotherapeutic agent for the cancer cells in an amount toxic to the cancer cells. In this way, an enhanced toxic effect on the cancer cells is obtained from the at least one chemotherapeutic agent while adverse side effects of the at least one chemotherapeutic agent on normal cells, including bone marrow and gastro-intestinal cells.
It has been further found that certain fluoro analogs of DPPE exhibit an enhanced potency in inhibiting normal cell proliferation and in promoting malignant cell proliferation and such compounds are novel compounds. Accordingly, in another aspect of the present invention, there is provided a compound having the formula:
wherein Y is fluorine, chlorine or bromine, Z is an alkylene group of 1 to 3 carbon atoms or a ═C═O group, or the phenyl groups are joined to form a tricyclic ring, and p is 0 or 1, R
1
and R
2
are each alkyl groups containing 1 to 3 carbon atoms or are joined together to form a hetero ring with the nitrogen atom and n is 1, 2 or 3, as well as pharmaceutically-acceptable salts of such compounds.
Such compounds may be prepared by any convenient procedure depending on the identity of the variable groups. For example, for compounds where Z is a carbonyl group, the compound may be made by reacting a hydroxy substituted fluoro-benzophenone with a chloro-substituted amino-substitute alkyl group.
REFERENCES:
patent: 5618846 (1997-04-01), Brandes
Goldberg Jerome D.
Sim & McBurney
University of Manitoba
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