TW200838521A - Indibulin therapy - Google Patents

Abstract

The invention provides combination therapy, wherein one or more other therapeutic agents are administered with indibulin or a pharmaceutically acceptable salt thereof and the combination is synergistic. Another aspect of the invention relates to the treatment of cancer with indibulin as a single agent. Another aspect of the invention relates to dosing regimen for administration of oral dosage forms of indibulin.

Description

200838521 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to combination therapy including indomethacin, treatment of cancer with sedative as a single agent, and terbutin for administration of an oral dosage form. The method of birth. [Prior Art] During mitosis, the DNA of a cell is replicated and then split into two new cells. The process of separating a newly replicated chromosome into two formed fine-cells involves a spindle constructed of microtubules, which itself is a long bond of smaller protein subunits called tubulin Formed. The bell microtubules are attached to the replicating chromosome and the replication is pulled to each side of the dividing cell. Without these microtubules, cell division is impossible. Therefore, microtubules are one of the most important subcellular targets in anticancer chemotherapy because they are present in all cells and are mitotic, interphase and cell-maintaining functions (eg, intercellular transport, cell shape) The development and maintenance, cell motility, and the possible knives of the molecules on the cell membrane. Compounds that interact with tubulin can interfere with the cell cycle by causing micro-g A white precipitation and sequestration. Interrupting many important biological functions of microcytoplasmic subcellular organelles. Therefore, these compounds have the potential to inhibit the proliferation of tumor cell lines derived from various organs. See, for example, Bacher et al. (200r) pureApplchem. 3(9) 1459-1464 and R〇winsky and D〇neh〇wer (1991)

Phamac· Ther_ 52 : 35-84. However, it is not the matrix of the transmembrane pump, and the new, synthetic small molecule chemistry that binds to tubulin 200838521, which interferes with the function of the axon microtubules, strongly increases the therapeutic rate in the treatment of malignant tumors. A series of synthetic molecules that can be evaluated in the normal phase or early clinical stage. One of them is a synthetic indibulin having the following structure:

Indolebumin is a synthetic small molecule tubulin inhibitor with significant antitumor activity in vivo and in vivo. It can make microtubule instability in tumor-free cell-free systems. The binding site t of the British Brin has a large number of microtubule eggs with a very long-term instability of the fistula (vincristine) or colchicine (c〇ichicine). In addition, the molecule also selectively blocks sputum in the medium term. It would be useful to use sedative to improve the hyperproliferative disease. SUMMARY OF THE INVENTION In a particular embodiment, the invention is directed to a method of treatment comprising administering a thiol-3-glyoxylate derivative. In a specific example, the mercapto-3-glyoxylic acid derivative is an N-substituted 吲哚 7 200838521 amine or a pharmaceutically acceptable salt thereof. In a particular embodiment, the thiol-3-glyoxylate derivative is indolin. In a specific embodiment, the cancer is selected from the group consisting of adenoid cystic carcinoma, renal cell carcinoma, breast cancer m prostate cancer, vulvar cancer I! glioblastoma, and lung cancer. In a specific embodiment, the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, π-stoma, prostate cancer, vulvar cancer, glioma, and lung cancer.

In a specific embodiment, the present invention relates to a method of treating cancer selected from the group consisting of adenoid cystic carcinoma, renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer. The base-glyoxylic acid derivative is preferably indolin. In a specific embodiment, the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer, which comprises administering a thiol-3 glyoxylate derivative, preferably a British cloth. forest. One aspect of the invention pertains to combination therapies wherein the thioglycolate derivative or a pharmaceutically acceptable salt thereof is administered with one or more additional therapeutic agents, and _纟-, ,, &颂 is not greater than the efficacy of the efficacy of either agent alone (eg, synergistic or additive anti-tumor effects). The combination therapy can be achieved by administering the individual components in the same, continuous or separate treatment. Another aspect of the month is the provision of combination therapies wherein indolin or a pharmaceutically acceptable salt thereof is administered together with one or more additional therapeutic agents and the combination exhibits greater efficacy than the effect of administering the agent alone (eg, synergistic or additive anti-tumor effects). The combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially or separately. In a specific embodiment, the succinyl-3-glyoxylate derivative is formulated with a serotonin I, hormonal therapeutic, dry therapy, radiation therapy, immunotherapy, gene therapy or Surgery is co-administered, preferably chemotherapy. The co-therapy may be a single formulation (e.g., spindle, tablet or liquid formulation) or an agent, such as two or more agents, which may be separately formulated. Another aspect of several months is a method for treating cancer comprising: combining a thiol-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof in another medicinal agent, the combination exhibiting greater than alone The work of administering the efficacy of the agent is, for example, a synergistic or additive antitumor effect. In a specific embodiment, the condition is selected from the group consisting of breast cancer, lung cancer, that is, nest cancer, and prostate cancer. Another aspect that is clarified is a method of treating cancer comprising: administering: dibrex or a pharmaceutically acceptable salt thereof in combination with another therapeutic agent, wherein the member exhibits an effect greater than the efficacy of administering the agent alone (eg, , Xiecheng's anti-tumor effect). In a particular embodiment, the cancer is selected from the group consisting of cancer, lung cancer, fine i, ovarian cancer, and prostate cancer. The second aspect of the acid is related to the kit, which includes ten bases-3-ethyl 3, its therapeutically acceptable salts, and another therapeutic agent. Another aspect of the invention is a therapeutic agent. "About the kit, which includes Indo-Brin, in an embodiment. DETAILED DESCRIPTION OF THE INVENTION In a specific embodiment, the method comprises administering a salt of a thiol group. In a specific embodiment, the lining. In a specific embodiment, Rabbit alum has a 3-acetic acid derivative for treating cancer or its pharmaceutically acceptable 'mercapto-3-glyoxylic acid derivative is inferior'. The cancer is selected from adenoid cystic carcinoma, kidney fine 9 200838521 Cell carcinoma, breast cancer, fine-grained, sliced,, hazelnut cancer, rotatable adenocarcinoma, vulvar cancer, glial cell slip, and lung cancer. In specific examples, cancer is selected from renal cell carcinoma, breast cancer, That is, nest cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer. In a specific embodiment, the present invention relates to a treatment selected from the group consisting of adenoid cystic carcinoma, breast cancer, breast cancer, vulvar cancer, and nerve Glioblastoma, and a method of cancer of lung cancer, comprising administering a thioglyoxylic acid derivative, 'Carriage is Indolin. In a specific embodiment, the cancer is selected from the group consisting of renal cell carcinoma, vulva Cancer, glioblastoma, And lung cancer comprising a fork to a mercapto glyoxylic acid derivative, preferably indolin. One aspect of the invention relates to a combination therapy wherein a mercaptoaldehyde derivative (eg, indometh) Lin) or a pharmaceutically acceptable salt thereof is administered together with a compound or a plurality of other therapeutic agents, and the combination exhibits an effect greater than the efficacy of administering one of the agents alone (for example, synergistic or additive antitumor effect) The combination therapy can be achieved by administering the individual components of the treatment simultaneously, continuously or separately. In a particular embodiment, the thiol-3-glyoxylate derivative suitable for use in the methods disclosed herein Or a pharmaceutically acceptable salt thereof, which is disclosed in U.S. Patent Nos. 6,008,231, 6, 232, 327, or 6, 693,119, the entire disclosure of which is hereby incorporated by reference herein in The acid derivative or a pharmaceutically acceptable salt thereof has the structure of the formula (1): 200838521

Formula (I) wherein: R is selected from hydrogen; (Ci-C6)-alkyl group, wherein the alkyl group is optionally a benzene ring (which is optionally halogen, (C "C6)-alkyl, (C3-C7) - a cycloalkyl group, a carboxyl group, a carboxyl group esterified with a CrC6-alkanol, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethyl carbonyl group, a benzyloxy group or a polysubstituted group) or a benzyl group (which is in the benzene group) a monomolecular or polysubstituted group of (CrCO-alkyl, halogen or trifluoromethyl mono- or polysubstituted); a benzyloxycarbonyl group; a third · butoxycarbonyl group; and an ethyl fluorenyl group; Benzene ring (optionally (CVCJ-alkyl, (CVC6)-alkoxy, cyano, dentate, trifluoromethyl, hydroxy, benzyloxy, nitro, amine, (crc6)-alkylamine) a (CVC6)-alkoxycarbonylamino group, a carboxyl group, or a mono- or poly-substituted carboxyl group esterified with a CV c6-alkanol); a pyridine structure of the formula (II):

Formula (II) or an N-oxide thereof (wherein the pyridine structure is selectively bonded to the ring carbon atom 2, 3 or 4' and, if necessary, the substituents are the same or different, and the term "you" is substituted by R5 And R6 substituted, wherein R5 and R6 are selected from (Ci_C6)-thrylenyl, (c3-c7)-cyclosporin 200838521*-yl, (CrC6)-alkoxy, cyclyl, amine, hydroxy, halogen, Trifluoromethyl, ethoxycarbonylamino, and carboxyalkoxy, wherein alkyl includes 1-4 C atom) 2- or 4-pyrimidinyl (wherein 2-pyrimidyl ring is optionally monosubstituted with methyl or Substituted); 2-, 3-, 4- or 8-quinolinyl (which may optionally be (Ci-C6:m-based, halogen, schlossyl, amine or (C^-C^)-leucine Substituted); 2-, 3- or 4-@-porphyrin methyl (wherein the ring carbon of the acridinyl group of the quinolyl group, and the 啥% f group are optionally taken as (C^CJ-alkyl, (C^) C: 6)-alkoxy, nitro, amine or (C--C6)-forcer oxo-amino-substituted), and propylamine-carbon-based 2-methylpropan-1-yl ; R! (in the case where R is hydrogen, methyl, benzyl, benzyloxycarbonyl, tris-butoxycarbon or acetamidine) One step is selected from <112(1:0011;_ch(ch3)-cooh;-(ch3)2-ch-(ch2)2-ch-coo_;h3c-h2c-ch(ch3)-ch(cooh)-;HO-H2C-CH(COOH)-;phenyl_CH2-CH(COOH)-;(4-Mentyl)-CH2-CH-(CO〇H)-; HN=(NH2)_ NH- (CH2)3-CH(COOH)- ; H2N-(CH2)4-CH(COOH)« ; H2N-CO-CH2-CH-(COOH)-; and H00C-(CH2)2-CH(C00H)- ;

Ri (in the case where R is hydrogen, benzyloxycarbonyl, tert-butoxymethyl, ethyl fluorenyl or a benzyl group) may be an acid group of a natural or unnatural amino acid (for example, α-glycine oxime) Base, α-inosine thiol, α-seramine sulfhydryl, α-phenylalanine fluorenyl, α-histamine sulfhydryl, α • amidoxime, α _ spermine sulfhydryl, α · aminoxime, --aspartame or α- glutamine sulfhydryl), wherein the amine group of the individual amino acid may be protected or unprotected, wherein suitable protecting groups include, but are not limited to, benzyloxycarbonyl, Tri-butoxycarbonyl or ethyl fluorenyl, and in the case where I is an aspartame or glutamine thiol group, the second, unbonded 12 200838521 methyl carboxyl group is a free carboxyl group or (^· ί: a 6-alkanol ester (such as an ester, ethyl ester or a third-butyl ester) exists in the form of a formula; the limiting strip R and Ri may further bond with the nitrogen atom - (III) The cyclic ring of the polypyrexine or the homopiperazine ring is R! is an amine alkylene group, wherein - R7 is a compound selected from the group consisting of alkyl groups; stupid groups (as needed (c "c6) -alkyl, ί Γ ^ v ^C6)-alkoxy, halogen, nitro, amine or monosubstituted or polysubstituted with (C^-C:6)-alkylamine; diphenylmethyl and bis-p-fluoro R2 is selected from hydrogen; (Ci-CJ-alkyl (wherein alkyl is required to be _, phenyl (wherein phenyl is optionally halogen, (CVC6)-alkyl, (c3-c7) - cycloalkyl, buffer, alcohol-stimulated, trifluoromethyl, methoxy, ethoxy or benzyloxy mono- or poly-substituted), 2-indolyl (optional) Mono- or poly-substituted with halogen, (cvc4)-alkyl or (cvc4)-alkoxy) or 2, 3 - or 4-° ratio (optional with halogen, (CrC4)-alkyl or ( C "C4)-alkoxy mono- or poly-substituted) mono- or poly-substituted); aryl fluorenyl (the benzene ring of the aryl group of the aryl group is optionally halogen, alkyl, (C3-C7)-cycloalkyl, carboxyl And (^-(^-co-alcoholic, Wei, tris, fluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy mono- or poly-substituted); R3 and R4 are the same or different And is selected from the group consisting of hydrogen, (CrC6)-alkyl, (C3-C7)-cycloalkyl., (CrC6)-alkane , (CVC6)-alkoxy, halogen 13 200838521 素, benzyloxy, nitro, amine, (c^c:4)-mono or dialkyl-substituted amine, (cvc:6)- Alkoxycarbonylamino and (κό)-alkoxycarbonylamino 彳Ci, C6), alkyl; Z is hydrazine or S. In a particular embodiment, R2 is selected from (Ci_C6> alkyl (wherein alkyl It is required to use a halogen, a phenyl group (wherein the phenyl group is optionally a halogen, (CrC6), an alkyl group, a (C3-C7)-cycloalkyl group, a carboxyl group, a carboxyl group esterified with a Crc6-alkanol, a monofluoromethyl group, or a hydroxyl group. , methoxy, ethoxy or benzyloxy mono- or poly-substituted), 2-quinolyl (optionally halogen or (Ci_c alkyl) or (c"c" Or a 2-, 3- or 4-° ratio of a thiol group (monosubstituted or polysubstituted), optionally substituted by halogen, (K4)-alkyl or (CVC4)-alkoxy) (wherein the aryl molecule moiety is optionally halogen, ((Vc6)-alkyl, (c3-c7)-cycloalkyl, carboxyl, carboxyl group esterified with Cl-c6-alkanol, trifluoromethyl, hydroxyl, Alkoxy, ethoxy or benzyloxy is mono- or polysubstituted). In a specific specific example, the α-β-mercapto-3-acetic acid derivative or a pharmaceutically acceptable salt thereof has the formula (IV):

R4 Ri Formula (IV) wherein: X is hydrogen, i, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, ring 200838521 steroid, aryl, heteroaryl, alkenyl, anthracene Alkenyl, fluorenyl, fluorenyl (_c=〇〇r), benzyl, functionally modified hydroxy (eg, decyloxy), ?3 N, human

Z 八 and 2 are independently ^^, 0 or 8, 苴 in 3 long aryl, 醯Λ 俨κ 1 octagonal, alkyl, earth, % alkenyl, heterocycloalkenyl, dilute, cyclic , Aminocarbonyl, |Kunyl, alkene R3 and R3, independently an alkyl group, a aryl group, or a ternary group, or X is NRSR9, 8 and 9 are independently hydrogen, remainder, f, p> ^ & benzyl, heterocycloalkyl, alkenyl, heterocycloalkenyl, fluorenyl, aryl or heteroaryl; AB, C and D are independently nitrogen or carbon, as follows: If it is nitrogen, then ^ is and if A is carbon, then ~ is hydrogen, _ or the base; if B is nitrogen, then the carbon of the shell J R5 疋 does not exist 'and if B is shell J a quinone, a cryptin or an alkyl group; and if c is a nitrogen if C is a carbon, then β Η γ , j I 疋虱 , halogen or a fluorene; and if D is #, if When D is nitrogen, then r7 is absent. Then, the reverse 7 is hydrogen, i, or alkyl; and 1 is hydrogen, alkyl, aryl, si or aryl...~ heteroaryl H hydrogen, alkyl , acid group, aryl group, alkoxy group; oxycarbonyl group, ring-burning oxygen group, Heterocyclic alkoxy thiol, anthracene, ring 15 200838521 •-enyloxycarbonyl and heterocycloalkenyloxycarbonyl. In a particular preferred embodiment, Ri is selected from the group consisting of alkyl, alkaryl, aryl and aryl. In a particularly preferred embodiment, 'R is a substituted benzyl group, more preferably a halogenated benzyl group (2-, 3- or ('deltaphenyl)methyl), and most preferably (4, a gas benzene) Base) 曱 base. In a particularly preferred embodiment, R4, r5, R6 and R7 are hydrogen atoms. In a particularly preferred embodiment, R3 or R3, any of which is hydrogen, and the remaining substituent (foot 3 or 3), is a bite group (bite ring). More preferably, either Han 3 or IV is hydrogen, and the remaining substituent (r3 or oxime) is a 4-pyridyl group. In a specific embodiment, the hydrazino-3-glyoxylic acid derivative is administered in combination with another therapeutic agent selected from the group consisting of erlotinib, CarboPlatin, 5- Fluorouracil, capecitabine, paclitaxel (Taxol), tamoxifen, vinorelbine, cisplaiin, gemcitabine ), estramustine, doxonibicin, vinblastine, etoposide, and prednis〇1〇ne. In a particular embodiment, the mercapto-3-glyoxylic acid derivative (eg, indolin) or a salt thereof is administered in combination with another therapeutic agent selected from the group consisting of Erlotinib, carboplatin, 5-fluorouracil, paclitaxel, tamoxifen, and vinorelbine. In certain such specific examples, the combinations are synergistic. In a specific alternative embodiment, the combination is additive 16 200838521. A In a specific embodiment, the «Ki·3·B (4)^ biological system is administered in combination with another therapeutic agent selected from the group consisting of Changchun Peanut (vinca 匕1〇ldS such as 'Changchun flower test, Changchun new And vinorelbine), taxanes (for example, paclitaxel and ducetaxel (UXel)), epipodophyllotoxins (eg, 1, bitter, tenip〇side) ), antibiotics (eg, dactin〇mycin (actinomycin D), daun〇rubicin, doxorubicin, and idarubicm), Anthracyclines, mitoxantrone, bleomyCins, plicamycin (mithramycin) and mitomycin (mitomycin), enzymes. (L-aspartate indolease, which can systemically metabolize L-aspartate and deprive cells that do not have their own aspartame; antiplatelet agents; anti-proliferative/anti-mitotic alkane a baseing agent, for example, a nitrogen mustard (for example, Mechlorethamine, ifosphamide, cyclophosphamide and the like, melphalan, chlorambucil, ethylimine And methylmelamines (eg, hexamethylmelamine and thiotepa), alkyl sulfonate (busulfan), succinyl urea (eg, carmustine) (carmustine; BCNU) and analogues, streptozocin, trazenes, dakarba chinensis 17 200838521 (dacarbazinine ) ( DTIC ); anti-proliferative/anti-mitotic antimetabolites, eg , folic acid analogs (eg, methotrexate), pyrimidine analogs (eg, fluorouracil, 5-fluorodeoxyuridine, and cytarabine), sputum-like analogs, and related inhibitors (eg, Tibetan noise) N-, thiophenanthene, pentostatin, and 2-chlorodeoxyadenosine; aromatase inhibitors (eg, anastroz〇le, exemestane) ) and come to the song (le) Tr〇zole ) ) •, as well as turning complexes (eg, cisplatin, carboplatin), procarbazine (pr〇carbazine), hydroxy gland, mitotane (mitotane), arnin glutethimide Hormone (eg, estrogen) and a hormonal agonist, for example, an yttrium-stimulating hormone (LHRH) agonist (eg, goserein (g〇sereHn), Liu Peilin) (leuprolide) and triptorelin (tHptorelin). Other chemotherapeutic agents may include dichloromethyl diacetic acid, camptotheciii, ifosfamide, tamoxifen, raloxifene, Jim ridgebine, and naveibine. Or any analog or derivative variant as described above. In a specific embodiment, the mercapto glyoxylic acid derivative is administered in combination with another therapeutic agent selected from the group consisting of a tubulin binding agent, a kinase inhibitor (eg, a receptor tyrosine kinase inhibitor) ), anti-metabolites, DNA synthesis inhibitors, and DNA damaging agents. One aspect of the invention provides a combination therapy wherein a mercaptoacetic acid derivative (e.g., indolin) or a pharmaceutically acceptable salt thereof. Or other therapeutic agents are administered, and the combination is beneficial to 200838521 /, methyl------------------------------------------------------------------------------- Carbs; (bcnu) and analogs, streptozotocin), Tracine-Dacarbazine (DTIC); anti-proliferative/anti-mitotic anti-optical π-element such as folic acid analogs (eg, Aminomethyl oxime), pyrimidine θ alpha (eg 'fluorine urinary sputum, 5 fluorodeoxyurethane, and arsenic hexapril), : guanidine analogs and related inhibitors (eg, thiol π, Thio birds > oxime, statin and 2-deoxyadenosine; aromatase inhibitors (eg, anastrozole, exemestane, and letrozole); and platinum complexes ( For example, cisplatin, carmine, procarbazine, transurea, mitoxantrone, aminoglutethimide; hormone f (eg, estrogen) and a hormone agonist, such as a steroid-producing hormone releasing hormone (LHRH) An agonist (eg, Gosser Lin, Liu Pei Lin, and Triptorelin). Other chemotherapeutic agents may include monoterpene methyl diacetate, camptothecin, ifosfamide, tamoxifen, ♦ roxifene, gemcitabine, noviben or any of the above: variants . In a specific embodiment, the penicillin is administered in combination with a therapeutic agent selected from the group consisting of a tubulin binding agent, a kinase inhibitor (eg, an acid kinase inhibitor), an anti-metabolite, and a And DNA damage agents. Further, another aspect of the present invention relates to a method for treating cancer, which comprises administering a derivative of the _3_B (tetra) derivative or a sceptive acceptable salt thereof, wherein the combination is It is beneficial to Gong 2 P1阽ΛΑ. It is excellent or additive. In specific specific real money, the present invention is a method for cancer of lung cancer, breast cancer, nest cancer, and prostate cancer = 20 200838521 In a specific example, the present invention relates to a method of treating cancer selected from the group consisting of lung cancer and breast cancer. In a specific embodiment, the thiol-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof has the formula (I) A further aspect of the invention relates to a method of treating cancer comprising administering indoprulin or a pharmaceutically acceptable salt thereof in combination with another therapeutic agent, wherein the combination is advantageous for efficacy, optionally Additive or synergistic. In a particular embodiment, the invention is directed to a method of treating a cancer selected from the group consisting of lung cancer, breast cancer, Indian cancer, and prostate cancer. In a particular embodiment, the invention is directed to treatment Cancer selected from lung cancer and breast cancer Methods of Treatment As used herein and as is well known in the art, "treatment" is a method of obtaining beneficial or desired results, including clinical outcomes. Advantageous or desirable clinical outcomes may include, but are not limited to, Relief or amelioration of one or more signs or symptoms, a reduction in the degree of disease, a stable (ie, not worsening) state of the disease, a prophylactic expansion of the disease, a delay or slowing of the disease, an improvement in the disease state, or Alleviation and mitigation (or no squeaking or all), whether detectable or undetectable. “Eight treatments” may also refer to prolonged survival compared to expectations of no treatment: live' or Compared with the control group patients who did not receive treatment, another aspect of the present invention relates to a kit comprising a scorpion turtle 'sour bamboo organism or a pot scorpion σΓ 4^. fly/, a salt of the west city And another therapeutic agent. In the specific example of the furnace a, 萁 虎 虎 十 , j 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋This rat urine _, Shiyi cedar, Thai Xifen, Changchun Ruibin, 始 始 姆 姆 姆 遽 遽 曾 、 、 、 、 、 、 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 多 多 多 多 多 多 多 多 多 多 多 多 多 多 多In a specific example of 4 inches, another therapeutic agent is 21 200838521 selected from the group consisting of erlotinib, carboplatin, s _, disorder uracil, paclitaxel, temamo 7~, vinca, pi. In a specific embodiment, The mercapto-3-glyoxylic acid or a pharmaceutically acceptable salt thereof has the structure of the formula (1). The other side of the present invention has a kit on the one hand, which includes the indigo ring. , a pharmaceutically acceptable salt, and another therapeutic agent. In a specific embodiment, the therapeutic d is selected from the group consisting of erlotinib, carboplatin, 5-fluorouracil, capecita, 'Pacific winter, cedar, and Temo Xifen, vinorelbine, cisplatin, Jim Sabina female Moss> Ding, doxorubicin, Changchun flower test, Itopop and the right side. In a particular embodiment, the additional therapeutic agent is selected from the group consisting of erlotinib, card face, 5-fluorourine. Bite, Pacific paclitaxel, tamoxifen, and vinorelbine. The administration of the mercapto-3-glyoxylic acid derivative can be carried out from several minutes to several days before or after the other therapeutic agent. In certain such specific embodiments, the sigma xylin-3·hydantoic acid derivative and the additional therapeutic agent can be about 5 minutes, about 10 minutes, about 30 minutes, about 60 minutes, about about 1 minute from each other. 2] 8 inches, about 4 hours, about 6 hours, 8 hours, about 1 hour, about 12 days), about 18 hours, about 24 hours, about 36 hours, or even about 48 inches or more. Cast. Preferably, the administration of the 0 thiol-3-acetic acid derivative and the additional therapeutic agent will be within about 1 minute, about 5 minutes, about 30 minutes, or even about 60 minutes of each other. In a particular embodiment, the mercapto-3-glyoxylic acid derivative and the other/therapeutic agent can be administered according to different dosing schedules (eg, indigridin can be administered, for example, once a day, and Another therapeutic agent can be administered only once every three weeks, so that in some instances, the administration of the mercapto-3-glyoxylate derivative and the other therapeutic agent 2008 20082121 will be about 60 in each other. Within minutes, and in other instances the administration of the <RTI ID=0.0>>>> The term "precursor method" as used herein is a predetermined time course of one or more therapeutic agents for treating cancer. Thus, when a therapeutic agent is administered "alone," the regimen does not include the use of another therapeutic agent to treat cancer.

In a specific example, the σ 朵 -3 -3 - methic acid derivative (for example, Indolin) is administered once a day for a total of 14 days every three weeks. In a particular embodiment, the administration is by oral administration, for example, by liquid or capsule. In a particular embodiment, when the mercapto-3-glyoxylic acid derivative is administered in a liquid form, the single dose comprises from about 20 to about 80 mg. In a particular embodiment, when the thiol-3-glyoxylic acid derivative is administered in a % oral dosage form, the dosage is from about 100 to about 250 mg or even more. In a particular embodiment, the dose per swallow may be from about 10 〇 to 2000 mg, about 25 〇.

To about 2000 mg or even about 500 to about 20 mg. In a specific specific case, the daily dose may be greater than or equal to 500 mg, 9 〇 () mg, 'i (^ mg, 1200 mg, 1500 mg, 1800 mg, 2 〇〇〇 mg or even 25 〇〇) In a 4 inch 疋 specific 巾 巾 , 十 十 十 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ May, every other day, every day, twice a day or even every three times, or by other conventional regimens (eg, continuous treatment). The administration can be three weeks, four weeks, five weeks or more. A period of time, such as six months, one year, two years or more. The term noun, /Q therapy used herein refers to a drug administration, wherein 23 200838521 ^ is not able to live for one day or at most two consecutive days For a bear that has not been administered, it is sufficient to have a 5: to a cup, for example, six months, one year, two years, years or even more. In a specific example, mercapto glyoxylic acid Derivatives (eg, indolin) are administered twice daily in an oral dosage form. In a specific embodiment, thiol_3 The glyoxylic acid derivative (for example, Central Brin) is administered in an oral dosage form preferably twice a day. In a specific embodiment, the thiol-3 glyoxylic acid derivative is in continuous treatment. In a particular embodiment, continuous treatment includes administration of an oral dosage form twice daily. Suitable oral dosage forms include, but are not limited to, capsules, for example, hard gelatin capsules. In these specific examples, the mothers include about 4 mg of σ 丨 丨 基 基 j-acetic acid derivative (for example, indolin) which is administered twice a day. A mercapto glyoxylic acid derivative (eg, indolin) is administered with food. In certain such specific instances, administration with food may increase bioavailability. In a particular embodiment The combination described herein may be synergistic in nature, meaning that the therapeutic effect of a combination of a thiol-3-acetyl acid derivative and another therapeutic agent is more than the sum of the individual effects. In a particular embodiment , the combination described here can be In essence, the additive effect means that the therapeutic effect of the combination of the 吲ti-based -3-3-aged acid derivative and another therapeutic agent is more than the effect of each agent (that is, the therapeutic effect is an individual effect) The sum of the compounds described herein can be administered in a variety of forms depending on the condition to be treated and the age, symptoms and weight of the patient, as in 24 200838521 in the art. For example, when the compound is administered orally, Kakuda, is sodium ingot, capsule granules, powder or mash; or for administration of non-information channels ^ / , ,, 匕They can be formulated as injectables (intravenous, intramuscular or subcutaneous) or in drops of liquid preparation. These formulations can be prepared by conventional methods and, if desired, the active ingredient and any conventional additives. Or excipients, surprises, for example, binders, disintegrating agents, lubricants, anti-adjuvants, solubilizers, auxiliaries, emulsifiers, envelopers, cyclodextrins and / 2 Buffering d ° will be based on the patient's signs, age and body The characteristics and severity of the disease to be treated or prevented, the route of administration, and the opening of the drug: Change: The amount which can be combined with the carrier material to produce the activity of the single dosage form to form h will generally be the amount of the compound which will produce a therapeutic effect. In a particular embodiment, the compounds described herein can be administered in the form of microparticles, preferably a water-soluble suspension of nanoparticles and at least one active agent selected from the group consisting of ionic surfactants, nonionic Interface active f4 j, zwitterionic surfactant, bio-derived surfactant, amine 5-germanium and derivatives thereof, and combinations thereof. The particulate compositions can be administered in any suitable manner including, but not limited to, oral or parenteral. In a particular embodiment, one or more of the chemistries described herein are in an amount from about 0. (10) to about 20% (weight/volume), more than ρ: from about _ to about (10) (weight/volume), Or even from: two: to about 10% (weight / volume) of the amount, but present in the composition. In a particular embodiment, the size of the particles will vary from about 15 nnl to 50 microf', preferably from about 50 nm to 10 microns, or even from about 5 〇 (10) to 2 microns. When the granules are prepared by injection, it is preferred that they have a particle size of from 25 200838521 to about 5 microns (microparticles) or even less than about 2 microns (nanoparticles). The particulate compositions described herein are also described in 2006/052712, the entire disclosure of which is incorporated herein by reference. The surfactant suitable for coating the particles in the present invention may be selected from the group consisting of an ionic surfactant, a nonionic surfactant, a zwitterionic surfactant, a phospholipid, a biologically derived surfactant or an amino acid, and Their derivatives. The ionic surfactant can be anionic or cationic. The surfactant is present in the composition in an amount from about 1% to about 1% by weight (weight/volume), and preferably from about 0.5% to about 5% (weight/volume). . Suitable β-negative surfactants include, but are not limited to, burning a certain acid salt, aryl sulfonate, alkyl phosphate, alkyl phosphonate, potassium laurate, sodium lauryl sulfate, twelve Sodium alkyl sulphate, alkyl polyoxyethylene sulphate, sodium alginate, phosphatidic acid and salts thereof, sodium carboxymethyl cellulose, bile acids and salts thereof (eg, citric acid, deoxycholic acid, hypoglycamine) a salt of acid, taurocholic acid and hypoglycine deoxycholic acid) and calcium carboxymethylcellulose 'stearic acid and its salts (for example, sodium stearate and stearic acid), sulphate, ten Sodium dicarbonate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium dioctylsuccinate (DOSS), dialkyl ester of sodium succinate, sodium lauryl sulfate and phospholipids . Suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitin, dodecyldimethyl chloride Benzyl ammonium, mercaptocarnitine hydrochloride, halogenated alkylpyrimidine, cetylpyrimidine chloride, cationic lipid, brominated polymethyl 26 200838521 dimethylammonium methacrylate, sulphate compound, sulfuric acid polyethylene Dipyridyl keto-2-dimethylamine ethyl methacrylate, hexamethyl bromide bromide, eutrophic compound, quaternary ammonium compound, benzyl bromide-di(2-chloro Ethyl) ethylammonium, chlorinated coconut trimethylammonium, brominated coconut trimethylammonium, chlorinated coconut decyl dihydroxyethylammonium, brominated coconut methyl dihydroxyethylammonium, ruthenium chloride Ethyl ammonium, decyl dimethyl hydroxyethyl ammonium chloride, ruthenium decyl hydroxyethyl ammonium bromide, dimethyl hydroxyethyl ammonium chloride, brominated c I ^ I 5 Methyl hydroxyethyl ammonium, chlorinated coconut dimethyl hydroxyethyl ammonium, brominated coconut dimercapto hydroxyethyl ammonium, tetradecyl trimethyl ammonium decyl sulfate, dodecyl chloride Methyl benzyl ammonium, dodecyl dimethyl benzyl ammonium bromide, eleven: k * benzyl monomethyl (oxyethylene) 4 ammonium, desert, didecyl dimethyl (oxygen) Vinyl) 4 ammonium, N-alkyl chloride (Cl 2 · 8) dimethyl benzyl ammonium, chlorinated ... alkyl (cm-u) dimethyl benzyl ammonium, N-tetradecyl chloride Dimethylbenzyl money monohydrate, dimethyldimethylammonium chloride, N-alkyl chloride and (CUM) dimethyl 1 methyl sulphate, dimethyl ammonium hydrazine s-alkyl-trimethyl Ammonium salt, dialkyl-dimethylammonium salt, dodecyltrimethylammonium chloride, ethoxylated alkylguanidinoalkyl carbodiylidene salt, ethoxylated trialkyl Ammonium salt; vaporized dialkyl benzene monoalkyl ammonium chloride, N-dimercaptodimethylammonium chloride, tetradecyldimethylbenzyl ammonium chloride monohydrate, cesium chloride _ alkyl (Ci2 Μ) dimethylnaphthylmethyl chloride, dodecyldimethylbenzylammonium chloride, dialkylphenylalkyl chloride, dodecyltrimethylammonium chloride, alkylbenzyl chloride Methylammonium, brominated benzyl dimethyl ammonium, brominated C12 trimethylammonium, brominated c15 trimethyl, desertified cn trimethylammonium, chlorinated ten Dialkylbenzyltriethylammonium, poly-diallyldi-f-ammonium chloride (DADMAC), dimethylammonium chloride, 27 200838521 Halogenated monomethylammonium chloride, trimethylsulfonium chloride Mercaptoammonium, bismuth bromide trimethyl sulphate, smelting eleven alkyl triethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, "POLYQUAT10" (a kind a mixture of polymerized quaternary ammonium compounds), tetrabutylammonium bromide, benzyltrimethylammonium bromide, decyl phthalate, dimethylammonium chloride, stearyl dimethylammonium chloride, brominated ten Hexaalkylpyrimidine, cetylpyrimidine chloride, a halogenated salt of a quaternized polyoxyethaneamine, an alkylpyrimidine salt, an amine, an amine salt, a guanidine imine salt, a protonated tetrapropylene S! Amine, methylated quaternary polymer, cationic guar gum, gasified phthalic acid ammonium chloride, desertified 12-yard trimethylammonium, triethanolamine, and poloxamines. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty alcohol, polyoxyethylene sorbitan fatty acid, polyoxyethylene fatty acid ester, sorbitan ester, glyceryl ester, single Glyceryl stearate, polyethylene glycol, polypropylene glycol, mu alcohol, stearyl alcohol, : ruthenium alcohol, aryl polyether alcohol, polyoxyethylene-polyoxypropylene copolymer, cypress =Sam (P〇l〇xamer), poloxamine, methylcellulose, ketone cellulose, methylcellulose, propylcellulose, propylmethylcellulose, amorphous cellulose, Polysaccharide, powder, starch derivative, ethyl starch, polyvinyl alcohol, vinyl pyrrolidone, triethanolamine stearate, amine oxide, sugar, glycerin, gum arabic, cholesterol, Tragacons, single Hardy glycerol, cetyl stearyl alcohol, cetmacrogoi m*, sorbitan, polyoxyethylene oxime ~ 4 'bubuji, polyoxyethylene oxime Sesame oil: substance, polyoxyethylene sorbitan fatty acid vinegar, polyethylene glycol, polyoxyethylene stearate, hydroxypropyl fiber Vitamins, A, Handmade Armor, Cellulose, Methylcellulose 28 200838521, Ethylcellulose, Hydroxypropylmethylcellulose, Non-crystalline Fibrin, Polyvinyl Alcohol, Polyvinylpyrrolidone, 4-03 , 3,3-tetramethylbutyl) polymer with deuterated ethylene and formaldehyde, poloxamer, alkyl aryl polyether, sucrose stearate and sucrose distearate, ci8H37CH2C ( 〇)N(CH3)CH2(CHOH)4(CH2OH)2, p-isodecyl phenyloxy poly(glycidol), fluorenyl-N-methylglucosamine, n-decyl-stone _ D-glucopyranoside, n-mercapto-callo-D-valerium maltoside, n-dodecyl _ /3 glucopyranoside, n-dodecyl cold-D-maltoside, Glycidylmethylglucosamine, n-heptyl-D-glucopyranoside, n-heptyl-callo-D-thioglucoside, n-heptyl-p-pyranoglucoside; · ν_ methyl glucosamine, n-decyl. No _D- η glucopyranoside, octyl Ν 甲基 甲基 methyl glucoside, n-octyl 召 D-glucopyranoside , octyl _ _ _ 〇 - thiopyranoside, PEG-cholesterol, PEG-cholesterol derivatives, peg-dimensional Element A, PEG- vitamin E, and random copolymers of vinyl acetate and vinylpyrrolidone. Zwitterionic surfactants are electrically neutral, but have a local positive and negative charge in the same molecule. The net charge on the molecule can be enthalpy according to pH, so at low pH, some of the zwitterionic surfactants can Λ > shell cationic surfactants, and at high pH, they can also act as anionic interfacial activity. Agent. Suitable zwitterionic surfactants include, but are not limited to, zwitterionic phospholipids. These phospholipids include phospholipid choline, phospholipid oxime ethanolamine, dimercapto-glyceryl-phosphoethanolamine (for example, bismuth S-mercapto-glyceryl-phosphoethanolamine (DMPE), dipalmitoyl-glyceryl-phosphate Ethanolamine (DPPE) 'distearyl-glyceryl-phosphoric acid 29 200838521

Ethanolamine (DSPE) and dioleyl-glyceryl-phosphoethanolamine (DOPE), PEGylated phospholipids, ? £0-phospholipid,? £0-dimercapto-glyceryl-phosphoethanolamine, PEG-phospholipid oxime ethanolamine, PEG-dimercapto-glyceryl-phosphoethanolamine PEG-di-glycidyl-glyceryl-phosphoethanolamine, PEG-dipal Mercapto-glyceryl-phosphoethanolamine, PEG-distearoyl-glyceryl-phosphoethanolamine, PEG-dioleyl-glyceryl-phosphoethanolamine, methoxypolyethylene glycol (mPEG)-phospholipid, mPEG-phospholipid choline, mPEG-dimercapto-glyceryl-phosphoethanolamine, mPEG-phosphoethanolamine, mPEG-dimercapto-glyceryl-phosphoethanolamine, mPEG-di-glycidyl-glyceryl-phosphoethanolamine mPEG-dipalmitoyl-glyceryl-phosphoethanolamine, mPEG-distearoyl-glyceryl-phosphoethanolamine, and mPEG-dioleyl-glyceryl-phosphoethanolamine. Phospholipid mixtures comprising anionic and zwitterionic phospholipids can be used in the present invention. Such mixtures include, but are not limited to, lysophospholipids, egg or soybean phospholipids, or any combination thereof. Suitable biologically derived surfactants include, but are not limited to, lipoproteins, gelatin, casein, lysozyme, albumin, casein, heparin, hirudin or other proteins. A preferred ionic surfactant is a bile salt, and a preferred sulfonium salt is deoxycholate. Preferred nonionic surfactants are polyalkoxy ethers, and preferred polyalkoxy ethers are polyoxyethylene-polyoxypropylene triblock copolymers, for example, poloxamer 188 and pelopa M 407. Another preferred surfactant is a lipid wherein the polyalkoxy ether is covalently attached to the lipid via an ether linkage. A preferred surfactant of this type is polyethylene glycol 30 phospholamine. Another preferred surfactant is a pegylated phospholipid methyl ether (e.g., "mPEG-distearoyl-glyceryl, acid glycolamine). In a preferred embodiment of the invention, the particles are water-soluble '", and the improvement thereof includes a pH adjusting agent. Suitable pH adjusting agents include, but are not limited to, 'chlorine oxides'. . Sodium, strontium, tris(hydroxyindenyl)aminomethane retarded, ° ° and - slowed with salt, citrate buffer, acid salt, glycerol + phosphate, glycerol 2 - phosphate, acetic acid Salt, lactic acid, tris(dimethyl)amine-based methylamine, amino sugar, mono-, di-, and tri-alkylated amines; violent glucosamine (NN 甲其诘祜他卜, T基) Dian & c) and amino acids. The water-soluble matrix may additionally include an osmotic urethrium, Zhou Zheng J, such as, but not limited to, glycerin, a monosaccharide such as (tetra)saccharide, a disaccharide (eg, Yan sugar, trehalose, and maltose), =) (eg ' Raffinose) and sugar alcohols (for example, mannitol and mountain "in the specific example of the present description, the water-soluble group (four) of the particle suspension composition" to form money particles. Method of removing the water-soluble matrix 疋& 'Artisan' any method known. One example is bursting. Another is cold; East is dry or μ. The dried granules can then be formulated into two::: Physical: Formula 'It includes but is not limited to, solution , (4), into the reservoir, sputum, detergent, emulsion, aerosol, powder, and J storage benefits or matrix devices, or percutaneous patch) diverticulum heart for holding,,, release (for example, planting Into the temple to change the temple. The water-soluble suspension of the present invention can also be cold-cold, cold; = stability: water-soluble suspension for improving stability 1 " F in the joint transfer and the same application US Patent Application 31 200838521, file number 10/270,267, complete within Incorporate by reference. Preferably, the composition comprises from 0.05% to 10% (by weight/water-soluble suspension of particles of the tubulin inhibitor, the particles are ionic to % to 5% (weight/volume)) a surfactant (such as a biliary I salt) or a zwitterionic surfactant (for example, di-di-glyceryl-phosphoethanolamine) and 〇〇 5% to 5% by weight of a polyalkoxy ether (for example, Pelosa) 188) is coated with glycerin to adjust the osmotic pressure of the formulation. _ The particle suspension of the present invention can be prepared by methods known in the art and described below. In a particular embodiment, The disclosed compounds can be administered as a pharmaceutical formulation, wherein the formulation comprises granules, a rice t-based, a methic acid derivative (for example, a lining bar at least 99% by volume of the granules) Having at least 2 〇 #m of particles at least: a hydrophilic surfactant and one or more other excipients. The pharmaceutical formulations are described herein by reference.疋 In a preferred embodiment, the micronized thiol The organism has less than 10/zm of j for at least 90% by volume of the particles having less than 10#m for at least "% by volume of the particles. In a particularly preferred embodiment, the micronized 1 thiol-3 : 物-有|& is an average particle size of 2 to 4 /zm. In a preferred embodiment of the present invention, the pharmaceutical formulation is packaged to an amount of about 5% by weight of π-bamboo- 3-ethylic acid derivative, about 32 200838521 10% by weight of at least one hydrophilic surfactant, and about to about 10% by weight of the amount of the seed-coated excipient, the three components of the total damage Is the weight % of i 加到 added to the pharmaceutical formulation. A hydrophilic surfactant is not subject to any particular limitation as long as it acts as an oil-to-water surfactant, i.e., one or more The hydrophilic surfactant is selected from the group consisting of polysorbate, poloxamer, hydrogenated kenaf oil (erem() phG〇, and m alcohol. :: type of polysorbate can be used 'but special ❸ ,, poly sorbate 疋 returned from poly sorbic acid bee 2 η, take 丨 』 _ wind to mountain 齩 salt 40, poly sorbate 6 〇 or Polysorbate 8 〇, more than the county of Chengwei 旯仏疋 自 self-supporting sorbate 8 〇. In addition, any type of poloxamer can also be made. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ m 嵌段 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋Enzyme eight private knife J knife. A typical sam suitable for the present invention is poloxamer 188 ^ ^ 乂 and 4 〇 7 ′ 4 inch is poloxamer 1 88. Klimo's fine sputum is made with oxidized yoghurt and sesame oil especially at about 35 moles! m Mo = a nonionic emulsifier obtained by the molar ratio reaction. Other common names are styrofoam glycerol trimeric E oleic acid 35 or polyoxy 35 castor oil. Typical hydrogenated anaesthetic oils are for example by BASF AG (Germany)

Cremophor 16 EL® adhesive excipients, which are conventional in the art, are suitable for use in the present invention. 4 彳 彳 ' 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该Shi Xi (gas phase dioxide; eve; aerosil) 〇if 堂, — 匕 赋形剂 excipients include microcrystalline cellulose, gelatin, 33 200838521 corn house powder and a mixture of yin _ $ 虱 矽. For example, the corn house powder and the microcrystalline cellulose can be used as the A-planting solid cerium dioxide (gas phase cerium oxide) technological "忒" to make the sap flow smooth. Recording adhesive, In the specific example of the car parent of the present invention, the granular composition of the pharmaceutical formulation is covered by the outer layer of the skin, which comprises starch (especially corn starch).

A rice knife), a mixture of intermittently dispersed oxidized hair and magnesium stearate. The outer layer is suitably encapsulated with granules. In the case of 疋/, 体体, the medicinal preparations are respectively a troche prepared by using the pharmaceutical preparation or a capsule filled with the pharmaceutical preparation. A pharmaceutical formulation of the steroid I-3-acetyl acid derivative (eg, indolin) can be based on the micronization of the compound's combined granulation process using a hydrophilic surfactant (eg, $sorbus) Acid salts, poloxamers, hydrogenated sesame oil) alpha and usual encapsulating excipients (eg, cellulose, starch, highly dispersed cerium oxide, etc.). In a particular embodiment, the mercapto glyoxylic acid derivative and the additional therapeutic agent may be in the same form, for example, both may be administered as a lozenge, or both may be administered intravenously, while being specifically replaceable In a specific example, the leuco--3-glyoxylic acid derivative and the other therapeutic agent may be in different forms (for example, one may be administered as a tablet and the other may be administered intravenously). The precise time and/or amount of composition that will result in the most effective outcome in specifying the patient's therapeutic efficacy will depend on the bioavailability of the particular compound, the bioavailability of the biologics, and the physiological condition of the patient ( This includes age, gender, type of disease and stage, general physical condition, reactivity to the specified dose of 34 200838521, and type of agent.), route of administration, etc. However, the above guidelines can be used as a basis for fine-tuning treatments, such as 'determining the optimal time and/or amount of administration, which requires no more than routine trials consisting of monitoring individuals and adjusting doses and/or times. As used herein, "pharmaceutically acceptable" refers to a ligand, material, composition, and/or dosage form that, within reasonable medical judgment, is suitable for use in contact with human and animal tissues without undue Toxicity, irritation, allergic reactions or problems or complications are equivalent to a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein, refers to a pharmaceutically acceptable material, composition or medium, for example, a liquid or solid filler, a diluent, an excipient, a solvent or Encapsulated material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, and is not a problem. Some examples of materials that are acceptable carriers for Lule include: (1) sugars such as lactose, glucose, and sugar; (2) m starches such as 'corn starch, potato powder and substituted Or unsubstituted cold agricultural extract, (3) cellulose and its derivatives, for example, slow methylcellulose sodium 'ethyl cellulose and cellulose acetate; (4) & (5) malt; (6) gelatin, (7) talc; (8) excipients 'for example, cocoa butter and suppository rings; (9) oils and fats, for example, peanut oil, cottonseed oil, safflower oil, Sesame oil, sassafras oil, corn oil and soybean oil; (1) gan, for example, propylene glycol; (11) polyhydric alcohol, for example, glycerin, sorbitol #litol and polyethylene glycol; (12) For example, ethyl oleate and ethyl laurate; (13) chronology of the genus, (I4) buffer, for example, oxyhydrogen 35 200838521 Huazhen and Hydroxide; (1 5) alginic acid; 1 6) pyrogen-free water; (1 7) specific salt solution; (18) Ringer's solution; (19) ethanol ·, (20) phosphate a solution; and (21) other non-toxic compatible substances used in the pharmaceutical formulation. In a particular embodiment, the pharmaceutical composition of the invention is pyrogen-free, that is, when administered to a patient No significant temperature rise is induced. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of an inhibitor. These salts may be in situ during the final isolation and purification of the inhibitor. Prepared, or prepared by reacting a purified inhibitor of the free base form with a suitable organic or inorganic acid, and isolating the salt formed. Representative salts include hydrobromide, hydrochloride, sulfuric acid Salt, hydrogen sulfate, phosphate, nitrate, acetate, trifluoroacetate, citrate, embQnate, f-sulphonate, valerate, oil

Acid salt, palmitate, stearic acid _, B ' hard sulphate salt, laurate salt, benzoate salt, lactate, strontium sulphate, sulphate, acetonide T, acid Salt, citrate, malonate, maleate, fumarate, sulphate, tartrate, naphthate, methanesulfonate, glucose 酴 _ _ Glucuronide, Glucose, Glycogen, and so on 2: Ethyl sulphate, sputum, sputum, sulphate, lauryl sulphonate, and amino acid salt, etc. (for example, 夂^ See Berge et al. (1977), "嫛乐盐, Seto", 5W·66 : 1 ·! 9 ). In other examples, there are ^ ^ ^ inhibitors that can be used in the method of the invention. One or more of the acidic functional beauty, soil and thus can form a pharmaceutically acceptable salt with a chemically acceptable base. It refers to the phase of the inhibitor.:::..." Field..., an inert inorganic or organic base addition 36 200838521 ^ Salt. These salts can likewise be prepared during the final isolation and purification of the inhibitor, or by the addition of the purified acid form of the inhibitor to the appropriate base (e.g., pharmaceutically acceptable metal cations of hydroxide). , citrate or bicarbonate), prepared with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of addition salts include diethylamine 'diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperene, and the like (see, for example, Berge et al., supra). Wetting agents, emulsifiers and lubricants (for example, sodium lauryl sulfate and sodium stearate) as well as coloring agents, release agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives and antioxidants, can also be composed Present in. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloric acid, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, for example φ For example, ascorbyl palmitate, butylhydroxymethoxybenzene (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelate Mixtures, for example, citrate, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartrazine, phosphoric acid, and the like. Formulations suitable for oral administration may be in the form of capsules, sachets, pills, spindles, man-shaped ingots (using a flavored base, usually sucrose and gum arabic or 4 inch Lagacons), powders, granules. Or a solution or suspension in a water-soluble or water-insoluble liquid, or a night body emulsion of oil or water in oil, or a panacea or syrup, or a tablet (using an inert substrate, 37 From 200838521, for example, gelatin and glycerin or sucrose and gum arabic) and/or mouthwash, etc., the parent contains a predetermined amount of an inhibitor as an active ingredient. The composition may also be administered in the form of a pellet, a saccharide or a paste. In a solid dosage form for oral administration (capsules, lozenges, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, for example, sodium citrate or hydrogen phosphate Dicalcium and/or any of the following: (1) fillers or supplements, for example, starch, cyclodextrin, sucrose, glucose, mannitol and/or citric acid; (2) binders such as ' Carboxymethyl cellulose, alginate, gelatin, I vinyl: rosinone, sucrose and/or gum arabic; (3) humectant, for example, glycerin; () collapse, for example, plucking _ 洋菜, Carbonated feed, potato or tree sacred powder, alginic acid, specific sulphate and sodium carbonate; (5) solution retardation d, for example, paraffin, (6) absorption accelerator, for example, quaternary ammonium compound; (7) wet agent 'for example , ethoxylated alcohol and glycerol monostearate; (1) absorption month 1 eg, southern territories and swelling clay; (9) lubricants, for example, talc, stearic acid (tetra), magnesium stearate, solid polyethylene glycol, Moon and its mixture; to ...) colorant. In capsules, keys, and pills: In the examples, the drug composition may also include a buffer. Similar types of solid electroforming: excipients such as lactose or milk sugar and high molecular weight 埴_寺 can also be used, and the use as a squeezing agent in soft and hard-filled gelatin capsules can be by compression or molding, It is prepared as needed with one or more auxiliary knives. Compressed tablets can be used as binders (eg, gelatin or methyl cellulose), slip agents, inert diluents, preservatives, disintegration 38 200838521 (eg, sodium starch glycolate or crosslinked hydroxyl group) Based on sodium cellulose), bound: active agent or dispersant. Molded tablets may be prepared by molding a mixture of powdered inhibitors which are wetted with an inert liquid diluent in a suitable machine.

Tablets and other solid dosage forms, e.g., dragees, capsules, pills, and granules, may optionally be scored or prepared with a coating and shell, for example, enteric film and other coatings well known in the art of pharmaceutical formulation. They may also be formulated to provide slow or controlled release of the active ingredient therein, using, for example, hydroxypropyl cellulose (in various ratios to provide the desired release data), other polymer matrices, liposomes and/or Or microspheres. They may be sterilized by filtration, for example, by a filter that fixes the bacteria, or by incorporation of a sterilizing agent in the form of a sterile solid composition or a portion of other sterile injectable base that is dissolved in sterile water immediately upon use. These compositions may also optionally contain opacifying agents and may be of a composition having only the active ingredient released or preferentially released in a particular portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and can be used. If appropriate, the active ingredient may also be in the form of a microencapsulation together with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and panacea. Liquid dosage forms may contain, in addition to the active ingredient, inert diluents conventionally employed in the art, such as water or other solvents, solubilizing agents, and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils and fats (especially cottonseed oil, peanut oil, corn 39 200838521 • - oil, germ oil, eucalyptus oil, castor oil and sesame oil), glycerin, four Hydrogen-furanol, polyethylene glycol, and fatty esters of sorbitan and mixtures thereof. Besides the inert diluent, the oral compositions may also include adjuvants such as <RTI ID=0.0>>"""""" In addition to the > tongue component, the suspension may also contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan, cerium crystalline cellulose, partial oxidative oxidation Aluminum, bentonite, Chinese cuisine _ aquarium and 'tratra plus kons and their mixtures. Pharmaceutical compositions of the present invention suitable for parenteral administration include one or more inhibitors in combination with one or more pharmaceutically acceptable salt solutions, aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or a sterile powder which can be redissolved into a sterile injectable solution or dispersion after use, which may contain an antioxidant, a buffer, a bacteriocin, an isotonic substance which allows the formulation to be isotonic with the blood of the intended recipient, or Suspending agent or thickener. Suitable water-soluble and water-insoluble agents which can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (for example, glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (for example) , eucalyptus oil) and injectable materials (for example, oleic acid ^). The flow can be maintained, for example, by the use of a coating material (e.g., egg fat), by maintaining a necessary particle size (in the case of dispersions), and by using an interfacial active agent. Suitable compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by incorporating a special anti-40 200838521 bacterial and antifungal agent, for example, _ 酴 sorbic acid. It may also be desirable to include "slight acid, chlorobutanol, and τ 希 1 to incorporate tension modifiers (such as petrochemicals, etc.) into the composition. In addition, it can be noted that: class, chlorine absorption can also be incorporated by delayed absorption. Caused by:, two: Changming and gelatin. Monostearic acid in some cases, in order to extend the role of drugs

Slow down the absorption of drugs from subcutaneous or intramuscular injections. For example, non-two: the delayed absorption of the drug form is achieved by suspending the lipid medium. (3) Capacitance or suspension in oil by H: The reservoir is in the form of a microencapsulated matrix of the inhibitor formed by the formation of a polyacrylic acid in a biodegradable polymer. And the rate at which the heart-specific polymerization 2 music is released can be controlled. Other biodegradable polymers: Examples include poly (original acid vinegar) and poly (wild). The reservoir injectable formulation is prepared by immersing the drug in a micro-wax or microemulsion that is compatible with body tissues. As used herein, the phrase "parenteral administration, and "parenteral tract = pre-" refers to a mode of administration other than enteral and topical administration, usually by injection 'and including but not limited to' veins Internal, intramuscular, intraarterial, intramembranous, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, intratracheal, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and perfusion The phrase "systemic administration," "systemic administration", "circumferential administration," and "administered around," refers to ligands, drugs 41 200838521 or other substances. Administration directly outside the central nervous system, allowing it to enter the human patient's system, and thus performing metabolic and other similar processes, for example, subcutaneous administration. Administration of the therapeutic composition of the invention to a patient will follow The general method for administering chemotherapeutic agents is to take into account toxicity (if any). It is expected that the cycle of treatment will be repeated, if necessary = also considered A, various criteria (4) therapy The accessory i cancer therapy and the surgery ^ intervention can be administered in combination with the illustrated arsenic agent. Regardless of the route of administration chosen, the inhibitors used in the appropriate hydrated form and/or the pharmaceutical compositions of the invention are Formulated into a pharmaceutically acceptable dosage form by conventional methods known in the art. The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied = flat in order to obtain an effective effect on achieving a particular disease, composition, and The administration mode has a desired therapeutic response, and the amount of the active ingredient which is not toxic to the patient is shown in order to more fully illustrate the preferred embodiment of the present invention. These examples should not be construed as Limitations of the invention are defined in the scope of the appended claims. EXAMPLES Indomethrin Combination: The monolayer analysis assay measures the in vitro antitumor activity of test compounds and their inhibition of survival and proliferation of established cell lines. Ability. These effects can be determined by measuring the DNA content using propidium iodide by establishing the number of viable cells. In the first step Indole Brin and its 42 200838521 were tested individually at ten different concentrations in the cell lines MCF-7 (breast cancer), A549 (NSCLC), SKOV3 (ovarian cancer), and PC3 (prostate cancer). Antitumor activity. 5,000 to 10,000 cells were seeded on a 96-well culture dish on dayday, and the compound was added after 1 day and cultured for 4 days. All compounds were at the concentrations shown in Table 1. Tested in a semi-logarithmic step. Activity is assessed by their IC5Q and IC70 values.

Table 1: Concentration range for single dose dose response test Cell line drug concentration (ng/mL) Low level MCF-7 ER-yang breast cancer 5-FU 10 300,000 Vinorelbine 0.003 100 Pacific paclitaxel 0.003 100 Tamoxifen 3 100,000 Indy Brin 0.1 3,000 A549 NSCLC Carb 3 35000 Etopox 3 1005000 Erlotinib 0.1 305000 Inline Brin 0.1 3,000 Growth IC50 and IC70 values (Table 2) were determined using the XLfit kit software, and Used to set the concentration range and drug ratio for the synergistic detection portion of the study. 43 200838521 , · Table 2 · A549 and MCF-7 cell line growth IC50 and IC70 numerical cell line: A549 compound IC50 (ng/mL) IC70 (ng/mL) Ka Ming 11,470 39,200 Itopopa 52 228 Erlotinib 7860 > 30,000 gemcitabine 1.7 2.5 Indigrin 38 140 Cell line: MCF7 Compound IC50 (ng/mL) IC70 (ng/mL) Vinorelbine 0.18 0.29 Pacific paclitaxel 0.3 1.0 Tamoxifen 110 3540 Indigo Brin 110 220 Cell line: SKOV3 Compound IC50 (/zgAnL) IC70 (/zg/mL) Cisplatin 2.15 5.25 Card Ming 27.27 69.04 Hexamelamine >100 >100 Jimsaitabine 0.015 0.055 Brin 0.061 4.66 Cell line: PC3 Compound IC50 (/Zg/mL) IC70 (//g/mL) Estrostatin 27.50 68.18 Goserelin>100 >100 Prednisolone 185.007 287.102 Indigo Brin 0.015 0.027

The Chou-Talalay median effect method is used to quantitatively characterize drug-drug interactions (Chou TC, the rationale for synergy and antagonism in drug binding studies, experimental design, and computerization 44 200838521) Rotational 'Pharmac〇l Rev. (September 2006), 58(3): 621_81). The test agent is applied to the cells at the same time, "fixed equal ratio, according to the previously determined individual _ Τ Ρ ΤΓ-, broad A iLso (for example, if (drug, 2 # Μ and IC5G (drug B) = 10 “Μ, the ratio is set to 15〇.) Prepare a mixture of drugs in multiples of their single dose of IC5G and serial dilutions of the mixture. In addition, the dose response of a single dose is also determined for the same/length range. Used in combination studies.

The interaction coefficient (CI (1(^)) at IC5〇 and the interaction coefficient (CI(e)) at the optimum experimental concentration were determined using the CalcuSyn kit software (Table 3, the test was performed in four replicates) , reported mean), the experimental values of CI< 〇·8 are considered to be synergistic, 〇.8 < Cl < 1 · 2 is additive. Table 3: Selected chemotherapeutic agents Synergistic effect with Indo-Brin, determined by the Zhou-Temple Interaction Coefficient (CI) method

Cell line: A549

— 0.32 1.43 1.05 Cell line: MCF7 Periwinkle test Pacific 1 € cefotaxime 5-fluorouracil CI (IC5〇) CI(e) CI(IC50) CI(IC< CI(e) CI(IC5〇) CI (e) CIQCc ^ 1.10 0.50 1.10 0.42 0.87 0.67 0.93 0.46 1.23 CI(e) 0.64 45 200838521 Cell line: SKOV3 顺次白卡# Jim 1 F Thames CI (IC50) CI(e) CI(IC,〇) CI (e) CI (IC, fl) CI(e) 1.29 0.77 1.42 0.73 1.43 0.65 Cell line: PC3 estramustine prednisolone CI (ICso) CI(e) CI(IC5n) Cl(e) 1.52 0.76 1.42 0.91

Growth of A549 cells and exposure to indolin and erlotinib as described above, and propidium iodide to measure DNA content were used to determine the number of viable cells. The concentrations used for the single agent as well as the composition are as follows (erlotinib: indoproil ratio 208: 1 ): erlotinib (ng/mL) 988 1975 3950 7900 15800 31600 63200 Indigbrin (ng/mL) 5 9 19 38 76 152 304 A549 cells were grown and exposed to indolin and card 4 as described above, and sulfonated propionate was measured for DNA content to determine the number of viable cells. The concentrations used for the single agent as well as the composition are as follows (carboplatin: inlinibrin ratio 3 0 3 : 1 ): initial (ng/mL) 180 359 719 1438 2875 5750 11500 23000 46000 92000 Indigo (ng/) mL) 0.6 1.2 2.4 4.7 9.5 19.0 38.0 75.9 151.8 303.6 MCF-7 cells were grown and exposed to indomethacin and 5-FU as described above, and the change in DNA content was determined for the determination of viable cells. number. The concentrations used for the single agent as well as the composition are as follows (5-FU: English 46 200838521 terbutin ratio 10.9:1): 5-FU (ng/mL) 15 30 60 120 240 480 960 Indigbury (ng/mL) 1.4 2.8 5.5 11.0 22.0 44.0 88.1 Growth of MCF-7 cells and exposure to indolin and vinorelbine as described above, and propidium iodide The DNA content was measured for the number of viable cells. The concentrations used for the single agent and composition are as follows (vinorelbine: indoproil ratio 0.016:1): vinorelbine (ng/mL) 0.023 0.045 0.090 0.180 0.360 0.720 1.440 indigrin (ng/mL) 1.37 2.75 5.49 10.98 21.96 43.92 87.84 MCF-7 cells were grown and exposed to indigrin and tamoxifen as described above, and propidium iodide to measure DNA content was used to determine the number of viable cells. The concentrations used for the single agent as well as the composition are as follows (temoxifene: indoprofen ratio 10 0 : 1 ): tamoxifen (ng/mL) 17.2 34.3 68.7 137.5 275 550 1100 2200 4400 8800 (ng/mL) 0.17 0.34 0.69 1.38 2.75 5.50 11.00 22.00 44.00 88.00

MCF-7 cells were grown and exposed to indolin and paclitaxel as described above, and propidium iodide to measure DNA content was used to determine the number of viable cells. The concentrations used for the single agent as well as the composition are as follows (pacific paclitaxel: indomethrin ratio 0.27:1): paclitaxel (ng/mL) 0.75 1.5 3 6 12 24 indigridin (ng/mL) 2.78 5.55 11.10 22.20 44.40 88.80 The inhibition constant (1C) for combination therapy is substantially lower than the inhibition constant for a single agent (see Table 4 below). 47 200838521

Cell line drug single agent (ng/mL) Composition (ng/mL) A549 Indiproxil ic4〇71 ic5〇92 IC4〇21 ic5〇30 Erlotinib IC40 20315 IC5〇38,525 4424 6200 Ingenic Brin IC7 〇95 IC5〇54 IC70 27 IC5〇11 Carboplatin IC70 15365 IC5〇5,827 8044 3481 Ingenic Brin IC6〇129 IC6〇68 Itoposide IC6〇177 94 MCF7 Ingenic Brin IC6〇62 IC5〇13 IC6〇 2.8 IC5〇5 5-FU IC6〇84 IC50 92 30 57 Indigenous Brin IC6〇18.1 IC50 13 IC6〇6 IC5〇8 Changchun Ruibin IC6〇0.26 IC50 0.19 0.10 0.08 Indigo Brin IC6〇18.1 IC50 13 IC6〇 6.4 IC50 4 Tamoxifen IC6〇3166 IC5〇1570 641 376 Yingdi Brin IC84 53 1C50 14 IC84 10 IC5〇4 Pacific Paclitaxel IC84 5.3 IC5〇111 2.7 L08 Ingenic Brin IC5〇13 IC5〇11 Dobby Star IC5〇7 3 SKOV3 Indigenous Brin IC, 〇415 IC5〇22 cisplatin IC, 〇773 780 Indigenous Brin IC, 〇415 IC5〇29 card flip IC, n 12,026 12,881 Indy Brin IC, 〇415 IC5〇47 Jim Saidabine ICso 11 12 PC3 Ingenic Brin IC, 〇34 IC5〇14 Estrostatin IC, 〇 29, 699 26, 466 Indobulin IC, 〇 34 IC5 〇 12 Prednisolone IC, 〇 137, 188 145, 659 Representative dose response curves for individual drugs and compositions are shown in Figures 1-6. Tubulin binding position: Example 1: (N-〇t-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]-glyoxyfuramide; also known as Indy Brin and D-24851) are shown below. 48 200838521

To further define the tubulin binding site of indolin, the indole-labeled indicin was cultured with purified bovine brain tubulin in the presence or absence of a long-term tubulin binding agent. As shown in Figures 7 and 8, 3H-Indolin or 3H-colchicine and biotin-labeled fetal bovine brain tubulin were cultured. When indicated, add 2 〇〇-mole excess of cold competitor. The tubulin heterodimer was then precipitated with streptavidin-coated SPA beads and the bound radioactivity was determined. "No microtubule = ..., 1 double white" shows the radioactivity of non-specific binding measured in the absence of biotin-labeled tubulin. Figure 7 shows that colchicine, nocodazole, and podophyllotoxin (p〇d〇phyU〇t〇xin) (both of which bind to the same tubulin binding site) compete with guayin Micro:: White combined 'and Changchun flower test and Taxi do not compete.帛8 figure shows Yingdi: Lin inhibits Xiao, the combination of 3H_colchicine. Nocodazole and podophyllotoxin completely inhibited binding, while Taxol and Vinca flower test did not work. The data of the second b and the previously published Indigo Brin did not compete for the binding of 3H_colchicine in the non-biotinylated Bach tubulin (G·Zecco raCaneer Res.61 ()), showing English The combination of sputum and succulent is different from colchicine, but with colchicine. Example 2: ^ Tubulin from neuronal tissue was post-translationally modified, and 49 200838521 increased the extent of modification during the development of the meridian. The neurons of the fetal bovine brain micro-quot; white and tubulin from other tissues, their post-translational modification is different from the tubulin of the bovine brain. The polymerization of purified fetal bovine brain microtubule protein was inhibited by increasing the concentration of indomethacin, with an IC5 of about 25:M. The value and the maximum suppression of 9〇%, as shown in Figure 9. Tubulin aggregation was administered as a percentage of the (d) DMS 〇 control group. The polymerization of tubulin in the bovine brain was only inhibited by indomethacin by 25% at the highest dose tested. Conversely, Changchunxin or colchicine inhibits the polymerization of fetal bovine and bovine brain tubulin to a similar extent. Indole Brin can't bind to the tubulin of neurons' supports previous clinical studies as well as the first! period

The lack of neurotoxicity of indomethacin was observed in clinical trials. Example 3: Central Boolean does not disrupt the axonal microtubules of rat pheochromocytoma (PC12) cells. The natural development of PC 12 protrusions is induced by NGF for 5-6 days. The cells were then treated with DMSO, indomethacin or colchicine for 24 hours (each 2xICSG concentration). The microtubules within the protuberances were visualized by immunostaining with antibodies recognizing the acetylated (axon) guanidin, leaving the cell bodies unstained. The DMSO control group and the cells treated with indomethacin showed the same staining pattern, indicating that indobumin did not affect the axonal microtubules. Conversely, treatment with colchicine results in a strong decrease in microtubules and a diffuse staining indicating that the microtubules are partially disrupted by colchicine. Example 4: In order to extend the observation of the anti-tumor activity of the earlier indole, the penicillin was tested in a series of cancer models including human glial maternal 50 200838521 tumor xenograft (U87). Figure 11 shows the growth of U87 glioblastoma xenografts by oral administration of indolin. 5 χ^ 〇 6 U87 glioblastoma cells were subcutaneously transplanted into immunodeficient nu/nu mice. Treatment was started when the tumor weight was about 〇·15 g (Day 0). Example 5:

As shown in Fig. 12, oral administration of indomethacin inhibited the growth of RENCA in murine renal cell carcinoma. ι·5χ1〇6 RENCA cells were injected into the subcapsular space of the kidney via the incision of the two flank (day i). Inulin was administered orally daily from day U0 (5x/week) at the indicated dose. On day 21, the mice were sacrificed and the weight and volume of the primary tumor, the weight and number of lung metastases, and the shift formation in the abdominal lymph nodes were determined. The reduction in tumor volume and weight by Indolin (D-2485 1) was statistically significant. The data transferred did not show; the number of lung metastases decreased, but not statistically significant. Tnp_47 has shown anti-tumor activity in different animal models and its use in RENCA has been established. Example 6: In order to extend the observation of the anti-tumor activity of the earlier indole, the penicillin was tested in a series of cancer models including murine renal cell carcinoma (turned CA), DMBA in rats Induced breast cancer, human hereditary cancer xenograft (SK-OV-3), human prostate cancer xenograft (pc_3), human vulvar squamous cell carcinoma xenograft (A431), human glioblastoma xenograft (U87) ), human breast disease (M, refractory L, MCF-7) and human lung cancer (A 549 ). In all models, the British T 夬 不 显 显 显 显 显 51 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 Importantly, at effective doses, animals did not show signs of neurotoxicity or weight loss associated with taxane or vinca alkaloid treatment. Significant differences in the pharmacokinetics and safety records of Indira Brin have made it a strong candidate for the development of time-course growth inhibition (%) for species that are anti-cancer drugs 0 tumor organs or sources of origin * MCF7 breast human 38.3 mg/kg/d5 4x (3x weeks) >100 DMBA breast rat 46.4 mg/kg/d, 2x (3x weeks) 99.5 U87 glial human 27.5 mg/kg/d5 3x (3x weeks) 88.8 RENCA kidney mice 17.5 mg/kg/d, d. 1-20 (5x weeks) 90 PC-3 prostate human 180 mg/kg/d, d. 0, 7,14 63 A431 vulvar human 27.5 mg/kg/d , 3x (3x weeks) 63 SKOV-3 Ovarian human 100 mg/kg/d, d· 0, 7, 14 53 * at the time of sacrifice in the control animals.

Example 7: The indole concentration, which shows anti-angiogenic activity in the pre-clinical mode, is well within the plasma concentration observed in the Phase I study in progress. In a recent study in the United States, three patients were treated with 400 mg BID of indigridin on the duration of continuous treatment. A 76-year-old man diagnosed with a papillary thyroid carcinoma showed stable disease after treatment; however, the first assessment of tumor measurement was reduced by 11%, and thyroglobulin levels were 15 days after administration. 34% less than baseline. The treatment is continuing. In addition, a 58 52 200838521-year-old woman diagnosed with ovarian cancer, along with brain metastases, had a cAl25 deficit of 11% less than baseline after 22 days of treatment with indole. The treatment is continuing. Equals: Using experiments that do not exceed routines, those skilled in the art will understand or be able to determine many equivalents to the compounds described herein and methods of use thereof. Such equivalents are considered to be within the scope of the present invention and are covered by the scope of the following claims.

All of the above cited kite documents and publications are hereby incorporated by reference. The entire contents of which are hereby incorporated by reference are hereby incorporated by reference in their entirety in the the the the the the the the the BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A shows the dose response curve of the indoline-erlotinib combination and A549 nslc cells, which are compared with the agents used alone. Figure 1B shows the indica and erlotinib IC4, alone and in combination. The concentration of (ng/mL), in which the γ_scale is normalized, so that the concentration of each single agent is set to 1%. Figure 2 shows the dose response curve of the indolin-carboplatin combination with Α549 NSLC cells compared to the agents used alone. The second panel shows the concentration of ICi (ng/mL) of indicole and carboplatin, alone and in combination, wherein the gamma-scale is normalized so that the concentration of each single agent is set to 100%. Figure 3 shows the dose response curve for the combination of the ingredient **5_FU and mcF7 cells compared to the agents used alone. 53 200838521 Figure 3B shows the concentration of ICB (ng/mL) in inches and in combination, in combination with 5-FU, where the Y-scale is normalized so that the concentration of each single agent is set to 100%. Figure 4A shows the dose response curves of indoline-vinorelbine combination and MCF7 cells compared to the agents used alone.

Figure 4B shows the concentration of ICBG (ng/mL), singapore and vinorelbine, alone and in combination, wherein the gamma-scale is normalized so that the concentration of each single agent is set to 100%. Figure 5A shows the dose response curve of the indole-temoxifene combination and MCF7 cells compared to the agents used alone. Figure 5B shows the IC6G (ng/mL) concentration of indomethacin and tamoxifen, alone and in combination, wherein the gamma scale is normalized so that the concentration of each single agent is set to 100%. Figure 6 shows the reaction curve of the indomethacin-pacific paclitaxel (taxol) combination with the CF7, and the field cell, which is compared with the agent used alone. Figure 6 shows the IC ( / & 84, g mL ) / Chen, which is used alone and in combination, and the paclitaxel (Taisu), which is the Y-scale hanging = each 'single' The concentration of the agent is set to 100%. Figure 7 shows the combination of colchicine, 诺常士士#拉/巧思f, and podophyllotoxin and 3Η-Yangdi Bulin. I burned alkali and as a vegetarian, but did not compete with the dog. The cup inhibited ~, nocodazole and h W υ / 0 3 Η · colchicine knot and ghost white 毋 元 全 3 3 I I I I I I I I I I Η 秋 秋 秋Combination of hormones, 54 200838521 While Taxol and Vinblastine have no effect. Figure 9 shows the effect of the polymerization of the British pipe protein: for the purification of the ... burdock The first chart shows the growth of oral control + pots of MCF7 breast cancer. Inhibition of U87 glianum in the xenotransplantation The π map shows that oral administration of indomethacin inhibits the growth of tumor xenografts.

Figure 12 shows that oral administration of indomethacin inhibits the growth of murine renal cell carcinoma RENCA. ' [Main component symbol description] None

55

Claims (1)

200838521 X. Patent application scope: '1 · hdibulin or a pharmaceutically acceptable salt thereof and use of one or more other therapeutic agents for the preparation of a medicament for treating cancer, wherein The combination shows greater efficacy than the efficacy of either agent alone. 2. The use of indolin or a 4-pharmaceutically acceptable salt thereof is orally administered according to the use of the scope of the patent application. 3. The use according to item 1 of the scope of the patent application, wherein indolin or a pharmaceutically acceptable salt thereof is administered intravenously. 4 • The use of indolin and one or more other therapeutic agents are synergistic according to the use of claim 1 of the scope of the patent application. 5. The use according to item 1 of the scope of the patent application, wherein indolin and one or more other therapeutic agents are additive. 6 · According to the application of the first application scope, the other therapeutic agents are transported from erl〇tinib, carboplatin, 5-fluorourine, capecitabine (capecitabine) ), paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin ( Doxorubicin ), vinblastine, etoposide, and prednisolone. 7. The use according to claim 1, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, ovarian cancer, and prostate cancer. S. The use according to item 1 of the scope of the patent application, wherein the compound and 56 200838521 - one or more other therapeutic agents are administered simultaneously. 9. The use according to item 1 of the scope of application of the patent, wherein one or more of the other/oral treatments are administered within about 5 minutes to about 48 hours before or after administration of the compound. 1 〇 According to the use of claim 9 of the patent application, one or more of the other therapeutic agents are administered within 5 minutes to about 1 hour before or after administration of the compound. 11 · According to the use of the first application of the scope of patent application, wherein the thiol_3_methanoic acid derivative is indolin. 12. A kit of 'integrins and selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, temoxim, vinorelbine, cisplatin, Jim Other therapeutic agents for saponin, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone. A use of a thiol-3-glyoxylic acid derivative of the formula (I), or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents for the preparation of a medicament for treating cancer, wherein The combination shows greater efficacy than the efficacy of either agent alone: Ri Formula (I) wherein: R is selected from hydrogen; (crC6)-alkyl, wherein the alkyl group is optionally η 57 200838521 " (which is optionally halogen, (CrC6)-alkyl, (C3-C7) ) «cyclodyl, rebel, ^--co-glycolized Wei, difluoromethyl, thio, methoxy, benzyloxy, mono- or polysubstituted) or benzyl (which a mono- or poly-substituted mono- or poly-substituted (Ci-C:6)-alkyl, halogen or trifluoromethyl group; a benzyloxycarbonyl group; a third-butoxycarbonyl group; Amidino group; R! is selected from a benzene ring (which may optionally be (C"C6)-alkyl, (Ci_c6)-alkoxy, cyano, halogen, trimethyl, benzyl, benzyloxy, Schiff base, amine group, dc^)·amine group, (cvd·oxygenated amino group, several groups or mono- or poly-substituted carboxyl group esterified with Ci-C6-alkanol); pyridyl bite of formula (II) structure: 3 2 Formula (II) Or an N-oxide thereof (wherein the fluorene structure is selectively bonded to the ring carbon atom 2, 3 or 4, and is optionally substituted with a substituent R5 and R6, wherein r5 and R6 are the same or different and are Selected from (cvg)-alkyl, (c3-c7)-cycloalkyl, (Crc 6)-alkoxy, wall group, amine group, mercapto group, halogen, tri-I methyl group, ethoxylated amine group, And a thiol alkoxy group, wherein the alkyl group includes a 1-4C atom; a 2 or a 4-pyrimidinyl group (wherein the 2-pyrimidinyl ring is optionally monosubstituted or substituted with a methyl group); 2-, 3-, 4- Or 8-quinolinyl (which is optionally substituted with (Cl_C6)-alkyl, halogen, nitro, amine or (CVC6)-alkylamino); 2-, 3- or 4-quinolinylmethyl ( Wherein the acridine methyl ring carbon, the quinolyl group, and the quinoline methyl group are optionally substituted by (CrC6)-alkyl, (CVC6)-alkoxy, nitro, amine 58 200838521 or alkoxycarbonylamine And: allylaminecarbonyl-2-methylpropan-1-yl; R! (in the case where R is hydrogen, methyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, or ethyl) Medium) is further selected from -CH2COOH; -ch(ch3)_cooh; -(ch3)2-ch-(ch2)2-ch_coo-; h 3c-h2c- CH(CH3)-CH(COOH)-; HO-H2C-CH(COOH)-; phenyl-ch2-CH(COOH)-; (4-imilinyl)-CH2-CH-(COOH)-; HN =(NH2)-NH-(CH2)3-CH(COOH)-; H2N-(CH2)4-CH(COOH)-; h2n-co-ch2Tch-(cooh)-; and HOOC-(CH2)2- CH(COOH)-; Ri (in the case where R is hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl, etidyl or benzyl) may be an acid group of a natural or unnatural amino acid (for example, --glycine thiol, α-inosine thiol, α-silylamine sulfhydryl, α-phenylalanine fluorenyl, α-histamine sulfhydryl, α-ammonium hydrazino, α-spermine thiol, α - An amidino group, an alpha-aspartate group or an alpha-glutamine group, wherein the amine group of the individual amino acid may be protected or unprotected, wherein suitable protecting groups include, but are not limited to, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, or an ethyl fluorenyl group, and in the case where h is an aspartame or a glutamine group, the second, unbonded carboxyl group is a free carboxyl group or a C. An ester of ^-Cr alkanol (for example, a mercapto ester, an ethyl ester or a third butyl ester) exists; R and Ri may further form a formula together with the nitrogen atom to which they are bonded ( III) The ring of the morphine ring or the homopiperazine ring, the limiting condition being an amine alkyl group, 59 200838521 N-R7 Formula (III) R7 is selected from the group consisting of phenyl; phenyl (which may optionally be (crc6)-alkyl, (cv c6)-alkoxy, halogen, nitro, amine or (Cl-C6) )-alkylamino mono- or poly-substituted); diphenyl fluorenyl and bis-p-fluorodiphenylmethyl; • R 2 is selected from hydrogen; (CVC6)-alkyl (wherein alkyl is optionally halogen, benzene a group (wherein the phenyl group is optionally a halogen, (crc6)-alkyl group, (c3-c7)-cycloalkyl group, a carboxyl group, a carboxyl group esterified with a Crc6-alkanol, a trifluoromethyl group, a hydroxyl group, Mono- or poly-substituted methoxy, ethoxy or benzyloxy), 2-quinolyl (optionally or optionally as a (crc4)-alkyl or (C"c4)-alkoxy group Substituted or 2-, 3- or 4-acridinyl (optionally substituted or substituted with halogen, (CVCV)-alkyl or (Ci-C^)-homolyl soap, or substituted) An aryl group (wherein the aryl group is optionally a halogen, (CrCJ-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl group esterified with a Crc6-alkanol, trifluoromethyl, hydroxy, Methoxy, ethoxy or benzyloxy mono- or polysubstituted); r3 and r4 are the same or different and are selected from hydrogen, (crc6)-alkyl, (c3-c7)-cycloalkyl, (cvc6)-alkylindenyl, (CVC6)-alkoxy, halogen, benzyloxy, nitro, amine, (crc4)-mono or dialkyl-substituted amine, (C"C6)-alkane Oxycarbonylamino and (CrC6)-alkoxycarbonylamino-(CrC6)-alkyl; Z is hydrazine or S. 14. The use according to item 13 of the patent application, which is selected from (Ci-CJ-alkane) Base (wherein alkyl is optionally halogen, phenyl (where phenyl 200838521) Depending on the carboxyl, (eve,) alkyl group, (c3-c7:l. cycloalkyl, carboxyl group, carboxyl group esterified with C]-Cr alkanol, trifluoromethyl, hydroxy, methoxy , ethoxy or benzamidine mono- or polysubstituted), 2-quinolyl (optionally substituted or substituted with halogen, (Cl_C4)·fluorenyl or (CVC4)-alkoxy), or 2 3_ or 4-pyridyl (monosubstituted or polysubstituted by halogen, (C1_C4)-alkyl or (CrC4)-alkoxide, mono- or polysubstituted); aryl-based (wherein the aryl moiety is optionally Halogen, (crc6)-alkyl, (crC7)-cycloalkyl, carboxyl, carboxylated with Ci-C6-alkanol, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy Single or multiple substitution). 15. The use according to claim 13 or 14, wherein the other therapeutic agent is selected from the group consisting of erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine , cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone. 16·—A kind of screaming. The use of a cytosine derivative for the treatment of a cancer selected from the group consisting of adenoid cystic carcinoma, renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer Pharmaceuticals 17 - The use of a thiol-3 - glyoxylic acid derivative in combination with another agent or a therapeutic method for the preparation of a medicament for the treatment of cancer. 18. Use according to item I of the scope of the patent application, wherein the other agent or therapy is selected from the group consisting of chemotherapy, radiation therapy, hormonal therapy, targeted therapy, immunotherapy, gene therapy or surgery. 19. Use according to item 18 of the scope of the patent application, wherein the other agent is 61 200838521 chemotherapeutic agent. 20. Use according to any one of claims 17 to 19 wherein the individual components of the combination are administered simultaneously, continuously or separately. 21. The use according to claim 20, wherein the mercapto glyoxylic acid derivative is indolin. 22. The use according to claim 21, wherein the cancer is selected from the group consisting of adenoid cystic carcinoma, renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer. 23. The use according to claim 22, wherein the cancer is selected from the group consisting of renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer. 24. Use for the treatment of cancer comprising administering a thiol-3-glyoxylate derivative in a daily dose of from 1 to 2 mg. 25. The use according to claim 24, wherein the daily dose is from about 250 to about 2000 mg. 26. The use according to item 25 of the scope of the patent application, wherein the thiol_3_acetic acid derivative is administered once a day. 27. The use according to claim 25, wherein the mercapto glyoxylic acid derivative is administered twice daily. 28. The use according to item b of the scope of the patent application, wherein the thiol 3-acetate derivative is administered in continuous treatment. XI. Schema: as the next page 62