HK1123970A - Compositions for the treatment of neoplasms - Google Patents

Description

Composition for treating tumor

Background

The present invention relates to the treatment of tumors (e.g., cancer).

Cancer is a disease characterized by uncontrolled growth of abnormal cells. Cancer cells have overcome the barriers imposed on normal cells with a limited lifespan, growing indefinitely. As cancer cells continue to grow, genetic alterations may continue to occur until the cancer cells have exhibited a more aggressive growth phenotype. If left untreated, metastasis, i.e., the spread of cancer cells to distant areas of the body via the lymphatic system or blood stream, must destroy healthy tissue.

The fact that there is considerable diversity even among one type of cancer has hindered the treatment of cancer. Certain cancers, for example, have the ability to invade tissues and exhibit an invasive growth process characterized by metastasis. These tumors are often associated with a poor prognosis for the patient. Ultimately, tumor diversity leads to the phenomenon of resistance to a wide range of drugs, i.e. resistance to a wide range of structurally unrelated cytotoxic anticancer compounds, j.h. gerlach et al, Cancer surfeys, 5: 25-46(1986). For example, the methods described by j.h. goldie and Andrew j.coldman, cancer research, 44: 3643-3653(1984), the underlying cause of the developed drug resistance may be due to the presence of a few drug-resistant cells in the tumor (e.g., mutant cells) during diagnosis. Treatment of such tumors with a single drug can result in remission, where the tumor shrinks in volume as a result of killing the dominant drug-sensitive cells. However, as the drug-sensitive cells disappear, the remaining drug-resistant cells can continue to multiply and eventually dominate the tumor cell population. Therefore, the reason why metastatic cancer develops pleiotropic (pleiotropic) resistance to all existing therapies and how to cope with this problem is the most pressing issue in cancer chemotherapy.

There is a need for reliable anti-cancer therapies for various types of tumors, particularly for aggressive tumors. Importantly, the treatment must be effective with minimal host toxicity. Although multiple combinations have been used for a long time for the treatment of cancer, in particular for the treatment of multi-drug resistant cancers, the positive results of using combination therapy are often still unpredictable. Particularly useful are those compositions comprising multiple combinations and formulated for delivery to a patient at the maximum effective dose over an extended period of time.

There is a need for reliable anti-cancer treatments for a wide range of tumor types, particularly suitable for aggressive tumors. It is important that the treatment be effective with minimal toxicity to the host. Despite the long history of cancer treatment with multi-drug combinations, particularly in the treatment of cancers resistant to multiple drugs, the positive results obtained with combination therapy are often unpredictable. Particularly useful are those compositions comprising multiple drug combinations and formulated to provide the maximum effective dose for delayed release to a patient.

Summary of The Invention

The present invention provides anti-tumor compositions of phenothiazine and/or anti-fungal/anti-protozoal compounds and methods of using the same, wherein the compositions are formulated to maintain plasma levels of the active component for a predetermined time effective to inhibit tumor growth in the patient being treated.

Thus, in a first aspect, the invention features a method of treating a human patient suffering from a neoplasm, said method comprising administering a composition comprising a compound of formula I and/or a compound of formula II, wherein a first plasma level of the compound of formula I between 0.3ng/ml and 3.5 μ g/ml and a second plasma level of the compound of formula II between 0.2ng/ml and 2.5 μ g/ml is maintained for at least 12 hours. In one embodiment, the first plasma level is between 0.3 μ g/ml and 3.5 μ g/ml. In another embodiment, the second plasma level is between 0.25 μ g/ml and 2.5 μ g/ml. The compound of formula I is a compound having the structure:

wherein

R¹、R³、R⁴、R⁵、R⁶、R⁷And R⁸Each independently is H, OH, F, OCF₃Or OCH₃；

R²Selected from CF₃Halogen radical, OCH₃、COCH₃、CN、OCF₃、COCH₂CH₃、CO(CH₂)₂CH₃And SCH₂CH₃；

R⁹Is selected from

R⁹Has the following structure:

wherein n is 0 or 1; z is NR³⁴R³⁵OR OR³⁶；R³¹、R³²、R³³、R³⁴、R³⁵And R³⁶Each independently is H, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl, C_2-6Heterocyclic group, C_6-12Aryl radical, C_7-14Alkylaryl group, C_3-10Alkylheterocyclyl, acyl or C_1-7A heteroalkyl group; or R³²、R³³、R³⁴、R³⁵And R³⁶Any of which may optionally form together with the intervening carbon or non-adjacent O, S or N atom one or more 5-to 7-membered rings optionally substituted with: H. halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_2-6Heterocyclic group, C_6-12Aryl radical, C_7-14Alkylaryl group, C_3-10Alkylheterocyclyl, acyl or C_1-7A heteroalkyl group; and

w is selected from

The compound of formula II has the formula or a pharmaceutically acceptable salt or prodrug thereof,

wherein

A is

Wherein

X and Y are each independently O, NR¹⁹Or S, R¹⁴And R¹⁹Each independently is H or C_1-6Alkyl radical, R¹⁵、R¹⁶、R¹⁷And R¹⁸Each independently is H, C_1-6Alkyl, halogen, C_1-6Alkoxy radical, C_6-18Aryloxy radical or C_6-18aryl-C_1-6Alkoxy, p is an integer from 2 to 6;

m and n are each independently an integer of 0 to 2;

R¹⁰and R¹¹Are each independently

Wherein

R²¹Is H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl or C_6-18An aryl group; r²²Is H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl, carbonyl (C)_1-6Alkoxy), carbonyl (C)_6-18aryl-C_1-6Alkoxy), carbonyl (C)_6-18Aryloxy) or C₆-C₁₈An aryl group; r²⁰Is H, OH or C_1-6Alkoxy, or R²⁰And R²¹Together represent

Wherein R is²³、R²⁴And R²⁵Each independently is H, C_1-6Alkyl, halogen or trifluoromethyl, R²⁶、R²⁷、R²⁸And R²⁹Each independently is H or C_1-6Alkyl radical, R³⁰Is H, halogen, trifluoromethyl, OCF₃、NO₂、C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl or C_6-18An aryl group; and

R¹²and R¹³Each independently is H, Cl, Br, OH, OCH₃、OCF₃、NO₂And NH₂Or R is¹²And R¹³Together form a single bond.

The tumor may for example be selected from: lung cancer, colon cancer, ovarian cancer, prostate cancer, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, hodgkin's disease, non-hodgkin's disease, waldenstrom's macroglobulinemia, heavy chain disease (heavy chain disease), hepatocellular carcinoma, non-small cell lung cancer, multiple myeloma, mucin-depleded foci (MDF), fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, and neuroblastoma, Rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwanoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Specific examples of tumors to be treated are lung, colon, ovarian and prostate cancer.

Methods of treating tumors by administering the compositions of the present invention can be performed using any formulation of the compositions or the methods of delivery described herein.

In another aspect, the invention features a composition including a compound of formula I and/or a compound of formula II, wherein the composition is administered to a human patient and the composition is formulated to maintain a first plasma level of the compound of formula I of 0.3ng/ml to 3.5 μ g/ml and/or a second plasma level of the compound of formula II of 0.2ng/ml to 2.5 μ g/ml for at least 12 hours. Preferably, the first plasma level is between 0.3 μ g/ml and 3.5 μ g/ml and the second plasma level is between 0.2 μ g/ml and 2.5 μ g/ml. For any of the compositions of the present invention comprising both a compound of formula I and a compound of formula II, the weight ratio of the compound of formula I to the compound of formula II may be from 1: 10 to 10: 1. Preferably, the weight ratio of the compound of formula I to the compound of formula II is from 1: 2 to 1: 5. Examples include a ratio of about 1: 2.5 and about 1: 4. The compounds of formula I and II are as defined above.

For any of the compositions of the present invention, preferably the compound of formula I is chlorpromazine and the compound of formula II is pentamidine.

In one embodiment, the composition is formulated as a delayed release formulation. In another embodiment, the composition is formulated for continuous perfusion. The predetermined first and second plasma levels may be maintained for 1 day, 2 days, 3 days, 7 days, 10 days, 14 days, 28 days, or 6 months. The composition may be administered once or more than once in order to maintain plasma levels of the compound of formula I and/or the compound of formula II.

In another embodiment, a predetermined plasma level of a compound of formula I and/or a compound of formula II is maintained for a predetermined period of time to inhibit the growth of a tumor in a human patient. Ideally, if the composition comprises a compound of formula I, the patient does not experience significant sedation during this process.

In another aspect, the invention features a composition including a compound of formula I and/or a compound of formula II, where the composition is formulated for administration of the compound of formula I at 0.1mg/m²Hour-15 mg/m²Per hour, preferably 1mg/m²Hour-5 mg/m²First infusion Rate per hour, Compound of formula II at 0.1mg/m²Hour-60 mg/m²Per hour, preferably 1mg/m²Hour-20 mg/m²A second infusion rate per hour by continuous intravenous infusion into a human patient. The compounds of formula I and II are as defined above.

In one embodiment, the composition is infused continuously for 12 hours, 1 day, 2 days, 3 days, 7 days, 10 days, 14 days, or 28 days. Non-limiting examples of infusion methods are the use of intravenous drip, peristaltic pumps, or osmotic pumps.

In another embodiment, when the composition comprises both a compound of formula I and a compound of formula II, administration of the composition at first and second predetermined infusion rates, respectively, for a compound of formula I and II for a predetermined time period inhibits growth of a tumor in a human patient. Ideally, the patient does not produce significant sedation during the procedure.

For any of the compositions of the present invention, the various active ingredients may be formulated with or without excipients. Non-limiting examples of excipients that are desirable are about 1% by weight to 10% by weight ascorbic acid and 3% by weight to 30% by weight mannitol, each of which may be combined with the active ingredient either alone or in admixture. Other non-limiting examples of excipients are tocopherol, cysteine, glutathione, acetone sodium bisulfite, BHA, BHT, sucrose, trehalose, sorbitol, povidone, lactose, acetate, citrate, glutamate, phosphate, glucose, and sodium sulfate. If one component of the composition or separately formulated compositions is a solid, it can be reconstituted with any physiologically acceptable diluent. Non-limiting examples of diluents are saline at standard or semi-standard concentrations and 1% by weight to 10% by weight glucose, preferably 5% by weight glucose, wherein the active ingredient, when dissolved or suspended in the diluent, constitutes about 0.005% by weight to 0.5% by weight, preferably about 0.01% by weight to 0.2% by weight. Other non-limiting examples of diluents are sterile water, ringer's injection (NaCl + KCl + CaCl)₂) Lactated ringer's injection (NaCl + KCl + CaCl)₂Sodium lactate) and various electrolytic solutions (different combinations of electrolytes, glucose, fructose and/or invert sugar). In addition, the diluent may also contain a suitable organic co-solvent, such as ethanol or DMSO, at 0.01% to 10% of the total volume.

In addition to the compound of formula I and/or the compound of formula II, any of the compositions of the present invention may further comprise one or more active agents. For example, the compositions of the present invention may comprise an antiproliferative agent (e.g., taxol) in combination with a compound of formula I (e.g., chlorpromazine) and/or a compound of formula II (e.g., pentamidine).

Definition of

The term "about" as used herein means plus or minus 10% of the stated value.

The term "acyl" denotes an alkyl group as defined herein or a hydrogen attached to the parent molecular moiety through a carbonyl group, examples of which are formyl, acetyl, propionyl, butyryl and the like. Exemplary unsubstituted acyl groups contain 2 to 7 carbon atoms.

The term "alkenyl" as used herein, unless otherwise specified, denotes a monovalent straight or branched chain group containing one or more carbon-carbon double bonds and having 2 to 6 carbon atoms, examples of which are vinyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term "C" as used herein_x-yAlkylaryl (alkaryl) "or" C_x-yAlkylene aryl "means a chemical substituent of the formula-RR ', wherein R is an alkyl group carbon (alkyl group carbon) and R' is an aryl group as defined elsewhere herein, wherein x-y is the range of carbon atoms that two groups contain. Also, the term "C_x-yAlkylheteroaryl (alkylheteroaryl) "," C_x-yAlkyleneheteroaryl "refers to a chemical substituent of the formula RR ', where R is an alkyl group having x-y carbon atoms, and R' is a heteroaryl group as defined elsewhere herein. Other groups preceded by the prefix "alk-" or "alkylene-" are defined in the same manner.

Unless otherwise indicated, the term "alkoxy" denotes a chemical substituent of formula-OR, wherein R is an alkyl group having 1 to 6 carbon atoms.

Unless otherwise indicated, the term "alkyl" and the prefix "alk-" as used herein include both straight and branched chain saturated groups having from 1 to 6 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-and isopropyl, n-, sec-, isobutyl and tert-butyl, neopentyl and the like, and may optionally be independently selected fromOne, two, three or four (in the case of alkyl having 2 or more carbon atoms) substituents of: (1) alkoxy having 1 to 6 carbon atoms; (2) alkylsulfinyl having 1 to 6 carbon atoms; (3) alkylsulfonyl groups having 1 to 6 carbon atoms; (4) an amino group; (5) an aryl group; (6) an arylalkoxy group; (7) aroyl; (8) an azide group; (9) carboxaldehydes (carboxaldehydes); (10) cycloalkyl having 3 to 8 carbon atoms; (11) a halo group; (12) a heterocyclic group; (13) (heterocyclic) oxy; (14) (heterocyclic) acyl; (15) a hydroxyl group; (16) an N-protected amino group; (17) a nitro group; (18) oxo; (19) a spiro alkyl group having 3 to 8 carbon atoms; (20) thioalkoxy groups having 1 to 6 carbon atoms; (21) a thiol; (22) -CO₂R^AWherein R is^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (23) -C (O) NR^BR^CWherein R is^BAnd R^cEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; (24) -SO₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (25) -SO₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; and (26) -NR^GR^HWherein R is^GAnd R^HEach independently selected from (a) hydrogen; (b) an N-protected group; (c) an alkyl group having 1 to 6 carbon atoms; (d) alkenyl having 2 to 6 carbon atoms; (e) alkynyl having 2 to 6 carbon atoms; (f) an aryl group; (g) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (h) cycloalkyl having 3 to 8 carbon atoms and (i) alkylcycloalkyl (alkylcycloalkyl), wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms, with the proviso that no two groups are linked to the nitrogen atom via a carbonyl or sulfonyl group.

The term "alkynyl" as used herein denotes a monovalent straight or branched chain group of 2 to 6 carbon atoms containing a carbon-carbon triple bond, examples of which are ethynyl, 1-propynyl, and the like.

In this contextThe term "amino" is used to denote-NH₂And (4) a base.

The term "aminoalkyl" as used herein, denotes an alkyl group, as defined herein, substituted with an amino group.

The term "aryl" as used herein denotes a monocyclic or bicyclic carbocyclic ring system containing one or two aromatic rings, examples of which are phenyl, naphthyl, 1, 2-dihydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl, fluorenyl, 2, 3-indanyl, indenyl, and the like, and may optionally be substituted with one, two, three, four or five substituents independently selected from: (1) alkanoyl having 1 to 6 carbon atoms; (2) an alkyl group having 1 to 6 carbon atoms; (3) alkoxy having 1 to 6 carbon atoms; (4) alkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (5) alkylsulfinyl having 1 to 6 carbon atoms; (6) alkylsulfinylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (7) alkylsulfonyl groups having 1 to 6 carbon atoms; (8) alkylsulfonylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (9) an aryl group; (10) arylalkyl, wherein the alkyl group has 1 to 6 carbon atoms; (11) an amino group; (12) aminoalkyl groups having 1 to 6 carbon atoms; (13) a heteroaryl group; (14) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (15) aroyl; (16) an azide group; (17) azidoalkyl groups having 1 to 6 carbon atoms; (18) a formaldehyde group; (19) (carboxaldehyde) alkyl wherein the alkylene has 1 to 6 carbon atoms; (20) cycloalkyl having 3 to 8 carbon atoms; (21) alkylcycloalkyl, wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms; (22) a halo group; (23) haloalkyl having 1 to 6 carbon atoms; (24) a heterocyclic group; (25) (heterocyclic) oxy; (26) (heterocyclic) acyl; (27) a hydroxyl group; (28) hydroxyalkyl having 1 to 6 carbon atoms; (29) a nitro group; (30) a nitroalkyl group having 1 to 6 carbon atoms; (31) an N-protected amino group; (32) n-protected aminoalkyl, wherein the alkylene has from 1 to 6 carbon atoms; (33) oxo; (34) thioalkoxy groups having 1 to 6 carbon atoms; (35) thioalkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (36) - (CH)₂)_qCO₂R^AWherein q is an integer of 0 to 4，R^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (37) - (CH)₂)_qCONR^BR^cWherein R is^BAnd R^cIndependently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (38) - (CH)₂)_qSO₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (39) - (CH)₂)_qSO₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; (40) - (CH)₂)_qNR^GR^HWherein R is^GAnd R^HEach independently selected from (a) hydrogen; (b) an N-protected group; (c) an alkyl group having 1 to 6 carbon atoms; (d) alkenyl having 2 to 6 carbon atoms; (e) alkynyl having 2 to 6 carbon atoms; (f) an aryl group; (g) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (h) cycloalkyl having 3 to 8 carbon atoms and (i) alkylcycloalkyl, wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms, provided that no two groups are attached to the nitrogen atom via a carbonyl or sulfonyl group; (41) oxo; (42) a thiol; (43) a perfluoroalkyl group; (44) a perfluoroalkoxy group; (45) an aryloxy group; (46) a cycloalkoxy group; (47) a cycloalkylalkoxy group; and (48) an arylalkoxy group.

The term "arylalkoxy" as used herein, means an alkylaryl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted arylalkoxy groups have 7 to 16 carbon atoms.

Unless otherwise indicated, the term "aryloxy" represents a chemical substituent of the formula-OR ', wherein R' is an aryl group having 6 to 18 carbon atoms.

The term "cancer" or "tumor cell" as used herein means a collection of cells that multiply in an abnormal manner. Cancer growth is uncontrolled and progressive, occurring without causing or causing cessation of normal cell proliferation.

The term "ascorbic acid" as used herein means ascorbic acid, the base form of ascorbic acid, or mixtures thereof. Non-limiting examples of the base form of ascorbic acid are sodium ascorbate, potassium ascorbate, calcium ascorbate and magnesium ascorbate. In a particular embodiment, ascorbic acid represents a 1: 1 mixture of ascorbic acid and sodium ascorbate.

The term "cycloalkyl" as used herein, unless otherwise specified, denotes a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon radical having 3 to 8 carbon atoms, examples of which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1 ] n]Heptyl, and the like. The cycloalkyl groups of the present invention may be optionally substituted with: (1) alkanoyl having 1 to 6 carbon atoms; (2) an alkyl group having 1 to 6 carbon atoms; (3) alkoxy having 1 to 6 carbon atoms; (4) alkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (5) alkylsulfinyl having 1 to 6 carbon atoms; (6) alkylsulfinylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (7) alkylsulfonyl groups having 1 to 6 carbon atoms; (8) alkylsulfonylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (9) an aryl group; (10) arylalkyl, wherein the alkyl group has 1 to 6 carbon atoms; (11) an amino group; (12) aminoalkyl groups having 1 to 6 carbon atoms; (13) an aryl group; (14) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (15) aroyl; (16) an azide group; (17) azidoalkyl groups having 1 to 6 carbon atoms; (18) a formaldehyde group; (19) (carboxaldehyde) alkyl wherein the alkylene has 1 to 6 carbon atoms; (20) cycloalkyl having 3 to 8 carbon atoms; (21) alkylcycloalkyl, wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms; (22) a halo group; (23) haloalkyl having 1 to 6 carbon atoms; (24) a heterocyclic group; (25) (heterocyclic) oxy; (26) (heterocyclic) acyl; (27) a hydroxyl group; (28) hydroxyalkyl having 1 to 6 carbon atoms; (29) a nitro group; (30) a nitroalkyl group having 1 to 6 carbon atoms; (31) an N-protected amino group; (32) n-protected aminoalkyl, wherein the alkylene has from 1 to 6 carbon atoms; (33) oxo; (34) thioalkoxy groups having 1 to 6 carbon atoms;(35) thioalkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (36) - (CH)₂)_qCO₂R^AWherein q is an integer of 0 to 4, R^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (37) - (CH)₂)_qCONR^BR^cWherein R is^BAnd R^cEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; (38) - (CH)₂)_qSO₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (39) - (CH)₂)_qSO₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; (40) - (CH)₂)_qNR^GR^HWherein R is^GAnd R^HEach independently selected from (a) hydrogen; (b) an N-protected group; (c) an alkyl group having 1 to 6 carbon atoms; (d) alkenyl having 2 to 6 carbon atoms; (e) alkynyl having 2 to 6 carbon atoms; (f) an aryl group; (g) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (h) cycloalkyl having 3 to 8 carbon atoms and (i) alkylcycloalkyl, wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms, provided that no two groups are attached to the nitrogen atom via a carbonyl or sulfonyl group; (41) oxo; (42) a thiol; (43) a perfluoroalkyl group; (44) a perfluoroalkoxy group; (45) an aryloxy group; (46) a cycloalkoxy group; (47) a cycloalkylalkoxy group; and (48) an arylalkoxy group.

"formulated for extended release" refers to a formulation that releases one or more active ingredients from a chemical matrix over a predetermined period of time when administered to a patient. Non-limiting examples of extended release formulations are controlled release, sustained release, timed release and delayed release formulations as well as long acting, transdermal or mucosal formulations.

By "antiproliferative agent" is meant an agent that slows or stops cell proliferation, such as any of the agents listed in table 1.

TABLE 1

Alkylating reagent	Busulfan medicine	Procarbazine
			Dacarbazine	Altretamine
	Isocyclophosphamide (ACS)	Estramustine phosphate
			Altretamine	Nitrogen mustard
	Thiotepa	Chain zotard
			Dacarbazine	Temozolomide
	Lomustine	Semustine
			Cyclophosphamide	Cis-platinum
	Chlorambucil
Platinum medicine	Spiroplatinum	Lobaplatin (Aeterna)
			Tetraplatin	Saplatium (Johnson Matthey)
	Oma platinum	BBR-3464(Hoffmann-La Roche)
			Iproplatin	SM-11355(Sumitomo)
	ZD-0473(AnorMED)	AP-5280(Access)
			Oxaliplatin
	Carboplatin
Antimetabolites	Azacytidine	Trimethotrexate
			Floxuridine	Deoxycefuroxime axetil
	2-Chlorodioxyadenosine	Pentostatin
			6-mercaptopurine	Hydroxyurea
	6-thioguanine	Decitabine (SuperGen)
			Cytarabine	Filfarabine (clofarabine) (Bioenvision)
	2-fluorodeoxycytidine	Ilovens (MGI Pharma)
			Methotrexate (MTX)	DMDC(Hoffmann-La Roche)
	Rubbing for obtaining	Alkyne cytidine (Taiho)
			Fludarabine	Gemcitabine
	Raltitrexed	Capecitabine
Topoisomerase inhibitors	Amsacrine	Ethanecane mesylate (Daiichi)
			Epirubicin	quinamed(ChemGenex)
	Etoposide	gimatecan(Sigma-Tau)
			Teniposide or mitoxantrone	diflomotecan(Beaufour-Ipsen)
	7-ethyl-10-hydroxy-camptothecin	TAS-103(Taiho)
			dexrazoxanet(TopoTarget)	Espressor (Spectrum)

Topoisomerase inhibitors	pixantrone(Novuspharma)	J-107088(Merck&Co)
			rebeccamycin analog (Exelixis)	BNP-1350(BioNumerik)
	BBR-3576(Novuspharma)	CKD-602(Chong Kun Dang)
			Rubitecan (SuperGen)	KW-2170(Kyowa Hakko)
	Irinotecan (CPT-11)	10-hydroxycamptothecin (SN-38)
			Topotecan
Antitumor antibiotics				Valrubicin	azonafide
	therarubicin	Anthracene pyrazole (anthrapyrazole)
			Idarubicin (Idarubicin)	oxantrazole
	Daunorubicin phenylhydrazone	Losoxantrone
			Precamycin	MEN-10755(Menarini)
	Pofilomycin	GPX-100(Gem Pharmaceuticals)
			Mitoxantrone (novantrone)	Epirubicin
	Amonafide (a. kan)	Mitoxantrone
				Doxorubicin
Antimitotic agents				Colchicine	E7010(Abbott)
	Vinblastine	PG-TXL(Cell Therapeutics)
			Vindesine	IDN 5109(Bayer)
	Dolastatin 10(NCI)	A 105972(Abbott)
			Rhizomycin (Fujisawa)	A 204197(Abbott)
	Rice-vobulin (Warner-Lambert)	LU 223651(BASF)
			Simadotin (BASF)	D 24851(ASTAMedica)
	RPR 109881A(Aventis)	ER-86526(Eisai)
			TXD 258(Aventis)	Combretastatin A4(BMS)
	epothilone B(Novartis)	isohomohalichondrin-B(PharmaMar)
			T 900607(Tularik)	ZD 6126(AstraZeneca)
	T 138067(Tularik)	AZ10992(Asahi)
			cryptophycin 52(Eli Lilly)	IDN-5109(Indena)
	Vinflunine (Fabre)	AVLB(Prescient NeuroPharma)
			auristatm PE(Teikoku Hormone)	azaepothilone B(BMS)
	BMS 247550(BMS)	BNP-7787(BioNumerik)
			BMS 184476(BMS)	CA-4 prodrug (OXIGENE)
	BMS 188797(BMS)	Dolastatin-10 (NIH)
			taxoprexin(Protarga)	CA-4(OXiGENE)
	SB 408075(GlaxoSmithKline)	Docetaxel
			Vinorelbine	Vincristine

Antimitotic agents		Paclitaxel
Aromatase amino inhibitors	Aminoglutethimide	YM-511(Yamanouchi)
			Astametam (BioMedicines)	Fumeitan
	Letrozole	Exemestane
			Anastrozole
Thymidylate synthase inhibitors				Pemetrexed (Eli Lilly)	Nolatrexed (exinias)
	ZD-9331(BTG)	CoFactorTM(BioKeys)
DNA antagonists	trabectedin(PharmaMar)	edotreotide(Novartis)
			Glufosfamide (Baxter International)	Horse phosphoramide (Baxter International)
	Albumin +32P (Isotrope solutions)	apaziquone(SpectrumPharmaceuticals)
			thymectacin(NewBiotics)
				O6 benzyl guanine (Paligent)
Farnesyl transferase inhibitors	arglabin(NuOncology Labs)				tipifarnib(Johnson & Johnson)
		lonafarnib(Schering-Plough)	Perilla alcohol (DOR BioPharma)
	BAY-43-9006(Bayer)
Pump inhibitors	CBT-1(CBA Pharma)				zosuquidar trihydrochloride (Eli Lilly)
		tariquidar(Xenova)	Bicifda dicitrate (Vertex)
	MS-209(Schering AG)
Histone acetyltransferase inhibitors	tacedinaline(Pfizer)				Pivaloyloxymethylbutyrate (Titan)
		SAHA(Aton Pharma)	Depsipeptide (Fujisawa)
	MS-275(Schering AG)
Metalloprotease inhibitors	New vastat (Aeterna Laboratories)				CMT-3(CollaGenex)
		Marimastat (British Biotcch)	BMS-275291(Celltcch)
Nucleoside reductase inhibitors				gallium maltolate(Titan)	tezacitabine(Aventis)
	triapine(Vion)	didox(Molecules for Health)
TNF alpha agonists/antagonists	Vilulizine (Lorus Therapeutics)	revimd(Celgene)
			CDC-394(Celgene)
Endothelin A receptor antagonists				Atrasentan (Abbott)	YM-598(Yamanouchi)

Endothelin A receptor antagonists	ZD-4054(AstraZeneca)
Vitamin A acid receptor agonists	Fenretinide (John)son & Johnson)	Aliwei A acid (Ligand)
			LGD-1550(Ligand)
Immunomodulator				Interferon	Dexosome therapeutic agents (Anosys)
	oncophage(Antigenics)	pentrix(Australian cancerTechnology)
			GMK(Progenics)
	Adenocarcinoma vaccine (Biomira)			ISF-154(Tragen)
		CTP-37(AVl BioPharma)	Cancer vaccine (Intercell)
	IRX-2(Immuno-Rx)			norelin(Biostar)
		PEP-005(Peplin Biotech)	BLP-25(Biomira)
	Synchrovax vaccine (CTL Immuno)			MGV(Progenies)
		Melanoma vaccine (CTL Immuno)	β-alethine(Dovetail)
	P21RAS vaccine (GemVax)			CLL therapeutic agent (Vasogen)
Hormones and anti-hormonal agents	Estrogen				Dexamethasone
		Conjugated estrogens	Prednisone
	Ethinyl estradiol			Methylprednisolone
		Clorenyl estrel ether	Prednisolone
	idenestrol			Aminoglutethimide
		Hydroxyprogesterone caproate	Liangpropilides for treating leukemia
	Medroxyprogesterone			Octreotide
		Testosterone	Mitotane (TM)
	Testosterone propionate;			P-04(Novogen)
		fluoromethyltestosterone	2-methoxyestradiol (EntreMed)
	Methandienone			Arzoxifene (Eli Lilly)
		Diethylstilbestrol	Tamoxifen
	Megestrol			Toremifene
		Bicalutamide	Goserelin
	Flutamide			Leuprorelin
		Nilutamide (I) salt	Bicalutamide
Photodynamic medicine				Talaporfin (Light Sciences)	Pd-bacteriopheophorbide(Yeda)
	Theralux(Theratechnologies)	lutetium texaphyrin(Pharmacyclics)
			Motesafen rolling (Pharmacyclics)	Hypericin and its preparation method
Kinase inhibitors				Imatinib (Novartis)	EKB-569(Wyeth)

Kinase inhibitors	Leflunomide (Sugen/Pharmacia)	kahalide F(PharmaMar)
			ZD1839(AstraZeneca)	CEP-701(Cephalon)
	erlotinib(Oncogene Science)	CEP-751(Cephalon)
			canertinib(Pfizer)	MLN518(Millenium)
	Squalamine (Genaera)	PKC412(Novartis)
			SU5416(Pharmacia)	Phenoxodiol(Novogen)
	SU6668(Pharmacia)	C225(ImClone)
			ZD4190(AstraZeneca)	rhu-Mab(Genentech)
	ZD6474(AstraZeneca)	MDX-H210(Medarex)
			vatalanib(Novartis)	2C4(Genentech)
	PKI166(Novartis)	MDX-447(Medarex)
			GW2016(GlaxoSmithKline)	ABX-EGF(Abgenix)
	EKB-509(Wyeth)	IMC-1C11(ImClone)
			Trastuzumab (Genentech)	Tyrosine phosphorylation inhibitors
		Gefitinib(Iressa)

TABLE 1 (continuation)

Mixed medicine
		SR-27897(CCK A inhibitor, Sanofi-Synthelabo)	ceflatatin (apoptosis promoter, ChemGenex)
Toradipin (Cyclic AMP agonists, Ribapharm)	BCX-1777(PNP inhibitor, BioCryst)
		alvocidib (CDK inhibitor, Aventis)	Ranpirnase (ribonuclease stimulant, Alfacell)
CV-247(COX-2 inhibitor, Ivy Medical)	Garubicin (RNA synthesis inhibitor, Dong-A)
		P54(COX-2 inhibitor, Phytopharm)	Tirapazamine (Reductant, SRI International)
CapCellTM(CYP450 excitation)Agent, Bavarian Nordic)	N-acetyl cysteine (reducing agent, Zambon)
		GCS-100(gal3 antagonist, GlycoGenesys)	R-flurbiprofen (NF-kappa B inhibitor, Encore)
G17DT immunogen (gastrin inhibitor, Aphton)	3CPA (NF-kappa B inhibitor, Active Biotech)
		cfaproxiral(oxyenator，Allos Therapeutics)	Seocalcitol (vitamin D receptor agonist, Leo)
PI-88 (heparanase inhibitor, Progen)	131-1-TM-601(DNA antagonist, Transmolecular)
		Tilmicofin (histamine antagonist, YMBioSciences)	Ifluornithine (ODC inhibitor, ILEX Oncology)
Minodronic acid (osteoplast inhibitor, Yamanouchi)
	Histamine (Histamine H)2Receptor agonists, Maxim)
		indisula (p53 stimulant, Eisai)
Thiazole furlin (IMPDH inhibitor Ribapharm)			aplidine (PPT inhibitor, PharmaMar)
	Cilengitide (integrin antagonist, Merck KGaA)	Giemmab (CD33 antibody, Wyeth Ayerst)
SR-31747(IL-1 antagonist, Sanofi-Synthelabo)			PG2 (hematopoiesis promoter, Pharmagenetics)
	CCI-779(mTOR kinase inhibitor, Wyeth)	ImmunolTM(triclosan mouthwash, Endo)

Exishulin (PDE V inhibitor, Cell Pathways)	Triacetyl uridine (uridine prodrug, Wellstat)
		CP-461(PDE V inhibitor, Cell Pathways)	SN-4071 (sarcoma medicine, Signature BioScience)
AG-2037(GART inhibitor, Pfizer)	TransMID-107TM(immunotoxin, KS Biomedix)
		WX-UK1 (plasminogen activator inhibitor, Wilex)	PCK-3145 (apoptosis promoting)Advances, Procyon)
doranidazole (apoptosis-promoting agent, Pola)
	PBI-1402(PMN agonists, ProMeticicLifeSciences)		CHS-828 (cytotoxic drug, Leo)
Trans-retinoic acid (NIH)
		bortezomib (proteasome inhibitor, Millennium)	MX6 (apoptosis promoter, MAXIA)
SRL-172(T cell agonist, SR Pharma)	apomine (apoptosis promoter, ILEX Oncology)
		TLK-286 (glutathione S transferase inhibitor, Telik)	urocidin (apoptosis promoter, Bioniche)
Ro-31-7453 (apoptosis promoter, La Roche)
	PT-100 (growth factor agonist, PointTherapeutics)		Brostaticin (apoptosis promoter, Pharmacia)
		Midostaurin (PKC inhibitor, Novartis)
Bryostatin-1 (PKC agonist, GPC Biotech)
		CDA-II (apoptosis promoter, Everlife)
SDX-101 (apoptosis promoter, Salmedix)
		Rituximab (CD20 antibody, Genentech)

The term "halide" or "halogen" or "halo" as used herein means bromine, chlorine, iodine or fluorine.

The term "heterocycle" or "heterocyclyl" as used herein, alternatively, unless otherwise specified, means a 5-, 6-or 7-membered ring containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has 0-2 double bonds, and the 6-and 7-membered rings have 0-3 double bonds. The term "heterocycle" also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above-described heterocycles are fused to one or two rings independently selected from an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocycle (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, benzofuranyl, benzothienyl, and the like). Heterocycles include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindolyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, pyrimidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyranyl, dihydropyranyl, dithiazolyl, morpholinyl, thiazolinyl, and the like, Benzofuranyl, benzothienyl, and the like. Heterocyclyl also includes compounds of the formula:

wherein

F' is selected from-CH₂-、-CH₂O-and-O-, G ' is selected from the group consisting of-C (O) -and- (C (R ') (R ')_v-, where R 'and R' are each independently selected from hydrogen or an alkyl group having 1 to 4 carbon atoms, and v is 1 to 3, and includes various groups such as 1, 3-benzodioxolyl, 1, 4-benzodioxane, and the like. Any of the heterocyclyl groups described herein may be optionally substituted with one, two, three, four or five substituents independently selected from: (1) alkanoyl having 1 to 6 carbon atoms; (2) an alkyl group having 1 to 6 carbon atoms; (3) alkoxy having 1 to 6 carbon atoms; (4) alkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (5) alkylsulfinyl having 1 to 6 carbon atoms; (6) alkylsulfinylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (7) alkylsulfonyl groups having 1 to 6 carbon atoms; (8) alkylsulfonylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (9) an aryl group; (10) arylalkyl, wherein the alkyl group has 1 to 6 carbon atoms; (11) an amino group; (12) aminoalkyl groups having 1 to 6 carbon atoms; (13) a heteroaryl group; (14) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (15) aroyl; (16) an azide group; (17) azidoalkanes having 1 to 6 carbon atomsA group; (18) a formaldehyde group; (19) (carboxaldehyde) alkyl wherein the alkylene has 1 to 6 carbon atoms; (20) cycloalkyl having 3 to 8 carbon atoms; (21) cycloalkylalkyl, wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms; (22) a halo group; (23) haloalkyl having 1 to 6 carbon atoms; (24) a heterocycle; (25) (heterocyclic) oxy; (26) (heterocyclic) acyl; (27) a hydroxyl group; (28) hydroxyalkyl having 1 to 6 carbon atoms; (29) a nitro group; (30) a nitroalkyl group having 1 to 6 carbon atoms; (31) an N-protected amino group; (32) n-protected aminoalkyl, wherein the alkylene has from 1 to 6 carbon atoms; (33) oxo; (34) thioalkoxy groups having 1 to 6 carbon atoms; (35) thioalkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (36) - (CH)₂)_qCO₂R^AWherein q is an integer of 0 to 4, R^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (37) - (CH)₂)_qCONR^BR^cWherein R is^BAnd R^cEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; (38) - (CH)₂)_qSO₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (39) - (CH)₂)_qSO₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; (40) - (CH)₂)_qNR^GR^HWherein R is^GAnd R^HEach independently selected from (a) hydrogen; (b) an N-protected group; (c) an alkyl group having 1 to 6 carbon atoms; (d) alkenyl having 2 to 6 carbon atoms; (e) alkynyl having 2 to 6 carbon atoms; (f) an aryl group; (g) alkaryl, wherein the alkylene has from 1 to 6 carbon atoms; (h) cycloalkyl having 3 to 8 carbon atoms and (i) cycloalkylalkyl, wherein cycloalkyl has 3 to 8 carbon atoms and alkylene has 1 to 10 carbon atoms, with the proviso that no two groups are linked to the nitrogen atom through a carbonyl or sulfonyl group; (41) oxo; (42) a thiol; (43) a perfluoroalkyl group; (44) a perfluoroalkoxy group; (45) aromatic hydrocarbonAn oxy group; (46) a cycloalkoxy group; (47) a cycloalkylalkoxy group; and (48) an arylalkoxy group.

The term "hydroxy" as used herein denotes an-OH group.

By "inhibiting the growth of a tumor" is meant slowing, stopping or reversing the growth rate of the tumor or tumor cells, as appropriate, in vitro or in vivo. Preferably, the growth rate is slowed by at least 20%, 30%, 50% or even 70%, as determined using a suitable assay to determine the cell growth rate (e.g., the cell growth assay described herein). Reversal of growth rate is usually achieved by necrotic or apoptotic mechanisms that initiate or accelerate cell death in tumor cells, resulting in tumor shrinkage.

By "infusion rate" is meant that the infusion rate of an active agent (e.g., a compound of formula I or II) in a composition varies by no more than 25% plus or minus the average infusion rate of the active agent over an extended period of time (e.g., over 12 hours).

"physiological saline" refers to a solution of sodium chloride having the same electrolyte balance as serum. The physiological saline solution was a 0.9% by weight aqueous sodium chloride solution. The semi-physiological aqueous salt solution was a 0.45% by weight aqueous sodium chloride solution.

The term "pharmaceutically acceptable salts" as used herein means those salts within the scope of sound medical judgment (sound medical judgment) that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, s.m.berge et al, in j.pharmaceutical Sciences 66: pharmaceutically acceptable salts are described in detail in 1-19, 1977. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reaction of the free basic groups with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, sulfate, salicylate, and mixtures thereof, Phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, valerates, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term "pharmaceutically acceptable prodrugs" as used herein means those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for the intended use and where possible, in zwitterionic form.

The term "prodrug" as used herein denotes a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. Prodrugs of the compounds of the present invention may be conventional esters. Some common esters used as prodrugs are phenyl esters, aliphatic (C)₈-C₂₄) Esters, acyloxymethyl esters, carbamates, and amino acid esters. For example, a prodrug form of a compound of the invention containing an OH group is acylated at this position. A more detailed discussion is described in T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14, the A.C.S.Symphosium Series, Edward B.Roche editions, Bioreversible Carriers in Drug DesignReverse vectors), the Synthetic Communications 26(23) of the American Pharmaceutical Association and Pergamon Press, 1987 and Judkins et al: 4351-4367, 1996, each of which is incorporated herein by reference.

"significant degree of sedation" refers to the amount of sedation that prevents the subject being treated from performing routine activities such as walking, talking, and eating.

Brief description of the drawings

Figure 1 illustrates the comparison of the observed serum plasma concentrations of the components of the chlorpromazine/pentamidine composition when the composition was administered by continuous infusion versus intraperitoneal bolus injection in a mouse tumor model study.

FIG. 2 illustrates the inhibition of tumor growth when the chlorpromazine/pentamidine composition is administered by intraperitoneal bolus injection or continuous infusion in a mouse tumor model study.

Figure 3 illustrates the reduction in weight of mice treated with a continuous infusion of a chlorpromazine/pentamidine composition versus intraperitoneal bolus injection of the chlorpromazine/pentamidine composition.

Detailed Description

Synergistic combinations of phenothiazines and antifungal/antiprotozoal drugs have been described as effective in inhibiting tumor growth (see U.S. patent application publication 20040116407). The invention features compositions of phenothiazine of formula I and/or an antifungal/antiprotozoal compound of formula II, wherein the compositions are formulated to maintain plasma levels of these compounds such that tumor growth in a treated patient is effectively inhibited. In addition to the side effects that may be reduced by administration of phenothiazine contained in those compositions, the compositions also have an improved safety profile.

Accordingly, in a first aspect, the invention features a composition formulated to maintain plasma levels of a compound of formula I at 0.3ng/ml (about 1.0 nanomolar) to 3.5 μ g/ml (about 10 micromolar) and/or plasma levels of a compound of formula II at 0.2ng/ml (about 1.0 nanomolar) to 2.5 μ g/ml (about 10 micromolar) for at least 12 hours in a subject being treated, wherein the compound of formula I is a compound of formula:

wherein

R¹、R³、R⁴、R⁵、R⁶、R⁷And R⁸Each independently is H, OH, F, OCF₃Or OCH₃；

R²Selected from CF₃Halogen radical, OCH₃、COCH₃、CN、OCF₃、COCH₂CH₃、CO(CH₂)₂CH₃And SCH₂CH₃；

R⁹Is selected from

R⁹Has the following structure:

wherein n is 0 or 1; z is NR³⁴R³⁵OR OR³⁶；R³¹、R³²、R³³、R³⁴、R³⁵And R³⁶Each independently is H, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl, C_2-6Heterocyclic group, C_6-12Aryl radical, C_7-14Alkylaryl group, C_3-10Alkylheterocyclyl, acyl or C_1-7A heteroalkyl group; or R³²、R³³、R³⁴、R³⁵And R³⁶Any of which may optionally form together with the intervening carbon or non-adjacent O, S or N atom one or more 5-to 7-membered rings optionally substituted with: H. halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_2-6Heterocyclic group, C_6-12Aryl radical, C_7-14Alkylaryl group, C_3-10Alkylheterocyclyl, acyl or C_1-7A heteroalkyl group; and

w is selected from

The compound of formula II is a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof,

wherein

A is

Wherein

X and Y are each independently O, NR¹⁹Or S, R¹⁴And R¹⁹Each independently is H or C_1-6Alkyl radical, R¹⁵、R¹⁶、R¹⁷And R¹⁸Each independently is H, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,Halogen, C_1-6Alkoxy radical, C_6-18Aryloxy radical or C_6-18aryl-C_1-6Alkoxy, p is an integer from 2 to 6;

m and n are each independently an integer of 0 to 2;

R¹⁰and R¹¹Are each independently

Wherein

R²¹Is H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl or C_6-18An aryl group; r²²Is H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl, carbonyl (C)_1-6Alkoxy), carbonyl (C)_6-18aryl-C_1-6Alkoxy), carbonyl (C)_6-18Aryloxy) or C_6-C18An aryl group; r²²Is H, OH or C_1-6Alkoxy, or R²⁰And R²¹Together represent

Wherein R is²³、R²⁴And R²⁵Each independently is H, C_1-6Alkyl, halogen or trifluoromethyl, R²⁶、R²⁷、R²⁸And R²⁹Each independently is H or C_1-6Alkyl radical, R³⁰Is H, halogen, trifluoromethyl, OCF₃、NO₂、C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl or C_6-18An aryl group; and

R¹²and R¹³Each independently is H, Cl, Br, OH, OCH₃、OCF₃、NO₂And NH₂Or R is¹²And R¹³Together form a single bond.

In one embodiment, the compound of formula I is chlorpromazine and the compound of formula II is pentamidine.

In another embodiment, the compound of formula I has a plasma level of 0.3 μ g/ml to 3.5 μ g/ml and/or the compound of formula II has a plasma level of 0.2 μ g/ml to 2.5 μ g/ml. In another embodiment, the plasma level of the compound of formula I is from 10ng/ml to 1 μ g/ml and/or the plasma level of the compound of formula II is from 10ng/ml to 1 μ g/ml. In yet another embodiment, the compound of formula I has a plasma level of 0.5 μ g/ml to 3.5 μ g/ml and/or the compound of formula II has a plasma level of 0.5 μ g/ml to 2.5 μ g/ml. The plasma level can be maintained for more than 12 hours, more than 24 hours, more than 3 days, more than 7 days, more than 14 days, more than 28 days or more than 6 months.

Preparation

The compositions of the present invention are formulated for delivery to a human patient such that the plasma level of the active ingredient is maintained at a predetermined level for a predetermined period of time. Methods for achieving extended release in accordance with conventional pharmaceutical practice are known in the art, see for example Remington: the Science and practice of Pharmacy, 20 th edition, 2000, edition A.R. Gennaro, edition Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of pharmaceutical Technology, J.Swarbrick and J.C. Boylan edition, 1988. supplement 1999, Marcel Dekker, New York.

A specific composition of the invention comprises chlorpromazine as the compound of formula I and pentamidine as the compound of formula II.

Non-limiting examples of suitable weight ratios of pentamidine/chlorpromazine are from 2: 1 to 4: 1, and include pentamidine/chlorpromazine ratios of 2: 1, 2.25: 1, 2.5: 1, 2.75: 1, 3: 1, 3.25: 1, 3.5: 1, 3.75: 1, and 4: 1. The composition components may be formulated separately or together. In one embodiment, the components of the composition are formulated together as a lyophilized powder. In another embodiment, the components of the composition are formulated separately, reconstituted and then combined.

Suitable excipients are known to those skilled in the art and are described in Remington, vide supra. In one embodiment, the composition comprises ascorbic acid (each from 1 wt% to 10 wt%, preferably from 2 wt% to 4 wt%). In another embodiment, the composition comprises mannitol (3% by weight to 30% by weight). In a further embodiment, the composition comprises ascorbic acid and mannitol, said composition comprising various such excipients in the above defined% weight range.

The solid formulation may be reconstituted in a suitable liquid (e.g., 1% by weight to 10% by weight dextrose solution or saline at semi-standard or standard concentrations) to form a composition of the present invention wherein the final concentration of the various active ingredients of the composition (i.e., the compounds of formulas I and II) is from about 0.005% by weight to 0.5% by weight.

Table 2 provides non-limiting examples of various components of the composition of the present invention, wherein the composition comprises chlorpromazine and pentamidine, and optionally comprises ascorbic acid and/or mannitol as excipients. Each formulation was dissolved in about 100ml to 500ml of standard saline or 5% by weight glucose to form a composition.

TABLE 2

Number (C)	The amounts of the components contained in one vial
						Chlorpromazine hydrochloride	Pentamidine isethionate	Ascorbic acid sodium salt	Ascorbic acid	Mannitol
	F1	50 mg/vial	120 mg/vial	2.5 mg/vial	2.5 mg/vial						43.7 mg/vial
F3						50 mg/vial	120 mg/vial	2.5 mg/vial	2.5 mg/vial
	F5	50 mg/vial	120 mg/vial								55 mg/vial
F6						50 mg/vial	200 mg/vial			21 mg/vial
	F7	50 mg/vial	120 mg/vial
F8						50 mg/vial	200 mg/vial

Administration of drugs

The compositions of the present invention may be administered in any suitable manner that results in a concentration of the active agent that is antitumor when the targeted area is reached. The compound may be contained in any suitable carrier material in any suitable amount. The composition may be administered in a dosage form suitable for: oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, nasal, vaginal, inhalation, dermal (plaque) or ocular routes of administration. Thus, the composition may be provided in a dosage form suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, intradermal, nasal, vaginal, inhalation, dermal (patch) or ocular routes of administration. Thus, the composition may be in the form of, for example, a tablet, capsule, pill, powder, granule, suspension, emulsion, solution, gel including hydrogel, paste, ointment, cream, plaster, infusion, isotonic drug delivery device, suppository, enema, injection, implant, spray or aerosol.

The compositions may be advantageously formulated for extended release by various methods. Two common methods include: 1) providing an extended release coating on the tablets or microspheres, wherein the active ingredient is slowly released by gradual permeation through or gradual disintegration of the coating; and 2) providing an extended release matrix, such as a fat, wax or polymeric material mixed with the active ingredient in the tablet itself. These substances are described, for example, in The Theory and Practice of Industrial pharmacy, Manual Robinson, chapter 14, edited by "Sustaned Action Dosage Forms" L.Lachman et al, published by Lea & Febiger, 2 nd edition, 1976.

Examples of the former approach include the use of osmotic devices known to controllably release a wide range of drugs. Known devices include tablets, troches, pills, capsules, or the like, and typically include a layer comprising one or more materials that erode or slowly dissolve in the environment of use, thereby gradually dispersing the active agent. Us patent 4,014,334 describes an osmotic device for controlled and continuous delivery of a drug, wherein the device comprises: a) a core comprising a drug and an osmotic agent; b) a semipermeable laminate surrounding the core comprising a semipermeable outer sheet and a semipermeable inner sheet; and c) a channel communicating the core with the exterior of the device. The two semi-permeable sheets maintain their chemical and physical integrity in the presence of the drug and fluids from the environment. The passageway comprises a hole through the laminate formed by mechanical means or by erosion of an erodable element (e.g., a gelatin plug) in the environment of use. Other similar osmotic devices are described in U.S. Pat. Nos. 3,845,770, 4,576,604, and 4,673,405. Us patent 5,558,879 describes a controlled release tablet of a water-soluble drug in which a passageway is formed in the environment of use, i.e. the gastrointestinal tract of the person receiving the formulation. More specifically, the controlled release tablet consists essentially of: a) a core comprising a drug, 5-20% by weight of a water-soluble osmotic agent, a water-soluble polymeric binder, and a drug carrier; and b) a bilayer film coating surrounding the core and consisting essentially of: (1) an internal delayed release coating comprising a plasticized water insoluble polymer and a water soluble polymer; and (2) an outer immediate release coating comprising a drug and a water soluble polymer. Us patent 4,810,502 describes an osmotic dosage form for delivery of pseudoephedrine (Ps) and brompheniramine (Br), which dosage form comprises: a) a core comprising Ps and Br; b) a wall surrounding the core comprising cellulose acylate and hydroxypropyl cellulose; c) a channel within the wall for delivering the drug; and d) a thin layer on the outside of the wall comprising Ps, Br, at least one of hydroxypropyl cellulose and hydroxypropyl methylcellulose, and poly (ethylene oxide) for improving the mechanical integrity and pharmacokinetics of the wall. U.S. patent 4,801,461 also describes an osmotic dosage form for the delivery of pseudoephedrine (Ps). More specifically, the osmotic dosage form comprises: a) a core comprising various amounts of Ps; b) a semipermeable wall surrounding the core comprising varying amounts of cellulose acetate or cellulose triacetate and varying amounts of hydroxypropyl cellulose; c) a channel within the wall for delivering the drug from the core; and optionally d) a thin layer comprising Ps on the outside of the wall. The core may further comprise one or more of sodium chloride, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate, and poly (vinyl pyrrolidone). The channels of the device may extend through the semipermeable wall alone or through both the semipermeable wall and the outer sheet. The channel also contains material that erodes or leaches (leach) under the use environment. Us patent 5,681,584 describes a controlled release drug delivery device comprising: a) a core comprising a drug, an optional osmotic agent, and an optional excipient; b) a delayed release interlayer surrounding the core comprising at least one binder, osmotic agent, and lubricant; c) a semipermeable membrane surrounding the delayed release jacket and optionally containing channels; d) a drug-containing layer outside the semipermeable membrane or between the semipermeable membrane and the delayed-release jacket; and e) an optional enteric coating outside the drug-containing layer, between the drug-containing layer and the semipermeable membrane, or outside the semipermeable membrane, when the drug-containing layer is positioned between the delayed-release jacket and the semipermeable membrane. U.S. Pat. No. 6,004,582 discloses an osmotic device similar to that described above containing a polymer coating of a water-soluble (vinyl pyrrolidone) - (vinyl acetate) copolymer between a semipermeable membrane and a layer containing a drug.

Examples of delayed release matrix formulations for use in the compositions of the present invention are those disclosed in U.S. patent 4,259,314, which describes a mixture of cellulose ether-hydroxypropyl methylcellulose ("HPMC") and hydroxypropyl cellulose to form an extended release matrix, wherein the cellulose ether mixture has a weight average viscosity (250-4500); us patent 5,451,409 describes a dry blended tablet wherein a mixture of hydroxypropyl cellulose and hydroxyethyl cellulose forms a delayed release matrix to which 0.5-10% HPMC is also added as a binder; and U.S. patent 4,369,172; 4,389,393 and 4,983,396, which use HPMC in various delayed release formulations.

Other examples of useful delayed release formulations include those disclosed in U.S. patent 6,586,005, which describes a delayed release formulation of etodolac for once daily administration; us patent 6,509,037 and 6,312,724 describe a delayed release formulation of diclofenac for once daily administration; us patent 6,372,252 describes a delayed release formulation of guaifenesin administered twice daily. Other useful delayed release formulations are described in U.S. Pat. nos. 3,916,899, 3,536,809, 3,598,123, 4,008,719, 4,710,384, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566.

For transdermal preparations, penetration enhancers may be used, such as glycolipids, non-esterified fatty acids, aliphatic alcohols, fatty acid esters of aliphatic alcohols, cyclohexanols, fatty acids, glycerides, glycols or aliphatic alcohol ethers. Other components such as stabilizers, solubilizers, surfactants, and plasticizers may be present in the transdermal device (see, e.g., U.S. patent application 20020127254).

Polymers have been used as therapeutic drug carriers to affect extended release. See, e.g., Leong et al, "Polymeric Controlled Drug Delivery", Advanced Drug Delivery Rev.1: 199-; langer, "new methods of Drug Delivery", Science 249: 1527-33, 1990; and Chien et al, Novel Drug Delivery Systems, 1982. These delivery systems can improve therapeutic efficiency and reduce overall toxicity. Examples of synthetic polymers that have been investigated as solid Biodegradable materials include Polyesters (Pitt et al, "Biodegradable Drug Delivery Systems Based on organic Polyesters: Applications to protective and Narcotic Antagonists (Aliphatic polyester-Based Biodegradable Drug Delivery Systems: Antagonists for contraception and anesthesia)," controlled release of bioactive materials, 19-44, Richard Baker edition, 1980); poly (amino acids) and pseudo-poly (amino acids) (Pulapura et al, "Trends in the Development of bioresorbable Polymers for Medical Applications", J.biomaterials application.6 (3): 216-50, 1992); polyurethanes (Bruin et al, "Biodegradable Lysine Diisocyanate-based Poly (Glycolide-epsilon-caprolactone) copolymer-polyurethane Network in Artificial skin," Biomaterials 11 (4): 291-95, 1990); polyorthoesters (Heller et al, "Release of Norethindrone from Poly (OrthoEsters) (Release of Normandiprone from polyorthoester)", Polymer Engineering Sci.21 (11): 727-31, 1981); and Polyanhydrides (Leong et al, "Polyanhydrides for Controlled release of Bioactive Agents", Biomaterials7 (5): 364-71, 1986).

Biodegradable block polymers suitable for use in the compositions of the invention for drug delivery and methods for their preparation are described in Kumar et al, adv. 23-44, 2001. The copolymers may be random, alternating or block (diblock or triblock), and may be linear or star or graft (comb) in configuration. The polymers can form hydrogels, which are three-dimensional hydrophilic polymer networks that hold large amounts of aqueous fluids. The polymers used in the hydrogels are rendered insoluble by crosslinking or other chemical addition.

Microparticles may be formed from polymeric microspheres encapsulating the composition of the present invention. Polymers for the microspheres include poly (lactic acid) or PLA; poly (glycolic acid) or PGA; and the copolymer PLA-PGA. The amount of active agent of the composition of the invention is released in a graded manner, e.g. by a burst of drug initially bound non-specifically to the outside of the particle, diffusion at a later stage, and erosion at a final stage controlled by the polymer composition, molecular weight, particle size and physiological conditions such as pH. Can be prepared from supercritical fluid such as supercritical carbon dioxide (scCO)₂) Microspheres were prepared.

The biodegradable implant can be prepared, for example, from at least one material selected from the group consisting of: starch; vinyl starch; dipropylene glycol diacrylate (DPGDA); tripropylene glycol diacrylate (TPGDA); pectin; cellulose acetate; cellulose propionate; cellulose acetate butyrate; cellulose Acetate Propionate (CAP); hydroxypropyl cellulose (HPC); hydroxypropyl cellulose/cellulose acetate propionate (HPC/CAP); methyl Methacrylate (MMA); butyl Methacrylate (BMA); hydroxymethyl methacrylate (HEMA); ethylhexyl acrylate (EHA); octadecyl methacrylate (ODMA); and Ethylene Glycol Dimethacrylate (EGDMA). See Gil et al, Boletim de biothenologic 72: 13-19, 2002.

In addition to various polymers, naturally occurring and synthetic lipids are useful in delayed release formulations. Depofoam^TM(Skye Pharma, London, England) form particles based on multivesicular lipids (liposomes) for encapsulating therapeutic drugs (see us patent 5,993,850; and Ye et al, j.controlled rel.64: 155-166, 2000). The lipid is an amphiphilic, sterol or zwitterionic lipid having a net negative charge, and the method for preparing the liposome is non-acidic.

Other lipids may also be used in the liposomes of the delayed release formulation. Plant polar lipids (e.g., wheat ceramide) are used to form gels with proteins (e.g., prolamines) in which one or more therapeutic agents can be placed for transdermal or transmucosal delivery (see, e.g., U.S. patent 6,410,048). Exemplary prolamines include gliadin and zein. Other naturally occurring polymers useful in delayed release pharmaceutical formulations and devices include collagen (EP-A-O621044), chitin (U.S. Pat. No. 4,393,373), and chitosan (in ｃA deacylated form of chitin).

Lipids and various types of polymers can also be used to form "nanoparticles" for delivery of the compositions of the invention (see Kumar J. pharm. Pharmaceut. Sci.3: 234-258, 20002).

Any of the compositions of the present invention can be formulated to be delivered by mechanical means to deliver the formulation over an extended period of time. The device may for example be a degradable implant; transdermal patches; a conduit; an implantable pump; a transdermal pump; an infusion pump; or an iontophoresis device. The mechanical delivery device may be used alone or in combination with a formulation for controlled, sustained, timed, delayed or extended release.

Infusion pumps are well known to those skilled in the art, see, for example, Burtles, "ContinuousInfusion Of Drugs: a Simple And Rational System for continuous infusion of drugs "Journal of cardio And Vascularnesthesia 5 (4): 362-364, 1991; and Tilden and Hopkins, "clinical Of Infusion Rates Of Vasoactive substations (calculation Of Infusion rate Of Substances acting on blood vessels)" Annals Of Emergeney Medicine 12: 697-99, 1983.

Implantable or non-implantable (external) other pumps for delivering the compositions of the invention include peristaltic pumps, fluorocarbon propellant pumps, or osmotic pumps including mini osmotic pumps. Peristaltic pumps deliver a fixed amount of the composition with each electrical pulse driving the pump head. The pump, electronics and energy source are located in a titanium housing that covers the silicone rubber. The composition reservoir is a silicone rubber bag that can withstand a substantial pressure (e.g., 60 psi). The stock solution can be refilled percutaneously through a polypropylene hole. Fluorocarbon pumps use fluorocarbon liquids to run the pump. Osmotic pumps use osmotic pressure to release drugs at a constant rate. An exemplary pump is a MiniMed micromd 407C pump (Medtronic, inc., Northridge, Calif.). In addition, an intrathecal drug delivery system (Medronic) containing two implantable components, an infusion pump and an intraspinal catheter, may be used. The pump is inserted into the subcutaneous pocket of the abdomen and the catheter is inserted into the sheath of the spine, opening a channel in the skin and connecting to the pump. The compositions of the invention may then be delivered at a constant or variable flow rate.

Examples

Adult SCID Hsd at 6-8 weeks of age was used: ICR9 CD-1 mice (Harlan, Indianapolis, IN) were subjected to animal experiments. About 1X 10⁶Was injected subcutaneously into the left and right flank of each animal with HCT116 or a549 human tumor cells (obtained directly from ATCC). Monitoring the growth of the tumor in the animal when the tumor volume reaches about 500mm³At times, animals were randomized into treatment groups (n-10).

The composition of chlorpromazine/pentamidine (CRx-026) in a 1: 2 weight ratio was administered as an intraperitoneal bolus injection in 5% glucose for two weeks at concentrations of 0.97mg/ml and 1.87mg/ml, respectively, or by an intraperitoneal implanted ALZET osmotic mini-pump in 5% glucose solution containing 10% ethanol for two weeks at concentrations of 23mg/ml and 44mg/ml, respectively. The amounts administered by each method were 5mg chlorpromazine/kg body weight and 10mg pentamidine/kg body weight.

During the course of treatmentTumors were measured three times a week using calipers. Tumor volume was calculated using the following formula: (Length X (Width)²/2). Blood and tumor tissue are extracted after the medicine is taken for 30 minutes to 24 hours. The concentration of CRx-026 component was determined by HPLC-MS-MS. Analysis of the atrioventricular model (Noncompartmental) was performed using WinNonlin 4.1.

As shown in FIG. 1, continuous infusion of the chlorpromazine/pentamidine composition resulted in a systemic serum exposure (systemic serum exposure) comparable to that observed with bolus i.v. administration. The pharmacokinetic parameters of the continuous infusion compositions are shown in table 3.

TABLE 3

Components	Serum Steady State (ng/ml)		Tumor homeostasis (ng/g)
					Average	SD	Average	SD
	Chlorpromazine	13.4	3.9	95.5					41.2
Pentamidine					83.7	252	848.2	443.2

As shown in figure 2, tumor volume decreased by 58% after 12 days of continuous infusion with the composition compared to vehicle treated animals (controls), comparable to the effect of decreased tumor growth observed with daily intraperitoneal administration of the composition. Furthermore, as illustrated in figure 3, administration of the composition by continuous infusion results in an improved safety profile, as evidenced by the reduction in body weight of treated animals compared to those animals given a bolus injection of the composition.

Other embodiments

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Having thus described the above invention in greater detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (77)

1. A method of treating a tumor in a human patient, comprising administering a composition comprising a compound of formula I and a compound of formula II, wherein a first plasma level of the compound of formula I is maintained between 0.3ng/ml and 3.5 μ g/ml and a second plasma level of the compound of formula II is maintained between 0.2ng/ml and 2.5 μ g/ml for at least 12 hours, wherein the compound of formula I is a compound of formula:

wherein

R¹、R³、R⁴、R⁵、R⁶、R⁷And R⁸Each independently is H, OH, F, OCF₃Or OCH₃；

R²Selected from CF₃Halogen radical, OCH₃、COCH₃、CN、OCF₃、COCH₂CH₃、CO(CH₂)₂CH₃And SCH₂CH₃；

R⁹Is selected from

R⁹Has the following structure:

wherein n is 0 or 1; z is NR³⁴R³⁵OR OR³⁶；R³¹、R³²、R³³、R³⁴、R³⁵And R³⁶Each independently is H, C_1-7Alkyl radical, C_2-7Alkenyl radical, C_2-7Alkynyl, C_2-6Heterocyclic group, C_6-12Aryl radical, C_7-14Alkylaryl group, C_3-10Alkylheterocyclyl, acyl or C_1-7A heteroalkyl group; or R³²、R³³、R³⁴、R³⁵And R³⁶Any of which may optionally form together with an intervening carbon or non-adjacent O, S or N atom one or more 5-to 7-membered rings optionally substituted with: H. halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_2-6Heterocyclic group, C_6-12Aryl radical, C_7-14Alkylaryl group, C_3-10Alkylheterocyclyl, acyl or C_1-7A heteroalkyl group; and

w is selected from

The compound of formula II is a compound of the formula:

wherein

A is

Wherein

X and Y are each independently O, NR¹⁹Or S, R¹⁴And R¹⁹Each independently is H or C_1-6Alkyl radical, R¹⁵、R¹⁶、R¹⁷And R¹⁸Each independently is H, C_1-6Alkyl, halogen, C_1-6Alkoxy radical, C_6-18Aryloxy radical or C_6-18aryl-C_1-6Alkoxy, p is an integer from 2 to 6;

m and n are each independently an integer of 0 to 2;

R¹⁰and R¹¹Are each independently

Wherein

R²¹Is H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl or C_6-18An aryl group; r²²Is H, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl, carbonyl (C)_1-6Alkoxy), carbonyl (C)_6-18aryl-C_1-6Alkoxy), carbonyl (C)_6-18Aryloxy) or C₆-C₁₈An aryl group; r²⁰Is H, OH or C_1-6Alkoxy, or R²⁰And R²¹Together represent

Wherein R is²³、R²⁴And R²⁵Each independently is H, C_1-6Alkyl, halogen or trifluoromethyl, R²⁶、R²⁷、R²⁸And R²⁹Each independently is H or C_1-6Alkyl radical, R³⁰Is H, halogen, trifluoromethyl, OCF₃、NO₂、C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl, hydroxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl, amino-C_1-6Alkyl or C_6-18An aryl group; and

R¹²and R¹³Each independently is H, Cl, Br, OH, OCH₃、OCF₃、NO₂And NH₂Or R is¹²And R¹³Together form a single bond.

2. The method of claim 1, wherein the first plasma level is maintained between 0.3 μ g/ml and 3.5 μ g/ml and the second plasma level is maintained between 0.25 μ g/ml and 2.5 μ g/ml.

3. The method of claim 1, wherein the first and second plasma levels in combination are effective to inhibit tumor growth in the patient.

4. The method of claim 3, wherein the first and second plasma levels in combination do not cause substantial sedation in the patient.

5. The process of claim 1, wherein the compound of formula I is chlorpromazine and the compound of formula II is pentamidine.

6. The method of claim 1, wherein the compound of formula I is present at 0.1mg/m²Hour-15 mg/m²A first infusion rate per hour, at 0.1mg/m of said compound of formula II²Hour-60 mg/m²A second infusion rate per hour, the composition being administered by continuous intravenous infusion.

7. The method of claim 6, wherein the first and second infusion rates are effective in combination to inhibit tumor growth in the patient.

8. The method of claim 7, wherein the first and second infusion rates in combination do not cause overt sedation in the patient.

9. A method of treating a tumor in a human patient, comprising administering a composition comprising a compound of formula I, wherein a plasma level of the compound of formula I from 0.3ng/ml to 3.5 μ g/ml is maintained for at least 12 hours.

10. The method of claim 9, wherein the plasma level is 0.3 μ g/ml to 3.5 μ g/ml.

11. The process of claim 9 wherein the compound of formula I is chlorpromazine.

12. A method of treating a tumor in a human patient, comprising administering a composition comprising a compound of formula II, wherein a plasma level of the compound of formula II is maintained from 0.2ng/ml to 2.5 μ g/ml for at least 12 hours.

13. The method of claim 12, wherein the plasma level is between 0.25 μ g/ml and 2.5 μ g/ml.

14. The method of claim 12, wherein the compound of formula II is pentamidine.

15. The method of any one of claims 1-14, wherein the composition is formulated for extended release.

16. The method of any one of claims 1-15, wherein the tumor is selected from the group consisting of: lung cancer, colon cancer, ovarian cancer, prostate cancer, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, hodgkin's disease, non-hodgkin's disease, waldenstrom macroglobulinemia, heavy chain disease, hepatocellular carcinoma, non-small cell lung cancer, multiple myeloma, mucin-depledfoci (mdf), fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, ewing's sarcoma, rhabdomyosarcoma, and so-kefir, Pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

17. The method of any one of claims 1-15, wherein the tumor is selected from the group consisting of: lung, colon, ovarian and prostate cancer.

18. The method of any one of claims 1-17, wherein the composition is administered by continuous intravenous infusion for at least 12 hours.

19. The method of any one of claims 1-17, wherein the composition is administered by continuous intravenous infusion for at least 3 days.

20. The method of any one of claims 1-17, wherein the composition is administered by continuous intravenous infusion for at least 7 days.

21. The method of any one of claims 1-20, wherein the composition is administered by osmotic or peristaltic pump.

22. The method of any one of claims 1-20, wherein the composition is administered by intravenous drip.

23. The method of any one of claims 1-22, wherein the composition further comprises ascorbic acid.

24. The method of claim 23, wherein the ascorbic acid is about 1% by weight to about 10% by weight.

25. The method of any one of claims 1-24, wherein the composition further comprises mannitol.

26. The method of claim 25, wherein the mannitol is about 3% by weight to about 30% by weight.

27. The method of any one of claims 1-26, wherein the composition further comprises an antiproliferative agent of table 1.

28. A composition comprising a compound of formula I and a compound of formula II, wherein the composition is formulated to maintain a first plasma level of the compound of formula I of 0.3ng/ml to 3.5 μ g/ml and a second plasma level of the compound of formula II of 0.2ng/ml to 2.5 μ g/ml for at least 12 hours when the composition is administered to a human patient.

29. The composition of claim 28, wherein the composition is formulated to maintain the first plasma level between 0.3 μ g/ml and 3.5 μ g/ml and the second plasma level between 0.2 μ g/ml and 2.5 μ g/ml.

30. The composition of claim 28, wherein said first and second plasma levels are each maintained for at least 24 hours.

31. The composition of claim 30, wherein said first and second plasma levels are each maintained for at least 3 days.

32. The composition of claim 31, wherein said first and second plasma levels are each maintained for at least 28 days.

33. The composition of claim 28, wherein the compound of formula I is chlorpromazine and the compound of formula II is pentamidine.

34. The composition of claim 33, wherein the weight ratio of pentamidine to chlorpromazine is from about 2/1 to about 5/1.

35. The composition of claim 34, wherein the weight ratio of pentamidine to chlorpromazine is about 2.5/1.

36. The composition of claim 34, wherein the weight ratio of pentamidine to chlorpromazine is about 4/1.

37. The composition of claim 28, wherein the first and second plasma levels in combination are effective to inhibit tumor growth in the patient.

38. The composition of claim 37, wherein said first and second plasma levels in combination do not cause substantial sedation in the patient.

39. GroupA composition comprising a compound of formula I and a compound of formula II, wherein the composition is formulated for administration of the compound of formula I at 0.1mg/m²Hour-15 mg/m²First infusion Rate per hour, Compound of formula II at 0.1mg/m²Hour-60 mg/m²The second infusion rate per hour is administered to the human patient by continuous intravenous infusion.

40. The composition of claim 39, wherein the infusion is maintained for at least 12 hours.

41. The composition of claim 39, wherein said first and second plasma levels are each maintained for at least 24 hours.

42. The composition of claim 39, wherein said first and second plasma levels are each maintained for at least 3 days.

43. The composition of claim 39, wherein the first and second infusion rates are effective in combination to inhibit tumor growth in the patient.

44. The composition of claim 43, wherein the first and second infusion rates in combination do not cause overt sedation in the patient.

45. The composition of claim 39, wherein the compound of formula I is chlorpromazine and the compound of formula II is pentamidine.

46. The composition of claim 45, wherein the weight ratio of pentamidine to chlorpromazine is from about 2/1 to about 5/1.

47. The composition of claim 45, wherein the weight ratio of pentamidine to chlorpromazine is about 2.5/1.

48. The composition of claim 45, wherein the weight ratio of pentamidine to chlorpromazine is about 4/1.

49. A composition comprising a compound of formula I, wherein the composition is formulated to maintain a plasma level of the compound of formula I of from 0.3ng/ml to 3.5 μ g/ml for at least 12 hours when the composition is administered to a human patient.

50. The composition of claim 49, wherein said composition is formulated to maintain said level at 0.3 μ g/ml to 3.5 μ g/ml.

51. The composition of claim 49, wherein said plasma levels are maintained for at least 24 hours.

52. The composition of claim 51, wherein said plasma levels are maintained for at least 3 days.

53. The composition of claim 52, wherein said plasma levels are maintained for at least 28 days.

54. The composition of claim 49, wherein the compound of formula I is chlorpromazine.

55. A composition comprising a compound of formula II, wherein the composition is formulated to maintain a plasma level of the compound of formula II of from 0.2ng/ml to 2.5 μ g/ml for at least 12 hours when the composition is administered to a human patient.

56. The composition of claim 55, wherein said composition is formulated for maintaining said level at 0.2 μ g/ml to 2.5 μ g/ml.

57. The composition of claim 55, wherein said plasma levels are maintained for at least 24 hours.

58. The composition of claim 57, wherein said plasma levels are maintained for at least 3 days.

59. The composition of claim 58, wherein said plasma levels are maintained for at least 28 days.

60. The composition of claim 55, wherein said compound of formula I is pentamidine.

61. A composition comprising a compound of formula I, wherein the composition is formulated for administration of the compound of formula I at 0.1mg/m²Hour-15 mg/m²The infusion rate per hour was given to human patients by continuous intravenous infusion.

62. The composition of claim 61, wherein the infusion is maintained for at least 12 hours.

63. The composition of claim 61, wherein said first and second plasma levels are each maintained for at least 24 hours.

64. The composition of claim 61, wherein said first and second plasma levels are each maintained for at least 3 days.

65. The composition of claim 61, wherein the compound of formula I is chlorpromazine.

66. A composition comprising a compound of formula II, wherein the composition is formulated for administration of the compound of formula II at 0.1mg/m²Hour-60 mg/m²The infusion rate per hour was given to human patients by continuous intravenous infusion.

67. The composition of claim 66, wherein the infusion is maintained for at least 12 hours.

68. The composition of claim 66, wherein said first and second plasma levels are each maintained for at least 24 hours.

69. The composition of claim 66, wherein said first and second plasma levels are each maintained for at least 3 days.

70. The composition of claim 66, wherein said compound of formula I is pentamidine.

71. The composition of any one of claims 28-70, wherein the composition is formulated for extended release.

72. The composition of any one of claims 28-71, wherein the composition further comprises ascorbic acid.

73. The composition of claim 72, wherein the ascorbic acid is from about 1% to about 10% by weight.

74. The composition of any one of claims 28-73, wherein the composition further comprises mannitol.

75. The composition of claim 74, wherein the mannitol is in a range of about 3% by weight to about 30% by weight.

76. The composition of any one of claims 28-75, wherein the composition further comprises glucose and/or saline at semi-standard or standard concentrations.

77. The composition of any one of claims 28-76, wherein the composition further comprises an antiproliferative agent of Table 1.