CA2206567C - Method and composition for reducing tumor development with a combination of a taxane compound and a tellurium and/or selenium compound - Google Patents
Method and composition for reducing tumor development with a combination of a taxane compound and a tellurium and/or selenium compound Download PDFInfo
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- CA2206567C CA2206567C CA002206567A CA2206567A CA2206567C CA 2206567 C CA2206567 C CA 2206567C CA 002206567 A CA002206567 A CA 002206567A CA 2206567 A CA2206567 A CA 2206567A CA 2206567 C CA2206567 C CA 2206567C
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- carbon atoms
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- carbons
- tellurium
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- -1 taxane compound Chemical class 0.000 title claims abstract description 52
- 229910052714 tellurium Inorganic materials 0.000 title claims abstract description 39
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229940065287 selenium compound Drugs 0.000 title claims abstract description 34
- 150000003343 selenium compounds Chemical class 0.000 title claims abstract description 34
- 229940123237 Taxane Drugs 0.000 title claims abstract description 33
- 239000000203 mixture Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title abstract description 13
- 230000005748 tumor development Effects 0.000 title 1
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- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 39
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 39
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- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 15
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 67
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- 125000004423 acyloxy group Chemical group 0.000 claims description 21
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- 239000011669 selenium Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 9
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- 239000003814 drug Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
There are provided compositions for, and a method of, treating malignancies which comprise effective amounts of a novel combined therapy comprising a taxane compound, e.g., paclitaxel, and a tellurium or selenium compound, e.g., ammonium trichloro(dioxoethylene-O,O-tellurate), and administering the respective compounds simultaneously or separately.
Description
-1_ METHOD AND COMPOSITION FOR tt~;, WITH A COMBINATION OF A TAXANE
AND/OR SELENIUM
BACKGROUND OF THE INVENTION
Field of the Invention:
This invention relates to a novel combination of chemotherapeutic agents which are useful in the treatment of neoplastic diseases.
The treatment is based on the sequential or concurrent administration of a taxane compound and a tellurium and/or a selenium compound in combination to provide an improved chemotherapeutic regimen for the treatment of neoplastic diseases or the treatment of malignant neoplasms. It has been discovered that the combination of a taxane compound and a tellurium and/or a selenium compound significantly reduces the development of tumor volume over what would be predicted from administration to tumor-infected mammals of either a taxane compound alone, or the tellurium and/or selenium compound, alone, or the tellurium compound in combination with cyclophosphamide.
In the prior art, paclitaxel and its precursors, isomers, analogs, isosteres, and derivatives (hereinafter "taxane compounds)") have been described for the treatment of malignant neoplasms, such as acute leukemias, solid tumors, and the like. Moreover, ammonium trichloro(dioxoethylene-0,0-tellurate) (AS101) and its precursors, analogs, isosteres, and derivatives (hereinafter "tellurium and/or selenium compounds)") have also been described for the treatment of such malignant neoplasms. It has also been suggested in the prior art to use tellurium compounds in combination with other chemotherapeutic agents for the treatment of such malignant neoplasms. In fact, it is known that a combination of ammonium trichloro(dioxoethylene-0,0-tellurate (AS101) and the known chemotherapeutic agent cyclophosphamide (CYP) shows synergism in extending the
AND/OR SELENIUM
BACKGROUND OF THE INVENTION
Field of the Invention:
This invention relates to a novel combination of chemotherapeutic agents which are useful in the treatment of neoplastic diseases.
The treatment is based on the sequential or concurrent administration of a taxane compound and a tellurium and/or a selenium compound in combination to provide an improved chemotherapeutic regimen for the treatment of neoplastic diseases or the treatment of malignant neoplasms. It has been discovered that the combination of a taxane compound and a tellurium and/or a selenium compound significantly reduces the development of tumor volume over what would be predicted from administration to tumor-infected mammals of either a taxane compound alone, or the tellurium and/or selenium compound, alone, or the tellurium compound in combination with cyclophosphamide.
In the prior art, paclitaxel and its precursors, isomers, analogs, isosteres, and derivatives (hereinafter "taxane compounds)") have been described for the treatment of malignant neoplasms, such as acute leukemias, solid tumors, and the like. Moreover, ammonium trichloro(dioxoethylene-0,0-tellurate) (AS101) and its precursors, analogs, isosteres, and derivatives (hereinafter "tellurium and/or selenium compounds)") have also been described for the treatment of such malignant neoplasms. It has also been suggested in the prior art to use tellurium compounds in combination with other chemotherapeutic agents for the treatment of such malignant neoplasms. In fact, it is known that a combination of ammonium trichloro(dioxoethylene-0,0-tellurate (AS101) and the known chemotherapeutic agent cyclophosphamide (CYP) shows synergism in extending the
-2-rate of survival of mice infected with Madison lung carcinoma tumor cells. Cancer Res. 51(5)1499-1503(1991).
It has now been discovered, and is the subject of the present invention, that a novel combination of the taxane compound paclitaxel and a tellurium and/or a selenium compound shows an unexpectedly strong synergistic effect on the reduction in tumor volume in mice infected with cells of the solid tumor B16 Melanoma.
Such findings are unexpected because the use of either the taxane compound alone or the tellurium and/or selenium compound alone at the same respective dosages produce tumor volume reductions which are shorter lasting and incrementally much closer to the saline control.
The present invention is concerned with a novel treatment regimen which combines a taxane compound and a tellurium and/or selenium compound. It also contemplates a novel composition with anti-neoplastic activity comprising a combination of a taxane compound and a tellurium and/or selenium compound. Among the preferred ZO features of the invention are regimens and novel therapeutic combinations wherein the ratios of the taxane compound and tellurium and/or selenium compound provide synergistic activity, especially in the reduction of solid tumor growth.
It is therefore an object of the invention to provide novel therapeutic regimens and compositions which are based on the sequential or concurrent administration of novel combination of a taxane compound and a tellurium and/or selenium compound to mammals infected with neoplasms.
It is also an object of this invention to provide a novel method for the treatment of neoplastic diseases which uses a particular dose of a novel combination of a taxane compound and a tellurium and/or selenium compound.
These and other objects of the invention will become apparent from a review of the specification.
It has now been discovered, and is the subject of the present invention, that a novel combination of the taxane compound paclitaxel and a tellurium and/or a selenium compound shows an unexpectedly strong synergistic effect on the reduction in tumor volume in mice infected with cells of the solid tumor B16 Melanoma.
Such findings are unexpected because the use of either the taxane compound alone or the tellurium and/or selenium compound alone at the same respective dosages produce tumor volume reductions which are shorter lasting and incrementally much closer to the saline control.
The present invention is concerned with a novel treatment regimen which combines a taxane compound and a tellurium and/or selenium compound. It also contemplates a novel composition with anti-neoplastic activity comprising a combination of a taxane compound and a tellurium and/or selenium compound. Among the preferred ZO features of the invention are regimens and novel therapeutic combinations wherein the ratios of the taxane compound and tellurium and/or selenium compound provide synergistic activity, especially in the reduction of solid tumor growth.
It is therefore an object of the invention to provide novel therapeutic regimens and compositions which are based on the sequential or concurrent administration of novel combination of a taxane compound and a tellurium and/or selenium compound to mammals infected with neoplasms.
It is also an object of this invention to provide a novel method for the treatment of neoplastic diseases which uses a particular dose of a novel combination of a taxane compound and a tellurium and/or selenium compound.
These and other objects of the invention will become apparent from a review of the specification.
-3-Brief Description of the Drawi The effect of administration of the saline control, the individual components and the combination of paclitaxel and the tellurium compound, ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) on the development of solid H16 tumor in vivo over a 25 day period in infected mice are presented in graphical form in the Drawing. The bottom set of data points represent the present invention. It can be seen that tumor volume with the instant combination remains unexpectedly constant for the full 25 days.
S_ummarY of the Invention In accordance with the present invention there is provided a method of treating malignancies which are sensitive to the combination of a taxane compound, and a tellurium and/or selenium compound, said method comprising administering, sequentially or concurrently, an amount of the combination which is effective to treat malignancies which are sensitive to the.combination.
Preferred features of the invention comprise administering the combination in weight ratios which are synergistically-effective to treat malignancies, especially solid tumors. Paclitaxel is preferred but other taxane compounds, such as the family of compounds known as taxoteres, can be used. Ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) is preferred but other tellurium and/or selenium compounds, such as dichlorodioxoethylene-O,0-tellurate, and the corresponding selenium isosteres, may be employed.
Detailed Description of the Invention Paclitaxel is a member of the taxane family of diterpenes. Paclitaxel and analogs, derivatives, and compounds useful in the present invention generally will have the structure shown below:
S_ummarY of the Invention In accordance with the present invention there is provided a method of treating malignancies which are sensitive to the combination of a taxane compound, and a tellurium and/or selenium compound, said method comprising administering, sequentially or concurrently, an amount of the combination which is effective to treat malignancies which are sensitive to the.combination.
Preferred features of the invention comprise administering the combination in weight ratios which are synergistically-effective to treat malignancies, especially solid tumors. Paclitaxel is preferred but other taxane compounds, such as the family of compounds known as taxoteres, can be used. Ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) is preferred but other tellurium and/or selenium compounds, such as dichlorodioxoethylene-O,0-tellurate, and the corresponding selenium isosteres, may be employed.
Detailed Description of the Invention Paclitaxel is a member of the taxane family of diterpenes. Paclitaxel and analogs, derivatives, and compounds useful in the present invention generally will have the structure shown below:
-4-R'o r~ H
z n O Ph O 12 1 ~ .- a s R g 3' ' 1' O - . 9 15 3 5 g IL 1 z c A
J ,I
Paclitaxel itself is a compound of the above structure wherein A and B together form an oxo; L and N
are hydroxy, D, E and J are hydrogen, G and R' are acetate; M and F together form an oxocyclobutyl ring; I
is benzoyloxy; and R is phenyl.
The compound paclitaxel was reported by Wani et - al. in JACS, 93, 2325, (1971) to exhibit significant anti-tumor properties. More specifically, paclitaxel shows strong cytotoxicity in KB cell structures and in several of the National Cancer Institute's~in vivo screens, including P-388, L-1210 and P-1534 mouse leukemias, the H-16 melanocarcinoma, the CX-1 colon xenograft, the LX-1 lung xenograft and the MX-1 breast xenograft. In addition, paclitaxel blocks cell replication in lieLa cells, especially in the mitotic phase of cell division. More specifically, it has been reported by Schiff et al in Nature, 277, 665 (1979) that paclitaxel promotes the assembly of microtubule proteins responsible for the formation of spindles during cell division.
Because of its promising anti-cancer activity and its unusual structure and mechanism of action, paclitaxel represents a prototype of a new class of chemotherapeutic agents.
Mertbers of the class are set forth in U.S.
4,876,399 and 4,814,470, and elsewhere. Preferred are those of the above structural formula wherein A and B are independently hydrogen or lower alkanoyloxy a
z n O Ph O 12 1 ~ .- a s R g 3' ' 1' O - . 9 15 3 5 g IL 1 z c A
J ,I
Paclitaxel itself is a compound of the above structure wherein A and B together form an oxo; L and N
are hydroxy, D, E and J are hydrogen, G and R' are acetate; M and F together form an oxocyclobutyl ring; I
is benzoyloxy; and R is phenyl.
The compound paclitaxel was reported by Wani et - al. in JACS, 93, 2325, (1971) to exhibit significant anti-tumor properties. More specifically, paclitaxel shows strong cytotoxicity in KB cell structures and in several of the National Cancer Institute's~in vivo screens, including P-388, L-1210 and P-1534 mouse leukemias, the H-16 melanocarcinoma, the CX-1 colon xenograft, the LX-1 lung xenograft and the MX-1 breast xenograft. In addition, paclitaxel blocks cell replication in lieLa cells, especially in the mitotic phase of cell division. More specifically, it has been reported by Schiff et al in Nature, 277, 665 (1979) that paclitaxel promotes the assembly of microtubule proteins responsible for the formation of spindles during cell division.
Because of its promising anti-cancer activity and its unusual structure and mechanism of action, paclitaxel represents a prototype of a new class of chemotherapeutic agents.
Mertbers of the class are set forth in U.S.
4,876,399 and 4,814,470, and elsewhere. Preferred are those of the above structural formula wherein A and B are independently hydrogen or lower alkanoyloxy a
-5-or A and H together form an oxo; L and D are independently hydrogen or hydroxy; E and F are independently hydrogen or lower alkanoyloxy or; E and F
together form an oxo; G and R' are hydrogen or lower alkanoxy or lower alkanoyloxy or aroyloxy or G and M
together form an oxo or methylene or G and M together form an oxocyclopropyl ring or M and F together form an oxocyclobutyl ring; J is hydrogen or aroyloxy or lower alkanoyloxy or I is hydrogen or aroyloxy; or I and J
taken together form an oxo; N is hydrogen, hydroxy or lower alkoxy; and R is aryl, lower alkyl, lower alkoxy or lower alkenyl. The hydroxyl and the carbonylamido substituents attached to carbons designated 2' and 3' in the formula may be transposed without departing from the preferred family of compounds. The alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to about six carbon atoms in the principal chain and up to about 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tent-butyl, amyl, hexyl, and the like. The lower alkoxy groups have the same carbon atom contents as above and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, Z5 amyloxy, hexyloxy, and the like. Exemplary alkanoyloxy groups include acetate, propionate, butyrate, valarate, isobutyrate and the like. The more preferred alkanoyloxy is acetate.
The aryl groups described hereinabove either alone or with various substituents contain from about 6 to about 10 carbon atoms and include phenyl, alpha-naphthyl or beta-naphthyl, etc. Phenyl is the more preferred aryl.
The lower alkenyl groups contain from 2 to about 6 carbon atoms in the principal chain and up to a total of about 10 carbon atoms. They may be straight or branched chain and include ethenyl, 1-propenyl, -s-isopropenyl, 1-butenyl, 2-butenyl. 3-butenyl, isobutenyl and the like.
Preferred values of the substituents A, H, L, D, G, F, G, M, I, J, and N are enumerated herein below:
A is hydrogen; B is hydrogen, or acetate or A and B together from an oxo: L is hydrogen or hydroxy; D is hydrogen or hydroxy; E is hydrogen, or acetate or E and F together form an oxo or M and F
together form an oxocyclobutyl ring; G is hydrogen or acetate or G'and M together form an oxo or methylene or oxocyclopropyl ring; J is hydrogen; I is hydroxy or aroyloxy, such as benzoyloxy or I and J together form an oxo; N is hydrogen, hydroxy or lower alkanoyloxy; R is phenyl or tent-butoxy; and R' is hydrogen or acetate.
All of the above-mentioned compounds, including paclitaxel itself can be made by methods set forth in the above-mentioned U.S. 4,876,399. Paclitaxel is commercially available as Taxol~
In addition, as set forth in U.S. 4,814,470, because of the difficulty of extracting paclitaxel from trunk barks of different species of Taxus (yew), the preparation of derivatives similar to paclitaxel from 10-deacetylbaccatin, which can be extracted relatively easily from yew leaves, has been proposed. The mentioned patent describes derivatives which demonstrate activity which is higher than that of paclitaxel. Such derivatives can also be used in the present invention.
They differ primarily in that they contain tert-butoxycarbonylamido groups instead of benzoylamido groups on the ring and in the side chains. They are embraced by the above formula and are known as taxotenes.
The ability of organic derivatives of tellurium and selenium type of the following general fonaulae (A) -(F) to protect mice from the adverse effects of the anti-neoplastic alkylating agent cyclophosphamide (CYP), has been demonstrated [[Cancer Res. 51(5)1499-1503(1991)], ~ 96/18401 PCT/US95/1609?
and see U.S. Patent 4,761,490.
f R' f O -- i R1 X (R= C - R3)t X. Q . (Ri C - Rs)u (A) X (Rs C '- Ry) I
, O i Re or R' is , f o c R1 I
(Ri C-Ra)t Te': (R~ C-Rs)n (B) X/ ( Rs C -Ry ) O C Rs or TeX~ ( C ) or TeOZ ( D ) or PhTeCl~ (E) or ( C6Hs ) fP ( TeCl~ ( O~C=H~ ) ) ( F ) wherein Q is Te or Se; t is 1 or 0; a is 1 or 0; v is 1 Or 0; R°, R1, RZ, R~, R~, Rs, R6, R~, R~ and R9 are the Same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, acyl, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to -g_
together form an oxo; G and R' are hydrogen or lower alkanoxy or lower alkanoyloxy or aroyloxy or G and M
together form an oxo or methylene or G and M together form an oxocyclopropyl ring or M and F together form an oxocyclobutyl ring; J is hydrogen or aroyloxy or lower alkanoyloxy or I is hydrogen or aroyloxy; or I and J
taken together form an oxo; N is hydrogen, hydroxy or lower alkoxy; and R is aryl, lower alkyl, lower alkoxy or lower alkenyl. The hydroxyl and the carbonylamido substituents attached to carbons designated 2' and 3' in the formula may be transposed without departing from the preferred family of compounds. The alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to about six carbon atoms in the principal chain and up to about 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tent-butyl, amyl, hexyl, and the like. The lower alkoxy groups have the same carbon atom contents as above and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, Z5 amyloxy, hexyloxy, and the like. Exemplary alkanoyloxy groups include acetate, propionate, butyrate, valarate, isobutyrate and the like. The more preferred alkanoyloxy is acetate.
The aryl groups described hereinabove either alone or with various substituents contain from about 6 to about 10 carbon atoms and include phenyl, alpha-naphthyl or beta-naphthyl, etc. Phenyl is the more preferred aryl.
The lower alkenyl groups contain from 2 to about 6 carbon atoms in the principal chain and up to a total of about 10 carbon atoms. They may be straight or branched chain and include ethenyl, 1-propenyl, -s-isopropenyl, 1-butenyl, 2-butenyl. 3-butenyl, isobutenyl and the like.
Preferred values of the substituents A, H, L, D, G, F, G, M, I, J, and N are enumerated herein below:
A is hydrogen; B is hydrogen, or acetate or A and B together from an oxo: L is hydrogen or hydroxy; D is hydrogen or hydroxy; E is hydrogen, or acetate or E and F together form an oxo or M and F
together form an oxocyclobutyl ring; G is hydrogen or acetate or G'and M together form an oxo or methylene or oxocyclopropyl ring; J is hydrogen; I is hydroxy or aroyloxy, such as benzoyloxy or I and J together form an oxo; N is hydrogen, hydroxy or lower alkanoyloxy; R is phenyl or tent-butoxy; and R' is hydrogen or acetate.
All of the above-mentioned compounds, including paclitaxel itself can be made by methods set forth in the above-mentioned U.S. 4,876,399. Paclitaxel is commercially available as Taxol~
In addition, as set forth in U.S. 4,814,470, because of the difficulty of extracting paclitaxel from trunk barks of different species of Taxus (yew), the preparation of derivatives similar to paclitaxel from 10-deacetylbaccatin, which can be extracted relatively easily from yew leaves, has been proposed. The mentioned patent describes derivatives which demonstrate activity which is higher than that of paclitaxel. Such derivatives can also be used in the present invention.
They differ primarily in that they contain tert-butoxycarbonylamido groups instead of benzoylamido groups on the ring and in the side chains. They are embraced by the above formula and are known as taxotenes.
The ability of organic derivatives of tellurium and selenium type of the following general fonaulae (A) -(F) to protect mice from the adverse effects of the anti-neoplastic alkylating agent cyclophosphamide (CYP), has been demonstrated [[Cancer Res. 51(5)1499-1503(1991)], ~ 96/18401 PCT/US95/1609?
and see U.S. Patent 4,761,490.
f R' f O -- i R1 X (R= C - R3)t X. Q . (Ri C - Rs)u (A) X (Rs C '- Ry) I
, O i Re or R' is , f o c R1 I
(Ri C-Ra)t Te': (R~ C-Rs)n (B) X/ ( Rs C -Ry ) O C Rs or TeX~ ( C ) or TeOZ ( D ) or PhTeCl~ (E) or ( C6Hs ) fP ( TeCl~ ( O~C=H~ ) ) ( F ) wherein Q is Te or Se; t is 1 or 0; a is 1 or 0; v is 1 Or 0; R°, R1, RZ, R~, R~, Rs, R6, R~, R~ and R9 are the Same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, acyl, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to -g_
6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -CORlo wherein Rlo is alkyl of from 1 to 6 carbons; and X is halogen. Although the ammonium salt is illustrated, it is understood that other pharmaceutically acceptable salts are within the scope of the invention. The compounds with the five membered rings are preferred.
As used herein, for compounds of formulae (A) and (B), the term alkyl of 1 to 6 carbon atoms includes straight and branched chain alkyl groups such as methyl; ethyl; n-propyl; n-butyl, and the like; the term hydroxyalkyl of 1 to 6 carbon atoms includes hydroxymethyl; hydroxyethyl;
hydroxy-n-butyl; the term haloalkyl of 1 to 6 carbon atoms includes chloromethyl; 2-iodoethyl; 4-bromo-n-butyle; iodoethyl; 4-bromo-n-pentyl and the like; the term alkanoyloxy of 1 to 6 carbon atoms includes acetyl, propionyl, butanoyl and the like; the term carboxyalkyl includes carboxymethyl, carboxyethyl, ethylenecarboxy and the like; the term alkylcarbonylalkyl includes methanoylmethyl, ethanoylethyl and the like; the term amidoalkyl includes -CHiCONHZ; -CH=CHzCONHZ; -CHICH2CHZCONH=
and the like; the term cyanoalkyl includes -CH2CN;
-CHzCHZCN; -CHZCHzCHZCN and the like; the term alkoxy of 1 to 6 carbon atoms includes methoxy, ethoxy, n-propoxy, n-pentoxy and the like; the terms halo and halogen are used to signify chloro, bromo, iodo and fluoro; the term aryl includes Ri6C0 wherein R16 is H, or alkyl of 1 to 6 carbons such as methanoyl, ethanoyl and the like; the term aryl includes phenyl, alkylphenyl and naphthyl; the term N-monoalkylamidoalkyl includes -CHzCHZCONHCH3, -CHzCONHCHICH3;
the term N,N-dialkylamidoalkyl includes -CHZCON(CH3)~;
CH=CHZCON ( CHZCH~ ) . Compounds which are based on tellurium are the presently preferred compounds of the invention.
Ammonium (trichloro(dioxoethylene-O,0-tellurate) is a compound of the structure _g_ C1 / O CH= NHi Cl - Te Cl ' O CHi This compound is a member of a family of organic 9,10,11 derivatives of tellurium and selenium found to have the ability to stimulate the in vivo and in vitro production of cytokines and their receptors. As is set forth in U.S.
Patent No. 4,761,490, these compounds may be utilized in the treatment of ceratin tumor, autoimmune diseases, immune diseases and infectious diseases.
The derivatives of tellurium or selenium that are useful in the present invention include those compounds of the above mentioned general formulas (A) - (F) which stimulate cells to produce lymphokines.
In a broad aspect, then, the present invention relates to a composition comprising a combination of a taxane compound and a tellurium or selenium compound in respective amounts effective to provide synergistic results in the treatment of malignancies, said tellurium or selenium compound being selected from the group consisting of those of the formulae:
~'+
Ro I
O ~ R~
X (RZ C R3) t X-- Q ( R4 C Rx ) a (A ) X ( R6 ~ R~ ) v O C .-- R8 Ry and Ro f O ~ R~
X~ ~ (RZ C-R3)c T a ( R~ .C -R5 ) a ( H ) X'~ ~ (R6;. C -R~) Y
O --r-- C
-9a-and TeX4 ( C ) and TeO, (D) and PhTeCl~ (E) and (C~H~,) q'P (TeCl~ (O~C2H4) )- (F) wherein q IS Te or Se; t is 1 or 0; a is 1 or 0; v is 1 or 0; R°, R-" R,,, R" R~, R5, R~, R" RR, and R~ are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyonalkyl of 1 to E
carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -CORlo wherein Rl~, is alkyl of from 1 to 6 carbons; and X is halogen.
In a further broad aspect, then, the present invention relates to use for treating malignancies whi~~h are sensitive to the combination of a taxane compound and a tellurium or selenium compound of, sequentially or concurrently, an amount of each drug which provides a synergistic effective in treating treat malignancies which are sensitive to the combination, said tellurium or_ selenium compound being selected from the group consisting of those of the formulae:
NH4+
R°
I
O . C Ri X ( RZ .---C - R3 ) z X=- Q ( R4 C -R5 ) ~
X ~ R6 C ~ RT ~ v O ~ Rg -9b-and Ro a O ~ Rt (Rz C R3) t Te (R4 C R5) ~
(R6 C R~) O t Re and T eX,, ( C ) and TeO: (D) and PhTeCl~
and (CFHS)'P (TeCl~ (02C~H.a) ) - (F) wherein Q is Te or Se; t is 1 or 0; a is 1 or 0; v is 1 or 0; R°, R" R~, R3, R4, R,, R5, R-" R~ or Rq are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 t.o 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 tc 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalky7. of 2 to 10 carbon atoms and -COR,~ wherein R1~; is alkyl of f:rorn 1 to 6 carbons; and X is halogen.
The compounds are made by combining substantially equimolar amounts of the reactants in a suitable reactor at=
room temperature or at elevated temperatures up to the reflux temperature. It is preferred to utilize a solvent.
that is capable of dissolving the reactants such as acetonitrile, benzene, toluene, xylene, dimethylsulfoxide, mixtures thereof and the like. Compounds of structure (A) are only obtained in acetonitrile. The preferred method requires heating the reaction mixture to the reflux temperature of the solvent while stirring the react=i.on mixture with a suitable magnetic or mechanical stirrer. The ' CA 02206567 2003-09-08 -9c-reacion may be carried out for a sufficient period of time to ensure complete reaction of the reactants. This time will vary with the reaction conditions, the particular compound being made and the nature of the solvents. The reaction may be run at atmospheric pressure but if desired may be carried out at reduced or elevated pressure. The reaction is practically carried out in the presence of an oxygen containing atmosphere such as air but inert atmospheres such as nitrogen, argon, helium or mixtures thereof may be utilized if desired. Reaction times of 1 minute to 168 hours may be used although reaction times of 6-=L6 hours are preferred.
The drugs may be given simultaneously or separately. It is preferred to administer the tellurium or selenium compound prior to or simultaneously with the taxane compound. When the drugs are administered i.n the same composition, the composition will have effective amounts of both drugs to be administered by the same route of administration which will be determined from the therapeutic regimen which is adopted for an ind=ividual patient to provide more than an additive effect which could be expected from the use of either drug alone. For example a single dose vial may be prepared which combines 30mg of paclitaxel and 3mg of ammonium (trichloro(dioxoethylene-O,O-tellurate) in an appropriat=e vehicle such as the vehicle which is commercially used for Taxol''.
Preferably the taxane compound comprises from. 1(0 to 90 parts by weight and the tellurium or selenium compound comprises from 90 to 10 parts by weight of the combination.
It has been found that a preferred two com~~oroent therapeutic regimen of the invention is based on the use of the following dosages of the two drugs:
(a) a taxane compound is administered at a dose of 1=~Om.g per M' (square meter of a patient's body) to 2lC~mg per l~l:
given by intravenous infusion once every 20 to 40 days, as necessary.
(b) the tellurium compound may be administered by the oral, intramuscular, intravenous, transdermal or intraperitoneal route. The oral dose will be 0.15 to 0.5 mg/kg of body weight daily and preferably from 0.03 to 0.3 -l0a-mg/kg of body weight daily in one dose or in divided doses. The parenteral dose will be 0.03 to 0.2 mg/kg of body weight daily and preferably from 0.006 to 0.02 mg/kg daily given as a bolus injection or as a continuous parenteral infusion.
The course of therapy may be carried out for a period of 2-52 weeks or longer. Depending on the therapeutic response and the manifestation of unacceptable side effects, the dose may be increased or decreased within the general description set forth r CA 02206567 1997-OS-30 herein.
The efficacy of the invention has been verified in a mouse model by a dosage regimen which begins three days after tumor implantation and uses 10 micrograms of tellurium or selenium compound/mouse IP every other day and to use 4 IP injections of paclitaxel at 17 mg/kg every other day starting on day 4 and continuing on days 6,8 and 10. The volume of the tumors is monitored (length X width) on a daily basis.
The drugs are preferably administered parenterally as a solution of the drug in normal or phosphate-buffered saline, and the like.
The invention may be used to treat benign tumor and malignancies which are sensitive to the described treatment regimen. The malignancies may be primary or metastatic such as solid tumors, leukemias or lymphomas.
These malignancies include colorectal carcinoma, espohageal carcinoma, stomach carcinoma, pancreatic carcinoma, liver carcinoma, small bowel carcinoma, lung tumors, CNIL, mesotheiloma, melanomas, biliary carcinoma, breast carcinoma and adenocarcinoma of unknown origin.
The effectiveness of the combination of the present invention have been demonstrated against the B16 melanoma cell line.
The~compound ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) was prepared according to the methods of Albeck and Sredni, U.S. Patent No. 4,761,490, Example 1. In this procedure, ethylene glycol and tellurium tetrachloride are refluxed in acetonitrile and, after cooling, the product precipitates from the reaction mixture as a white precipitate.
The tellurium compound may be diluted in a phosphate-buffered saline at pH 7.4 and maintained at 4'C.
Before use, it may be diluted to the desired concentration'in phosphate-buffered saline.
Paclitaxel is obtained by macerating ground non-dried leaves of Taxus baccata L, in accordance with ~O 96118401 PGTIUS95/16097 known methods. See, for example, Colin, Guenard, Gueritte-Voegelein, and Potier, U.S. 4,814,470 and the 1994 PDR pp6?0-672.
Paclitaxel is chemically known as 5!3,20-Epoxy-1,2a,4,7J3, lOJ3, 13a-hexahydroxytax-11-en-9-one 4,10 diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl -3-phenylisoserine.
The paclitaxel powder (6mg/ml) is suspended in 527mg of CremophoreEL and 49.?%v/v of dehydrated alcohol.
IO Other formulations of the taxane compounds may be prepared as required for specific applications.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples are given to illustrate the invention and it is understood that they do not limit the scope of the invention.
EXAMPLE I
This example demonstrates the anti-neoplastic activity of ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) in combination with paclitaxel.
C5?/H1 mice ware injected S.C. with 400,000 H16 Melanoma cells. Three days after tumor implantation, mice were divided'into four groups of 8 mice each. One of the groups of mice (control) was injected with Saline every other day. ~'he second group of mice (ASI01) was injected ZS with 10 micrograms of AS101/mouse I.P. every other day.
The third group (paclitaxel) received 4 I.P. injections of 1? mg/kg Qf paclitaxel every other day starting on day 4. The laat group (ASIOI+paclitaxel) received both treatments. Groups Z and 4 received AS101 injections every other day until the end of the experiment.
Experimental Protocol Day 0 Tumor implantation Group 1 - Day 3, Saline every other day until the end of the experiment Group 2 - Day 3, AS101, every other day until the end of the experiment.
Group 3 - Day 4,6,8,10, paclitaxel Group 4 - Day 3, AS101, every other day until the end of the experiment; Days 4,6,8,10, paclitaxel.
Every day the volume of the tumors was monitored (length X width). The results of the experiments are set forth as a graph in the Drawing.
It can be seen that tumor growth is reduced with ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) and paclitaxel alone in comparison with the control, but that tumor growth is completely inhibited when AS 101 is administered in combination with paclitaxel in accordance with the present invention.
The data establishes that the combined use of the organotellurium compound (AS101) and paclitaxel provides a substantial increase in the cytotoxicity exhibited by either compound alone. Moreover the increase is of such magnitude that it is more than a merely additive effect and therefore is unexpected. This increase in anti-neoplastic activity allows the clinician to achieve a therapeutic effect which is much greater than would be expected from the use of organotellurium compound AS101 in combination with other chemotherapeutic agents known'in the prior art, specifically, the combination of AS101 and cyclophosphamide, which merely extended the~lives of the test subjects, but had no reported effect on the size of the tumors.
If the procedure of Example 1 is repeated, substituting, respectively, for the paclitaxel and the ammonium trichloro(dioxoethylene-O,O-tellurate) equivalent weight amounts of a taxane compound of the formula R
L D
ld 110 9 1~ 19 o en o ~ Iz 1 -. y a R R 3' 1' o-- 7 1 3 ~ 51 1 ~16 H OH 1 ~ F
M C
P
J I
wherein R is tert-butyloxy, and R' is hydrogen (U. S.
4,814,470 (Example 2)) and an organotellurium compound of formula (B) above wherein X is C1, and t, u, and v ate 0 (U. S. 4,761,490) (Example 2), a composition in accordance with the present invention will be obtained.
v 'O 96/18401 PCT/US95/16097 if the procedure of Example 1 is repeated, substituting, respectively, for the paclitaxel and the ammonium trichloro(dioxoethylene-O,O-tellurate) equivalent weight amounts of a taxol compound of the formula in Example 2 wherein R' is acetoxy, and R is tert-butyloxy, and an organotellurium compound of formula (A) wherein R is methyl and t, u, and v are 0 (U. S.
4,761,490)(Example 16), a composition in accordance with the instant invention will be obtained:
The present invention also provides pharmaceutical compositions containing a combination of a taxane compound and a tellurium or selenium compound as defined above, in further combination with one or more pharmaceutically acceptable, inert or physiologically active, diluents or adjuvants. These compositions may be presented in~any form appropriate for the administration route envisaged. The parenteral route, and especially the intravenous route, is the preferred route for administration.
The compositions according to the invention for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be used as the solvent or the vehicle. These compositions may also contain adjuvants, especially wetting agents, emulsifiers or dispersants. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or any other injectable sterile medium.
WO 96118401 PCTlUS95/16097 Many variations of the present invention will suggest themselves to those skilled in this art in light of the above; detailed description. For example, instead of a tellurium compound, the corresponding selenium compound can be used. All such obvious variations are within the full intended scope of the appended claims.
As used herein, for compounds of formulae (A) and (B), the term alkyl of 1 to 6 carbon atoms includes straight and branched chain alkyl groups such as methyl; ethyl; n-propyl; n-butyl, and the like; the term hydroxyalkyl of 1 to 6 carbon atoms includes hydroxymethyl; hydroxyethyl;
hydroxy-n-butyl; the term haloalkyl of 1 to 6 carbon atoms includes chloromethyl; 2-iodoethyl; 4-bromo-n-butyle; iodoethyl; 4-bromo-n-pentyl and the like; the term alkanoyloxy of 1 to 6 carbon atoms includes acetyl, propionyl, butanoyl and the like; the term carboxyalkyl includes carboxymethyl, carboxyethyl, ethylenecarboxy and the like; the term alkylcarbonylalkyl includes methanoylmethyl, ethanoylethyl and the like; the term amidoalkyl includes -CHiCONHZ; -CH=CHzCONHZ; -CHICH2CHZCONH=
and the like; the term cyanoalkyl includes -CH2CN;
-CHzCHZCN; -CHZCHzCHZCN and the like; the term alkoxy of 1 to 6 carbon atoms includes methoxy, ethoxy, n-propoxy, n-pentoxy and the like; the terms halo and halogen are used to signify chloro, bromo, iodo and fluoro; the term aryl includes Ri6C0 wherein R16 is H, or alkyl of 1 to 6 carbons such as methanoyl, ethanoyl and the like; the term aryl includes phenyl, alkylphenyl and naphthyl; the term N-monoalkylamidoalkyl includes -CHzCHZCONHCH3, -CHzCONHCHICH3;
the term N,N-dialkylamidoalkyl includes -CHZCON(CH3)~;
CH=CHZCON ( CHZCH~ ) . Compounds which are based on tellurium are the presently preferred compounds of the invention.
Ammonium (trichloro(dioxoethylene-O,0-tellurate) is a compound of the structure _g_ C1 / O CH= NHi Cl - Te Cl ' O CHi This compound is a member of a family of organic 9,10,11 derivatives of tellurium and selenium found to have the ability to stimulate the in vivo and in vitro production of cytokines and their receptors. As is set forth in U.S.
Patent No. 4,761,490, these compounds may be utilized in the treatment of ceratin tumor, autoimmune diseases, immune diseases and infectious diseases.
The derivatives of tellurium or selenium that are useful in the present invention include those compounds of the above mentioned general formulas (A) - (F) which stimulate cells to produce lymphokines.
In a broad aspect, then, the present invention relates to a composition comprising a combination of a taxane compound and a tellurium or selenium compound in respective amounts effective to provide synergistic results in the treatment of malignancies, said tellurium or selenium compound being selected from the group consisting of those of the formulae:
~'+
Ro I
O ~ R~
X (RZ C R3) t X-- Q ( R4 C Rx ) a (A ) X ( R6 ~ R~ ) v O C .-- R8 Ry and Ro f O ~ R~
X~ ~ (RZ C-R3)c T a ( R~ .C -R5 ) a ( H ) X'~ ~ (R6;. C -R~) Y
O --r-- C
-9a-and TeX4 ( C ) and TeO, (D) and PhTeCl~ (E) and (C~H~,) q'P (TeCl~ (O~C2H4) )- (F) wherein q IS Te or Se; t is 1 or 0; a is 1 or 0; v is 1 or 0; R°, R-" R,,, R" R~, R5, R~, R" RR, and R~ are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyonalkyl of 1 to E
carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -CORlo wherein Rl~, is alkyl of from 1 to 6 carbons; and X is halogen.
In a further broad aspect, then, the present invention relates to use for treating malignancies whi~~h are sensitive to the combination of a taxane compound and a tellurium or selenium compound of, sequentially or concurrently, an amount of each drug which provides a synergistic effective in treating treat malignancies which are sensitive to the combination, said tellurium or_ selenium compound being selected from the group consisting of those of the formulae:
NH4+
R°
I
O . C Ri X ( RZ .---C - R3 ) z X=- Q ( R4 C -R5 ) ~
X ~ R6 C ~ RT ~ v O ~ Rg -9b-and Ro a O ~ Rt (Rz C R3) t Te (R4 C R5) ~
(R6 C R~) O t Re and T eX,, ( C ) and TeO: (D) and PhTeCl~
and (CFHS)'P (TeCl~ (02C~H.a) ) - (F) wherein Q is Te or Se; t is 1 or 0; a is 1 or 0; v is 1 or 0; R°, R" R~, R3, R4, R,, R5, R-" R~ or Rq are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 t.o 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 tc 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalky7. of 2 to 10 carbon atoms and -COR,~ wherein R1~; is alkyl of f:rorn 1 to 6 carbons; and X is halogen.
The compounds are made by combining substantially equimolar amounts of the reactants in a suitable reactor at=
room temperature or at elevated temperatures up to the reflux temperature. It is preferred to utilize a solvent.
that is capable of dissolving the reactants such as acetonitrile, benzene, toluene, xylene, dimethylsulfoxide, mixtures thereof and the like. Compounds of structure (A) are only obtained in acetonitrile. The preferred method requires heating the reaction mixture to the reflux temperature of the solvent while stirring the react=i.on mixture with a suitable magnetic or mechanical stirrer. The ' CA 02206567 2003-09-08 -9c-reacion may be carried out for a sufficient period of time to ensure complete reaction of the reactants. This time will vary with the reaction conditions, the particular compound being made and the nature of the solvents. The reaction may be run at atmospheric pressure but if desired may be carried out at reduced or elevated pressure. The reaction is practically carried out in the presence of an oxygen containing atmosphere such as air but inert atmospheres such as nitrogen, argon, helium or mixtures thereof may be utilized if desired. Reaction times of 1 minute to 168 hours may be used although reaction times of 6-=L6 hours are preferred.
The drugs may be given simultaneously or separately. It is preferred to administer the tellurium or selenium compound prior to or simultaneously with the taxane compound. When the drugs are administered i.n the same composition, the composition will have effective amounts of both drugs to be administered by the same route of administration which will be determined from the therapeutic regimen which is adopted for an ind=ividual patient to provide more than an additive effect which could be expected from the use of either drug alone. For example a single dose vial may be prepared which combines 30mg of paclitaxel and 3mg of ammonium (trichloro(dioxoethylene-O,O-tellurate) in an appropriat=e vehicle such as the vehicle which is commercially used for Taxol''.
Preferably the taxane compound comprises from. 1(0 to 90 parts by weight and the tellurium or selenium compound comprises from 90 to 10 parts by weight of the combination.
It has been found that a preferred two com~~oroent therapeutic regimen of the invention is based on the use of the following dosages of the two drugs:
(a) a taxane compound is administered at a dose of 1=~Om.g per M' (square meter of a patient's body) to 2lC~mg per l~l:
given by intravenous infusion once every 20 to 40 days, as necessary.
(b) the tellurium compound may be administered by the oral, intramuscular, intravenous, transdermal or intraperitoneal route. The oral dose will be 0.15 to 0.5 mg/kg of body weight daily and preferably from 0.03 to 0.3 -l0a-mg/kg of body weight daily in one dose or in divided doses. The parenteral dose will be 0.03 to 0.2 mg/kg of body weight daily and preferably from 0.006 to 0.02 mg/kg daily given as a bolus injection or as a continuous parenteral infusion.
The course of therapy may be carried out for a period of 2-52 weeks or longer. Depending on the therapeutic response and the manifestation of unacceptable side effects, the dose may be increased or decreased within the general description set forth r CA 02206567 1997-OS-30 herein.
The efficacy of the invention has been verified in a mouse model by a dosage regimen which begins three days after tumor implantation and uses 10 micrograms of tellurium or selenium compound/mouse IP every other day and to use 4 IP injections of paclitaxel at 17 mg/kg every other day starting on day 4 and continuing on days 6,8 and 10. The volume of the tumors is monitored (length X width) on a daily basis.
The drugs are preferably administered parenterally as a solution of the drug in normal or phosphate-buffered saline, and the like.
The invention may be used to treat benign tumor and malignancies which are sensitive to the described treatment regimen. The malignancies may be primary or metastatic such as solid tumors, leukemias or lymphomas.
These malignancies include colorectal carcinoma, espohageal carcinoma, stomach carcinoma, pancreatic carcinoma, liver carcinoma, small bowel carcinoma, lung tumors, CNIL, mesotheiloma, melanomas, biliary carcinoma, breast carcinoma and adenocarcinoma of unknown origin.
The effectiveness of the combination of the present invention have been demonstrated against the B16 melanoma cell line.
The~compound ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) was prepared according to the methods of Albeck and Sredni, U.S. Patent No. 4,761,490, Example 1. In this procedure, ethylene glycol and tellurium tetrachloride are refluxed in acetonitrile and, after cooling, the product precipitates from the reaction mixture as a white precipitate.
The tellurium compound may be diluted in a phosphate-buffered saline at pH 7.4 and maintained at 4'C.
Before use, it may be diluted to the desired concentration'in phosphate-buffered saline.
Paclitaxel is obtained by macerating ground non-dried leaves of Taxus baccata L, in accordance with ~O 96118401 PGTIUS95/16097 known methods. See, for example, Colin, Guenard, Gueritte-Voegelein, and Potier, U.S. 4,814,470 and the 1994 PDR pp6?0-672.
Paclitaxel is chemically known as 5!3,20-Epoxy-1,2a,4,7J3, lOJ3, 13a-hexahydroxytax-11-en-9-one 4,10 diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl -3-phenylisoserine.
The paclitaxel powder (6mg/ml) is suspended in 527mg of CremophoreEL and 49.?%v/v of dehydrated alcohol.
IO Other formulations of the taxane compounds may be prepared as required for specific applications.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples are given to illustrate the invention and it is understood that they do not limit the scope of the invention.
EXAMPLE I
This example demonstrates the anti-neoplastic activity of ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) in combination with paclitaxel.
C5?/H1 mice ware injected S.C. with 400,000 H16 Melanoma cells. Three days after tumor implantation, mice were divided'into four groups of 8 mice each. One of the groups of mice (control) was injected with Saline every other day. ~'he second group of mice (ASI01) was injected ZS with 10 micrograms of AS101/mouse I.P. every other day.
The third group (paclitaxel) received 4 I.P. injections of 1? mg/kg Qf paclitaxel every other day starting on day 4. The laat group (ASIOI+paclitaxel) received both treatments. Groups Z and 4 received AS101 injections every other day until the end of the experiment.
Experimental Protocol Day 0 Tumor implantation Group 1 - Day 3, Saline every other day until the end of the experiment Group 2 - Day 3, AS101, every other day until the end of the experiment.
Group 3 - Day 4,6,8,10, paclitaxel Group 4 - Day 3, AS101, every other day until the end of the experiment; Days 4,6,8,10, paclitaxel.
Every day the volume of the tumors was monitored (length X width). The results of the experiments are set forth as a graph in the Drawing.
It can be seen that tumor growth is reduced with ammonium trichloro(dioxoethylene-O,O-tellurate) (AS101) and paclitaxel alone in comparison with the control, but that tumor growth is completely inhibited when AS 101 is administered in combination with paclitaxel in accordance with the present invention.
The data establishes that the combined use of the organotellurium compound (AS101) and paclitaxel provides a substantial increase in the cytotoxicity exhibited by either compound alone. Moreover the increase is of such magnitude that it is more than a merely additive effect and therefore is unexpected. This increase in anti-neoplastic activity allows the clinician to achieve a therapeutic effect which is much greater than would be expected from the use of organotellurium compound AS101 in combination with other chemotherapeutic agents known'in the prior art, specifically, the combination of AS101 and cyclophosphamide, which merely extended the~lives of the test subjects, but had no reported effect on the size of the tumors.
If the procedure of Example 1 is repeated, substituting, respectively, for the paclitaxel and the ammonium trichloro(dioxoethylene-O,O-tellurate) equivalent weight amounts of a taxane compound of the formula R
L D
ld 110 9 1~ 19 o en o ~ Iz 1 -. y a R R 3' 1' o-- 7 1 3 ~ 51 1 ~16 H OH 1 ~ F
M C
P
J I
wherein R is tert-butyloxy, and R' is hydrogen (U. S.
4,814,470 (Example 2)) and an organotellurium compound of formula (B) above wherein X is C1, and t, u, and v ate 0 (U. S. 4,761,490) (Example 2), a composition in accordance with the present invention will be obtained.
v 'O 96/18401 PCT/US95/16097 if the procedure of Example 1 is repeated, substituting, respectively, for the paclitaxel and the ammonium trichloro(dioxoethylene-O,O-tellurate) equivalent weight amounts of a taxol compound of the formula in Example 2 wherein R' is acetoxy, and R is tert-butyloxy, and an organotellurium compound of formula (A) wherein R is methyl and t, u, and v are 0 (U. S.
4,761,490)(Example 16), a composition in accordance with the instant invention will be obtained:
The present invention also provides pharmaceutical compositions containing a combination of a taxane compound and a tellurium or selenium compound as defined above, in further combination with one or more pharmaceutically acceptable, inert or physiologically active, diluents or adjuvants. These compositions may be presented in~any form appropriate for the administration route envisaged. The parenteral route, and especially the intravenous route, is the preferred route for administration.
The compositions according to the invention for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be used as the solvent or the vehicle. These compositions may also contain adjuvants, especially wetting agents, emulsifiers or dispersants. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or any other injectable sterile medium.
WO 96118401 PCTlUS95/16097 Many variations of the present invention will suggest themselves to those skilled in this art in light of the above; detailed description. For example, instead of a tellurium compound, the corresponding selenium compound can be used. All such obvious variations are within the full intended scope of the appended claims.
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition comprising a combination of a taxane compound and a tellurium or selenium compound in respective amounts effective to provide synergistic results in the treatment of malignancies, said tellurium or selenium compound being selected from the group consisting of those of the formulae:
and TeX4 (C) and TeO2 (D) and PhTeCl3 (E) and (C6H5)4+P(TeCl3(O2CH4))- (F) wherein Q IS Te or Se; t is 1 or 0; a is 1 o.r 0; v is 1 or 0; R°, R1, R2, R3, R4, R5, R6, R7, R8, and R9, are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -COR10, wherein R10 is alkyl of from 1 to 6 carbons; and X is halogen.
and TeX4 (C) and TeO2 (D) and PhTeCl3 (E) and (C6H5)4+P(TeCl3(O2CH4))- (F) wherein Q IS Te or Se; t is 1 or 0; a is 1 o.r 0; v is 1 or 0; R°, R1, R2, R3, R4, R5, R6, R7, R8, and R9, are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -COR10, wherein R10 is alkyl of from 1 to 6 carbons; and X is halogen.
2. A composition as defined in Claim 1 wherein the taxane compound is of the formula:
wherein A and B are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or A and B together form an oxo;
L and D are independently hydrogen or hydroxy;
E and F are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or;
E and F together form an oxo;
G and R'O are hydrogen or alkanoxy having 1-6 carbon atoms or alkanoyloxy having 1-6 carbon atoms or aroyloxy having 6-10 carbon atoms or G and M together form an oxo or methylene or G and M together form an oxocyclopropyl ring or M and F together form an oxocyclobutyl ring;
J is hydrogen or aroyloxy having 6-10 carbon atoms or alkanoyloxy having 1-6 carbon atoms or I is hydrogen or aroyloxy having 6-10 carbon atoms; or I and J taken together form an oxo;
N is hydrogen, hydroxy or alkoxy having 1-6 carbon atoms; and R is aryl having 6-10 carbon atoms, alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms or alkenyl having 1-6 carbon atoms; and the hydroxyl and the carbonylamido substituents attached to carbons designated 2' and 3' in the formula may be transposed.
wherein A and B are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or A and B together form an oxo;
L and D are independently hydrogen or hydroxy;
E and F are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or;
E and F together form an oxo;
G and R'O are hydrogen or alkanoxy having 1-6 carbon atoms or alkanoyloxy having 1-6 carbon atoms or aroyloxy having 6-10 carbon atoms or G and M together form an oxo or methylene or G and M together form an oxocyclopropyl ring or M and F together form an oxocyclobutyl ring;
J is hydrogen or aroyloxy having 6-10 carbon atoms or alkanoyloxy having 1-6 carbon atoms or I is hydrogen or aroyloxy having 6-10 carbon atoms; or I and J taken together form an oxo;
N is hydrogen, hydroxy or alkoxy having 1-6 carbon atoms; and R is aryl having 6-10 carbon atoms, alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms or alkenyl having 1-6 carbon atoms; and the hydroxyl and the carbonylamido substituents attached to carbons designated 2' and 3' in the formula may be transposed.
3. A composition as defined in Claim 2 wherein the taxane compound is taxol, a compound of the said formula wherein A and B together form an oxo; L and N are hydroxy, D, E and J are hydrogen, G is acetate; M and F together form an oxocyclobutyl ring; I is benzoyloxy; and R is phenyl.
4. A composition as defined in Claim 1 wherein the tellurium or selenium compound is ammonium trichloro(dioxoethylene-O,O-tellurates), a compound of formula (A) wherein Q is tellurium; R°, R1, R8 and R9 are hydrogen; and t, u, and v are 0.
5. A composition as defined in Claim 1 wherein the taxane compound comprises from 10 to 90 parts by weight and the tellurium or selenium compound comprises from 90 to parts by weight of the combination.
6. Use for treating malignancies which are sensitive to the combination of a taxane compound and a tellurium or selenium compound of, sequentially or concurrently, an amount of each drug which provides a synergistic effective in treating malignancies which are sensitive to the combination, said tellurium or selenium compound being selected from the group consisting of those of the formulae:
and TeX4 (C) and TeO2 (D) and PhTeCl3 (E) and (C6H5)4P+(TeCl3(O2C2H4))- (F) wherein Q is Te or Se; t is 1 or 0; a is 1 or 0; v is 1 or 0; R°, R1, R2, R3, R4, R5, R6, R7, R8 or R9 are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -COR10 wherein R10 is alkyl of from 1 to 6 carbons; and X is halogen.
and TeX4 (C) and TeO2 (D) and PhTeCl3 (E) and (C6H5)4P+(TeCl3(O2C2H4))- (F) wherein Q is Te or Se; t is 1 or 0; a is 1 or 0; v is 1 or 0; R°, R1, R2, R3, R4, R5, R6, R7, R8 or R9 are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 6 carbons, hydroxy, alkyl of from 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 6 carbon atoms, carboxyalkyl of 1 to 6 carbon atoms, amido, cyano, amidoalkyl of 1 to 6 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and -COR10 wherein R10 is alkyl of from 1 to 6 carbons; and X is halogen.
7. Use as defined in Claim 6 wherein the taxane compound is selected from those of the formula:
wherein A and B are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or A and 73 together form an oxo;
L and D are independently hydrogen or hydroxy;
E and F are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or;
E and F together form an oxo;
G and R'O are hydrogen or alkanoxy having 1-6 carbon atoms or alkanoyloxy having 1-6 carbon atoms or aroyloxy having 6-10 carbon atoms or G and M together form an oxo or methylene or G and M together form an oxocyclopropyl ring or M and F together form an oxocyclobutyl ring;
J is hydrogen or aroyloxy having 6-10 carbon atoms or alkanoyloxy having 1-6 carbon atoms or I is hydrogen or aroyloxy having 6-10 carbon atoms; or I and J taken together form an oxo;
N is hydrogen, hydroxy or alkoxy having 1-6 carbon atoms; and R is aryl having 6-10 carbon atoms, alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms or alkenyl having 1-6 carbon atoms; and the hydroxyl and the carbonylamido substituents attached to carbons designated 2' and 3' in the formula may be transposed.
wherein A and B are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or A and 73 together form an oxo;
L and D are independently hydrogen or hydroxy;
E and F are independently hydrogen or alkanoyloxy having 1-6 carbon atoms or;
E and F together form an oxo;
G and R'O are hydrogen or alkanoxy having 1-6 carbon atoms or alkanoyloxy having 1-6 carbon atoms or aroyloxy having 6-10 carbon atoms or G and M together form an oxo or methylene or G and M together form an oxocyclopropyl ring or M and F together form an oxocyclobutyl ring;
J is hydrogen or aroyloxy having 6-10 carbon atoms or alkanoyloxy having 1-6 carbon atoms or I is hydrogen or aroyloxy having 6-10 carbon atoms; or I and J taken together form an oxo;
N is hydrogen, hydroxy or alkoxy having 1-6 carbon atoms; and R is aryl having 6-10 carbon atoms, alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms or alkenyl having 1-6 carbon atoms; and the hydroxyl and the carbonylamido substituents attached to carbons designated 2' and 3' in the formula may be transposed.
8. Use as defined in Claim 7 wherein the taxane compound is taxol, a compound of the said formula wherein A
and B together form an oxo; L and N are hydroxy, D, E and J
are hydrogen, G is acetate; M and F together form an oxocyclobutyl ring; I is benzoyloxy; and R is phenyl.
and B together form an oxo; L and N are hydroxy, D, E and J
are hydrogen, G is acetate; M and F together form an oxocyclobutyl ring; I is benzoyloxy; and R is phenyl.
9. Use as defined in Claim 6 wherein the tellurium or selenium compound is ammonium trichloro(dioxoethylene-O,O-tellurate), a compound of formula (A) wherein is tellurium; R°, R1, R8 and R9 are hydrogen; and t, u, and v are 0.
10. Use as defined in Claim 6 wherein the taxane compound comprises from 10 to 90 parts by weight and the tellurium or selenium compound comprises from 90 to 10 parts by weight of the combination.
11. Use as defined in Claim 6 wherein the taxane compound and the tellurium or selenium compound are for sequential administration.
12. A pharmaceutical composition which contains a taxane compound and a tellurium or selenium compound according to Claim 1, in combination, further combined with one or more pharmaceutically acceptable, inert or physiologically active diluents or adjuvants.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US35712894A | 1994-12-15 | 1994-12-15 | |
US08/357,128 | 1994-12-15 | ||
PCT/US1995/016097 WO1996018401A1 (en) | 1994-12-15 | 1995-12-12 | Method and composition for reducing tumor development with a combination of a taxane compound and a tellurium and/or selenium compound |
Publications (2)
Publication Number | Publication Date |
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CA2206567A1 CA2206567A1 (en) | 1996-06-20 |
CA2206567C true CA2206567C (en) | 2006-09-05 |
Family
ID=36968373
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002206567A Expired - Fee Related CA2206567C (en) | 1994-12-15 | 1995-12-12 | Method and composition for reducing tumor development with a combination of a taxane compound and a tellurium and/or selenium compound |
Country Status (1)
Country | Link |
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CA (1) | CA2206567C (en) |
-
1995
- 1995-12-12 CA CA002206567A patent/CA2206567C/en not_active Expired - Fee Related
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CA2206567A1 (en) | 1996-06-20 |
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