CN101296697A - Methods of using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of cancer - Google Patents

Abstract

Methods of treating, preventing or managing cancer, including certain leukernias are disclosed. The methods encompass the administration of enantiomerically pure (+)-l,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-l-pyrrolidinyl]-4-oxo-l-(2-thiazolyl)-l,8- naphthyridine-3-carboxylic acid. Also provided are methods of treatment using this compound with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy. Pharmaceutical compositions and single unit dosage forms suitable for use in the methods are also disclosed.

Description

Use (+)-1,4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid treatment method for cancer

The application requires the Application No. 11/218 of JIUYUE in 2005 application on the 2nd, 387 and 11/218,653 (and now transferring U.S. Provisional Application to), with the U.S. Provisional Application of on April 3rd, 2006 application number 60/789,093 and 60/788, the priority of the U.S. Provisional Application 60/810,285 of application on June 1st, 927 and 2006.All above-mentioned applications all are incorporated herein by reference in full.

1. technical field

The invention provides by giving optically pure (+)-1,4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid is called SNS-595 or AG-7352 again and treats, prevents or control to comprise specific leukemic method for cancer.Dosage, dosage regimen and the consumption of SNS-595 and administration thereof also are provided.

2. background technology

The chemical name of SNS-595 is (+)-1,4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid, it has following structural formula:

SNS-595 since its active anticancer by known.Mention available SNS-595 in the document and treat following cancer: bladder cancer, breast carcinoma, cervical cancer, colon cancer, the esophageal carcinoma, head and cervical region cancer, hepatocarcinoma, pulmonary carcinoma, melanoma, myeloma, neuroblastoma (being the CNS cancer), ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, sarcoma, skin carcinoma, gastric cancer, carcinoma of testis, thyroid carcinoma and uterus carcinoma.Reported multiple dosage regimen, for example, referring to U.S. Patent Application Publication No. 2005-0203120,2005-0215583 and 2006-0025437, all above-mentioned open all full text are incorporated herein by reference.

When treating, preventing with the SNS-595 administration or controlling the multiple cancer that comprises leukemia, still need safe and effective consumption and dosage regimen.

3. summary of the invention

SNS-595 is a kind of known cytotoxicity preparation that anticancer effectiveness is arranged.The present invention has discussed and has comprised the specific leukemic novel method of treatment of treatment.In addition, unique dosage range, dosage regimen and drug dose have also been described.

This description has been described with SNS-595, its pharmaceutical composition and unique dosage treatment, prevention or control cancer.Usually, the cancer types of available method treatment provided by the present invention, prevention or control includes but not limited to: bladder cancer, breast carcinoma, cervical cancer, colon cancer (comprising rectal cancer), the esophageal carcinoma, head and cervical region cancer, hepatocarcinoma, pulmonary carcinoma (minicell and non-small cell), melanoma, bone marrow cancer, neuroblastoma (being the CNS cancer), ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, sarcoma (comprising osteosarcoma), skin carcinoma (comprising squamous cell carcinoma), gastric cancer, carcinoma of testis, thyroid carcinoma and uterus carcinoma.These cancers can be recurrence, intractable or conventional therapy are had toleration.

In certain embodiments, described cancer comprises malignant hematologic disease, includes but not limited to leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin (being also referred to as Hodgkin lymphoma) and myeloma.Different types of leukemia includes but not limited to: chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukaemia and acute myeloblastic leukemia.This leukemia can be recurrence, intractable or chemical sproof.In certain embodiments, this malignant hematologic disease is promyelocytic leukemia, T-chronic myeloid leukemia or Lymphocytic leukemia.

The present invention further provides by giving SNS-595 in some way and treated, prevented or controlled method for cancer.In certain embodiments, this method comprises that giving dosage according to body surface area to mammal is about 1mg/m ²To 150mg/m ², about 1mg/m ²To 100mg/m ², 1mg/m ²To 75mg/m ², 15mg/m ²To 80mg/m ², or about 3mg/m ²To 24mg/m ²SNS-595.In certain embodiments, this method comprises that giving dosage according to body surface area to mammal is about 15g/m ², 25g/m ²Or 50mg/m ²SNS-595.Other dosage and dosage regimen have more detailed description hereinafter.

The present invention also provides at the dosage of solid tumor and dosage regimen.The dosage of SNS-595 can be passed through single dose, for example 10-15 minute IV injects and sends (for example single bolus injection), perhaps in a period of time, for example during 24 hours (for example continue transfusion or gradation bolus injection) in time sends and repeats as required, for example stable or recover up to conditions of patients, or get along with or produce unacceptable toxicity up to conditions of patients.

In some embodiments, can give SNS-595 to patient's circulation.Circulation treatment comprises and gives this active agent a period of time, thereupon drug withdrawal a period of time and repeat this order of administration.Circulation treatment can reduce one or more treatments are produced drug resistance, avoids or reduces a kind of side effect of treatment and/or improve curative effect.

In another embodiment, SNS-595 and another kind of medicine (" second active agent ") or the another kind of conventional therapy that is used for the treatment of, prevents or control cancer are united use, or SNS-595 medication described in the invention can be used to the environment of therapeutic alliance.Second active agent comprises known micromolecule, anticancer, antitumor or cytotoxic reagent and macromole (as protein and antibody), and its example provides at this, and stem cell and umbilical blood.The example of conventional therapy includes but not limited to: surgical operation, chemotherapy, X-ray therapy, hormonotherapy, biotherapy, immunotherapy, blood transfusion and combination thereof.

Therefore, in certain embodiments, the invention provides the associating of treatment, prevention and controlled entity tumor.In other embodiments, the invention provides treatment, prevention and control leukemia and lymphadenomatous associating.

The present invention also provides and has comprised SNS-595 and second or the pharmaceutical composition of other active agent, single unit dosage forms and dosage regimen.Second active agent comprises particular combinations or " the cocktail mixing " of medicine or treatment, or both.

4, description of drawings

Fig. 1 has described with the SNS-595 blood drug level in different patient's groups of qwk * 3 scheme administrations over time;

Fig. 2 has shown the formation with the nuclear focus of HCT116 cell after SNS-595, etoposide, bleomycin and the plus cisplatin in treatment;

Fig. 3 has described that to carry out focus quantitative by measuring the focus fluorescence intensity;

Fig. 4 has shown focus formation and the dependency relationships of dosage and time;

Fig. 5 will be shown as the function of time and SNS-595 concentration greater than the cell of 2 focuses;

Fig. 6 has shown to be had and not to have under the condition of caffeine (it is ATM and ATR inhibitor) by SNS-595 and the inductive DNA damage of etoposide;

Fig. 7 has shown under the condition of DNA-PK is arranged (MO59K cell) and no DNA-PK (MO59J cell) by SNS-595 and the inductive DNA damage of etoposide;

Fig. 8 a-c has shown the working in coordination with/additive effect HCT 116 colon cancer cell drug combinations with SNS-595 and differential cytotoxicity preparation;

Fig. 8 d has shown the working in coordination with/additive effect H460 lung carcinoma cell drug combination with SNS-595 and differential cytotoxicity preparation;

Fig. 9 has shown the index that share when the SKOV3 ovarian cancer cell line of expressing p53 (+/+) and not expressing p53 (/-) used SNS-595 and DNA damage agent of selecting for use and antimetabolite simultaneously, represents with black and Lycoperdon polymorphum Vitt rhombus respectively;

Figure 10 a-d has shown SNS-595 and the differential cytotoxicity preparation effect to HCT 116 colon cancer cell drug combinations;

Figure 11 provide to late period patients with solid tumor give weekly dose (qwk * 3 three times; Circle=first week; Triangle=second week) and per three the week dosage (q3wk; Rhombus) the dosage linear relationship of SNS-595;

Figure 12 provides the anti-tumor activity of SNS-595, etoposide, doxorubicin and irinotecan in the CCRF-CEM heteroplastic transplantation model to compare;

Figure 13 provides the anti-tumor activity of SNS-595 in the LM3-Jck heteroplastic transplantation model (20mg/kg and 25mg/kg), etoposide, doxorubicin and irinotecan to compare;

Figure 14 has shown the medullary cell structure of the initial female CD-1 mice of injection of SNS-595 after 6 days.SNS-595 gave at the 0th day and the 4th day.All images amplification 10 shows to be shown;

Figure 15 provides the neutrophil cell reaction to SNS-595 dosage;

Figure 16 provides under the different SNS-595 dosage the 8th day neutrophil cell counting;

Figure 17 provides under the different SNS-595 dosage the 8th day WBC counting;

Figure 18 provides under the different SNS-595 dosage the 8th day platelet count;

Figure 19 provides and has given different time body weight change percentage ratio at interval behind the SNS-595; With

Figure 20 has shown behind the SNS-595 that gives 20mg/kg the bone marrow bounce-back at the 12nd day.

5. definition

Except as otherwise noted, employed scientific and technical terminology has the implication that those of ordinary skills understand usually among the present invention. The patent of all references, application, disclosed application and other publication all are incorporated herein by reference in full. If there is multiple implication in the term in this specification, unless otherwise stated, be as the criterion with the definition in this part.

Optically pure (+)-1 among the present invention, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid does not contain (-)-1 substantially, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid (being the enantiomeric excess form). In other words, " (+) " form 1,4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid does not contain this compound of " (-) " form substantially, thereby is the enantiomeric excess for " (-) " form. Term " optically pure " or " pure enantiomer " expression contains the compound that percentage by weight surpasses 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% enantiomer.

Except as otherwise noted, used term among the present invention " optically pure (+)-1; 4-dihydro-7-[(3s; 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1; 8-naphthyridines-3-carboxylic acid " refer to contain (+)-1 at least about 80% percentage by weight, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid and (-)-1 of about 20% percentage by weight at the most, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid, (+)-1 at least about 90% percentage by weight, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid and (-)-1 of about 10% percentage by weight at the most, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid, (+)-1 at least about 95% percentage by weight, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid and (-)-1 of about 5% percentage by weight at the most, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid, (+)-1 at least about 97% percentage by weight, 4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid and (-)-enantiomer of about 3% percentage by weight at the most.

Except as otherwise noted, used term " treatment " refers to alleviate or reduce the seriousness of the symptom relevant with treatment disease or situation among the present invention.

Term " prevention " comprises the symptom that suppresses specified disease or illness. In some embodiments, there is the patient of cancer family history to be the candidate of prevention scheme. Usually, term " prevention " refers to administration before paresthesia epilepsy, especially to high-risk cancer patient.

Except as otherwise noted, employed term " control " comprises that prevention once suffered from the recurrence of this disease among the patient of specified disease or illness or illness among the present invention, prolong the time that the patient who suffers from this disease or illness is in relieved state, reduce patient's the death rate, and/or the seriousness of the symptom relevant with the disease for the treatment of or situation is maintained the reduction level or avoids this symptom.

Employed among the present invention " individuality " is animal, is generally mammal, comprises the mankind, such as the patient.

Employed term " cancer " includes but not limited to solid tumor and haematogenous tumour among the present invention. Term " cancer " refers to skin histology, organ, blood and vascular diseases, includes but not limited to: carcinoma of urinary bladder, osteocarcinoma or leukemia, the cancer of the brain, breast cancer, cervical carcinoma, chest cancer, colon cancer, carcinoma of endometrium (endrometrium), the cancer of the esophagus, cancer eye, head cancer, kidney, liver cancer, lung cancer, carcinoma of mouth, neck cancer, oophoroma, cancer of pancreas, prostate cancer, the carcinoma of the rectum, cancer of the stomach, carcinoma of testis, laryngocarcinoma and the cancer of the uterus.

Employed among the present invention " malignant hematologic disease " refers to that health blood forms system and immune system-marrow and adenoid cancer. This cancer comprises leukaemia, lymthoma (NHL), Hodgkin's disease (being also referred to as Hodgkin lymphoma) and myeloma.

Term " leukemia " refers to the malignant tumor of blood formative tissue.This leukemia includes but not limited to: chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukaemia and acute myeloblastic leukemia.This leukemia can be recurrence, intractable or conventional therapy had toleration.

Employed among the present invention " promyelocytic leukemia " or " acute promyelocytic leukemia " refer to lack ripe blood cell in the myeloid cell, but the malignant tumor of the bone marrow of the excessive immature cell that is called promyelocyte is arranged.Its common feature is that chromosome dyad 15 and 17 exchanges.

Employed among the present invention " acute lymphoblastic leukemia (ALL) " is also referred to as " acute lymphoblast leukemia " and refers to by the thin born of the same parents' misgrowth of early stage agranular leukocyte or lymph and grow the malignant disease that is caused.

Lymphoid some cell that employed among the present invention " T chronic myeloid leukemia " refers to wherein to be called T lymphocyte or T cell is virulent disease.The T cell is usually can the challenge virus infection cell, external cell, cancerous cell and produce the leukocyte of the material of regulating immune response.

Term " recurrence " refers to by treating back its cancerous cell of patient of being eased of cancer repeatedly situation again.

Term " intractable or toleration is arranged " still has the situation of residual cancer cell even refer to through behind the intensive treatment in patient's body.

Employed IC among the present invention ₅₀Finger reaches amount, concentration or the dosage of the concrete test compounds of 50% maximum depression effect in the test that detects described effect.

Except as otherwise noted, " the treatment effective dose " of employed term chemical compound and " effective dose " refer to the amount that enough produces therapeutic effect in treatment, prevention and/or control disease, delay or reduce the symptom relevant with disease of being treated or disease among the present invention.Term " treatment effective dose " and " effective dose " can comprise the raising comprehensive therapeutic effect, reduce or eliminate the symptom or the cause of disease of disease or disease, or improve the amount of the curative effect of another kind of treatment reagent.

Except as otherwise noted, employed term " pharmaceutically acceptable salt " includes but not limited to be present in the acidity in the chemical compound provided by the present invention or the salt of basic group among the present invention.Under some acid condition, described chemical compound can form various salt with multiple inorganic and organic acid.The acid that can be used to prepare the pharmaceutically acceptable salt of this alkali compounds is meant that those formation contain the acid of pharmaceutically acceptable anionic salt, include but not limited to: acetic acid, benzenesulfonic acid, benzoic acid, heavy carbonic, acid tartaric acid, bromide, Ca-EDTA, d-camphorsulfonic acid, carbonic acid, chloride, bromide, iodide, citric acid, dihydrochloride, edetic acid, ethionic acid, rely on acid, piminodine ethylsulfonic acid (esylate), fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycollylarsanilate, hexylresorcinate, breathe out amine (hydrabamine), carbonaphthoic acid, hydroxyethylsulfonic acid., lactic acid, lactobionic acid, malic acid, maleic acid, mandelate, methanesulfonic acid, methylsulfuric acid, muscate, LOMAR PWA EINECS 246-676-2, nitric acid, pantothenic acid, phosphoric acid/diphosphonic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, sulphuric acid, tannin, tartaric acid, tea chloric acid (teoclate), three second iodide (triethiodide) and pounce on acid.Under some alkali condition, described chemical compound can form basic salt with multiple pharmaceutically acceptable cation.The nonrestrictive example of this salt comprises alkali metal salt or alkali salt, especially calcium salt, magnesium salt, sodium salt, lithium salts, zinc salt, potassium salt and iron salt.

Except as otherwise noted, employed term " hydrate " refers to compound or its salt provided by the present invention among the present invention, and it also comprises with the water bonded stoichiometry of non-covalent intermolecular force or the non-stoichiometry amount.

Except as otherwise noted, employed term " solvate " refers to that one or more solvent molecules combine formed a kind of solvate with chemical compound provided by the present invention among the present invention.Term " solvate " comprises hydrate (for example monohydrate, dihydrate, trihydrate, tetrahydrate or the like).

Term " altogether administration " and " associating " comprise side by side, concurrently or under the situation of no standard time restriction, one after the other give two kinds and treat reagent (for example SNS-595 and another kind of anticarcinogen or second reagent).In one embodiment, two kinds of reagent are present in the cell simultaneously or in patient's body, perhaps bring into play biology or therapeutic effect simultaneously.In one embodiment, two kinds of treatment reagent are in same compositions or unit dosage forms.In another embodiment, two kinds of treatment reagent are in compositions of separating or unit dosage forms.

Term " supportive care reagent " refers to any treatment, prevention or controls the material of the ill effect that is caused by the SNS-595 treatment.

6. Fa Ming detailed description

6.1SNS-595

Used chemical compound is optically pure (+)-1 in the our bright Treatment and composition for, 4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid is also referred to as SNS-595 or AG-7352.SNS-595 has following chemical constitution:

In certain embodiments, the pharmaceutically acceptable salt of SNS-595, solvate, hydrate or prodrug are used in the method and composition of the present invention.

SNS-595 can prepare by means commonly known in the art, for example the title of announcing on October 6th, 1998 is " chemical compound; its preparation method and anti-tumor agent comprising salmosin (Compounds; processes for thepreparation thereof and antitumor agents) " United States Patent (USP) 5,817, the Japanese patent application Hei 10-173986 of preparation method in 669 Embodiment C-1 and Chikugi etc., these two parts of patents all are incorporated herein by reference in full.Comprise SNS-595 pharmaceutical composition some examples with and using method in U.S. Patent Application Publication No. 2005-0203120,2005-0215583 and 2006-0025437, describe, these applications all are incorporated herein by reference.

6.2 using method

The four-stage of proliferative cell experience cell cycle: G ₁, S, G ₂And M.These stages are at first determined by carry out observing splitted cell when DNA synthesizes (it is called as the synthesis phase or the S stage of cell cycle) and mitosis (being also referred to as mitosis stage or the M stage or the S stage of cell cycle) at cell.Be accomplished between the mitosis and mitosis is respectively G to the time slot that observes between the next DNA synthesis cycle in that DNA is synthetic ₁Stage and G ₂Stage.Keep the non-proliferative cell of multiplication capacity under optimum conditions to be in dormancy or G ₀State, its typical characteristic are to have broken away from cell cycle.

SNS-595 is a kind of cell cycle inhibitor, can be at G ₂Stage is caught cell.Be not subjected to concrete one theory, the SNS-595 mediation finally causes the activation in the DNA-PK path of apoptotic cell death.These incidents are that the S stage is peculiar, and promptly they only betide the cell cycle S stage.Be not subjected to concrete one theory, cause the double-stranded DNA fracture number increase that the S stage forms with SNS-595 treatment, this damage has hindered the ability of cell synthetic DNA, and has prolonged the time that cell is in the S stage.In case detect DNA damage in the cell, the apoptosis label occurs rapidly.Seemingly p73 is dependent in the rapid generation of apoptosis, because compare with containing the p73 cell, the sensitivity of SNS-595 descends above 11 times in the p73 null cell.

As shown in Figure 7, the formation of double-strand break activates the DNA-PK mediation in the dose dependent mode and repairs and apoptotic cells mechanism, and include but not limited to: i) DNA-PK expresses; Ii) H2AX phosphorylation; Iii) c-Abl phosphorylation; Iv) p 53 phosphorylations; V) p73 phosphorylation; Vi) p21 expresses; Vii) Caspase (Caspases)-9 activation; Viii) Caspase (Caspases)-3 activation.If DNA damage is very serious, to such an extent as to when connecting (NHEJ) and can not repair double-strand break by non-homogeneous end, cell enters apoptosis rapidly.Some cells can arrive G ₂Stage, but these cells are captured owing to damage can not enter the M stage (by the mediation of cdc2/ cell periodic protein B), and final apoptosis.Be not subjected to concrete one theory, because it is SNS-595 has S-stage selectivity, fatal for non-proliferative cell right and wrong to the deleterious SNS-595 dosage of proliferative cell (therefore just experiencing and comprising the S stages of cell cycle).

6.2.1 solid tumor

Therefore, the invention provides the method for treatment, control or prophylaxis of cancer, this method comprises that the mammal to this treatment of needs, control or prevention gives 1mg/m ²To about 100mg/m ²The SNS-595 of dosage.Cancer types includes but not limited to: bladder cancer, breast carcinoma, cervical cancer, colon cancer (comprising rectal cancer), the esophageal carcinoma, head and cervical region cancer, hepatocarcinoma, pulmonary carcinoma (small cell lung cancer and nonsmall-cell lung cancer), melanoma, myeloma, neuroblastoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, sarcoma (comprising osteosarcoma), skin carcinoma (comprising squamous cell carcinoma), gastric cancer, carcinoma of testis, thyroid carcinoma and uterus carcinoma.In one embodiment, this method comprises tumor, liposarcoma, melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, renal carcinoma, salivary gland carcinoma, small cell lung cancer or carcinoma sarcomatodes in treatment, prevention or control colon cancer, cancer of pancreas, breast carcinoma, mesothelioma, cancer of biliary duct, the smooth muscle.

6.2.2 leukemia

In one embodiment, method provided by the present invention comprises treatment, prevents or controls various types of leukemia, as chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myeloid leukaemia and acute myeloblastic leukemia.

In some embodiments, described method comprises treatment, prevention or control acute leukemia, for example AML includes but not limited to undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 anomaly [M3V]), myelomonocytic leukemia (M4 or M4 eosinophilia anomaly [M4E]), monocytic leukemia (M5), erythroleukemia (M6), acute megakaryocytic leukemia (M7).In some embodiments, acute lymphoblastic leukemia (ALL) comprises the leukemia that comes from haematogonium (B-cell), thymocyte cell (T-cell) and lymph node.According to Fa-Mei-Ying (FAB) morphological classification table, acute lymphoblastic leukemia can be divided into L1-mature form lymphoblast (T-cell or preceding-B-cell), L2-is immature and pleomorphism (multiple shape) lymphoblast (T-cell or preceding-B-cell) and L3-lymphoblast (B-cell; The Burkitt cell).

In one embodiment, acute myeloid leukaemia is undifferentiated AML (M0).

In one embodiment, acute myeloid leukaemia is myeloblastic leukemia (M1).

In one embodiment, acute myeloid leukaemia is myeloblastic leukemia (M2).

In one embodiment, acute myeloid leukaemia is promyelocytic leukemia (M3 or a M3 anomaly [M3V]).

In one embodiment, acute myeloid leukaemia is myelomonocytic leukemia (M4 or a M4 eosinophilia anomaly [M4E]).

In one embodiment, acute myeloid leukaemia is monocytic leukemia (M5).

In one embodiment, acute myeloid leukaemia is erythroleukemia (M6).

In one embodiment, acute myeloid leukaemia is acute megakaryocytic leukemia (M7).

In one embodiment, acute lymphoblastic leukemia is caused by haematogonium (B-cell).

In one embodiment, acute lymphoblastic leukemia is caused by thymocyte cell (T-cell).

In one embodiment, acute lymphoblastic leukemia is caused by lymph node.

In one embodiment, acute lymphoblastic leukemia is to be the L1 type of feature with mature form lymphoblast (T-cell or preceding-B-cell).

In one embodiment, acute lymphoblastic leukemia is to be the L2 type of feature with immature and pleomorphism (multiple shape) lymphoblast (T-cell or preceding-B-cell).

In one embodiment, acute lymphoblastic leukemia is with lymphoblast (B-cell; The Burkitt cell) is the L3 type of feature.

In certain embodiments, acute myeloid leukaemia is promyelocytic leukemia, perhaps Lymphocytic leukemia.In certain embodiments, acute lymphoblastic leukemia refers to the T-chronic myeloid leukemia.In one embodiment, method provided by the present invention comprises the method for treatment, prevention or control promyelocytic leukemia, T-chronic myeloid leukemia or Lymphocytic leukemia.In one embodiment, the T-chronic myeloid leukemia refers to peripheral t-chronic myeloid leukemia, T-cell lymphocyte leukemia, skin T-chronic myeloid leukemia and adult T cell leukemia.

In some embodiments, SNS-595 is used to treat chemical sproof leukemia, as chronic myelogenous leukemia (CML).Thereby, can there be the patient of response that a kind of selection is provided to other Therapeutic Method for those with the SNS-595 treatment.In some embodiments, these other Therapeutic Method comprise usefulness

Treat.The method of treatment Philadelphia chromatin-positive chronic myelogenous leukemia (Ph+CML) is provided in some embodiments.In some embodiments, provide treatment right

The method that chemical sproof Philadelphia chromosome positive chronic myelogenous leukemia (Ph+CML) is arranged.

Method provided by the present invention comprises to having accepted treatment of cancer before but to the responseless patient of standard care, and the patient who did not accept before to treat treats.Although some diseases or disease are commonplace in certain age group, the present invention also provides the treatment patient's who need not to consider patient age method.Further, also provide carrying out the method for operation so that the disease of tissue or the patient that treats of situation and the patient that do not carry out above-mentioned treatment are treated.Because the cancer patient has different clinical manifestations and produces different clinical effectiveness, thus give patient's Therapeutic Method can be according to his/her prognosis difference.Need not undue experimentation, experienced clinician can determine to can be used to treat effectively the concrete second class grade chemical, type of surgery of cancer individual patient easily, not based on the type of the standard care of medicine.

The dosage of SNS-595 can pass through single dose, for example 10-15 minute IV injects and sends (for example single bolus injection), perhaps in a period of time, for example during 24 hours (for example continue transfusion or gradation bolus injection) in time sends and repeats as required, for example stable or recover up to conditions of patients, or get along with or produce unacceptable toxicity up to conditions of patients.For example, the solid tumor stable disease is often referred to the perpendicular diameter that can measure focus and is no more than 25% than measuring last time to increase, referring to, ResponseEvaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the NationalCancer Institute 92 (3): 205-216 (2000).Stable disease or instability can judge that as the assessment of patient's symptom, physical examination uses X-ray, CAT, PET or MRI scanning imagery to make tumor visual, and other evaluation methodology of generally adopting by known method.

In another embodiment, described dosage is about 10mg/m ²-100mg/m ²In another embodiment, this dosage is about 30mg/m ²-75mg/m ²In another embodiment, this dosage is about 40mg/m ²-80mg/m ²In another embodiment, this dosage is about 50mg/m ²-90mg/m ²In another embodiment, this dosage is about 15mg/m ²-80mg/m ²

In another embodiment, described dosage is about 20mg/m ²-30mg/m ²In another embodiment, this dosage is about 25mg/m ²-35mg/m ²In another embodiment, this dosage is about 40mg/m ²-50mg/m ²In another embodiment, this dosage is about 45mg/m ²-55mg/m ²In another embodiment, this dosage is about 50mg/m ²-60mg/m ²In another embodiment, this dosage is about 55mg/m ²-65mg/m ²In another embodiment, this dosage is about 60mg/m ²-70mg/m ²In another embodiment, this dosage is about 65mg/m ²-75mg/m ²In another embodiment, this dosage is about 70mg/m ²-80mg/m ²In another embodiment, this dosage is about 75mg/m ²-85mg/m ²In another embodiment, this dosage is about 80mg/m ²-90mg/m ²In another embodiment, this dosage is about 85mg/m ²-95mg/m ²In another embodiment, this dosage is about 90mg/m ²-100mg/m ²

In other embodiments, SNS-595 and another medicine (" second active agent ") or the method for another treatment, control or prophylaxis of cancer are united use.Second active agent comprises micromolecule and macromole (being protein and antibody), and its example provides in the present invention, and stem cell or umbilical blood.Can include but not limited to the current surgical operation that is used for the treatment of, prevents or control cancer, immunotherapy, biotherapy, X-ray therapy and other non-drug therapy with method or the Therapeutic Method that SNS-595 unites use.The present invention has discussed the individually dosed and/or different dosing regimes in therapeutic alliance of SNS-595.

The present invention also provides the pharmaceutical composition that can be used for method of the present invention (being single unit dosage forms), especially comprises the pharmaceutical composition of the SNS-595 and second active agent.

6.3 dosage and dosage regimen

In one embodiment, the present invention treatment, prevention or control method for cancer comprise according to the patient skin surface area and give dosage about 1mg/m ²To 150mg/m ²SNS-595.In another embodiment, this method comprises that giving dosage is about 1mg/m ²To 100mg/m ²SNS-595.In another embodiment, this method comprises that to dosage be about 1mg/m ²To 75mg/m ²SNS-595.In another embodiment, this method comprises that giving to dosage is about 1mg/m ²To 60mg/m ²SNS-595.In another embodiment, this method comprises that giving dosage is about 1mg/m ²To 50mg/m ²SNS-595.In another embodiment, this method comprises that to dosage be about 1mg/m ²To 48mg/m ²SNS-595.In another embodiment, this method comprises that giving dosage is about 1mg/m ²To 24mg/m ²SNS-595.In another embodiment, this method comprises that giving dosage according to body surface area is about 3mg/m ²To 27mg/m ²SNS-595.In another embodiment, this method comprises that giving to dosage according to body surface area is about 3mg/m ²To 24mg/m ²SNS-595.In another embodiment, this method comprises that giving dosage according to body surface area is about 10mg/m ²To 90mg/m ²SNS-595.In another embodiment, this method comprises that giving dosage according to body surface area is about 15mg/m ²To 80mg/m ²SNS-595.Body surface area can calculate, and for example calculates according to the Mosteller formula:

BSA (m ²): the square root of=[(highly (cm) * body weight (kg)/3600]

In another embodiment, described dosage is the 3mg/m based on body surface area ²To 24mg/m ²In another embodiment, this dosage is the 3mg/m based on body surface area ²To 18mg/m ²In another embodiment, this dosage is 3mg/m ²To 15mg/m ²In another embodiment, this dosage is the 1mg/m based on body surface area ², 2mg/m ², 3mg/m ², 4mg/m ², 5mg/m ², 6mg/m ², 7mg/m ², 8mg/m ², 9mg/m ², 10mg/m ², 11mg/m ², 12mg/m ², 13mg/m ², 14mg/m ², 15mg/m ², 16mg/m ², 17mg/m ², 18mg/m ², 19mg/m ², 20mg/m ², 21mg/m ², 22mg/m ², 23mg/m ², 24mg/m ², 25mg/m ², 26mg/m ², 27mg/m ², 30mg/m ², 36mg/m ², 42mg/m ², 48mg/m ², 50mg/m ², 55mg/m ², 60mg/m ²Perhaps 65mg/m ²In another embodiment, this dosage is 3mg/m ², 6mg/m ², 9mg/m ², 12mg/m ², 15mg/m ², 18mg/m ², 21mg/m ², 24mg/m ², 25mg/m ², 27mg/m ², 36mg/m ², 48mg/m ²Perhaps 50mg/m ²

In one embodiment, described dosage is the 15mg/m based on body surface area ²In another embodiment, this dosage is the 25mg/m based on body surface area ²In another embodiment, this dosage is the 30mg/m based on body surface area ²In another embodiment, this dosage is the 50mg/m based on body surface area ²

In another embodiment, described dosage is the 15mg/m based on body surface area ²To 80mg/m ²In another embodiment, this dosage is the 15mg/m based on body surface area ²To 75mg/m ²In another embodiment, this dosage is 30mg/m ²To 50mg/m ²In another embodiment, this dosage is the 15mg/m based on body surface area ², 20mg/m ², 25mg/m ², 30mg/m ², 35mg/m ², 40mg/m ², 45mg/m ², 50mg/m ², 55mg/m ², 60mg/m ², 65mg/m ², 70mg/m ², 75mg/m ²Or 80mg/m ²

The dosage of SNS-595 can be used mg/m ²Outside measurement unit represent.For example, available mg/kg represents dosage.Those of ordinary skills can easily realize mg/m according to the height of the individuality that provides or body weight or height and body weight ²To the conversion of mg/kg (referring to http: ///www.fda.gov/cder/cancer/animalframe.htm).For example, to body weight be the people 1mg/m of 65kg ²To 30mg/m ²Dosage approximate 0.026mg/kg to 0.79mg/kg.In another example, be the people 3mg/m of 65kg to body weight ²Dosage approximate 0.078mg/kg.In another example, be the people 15mg/m of 65kg to body weight ²To 80mg/m ²Dosage approximate 0.39mg/kg to 2.11mg/kg.

In certain embodiments, SNS-595 can pass through single dose, for example 10-15 minute IV injects and sends (for example single bolus injection), perhaps in a period of time, for example during 24 hours (for example continue transfusion or gradation bolus injection) in time sends and repeats as required, for example up to stable disease or recovery, or get along with or produce unacceptable toxicity up to conditions of patients.For example, stable disease or instability are judged by known method, such as the assessment of patient's symptom, physical examination and other generally accepted assessment mode.

The amount of method of the present invention institute administered agents compositions depends on the order of severity, administering mode, administration frequency and the prescription doctor's of the symptom of mammal, disease or the disease of being treated judgement.

In some embodiments, administration frequency is for arriving approximately approximately every month once a day once.In certain embodiments, administration for once a day, once, biweekly, once in a week, biweekly every other day, three weeks are once or all around once.In one embodiment, pharmaceutical composition provided by the present invention is given weekly.

In certain embodiments, carry out the SNS-595 cyclical administration to the patient.Cyclical administration comprises and gives active medicine a period of time, drug withdrawal a period of time thereupon, and repeat this order administration.Periodically treatment can reduce one or more treatment generation tolerations, avoids or reduces a kind of side effect of treatment, and/or improve the effect of treatment.

Therefore, in one embodiment, SNS-595 gave with single dose or the dosage that separates weekly in three weeks to the cycle in six weeks, and drug withdrawal about 1 day to about 30 days.In another embodiment, SNS-595 gives weekly with single dose or the dosage that separates, continue a week, two weeks, three weeks, all around, five week or six weeks, and drug withdrawal 1,3,5,7,9,12,14,16,18,20,22,24,26,28,29 or 30 days.In some embodiments, be 14 days the waiting period.In some embodiments, be 28 days the waiting period.In one embodiment, be the waiting period up to there being enough bone marrow to recover.The frequency in the cycle of dosed administration, quantity and length can increase or reduce.Therefore, another embodiment comprises when SNS-595 is individually dosed, gives than the more treatment cycle of typical therapy.

In one embodiment, method provided by the present invention comprises: i) giving dosage to the patient is 1mg/m ²To 150mg/m ²SNS-595; Ii) wait at least one day, do not give SNS-595 during this period to this mammal; Iii) use another dosage to be 1mg/m to the patient ²To 150mg/m ²SNS-595.In one embodiment, step I i)-iii) repeat repeatedly.In another embodiment, this method is included in step I) and iii) in give 1mg/m ²-100mg/m ²Dosage.

For example, in one embodiment, in certain leukemic method of treatment, method provided by the present invention comprises: i) give dosage to mammal and be about 10mg/m ²-150mg/m ²SNS-595; Ii) wait at least one day, do not give SNS-595 during this period to this mammal; Iii) give another dosage and be about 10mg/m to this mammal ²-150mg/m ²SNS-595; With, iv) repeating step is ii)-iii) repeatedly.In another embodiment, this method is included in step I) and iii) in give 1mg/m ²-100mg/m ²Dosage.

In one embodiment, method provided by the present invention comprises: i) giving dosage to the patient is about 1mg/m ²-75mg/m ²SNS-595; Ii) wait at least one day, do not give SNS-595 during this period to this mammal; Iii) giving another dosage to this patient is 1mg/m ²-75mg/m ²SNS-595.In one embodiment, step I i)-iii) repeat repeatedly.

In one embodiment, method provided by the present invention comprises: i) giving dosage to the patient is about 1mg/m ²-48mg/m ²SNS-595; Ii) wait at least one day, do not give SNS-595 during this period to this mammal; Iii) giving another dosage to this patient is 1mg/m ²-48mg/m ²SNS-595.In one embodiment, step I i)-iii) repeat repeatedly.

In one embodiment, method provided by the present invention comprises: i) giving dosage to the patient is about 1mg/m ²-24mg/m ²SNS-595; Ii) wait at least one day, do not give SNS-595 during this period to this mammal; Iii) giving another dosage to this patient is about 1mg/m ²-24mg/m ²SNS-595.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, described method is included in step I) and iii) in about 3mg/m ²To 24mg/m ²Dosage.And in another embodiment, this method is included in step I) and iii) in about 15mg/m ²Dosage.In another embodiment, this method is included in step I) and iii) in give 1mg/m ²To 40mg/m ², about 1.5mg/m ²To 30mg/m ², about 2mg/m ²To 25mg/m ²Perhaps about 3mg/m ²To 24mg/m ²Dosage.

In another embodiment, described method is included in step I) and iii) in about 15mg/m ²To 80mg/m ²Dosage.And in another embodiment, this method is included in step I) and iii) in about 15mg/m ²To 75mg/m ²Dosage.And in another embodiment, this method is included in step I) and iii) in about 20mg/m ²To 65mg/m ², about 30mg/m ²To 50mg/m ², about 35mg/m ², about 40mg/m ²Perhaps about 45mg/m ²Dosage.

In said method, for instance, if the waiting period be 6 days, gave the SNS-595 (step I) of predose so at the 1st day; The waiting period be 6 days (step I i); Gave the SNS-595 of next dosage (step I ii) at the 8th day.Comprise 2 days during other is typical, 3 days, 5 days, 7 days, 10 days, 12 days, 13 days, 14 days, 15 days, 17 days, 20 days, 27 days and 28 days.In another embodiment, be at least the waiting period 2 days and step I i) to iii) triplicate at least.In another embodiment, be at least the waiting period 3 days and step I i) to iii) repeating at least five times.In another embodiment, be at least the waiting period 3 days and step I i) to iii) triplicate at least.In another embodiment, be at least the waiting period 3 days and step I i) to iii) repeating at least five times.In another embodiment, be at least the waiting period 6 days and step I i) to iii) triplicate at least.In another embodiment, be at least the waiting period 6 days and step I i) to iii) repeating at least five times.In another embodiment, be at least the waiting period 14 days and step I i) to iii) triplicate at least.In another embodiment, be at least the waiting period 20 days and step I i) to iii) triplicate at least.In another embodiment, be at least the waiting period 20 days and step I i) to iii) repeating at least five times.In another embodiment, be at least the waiting period 28 days and step I i) to iii) triplicate at least.In another embodiment, be at least the waiting period 27 days and step I i) to iii) repeating at least five times.In another embodiment, be at least the waiting period 28 days and step I i) to iii) repeating at least five times.

In another embodiment, described medication comprises to mammal and gives twice SNS-595 (administration in the 1st, 4,8 and 11 day) weekly.In another embodiment, this medication comprises to mammal and gives SNS-595 weekly one time.In another embodiment, this medication comprises that per two circumferential mammals give SNS-595 one time.In another embodiment, this medication comprises that per three circumferential mammals give SNS-595 one time.In another embodiment, medication gives SNS-595 one time to mammal around comprising whenever.

In another embodiment, described medication comprises the cycle, and wherein this cycle comprises weekly and gives SNS-595 one time to mammal, continues for three weeks, then at least 14 days during in do not give SNS-595 to this mammal, repeat this cycle repeatedly.In another embodiment, do not give SNS-595 during be 14 days.In another embodiment, do not give SNS-595 during be 21 days.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to mammal and be about 1mg/m ²To 100mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 1mg/m ²To 100mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to mammal and be about 1mg/m ²To 75mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 1mg/m ²To 75mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, the method that is provided comprises: i) give dosage once in a week to this mammal and be about 1mg/m ²To 60mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 1mg/m ²To 60mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, the method that is provided comprises: i) give dosage once in a week to this mammal and be about 1mg/m ²To 50mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 1mg/m ²To 50mg/m ²SNS-595, continued for three weeks; Iv) repeating step ii)-iii) repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 1mg/m ²To 48mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 1mg/m ²To 48mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 1mg/m ²To 24mg/m ²SNS-595; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 1mg/m ²To 24mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 2mg/m ²To 40mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 2mg/m ²To 40mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to mammal and be about 3mg/m ²To 24mg/m ²SNS-595, continued for three weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 3mg/m ²To 24mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to mammal and be about 3mg/m ²To 24mg/m ²SNS-595, continue three weeks (promptly administration in the 1st, 8 and 15 day); Ii) wait at least 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 3mg/m ²To 24mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage weekly for twice to mammal and be about 3mg/m ²To 24mg/m ²SNS-595, continue two weeks (administration in the 1st, 4,8 and 11 day); Ii) wait at least 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage weekly for twice to this mammal again and be about 3mg/m ²To 24mg/m ²SNS-595, continue two weeks (administration in the 1st, 4,8 and 11 day).In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 3mg/m ²To 24mg/m ²SNS-595, continue three weeks (promptly administration in the 1st, 4 and 15 day); Ii) wait at least 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 3mg/m ²To 24mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage weekly for twice to mammal and be about 3mg/m ²To 24mg/m ²SNS-595, continue 2 weeks (administration in the 1st, 4,8 and 11 day); Ii) wait for 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage weekly for twice to this mammal again and be about 3mg/m ²To 24mg/m ²SNS-595, continue 2 weeks (administration in the 1st, 4,8 and 11 day).In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 15mg/m ²To 80mg/m ²SNS-595, continued for 3 weeks; Ii) wait for 14 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 15mg/m ²To 80mg/m ²SNS-595, continued for 3 weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 15mg/m ²To 80mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day); Ii) wait at least 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 15mg/m ²To 80mg/m ²SNS-595, continued for 3 weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage weekly for twice to mammal and be about 15mg/m ²To 80mg/m ²SNS-595, continue 2 weeks (administration in the 1st, 4,8 and 11 day); Ii) wait at least 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage weekly for twice to this mammal again and be about 15mg/m ²To 80mg/m ²SNS-595, continue 2 weeks (administration in the 1st, 4,8 and 11 day).In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage once in a week to this mammal and be about 15mg/m ²To 80mg/m ²SNS-595, continue three weeks (for example, administration in the 1st, 8 and 15 day); Ii) wait for 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage once in a week to this mammal again and be about 15mg/m ²To 80mg/m ²SNS-595, continued for three weeks.In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, method provided by the present invention comprises: i) give dosage weekly for twice to mammal and be about 15mg/m ²To 80mg/m ²SNS-595, continue two weeks (administration in the 1st, 4,8 and 11 day); Ii) wait for 28 days, do not give any SNS-595 in during this period to this mammal; Iii) give dosage weekly for twice to this mammal again and be about 15mg/m ²To 80mg/m ²SNS-595, continue two weeks (administration in the 1st, 4,8 and 11 day).In one embodiment, step I i)-iii) repeat repeatedly.

In another embodiment, described method comprises that giving patient dose once in a week is about 1mg/m ²To 100mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, this method comprises that giving patient dose once in a week is about 1mg/m ²To 75mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, this method comprises that giving patient dose once in a week is about 1mg/m ²To 60mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, method comprises that giving patient dose once in a week is about 1mg/m ²To 48mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, method comprises that giving patient dose once in a week is about 1mg/m ²To 24mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, weekly used dosage is about 2mg/m ²To 40mg/m ², wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, described dosage is about 3mg/m ²To 24mg/m ², weekly, wherein this week during comprise that treatment cycle and this treatment cycle repeat three times at least.In another embodiment, described dosage is about 15mg/m ², weekly, comprise that wherein treatment cycle and this treatment cycle repeat three times at least this week.

In another embodiment, described method comprises that giving dosage once in a week to the patient is 15mg/m ²To 80mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this cycle repeat three times at least.In another embodiment, this method comprises that giving dosage once in a week to the patient is 15mg/m ²To 75mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this cycle repeat three times at least.In another embodiment, this method comprises that giving dosage once in a week to the patient is 20mg/m ²To 65mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this cycle repeat three times at least.In another embodiment, this method comprises that giving dosage once in a week to the patient is 30mg/m ²To 50mg/m ²SNS-595, wherein this week during comprise that treatment cycle and this cycle repeat three times at least.

In some embodiments, described method comprises that giving dosage once in a week to the patient is about 1mg/m ²To 40mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon at least 28 days the waiting period.In some embodiments, this method comprises that giving dosage weekly for twice to the patient is about 1mg/m ²To 40mg/m ²SNS-595 (administration in the 1st, 4,8 and 11 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon at least 28 days the waiting period.In some embodiments, this method comprises that giving dosage once in a week to the patient is about 1mg/m ²To 40mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon 28 days the waiting period.In some embodiments, this method comprises that giving dosage weekly for twice to the patient is about 1mg/m ²To 40mg/m ²SNS-595 (administration in the 1st, 4,8 and 11 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon 28 days the waiting period.

In some embodiments, described method comprises that giving dosage once in a week to the patient is about 3mg/m ²To 24mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon at least 28 days the waiting period.In some embodiments, this method comprises that giving dosage weekly for twice to the patient is about 3mg/m ²To 24mg/m ²SNS-595 (administration in the 1st, 4,8 and 11 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon at least 28 days the waiting period.In some embodiments, this method comprises that giving dosage once in a week to the patient is about 3mg/m ²To 24mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon 28 days the waiting period.In some embodiments, this method comprises that giving dosage weekly for twice to the patient is about 3mg/m ²To 24mg/m ²SNS-595 (administration in the 1st, 4,8 and 11 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon 28 days the waiting period.

In some embodiments, described method comprises that giving dosage once in a week to the patient is about 15mg/m ²To 80mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon at least 28 days the waiting period.In some embodiments, this method comprises that giving dosage weekly for twice to the patient is about 15mg/m ²To 80mg/m ²SNS-595 (promptly administration in the 1st, 4,8 and 11 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon at least 28 days the waiting period.In some embodiments, this method comprises that giving dosage once in a week to the patient is about 15mg/m ²To 80mg/m ²SNS-595 (promptly administration in the 1st, 8 and 15 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon 28 days the waiting period.In some embodiments, this method comprises that giving dosage weekly for twice to the patient is about 15mg/m ²To 80mg/m ²SNS-595 (administration in the 1st, 4,8 and 11 day), comprise between this one-period that wherein treatment cycle and this cycle repeat three times at least, be thereupon 28 days the waiting period.

In another embodiment, described method comprises that giving dosage once in a week to mammal is about 1mg/m ²-50mg/m ²SNS-595, comprise between this one-period that wherein treatment cycle and this cycle repeat at least twice.In another embodiment, described dosage is about 2mg/m ²-40mg/m ²In another embodiment, described dosage is about 3mg/m ²-24mg/m ²In another embodiment, described dosage is about 4mg/m ²-20mg/m ²

6.4 typical dosage regimen

Below provide particular cancers relevant typical dosage regimen.These dosage regimens aim to provide explanation, are not exclusive.

The method of treatment solid tumor is provided on the one hand.This method comprises:

I) give dosage to the patient and be about 1mg/m ²To 100mg/m ²SNS-595;

Ii) wait at least 6 days, do not give any SNS-595 in during this period to this individuality;

Iii) giving another dosage to the patient is 1mg/m ²To 100mg/m ²SNS-595; With

Iv) repeating step ii)-iii) repeatedly.

On the other hand, the method for treatment solid tumor comprises that giving dosage once in a week to the patient is about 1mg/m ²To 75mg/m ²SNS-595, wherein comprise a treatment cycle and this treatment cycle between this one-period and repeat at least twice.In another embodiment, described dosage is about 15mg/m ²To 80mg/m ²In another embodiment, described dosage is about 3mg/m ²To 24mg/m ²

On the other hand, the method for treatment solid tumor comprises that giving dosage once in a week to the patient is about 15mg/m ²To 40mg/m ²SNS-595, continued for three weeks, then at least two weeks do not give SNS-595, and wherein this treatment cycle repeats repeatedly to described individuality.In another embodiment, described dosage is about 15mg/m ²To 35mg/m ²In another embodiment, described dosage is about 20mg/m ²To 30mg/m ²In another embodiment, described dosage is about 20mg/m ²To 25mg/m ²

On the other hand, the method for treatment solid tumor be included in three weeks during in once to give patient dose be 35mg/m ²To 80mg/m ²SNS-595, comprise during this three week that wherein treatment cycle and this cycle repeat at least twice.

On the other hand, the invention provides the method for treatment malignant hematologic disease.In certain embodiments, this method comprises that giving dosage to the patient is about 20mg/m ²To 60mg/m ²SNS-595.

Be considered to the patient (" severe pretreat patient ") of severe pretreat for those, giving patient's dose in described method is included in during three weeks is 35mg/m ²To 60mg/m ²SNS-595, comprise during this three week that wherein treatment cycle and this treatment cycle repeat twice at least.In another embodiment, severe pretreat patient's Therapeutic Method is comprised give 40mg/m ²To 50mg/m ²Dosage.In another embodiment, severe pretreat patient's Therapeutic Method is comprised give 45mg/m ²To 50mg/m ²Dosage.Severe pretreat patient's definition such as Tolcher etc. J.Clin.Oncol.19:2937-2947 (2001) description, be meant the chemotherapy regimen that contains alkylating reagent of once accepting to surpass six courses of treatment, the carboplatin or the ametycin that surpass two courses of treatment, any early stage the nitroso ureas scheme, the radiotherapy of 25% bone marrow area, the high-dose chemotherapy that needs hematopoietic stem cell to feed back, the perhaps patient of large tracts of land bone transfer.

Those did not carry out treatment of solid tumors or accepted treatment but do not think the patient of severe pretreat, were considered to the patient (" slight pretreat patient ") of slight pretreat.For slight pretreat patient, described method is included in and gives dose to the patient in three weeks is 45mg/m ²To 80mg/m ²SNS-595, wherein this three week comprises that treatment cycle and this treatment cycle repeat twice at least at time limit.In another embodiment, slight pretreat patient's Therapeutic Method is comprised give 50mg/m ²To 75mg/m ²Dosage.In another embodiment, slight pretreat patient's Therapeutic Method is comprised give 55mg/m ²To 70mg/m ²Dosage.In another embodiment, slight pretreat patient's Therapeutic Method is comprised give 55mg/m ²To 65mg/m ²Dosage.

On the other hand, treatment neoplastic hematologic disorder such as leukemia and lymphadenomatous method are provided.This method comprises:

I) giving dosage to the patient is 10mg/m ²-50mg/m ²SNS-595;

Ii) wait at least two days, do not give any SNS-595 in during this period to this individuality;

Iii) giving another dosage to the patient is 10mg/m ²-50mg/m ²SNS-595; With

Iv) repeating step ii)-iii) repeatedly.

In one embodiment, the waiting period of described is six days.In another embodiment, this waiting period be two days.In another embodiment, this waiting period be three days.

In one embodiment, the method for treatment malignant hematologic disease comprises that giving patient dose once in a week is about 20mg/m ², 22mg/m ², 25mg/m ², 27mg/m or 30mg/m ²SNS-595, comprise that wherein treatment cycle and this treatment cycle repeat twice at least this week.In one embodiment, the method for treatment malignant hematologic disease comprises that giving patient dose once in a week is about 25mg/m ²SNS-595, comprise that wherein treatment cycle and this treatment cycle repeat twice at least this week.

Other dosage that can be used for treating patients with malignant hematological diseases comprises twice about 25mg/m weekly ²To 50mg/m ², continued for two weeks.In another embodiment, the dosage that is used for the treatment of malignant hematologic disease comprises twice about 30mg/m weekly ²To about 45mg/m ², continued for two weeks.In another embodiment, the dosage regimen of treatment malignant hematologic disease comprises and gives 30,35,40 or 45mg/m weekly for twice ², continued for two weeks.

In one embodiment, the method for treatment malignant hematologic disease comprises that per two circumferential patients give dose and are about 40mg/m ², 45mg/m ², 50mg/m ², 55mg/m ²Or 60mg/m ²SNS-595, wherein comprise treatment cycle during this two week.In one embodiment, the method for treatment malignant hematologic disease comprises that per two circumferential patients give dose and are about 50mg/m ²SNS-595, wherein comprise treatment cycle during this two week.

6.5 therapeutic alliance

In method and composition provided by the invention, SNS-595 can unite use with other pharmaceutically active compounds (" second active agent ").Believe that some cancer of uniting the treatment particular type has synergism.And SNS-595 can alleviate the ill effect that some second active agent causes, and some second active agents also can alleviate the ill effect that SNS-595 causes.

6.5.1 second active agent

In the method and composition provided by the invention, one or more second active components or second active agent can use with SNS-595.Second active agent can be macromole (as protein) or micromolecule (as synthesizing inorganic molecule, organic metal molecule or organic molecule).

The example of macromole active agent includes but not limited to: hemopoietic growth factor, the therapeutic antibodies of cytokine and monoclonal and polyclonal antibody, especially cancer antigen.Typical macromole active agent is a biomolecule, as natural or artificial protein.Useful especially protein comprises that but those hemopoietic CFU-GM and immunocompetences in external or body produce the protein of cell (poieticcells) survival and/or propagation in the inventive method and compositions.Other protein is in external or directed CFU-E division of body internal stimulus and differentiation.Concrete protein includes but not limited to: the interleukin class, as IL-2 (comprising reorganization IL-II (" rIL2 ") and canary rash (canarypox) IL-2), IL-10, IL-12 and IL-18; Interferons is as Intederon Alpha-2a, Interferon Alpha-2b, interferon alfa-n1, Alferon N, interferon beta-Ia and interferon gamma-Ib; GM-CF and GM-CSF; And EPO.

The concrete protein that can be used for the inventive method and compositions includes but not limited to: in the U.S. with trade name

(Amgen, Thousand Oaks CA) and its derivant, include but not limited to the Pegylation filgrastim to the filgrastim of selling; In the U.S. with trade name

The Sargramostim of selling ((Immunex, Seattle, WA); In the U.S. with trade name

The recombinant epo of selling (Amgen, Thousand Oaks, CA); Epoetin Alfa and A Fadabeiting.

The reorganization and the GM-CSF of mutant form can be as U.S. Patent numbers 5,391, and 485,5,393,870 and 5,229,496 described preparations, these patents all are incorporated herein by reference.The G-CSF of reorganization and mutant form can be as U.S. Patent number 4,810,643,4,999,291,5,528,823 and 5,580,755 described preparations, and these patents all are incorporated herein by reference.

The present invention also provides the native protein and the recombinant protein of uniting use with SNS-595.The present invention further comprise can show in vivo its based on the mutant and the derivant (for example modified forms) of native protein of described proteinic at least a portion pharmacologically active.The example of mutant includes but not limited to have the protein of one or more amino acid residues different with the corresponding residue in the native protein.Term " mutant " also comprises and lacks the protein (being non-glycosylated form) that is present in the carbohydrate group in the native protein usually.The example of derivant includes but not limited to polyethylene glycol derivative and fused protein, as the protein by IgGl or IgG3 and protein or the fusion of protein of interest matter active part are formed.Referring to, Penichet, M.L. and Morrison, S.L., J.Immunol.Methods248:91-101 (2001).

Can comprise monoclonal and polyclonal antibody with the antibody that SNS-595 unites use.The example of antibody includes but not limited to: trastuzumab (

), Mabthera ( ), bevacizumab (Avastin ^TM), handkerchief trastuzumab (Omnitarg ^TM), tositumomab (

), edrecolomab ( ) and G250.SNS-595 also can with anti-TNF-Alpha antibodies, and/or anti-EGFR-antibodies as Or handkerchief Buddhist nun monoclonal antibody combination or unite use.

The macromole active agent can be used as anti-cancer vaccine and uses.For example, can secrete or cause the vaccine of secrete cytokines such as IL-2, G-CSF and GM-CSF to can be used in method provided by the present invention and the drug component.Referring to, L.A., etc., Curr.Opinion Mol Ther.3 (1): 77-84 (2001).

Make additive properties or the maximized universal law of concertedness on the contrary (referring to Page with the medicine of selecting the different mechanisms of action for use, R. and Takimoto, C, " Principles of Chemotherapy ", CancerManagement:A Multidisciplinary Approach (2001), p.23), comprise SNS-595 and also can stop the compositions of synthetic second active agent of DNA to be found to have additivity or cooperative effect.

In the present invention, when reagent directly or indirectly influenced the ability of cell synthetic DNA or DNA plerosis damage, it had stoped DNA synthetic.This reagent can be directly interact (for example in conjunction with or insert) with DNA or with participate in conjugated protein the combining of DNA-that DNA is synthetic or DNA repairs.Usually, stop the synthetic reagent of DNA to have activity but do not need and possess the S phase specificity in the S stage.

Because SNS-595 influences the DNA-PK path, second reagent can be to mediate its Cytotoxic reagent by the DNA-PK path.An example is to suppress non-homogeneous terminal reagent such as the DNA-PK inhibitor of repairing that connect.Except as otherwise noted, " DNA-PK inhibitor " used herein refers to the reagent of the signal path that can suppress or disturb the DNA-PK mediation.Active inhibition can be direct (for example catalytic inhibitor of DNA-PK itself) or indirect (for example reagent of interferon activity DNA-PK complex (DNA-PK, Ku70 and Ku80) formation) to DNA-PK.Other example includes but not limited to: ligase IV inhibitor and apoptosis dose, and such as but not limited to Caspase (caspase)-9 activator, Caspase-3 activator and Hsp90 inhibitor.

Micromolecule second active agent also can be used to alleviate the ill effect that is caused by SNS-595.Yet,, also can produce cooperative effect when believing many micromolecule second active agents with SNS-595 (before, afterwards or simultaneously) administration just as some macromole.The example of micromolecule second active agent includes but not limited to: antitumor and anticancer agent, antibiotic, immunosuppressant and steroid.

The example of antitumor and anticancer agent includes but not limited to: alkylating reagent, antitumor drug, antimetabolite (for example urea of folacin, purine analogue, neplanocin, pyrimidine analogue and replacement), platinum coordination complex, topoisomerase II inhibitor and radiation.

Concrete antitumor and anticancer agent includes but not limited to: acivicin, aclarubicin, the hydrochloric acid acodazole, acronine, adozelesin, aldesleukin, altretamine, ambomycin, the acetic acid ametantrone, amsacrine, Anastrozole, antramycin, asparaginase, asperlin, azacitidine, azatepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, two methanesulfonic acid bisnafides, bizelesin, Bleomycin Sulphate, brequinar sodium, bropirimine, busulfan, actinomycetes C, calusterone, capecitabline (capecitabine capecitabine), caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, celecoxib (cox 2 inhibitor), chlorambucil, cirolemycin, cisplatin, cladribine, the methanesulfonic acid crisnatol, cyclophosphamide, cytosine arabinoside, dacarbazine, actinomycetes D, daunorubicin hydrochloride, decitabine, dexormaplatin, Dezaguanine, the methanesulfonic acid Dezaguanine, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, Eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, erlotinib, esorubicin hydrochloride, estramustine, phosphoric acid estramustine sodium, etanidazole, etoposide, the phosphoric acid etoposide, etoprine, CGS-16949A, fazarabine, fenretinide, azauridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gefitinib, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, iproplatin, irinotecan, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprorelin acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, the hydrochloric acid dichloromethyldiethylamine, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, rice holder jinx, silk splits erythroderma, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, Mycophenolic Acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pemetrexed, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, the hydrochloric acid piroxantrone, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, Safingol, the hydrochloric acid Safingol, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium, taxotere, tegafur, teloxandrone hydrochloride, temoporfin, teniposide, teroxirone, Testolactone, thiamiprine, thioguanidine, thioguanine, plug is for group, the formamido thiazole, tirapazamine, FC-1157a, trestolone acetate, the phosphoric acid triciribine, trimetrexate, husky glucuronic acid front three song, triptorelin, tubulozole hydrochloride, NSC-34462, uredepa, vapreotide, Verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, the sulphuric acid vinepidine, the sulphuric acid vinglycinate, the sulphuric acid vinleurosine, vinorelbine tartrate, the sulphuric acid vinrosidine, the sulphuric acid vinzolidine, vorozole, zeniplatin, zinostatin, and zorubicin hydrochloride.

Other antitumor and anticancer agent comprises; but be not limited to: 20-epi-1; 25 dihydroxyvitamin D3s; 5-ethinyluracil; abiraterone; aclarubicin; the acyl group fulvene; the gland cyclopentanol; adozelesin; aldesleukin; the ALL-TK antagonist; altretamine; ambamustine; amidox (2; 4-Dichlorophenoxyaceticacid 2; 4 dichlorphenoxyacetic acids); amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; Anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; Antarelix; anti-dorsalization morphogenetic proteins-1; androgen antagonist; carcinoma of prostate; estrogen antagonist; antitumorigenic substance; antisense oligonucleotide; the aphidicolin glycine; apoptosis gene is modified; the apoptosis instrumentality; apurinic acid; ara-CDP-DL-PTBA; the arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; Azalomvcin; azatyrosine; baccatin III derivative; balanol; batimastat; the BCR/ABL antagonist; benzochlorins; benzoylstaurosporine; the beta-lactam derivant; beta-alethine; betaclamycinB; belulinic acid Betulinic acid; the bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; fourth Guang sulfenimide; calcipotriol; calphostin C; camptothecin derivative; capecitabine; amide-aminotriazole(ATA); carboxyl ammonia imidazoles; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase 2 enzyme inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; the nefrosulfin 1,4-Benzodiazine; cicaprost; along porphyrin; cladribine; the clomifene analog; clotrimazole; collismycin A; collismycin B; combretastatin A4; the combretastatin analog; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivant; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; the dehydrogenation didemnun B; deslorelin; dexamethasone; right ifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnun B; didox; diethylnorspermine; dihydro-5-azacytidine; the dihydro paclitaxel, 9-; two oxymycins; the hexichol spiromustine; docetaxel; tadenan; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; the estramustine analog; estrogen agonist; estrogen antagonist; etanidazole; the phosphoric acid etoposide; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloric acid; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; Ganite (Fujisawa).; galocitabine; ganirelix; the gelatinase inhibitor; gemcitabine; the glutathion inhibitor; hepsulfam; heregulin; HMBA; hypericin; ibandronic acid; idarubicin; idoxifene; Idramantone; ilmofosine; Ilomastat; imatinib (as

), imiquimod, the peptide immunostimulant, the individual inhibitor of para-insulin growth factor-1, the interferon agonist, interferon, interleukin, iobenguane, iododoxorubicin, Rhizoma Dioscoreae esculentae alcohol, 4-, iroplact, irsogladine, isobengazole, isohomohalicondrinB, itasetron, jasplakinolide, kahalalide F, triacetic acid sheet spiral shell element-N, Lanreotide, leinamycin, lenograstim, the sulphuric acid lentinan, leptolstatin, letrozole, leukaemia inhibitory factor, the leukocyte interferon-alpha, leuprorelin acetate+estrogen+Progesterone, leuprorelin, levamisole, liarozole, the linear amine analog, lipophilic two glycopeptides, the lipophilic platinum compounds, lissoclinamide 7, lobaplatin, earthworm Yin phospholipid, lometrexol, lonidamine, losoxantrone, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, the dissolving peptide, maitansine, mannostatin A, Marimastat, masoprocol, maspin, the matrilysin inhibitor, matrix metallo-proteinase inhibitor, menogaril, merbarone, meterelin, methioninase, metoclopramide, the MIF inhibitor, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, mitomycin analogs, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofarotene, molgramostim, Erbitux, human chorionic gonadotropin, monophosphoryl lipid A+myobacterium cell wall sk, mopidamol, the mustard anticarcinogen, Indian Ocean sponge B, the mycobacteria cell wall extracts, myriaporone, N-acetyldinaline, the N-substituted benzamide, nafarelin, nagrestip, naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin, Nemorubicin, neridronic acid, nilutamide, nisamycin, nitrogen oxide is modified, the nitroxide antioxidant, nitrullyn, Ao Limosen (

), O ⁶-benzyl guanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; Stomatocyte factor derivant; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; paclitaxel derivant; palauamine; palmitoylrhizoxin; Pamidronic Acid; the panaxytiol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; Pentosan Polysulfate Sodium; pentostatin; pentrozole; perflubron; perfosfamide; perilla alcohol; phenazinomycin; phenylacetate; inhibitors of phosphatases; pieze Barney; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum three amine complexes; porfimer sodium; porfiromycin; prednisone; propyl group two acridones; prostaglandin J2; proteasome inhibitor; a-protein base imnlune modulator; inhibitors of protein kinase C; the inhibitors of protein kinase C class, microalgae; protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; alizarinopurpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; the raf antagonist; Raltitrexed; ramosetron; the ras farnesyl protein transferase inhibitor; the ras inhibitor; the ras-GAP inhibitor; the demethylation retelliptine; rhenium Re 186 diphosphate; rhizomycin; ribozyme; the RII VAAE; rohitukine; romurtide; Roquinimex; rubiginone B1; ruboxyl; Safingol; saintopin; SarCNU; sarcophytol A; Sargramostim; Sdi 1 analogies; semustine; old and feeble derivatives inhibitors 1; MODN is arranged; signal transduction inhibitor; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin is conjugated protein; sonermin; sparfosic acid; spicamycin D; spiromustine; the spleen pentapeptide; spongistatin 1; Squalamine; stipiamide; the stromelysin inhibitor; sulfinosine; potent vasoactive peptide antagonists; suradista; suramin; (.+-.)-Swainsonine; tallimustine; the methiodide tamoxifen; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; the terminal enzyme inhibitor; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; the individual agonist of thymopoietin; Thymotrinan; thyroid-stimulating hormone; ethyl stannum is C.I. Natural Red 8 just; tirapazamine; the luxuriant titanium of dichloride; topsentin; toremifene; translational inhibitor; tretinoin; Triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrphostins; the UBC inhibitor; ubenimex; the urogenital sinus growth inhibiting factor of deriving; the urokinase receptor antagonist; vapreotide; variolin B; velaresol; veramine; verdins; Verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and Zinostatin stimalamer.

The second concrete active agent includes but not limited to: Rituximab, Ao Limosen (

), remicade, docetaxel, celecoxib, melphalan, dexamethasone (

), steroid, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temozolomide (temodar), carboplatin, procarbazine, gliadel, tamoxifen, hycamtin, methotrexate,

Paclitaxel, taxotere, fluorouracil, formyl tetrahydrofolic acid, irinotecan, xeloda, CPT-11, interferon-ALPHA, glycol interferon alpha (as PEG INTRON-A), capecitabine, cisplatin, plug is for group, fludarabine, carboplatin, daunorubicin liposome, cytosine arabinoside, Docetaxel (doxetaxol), Paclitaxel (pacilitaxel), vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, than Ah Xin (biaxin), busulfan, prednisone, diphosphonate, arsenic trioxide, vincristine, doxorubicin (

), paclitaxel, ganciclovir, doxorubicin, phosphoric acid estramustine sodium (

), sulindac and etoposide.

In certain embodiments, described second active agent is etoposide, daunomycin, actinomycin D, ametycin, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, gemcitabine, geldanamycin or its compositions.

In other embodiments, described second active agent is a supportive care reagent.The example of supportive care reagent is an antiemetic.Concrete antiemetic includes but not limited to: phenothiazines, butyrophenones, benzodiazepine, corticosteroid, serotonin antagonist class, Cannabinoids and NK ₁The receptor antagonist class.The example of phenothiazine antiemetic includes but not limited to: prochlorperazine and trimethobenzamide.The example of butyrophenone antiemetic includes but not limited to haloperidol.The example of benzene phenodiazine antiemetic includes but not limited to lorazepam.The example of cortex steroid antiemetic includes but not limited to dexamethasone.The example of serotonin antagonist antiemetic includes but not limited to ondansetron, granisetron and dolasetron.The example of cannabinoid antiemetic includes but not limited to dronabinol.NK ₁The example of receptor antagonist includes but not limited to aprepitant.The dosage of antiemetic and dosage regimen depend on concrete indication, patient's age and the situation of being treated and the order of severity of ill effect, and can correspondingly be regulated by those skilled in the art.For example, can be with reference to dosage and the dosage regimen among ThePhysician ' the s Desk Reference.

6.5.2 the typical method of therapeutic alliance

In certain embodiments, method provided by the invention comprises SNS-595 and the associating of one or more second active agents, and/or unites use with radiotherapy or surgical operation.Giving SNS-595 and second active agent to the patient can be by identical or different route of administration simultaneously or carry out successively.To depend on active agent itself (for example can orally give and before entering blood flow, do not decompose) and the disease of being treated at the well-formedness of the concrete route of administration of concrete active agent.The route of administration of second active agent of recommending is that prior art is known, referring to Physicians ' Desk Reference (the 60th edition, 2006).

In one embodiment, intravenous injection or subcutaneous injection give described second active agent, and once a day or twice, dosage is about 1mg to about 1, and 000mg, about 5mg arrive about 375mg or about 50mg arrives about 200mg to about 500mg, about 10mg.In one embodiment, this second active agent be Rituximab, Ao Limosen (oblimersen) ( ), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, retinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, cox 2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine or its combination.In certain embodiments, this second active agent is that etoposide, daunorubicin, actinomycin D, silk split mould C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, wortmannin, geldanamycin, gemcitabine or its combination.

In another embodiment, the method of treatment provided by the present invention, prevention and/or control malignant hematologic disease, this method comprises SNS-595 is combined with conventional treatments that (for example, during or afterwards) use, and conventional treatments includes but not limited to be used for the treatment of at present, prevent or control surgical operation, immunotherapy, biotherapy, X-ray therapy or its non-drug therapy of cancer.Be not subjected to concrete one theory, when using simultaneously with conventional therapy, SNS-595 can provide and add and or synergy.

In certain embodiments, described second active agent and SNS-595 use simultaneously or postpone and used in 1-50 hour.In certain embodiments, SNS-595 at first uses, and then uses second active agent after postponing 1-50 hour.In other embodiments, at first use second active agent, then after postponing 1-50 hour, use SNS-595.In some embodiments, be 24 hours time delay.

In one embodiment, before the conventional therapy, during or afterwards, SNS-595 can unite use separately or with second active agent disclosed in this invention, used SNS-595 dosage is about 1 to about 75mg/m ², 1 to about 60mg/m ², 1 to about 48mg/m ², 1 to about 24mg/m ², 1 to about 50mg/m ², about 1 to about 40mg/m ², about 1 to about 30mg/m ², about 3 to about 30mg/m ², about 3 to about 24mg/m ²

In another embodiment, method provided by the present invention comprises: a) give dosage to the patient of needs and be about 1mg/m ²To 75mg/m ²SNS-595, and b) treat the supportive care reagent of effective dose to the patient.

In one embodiment, described second reagent is alkylating reagent.In another embodiment, this alkylating reagent is that the alkylsulfonate and the cancer of being treated are leukemia or lymphoma.In another embodiment, this alkylsulfonate is a busulfan.In another embodiment, this alkylsulfonate is that busulfan and treatment effective dose are the every day of 1mg at least.In another embodiment, this alkylsulfonate is that busulfan and treatment effective dose are about every day about 2mg to the oral dose of 8mg.In another embodiment, this alkylsulfonate is that busulfan and treatment effective dose are about every day about 1mg to the oral dose of 3mg.

In another embodiment, described alkylating reagent is that the chlormethine and the cancer of being treated are bladder cancer, breast carcinoma, Hodgkin, leukemia, pulmonary carcinoma, melanoma, ovarian cancer or carcinoma of testis.In another embodiment, this chlormethine is a chlorambucil.In another embodiment, this chlormethine is that chlorambucil and treatment effective dose are 0.1mg/kg at least.In another embodiment, this chlormethine be chlorambucil and treatment effective dose be every day about 0.1mg/kg to the oral dose of about 0.2mg/kg, lasting three to six weeks.In another embodiment, this chlormethine be chlorambucil and treatment effective dose be per three to around the dosage of 0.4mg/kg.In another embodiment, this chlormethine is a cyclophosphamide.In another embodiment, this chlormethine is that cyclophosphamide and treatment effective dose are the intravenously administrable dosage of 10mg/kg at least.In another embodiment, this chlormethine is that cyclophosphamide and treatment effective dose are the intravenously administrable dosage that per seven to ten days about 10mg/kg arrive about 15mg/kg.In another embodiment, this chlormethine be cyclophosphamide and treatment effective dose be every day about 1mg/kg to the oral dose of 5mg/kg.In another embodiment, this chlormethine is a melphalan.In another embodiment, this chlormethine is that melphalan and treatment effective dose are the every day of 2mg oral dose at least.In another embodiment, this chlormethine is that melphalan and treatment effective dose are the oral dose of 6mg every day in two weeks to three weeks, stop using two to around every day, about 2mg arrived about 4mg oral dose again behind the melphalan.In another embodiment, to be melphalan and treatment effective dose be the 10mg/m four day every day in six weeks around every to chlormethine ²Oral dose.

In another embodiment, described alkylating reagent is that the nitroso ureas and the cancer of being treated are the cerebral tumor, rectal cancer, Hodgkin, hepatocarcinoma, pulmonary carcinoma, lymphatic cancer or melanoma.In another embodiment, this nitroso ureas is a carmustine.In another embodiment, this nitroso ureas is that carmustine and treatment effective dose are 150mg/m at least ²In another embodiment, this nitroso ureas is that carmustine and treatment effective dose are about 150mg/m of per six to eight weeks ²To 200mg/m ²Intravenously administrable dosage.

In another embodiment, described alkylating reagent is that the triazenes and the cancer of being treated are Hodgkin, melanoma, neuroblastoma or soft tissue sarcoma.In another embodiment, this triazenes is a dacarbazine.In another embodiment, to be dacarbazine and treatment effective dose arrive the intravenously administrable dosage of about 4.5mg/kg for the about 2.0mg/kg ten day every day in around every to this triazenes.In another embodiment, this triazenes is that dacarbazine and treatment effective dose are the 250mg/m five day every day in per three weeks ²Intravenously administrable dosage.In another embodiment, this triazenes is that dacarbazine and treatment effective dose are per 16 days 375mg/m ²Intravenously administrable dosage.In another embodiment, to be dacarbazine and treatment effective dose be the 150mg/m five day every day in around every to this triazenes ²Intravenously administrable dosage.

In another embodiment, described second reagent is that the antitumor antibiotics and the cancer of being treated are bladder cancer, breast carcinoma, cervical cancer, head and cervical region cancer, Hodgkin, leukemia, multiple myeloma, neuroblastoma, ovarian cancer, sarcoma, skin carcinoma, carcinoma of testis or thyroid carcinoma.In another embodiment, this antibiotic is a bleomycin.In another embodiment, this antibiotic is that bleomycin and treatment effective dose are at least 10 units/m ²In another embodiment, to be bleomycin and treatment effective dose be twice 10 units/m once in a week or weekly with this antibiotic ²To 20 units/m ²Vein, subcutaneous or intramuscular injection dosage.In another embodiment, this antibiotic is an actinomycin D.In another embodiment, this antibiotic is that actinomycin D and treatment effective dose are 0.01mg/kg at least.In another embodiment, this antibiotic is that actinomycin D and treatment effective dose are the intravenously administrable dosage that about 0.010mg/kg five day every day in per three weeks arrives about 0.015mg/kg.In another embodiment, this antibiotic is that actinomycin D and treatment effective dose are per three week or 2mg/m all around ²Intravenously administrable dosage.In another embodiment, this antibiotic is a daunorubicin.In another embodiment, this antibiotic is that daunorubicin and treatment effective dose are 30mg/m at least ²In another embodiment, this antibiotic is that daunorubicin and treatment effective dose are about 30mg/m every day ²To about 45mg/m ²Intravenously administrable dosage, continue three days.In another embodiment, this antibiotic is that liposome daunorubicin and treatment effective dose are per two all 40mg/m ²Intravenously administrable dosage.In another embodiment, this antibiotic is a doxorubicin.In another embodiment, this antibiotic is that doxorubicin and treatment effective dose are 15mg/m at least ²In another embodiment, this antibiotic is that doxorubicin and treatment effective dose are about 60mg/m of per three weeks ²To about 90mg/m ²Intravenously administrable dosage.In another embodiment, this antibiotic is that doxorubicin and treatment effective dose are about 15mg/m weekly ²To about 20mg/m ²Intravenously administrable dosage.In another embodiment, this antibiotic is that doxorubicin and treatment effective dose are one-period, comprises 30mg/m weekly ²Intravenously administrable dosage continued for two weeks, stopped using two weeks of doxorubicin subsequently.

In another embodiment, described second reagent is antimetabolite.In another embodiment, this antimetabolite is a folacin, and the cancer of being treated is breast carcinoma, head and cervical region cancer, leukemia, pulmonary carcinoma, non-Hodgkin lymphatic cancer or osteosarcoma.In another embodiment, this folacin is a methotrexate.In another embodiment, this folacin is a methotrexate, and the treatment effective dose is 2.5mg at least.In another embodiment, this folacin is a methotrexate, and the treatment effective dose be every day about 2.5mg arrive the oral dose of about 5mg.In another embodiment, this folacin is a methotrexate, and the treatment effective dose is twice about 5mg/m weekly ²To about 25mg/m ²Dosage.In another embodiment, this folacin is a methotrexate, and the treatment effective dose is per two to three all 50mg/m ²All intravenously administrable dosage.In another embodiment, this folacin is a pemetrexed.In another embodiment, this folacin is a pemetrexed, and the treatment effective dose is 300mg/m at least ²In another embodiment, this folacin is a pemetrexed, and the treatment effective dose is per two weeks or about 300mg/m of three weeks ²To about 600mg/m ²Intravenously administrable dosage.In another embodiment, this folacin is a pemetrexed, and the treatment effective dose is per three all 500mg/m ²Intravenously administrable dosage.

In another embodiment, described antimetabolite is a purine analogue, and the cancer of being treated is rectal cancer, leukemia or bone marrow cancer.In another embodiment, this purine analogue is a mercaptopurine.In another embodiment, this purine analogue is a mercaptopurine, and the treatment effective dose is 1.5mg/kg at least.In another embodiment, this purine analogue is a mercaptopurine, and the treatment effective dose be every day about 1.5mg/kg arrive the oral dose of about 5mg/kg.In another embodiment, this purine analogue is sulfo-guanidine (thioguanidine).In another embodiment, this purine analogue is the sulfo-guanidine, and dose therapeutically effective is 2mg/kg at least.In another embodiment, this purine analogue is the sulfo-guanidine, and dose therapeutically effective be every day about 2mg/kg to the 3mg/kg oral dose.

In another embodiment, described antimetabolite is a neplanocin, and the cancer of being treated is leukemia or lymphoma.In another embodiment, this neplanocin is a cladribine.In another embodiment, this neplanocin is a cladribine, and the treatment effective dose is 0.09mg/kg at least.In another embodiment, this neplanocin is a cladribine, and the treatment effective dose is the intravenously administrable dosage of 0.09mg/kg every day, continues seven days.In another embodiment, this neplanocin is a cladribine, and the treatment effective dose is 4mg/m every day ²Intravenously administrable dosage, continue seven days.In another embodiment, this neplanocin is a pentostatin.In another embodiment, this neplanocin is a pentostatin, and the treatment effective dose is 4mg/m ²In another embodiment, this neplanocin is a pentostatin, and the treatment effective dose is 4mg/m week about ²Intravenously administrable dosage.In another embodiment, this neplanocin is a pentostatin, and the treatment effective dose is per three all 4mg/m ²Intravenously administrable dosage.

In another embodiment, described antimetabolite is a pyrimidine analogue, and the cancer of being treated is bladder cancer, breast carcinoma, rectal cancer, the esophageal carcinoma, head and cervical region cancer, leukemia, hepatocarcinoma, lymphoma, ovarian cancer, cancer of pancreas, skin carcinoma or gastric cancer.In another embodiment, this pyrimidine analogue is a cytosine arabinoside.In another embodiment, this pyrimidine analogue is a cytosine arabinoside, and the treatment effective dose is 100mg/m at least ²In another embodiment, this pyrimidine analogue is a cytosine arabinoside, and the treatment effective dose is 100mg/m every day ²Intravenously administrable dosage, continue seven days.In another embodiment, this pyrimidine analogue is a capecitabine.In another embodiment, this pyrimidine analogue is a capecitabine, and the treatment effective dose is 2000mg/m at least ²Daily dose.In another embodiment, this pyrimidine analogue is a capecitabine, and the treatment effective dose is twice about 1200mg/m every day ²To about 1300mg/m ²Oral dose continues 14 days.In another embodiment, this pyrimidine analogue is a capecitabine, and the treatment effective dose be the cycle in three weeks, wherein every day twice 1250mg/m ²Dosage, continue 14 days, one week of drug withdrawal subsequently.In another embodiment, this pyrimidine analogue is a fluorouracil.In another embodiment, this pyrimidine analogue is a fluorouracil, and the treatment effective dose is 10mg/kg at least.In another embodiment, this pyrimidine analogue is a fluorouracil, and the treatment effective dose is about 300mg/m every day ²To about 500mg/m ²Intravenously administrable dosage, continue at least three days.In another example, this pyrimidine analogue is a fluorouracil, and the treatment effective dose is the intravenously administrable dosage of about 12mg/kg every day, lasting 3 to 5 days.In another embodiment, this pyrimidine analogue is that fluorouracil and treatment effective dose are weekly the intravenously administrable dosage of about 10mg/kg to about 15mg/kg.

In another embodiment, the urea of described antimetabolite for replacing, the cancer of being treated is head and cervical region cancer, leukemia, melanoma or ovarian cancer.In another embodiment, the urea of this replacement is a hydroxyurea.In another embodiment, the urea of this replacement is a hydroxyurea, and the treatment effective dose is 20mg/kg at least.In another embodiment, the urea of this replacement is a hydroxyurea, and the treatment effective dose is the oral dose of per three days 80mg/kg.In another embodiment, the urea of this replacement is a hydroxyurea, and the treatment effective dose be every day about 20mg/kg arrive the oral dose of about 30mg/kg.

In another embodiment, described second reagent is the platinum coordination complex, and the cancer of being treated is bladder cancer, breast carcinoma, cervical cancer, colon cancer, head and cervical region cancer, leukemia, pulmonary carcinoma, lymphoma, ovarian cancer, sarcoma, carcinoma of testis or uterus carcinoma.In another embodiment, this platinum coordination complex is a carboplatin.In another embodiment, this platinum coordination complex is a carboplatin, and the treatment effective dose is 300mg/m at least ²In another embodiment, this platinum coordination complex is a carboplatin, and the treatment effective dose be every all around 300mg/m at least ²Dosage.In another embodiment, this platinum coordination complex is a carboplatin, and the treatment effective dose is every 300mg/m all around ²Dosage.In another embodiment, this platinum coordination complex is a carboplatin, and the treatment effective dose be every all around 360mg/m at least ²Dosage.In another embodiment, this platinum coordination complex is a cisplatin.In another embodiment, this platinum coordination complex is a cisplatin, and the treatment effective dose is 20mg/m at least ²In another embodiment, this platinum coordination complex is a cisplatin, and the treatment effective dose be per three to around in four to five days in every day 20mg/m ²Intravenously administrable dosage.In another embodiment, this platinum coordination complex is a cisplatin, and the treatment effective dose is per three all 50mg/m ²Intravenously administrable dosage.In another embodiment, this platinum coordination complex is an oxaliplatin.In another embodiment, this platinum coordination complex is an oxaliplatin, and the treatment effective dose is 75mg/m at least ²In another embodiment, this platinum coordination complex is an oxaliplatin, and the treatment effective dose is about 50mg/m ²To about 100mg/m ²In another embodiment, this platinum coordination complex is an oxaliplatin, and the treatment effective dose is about 50mg/m of per two weeks ²To about 100mg/m ²The IV amount of infusion.In another embodiment, this platinum coordination complex is an oxaliplatin, and the treatment effective dose is about 80mg/m of per two weeks ²To about 90mg/m ²The IV amount of infusion.In another embodiment, this platinum coordination complex is an oxaliplatin, and the treatment effective dose is the 85mg/m in per two two hours weeks ²The IV amount of infusion.

In another embodiment, described second reagent is the topoisomerase II inhibitor, and the cancer of being treated is Hodgkin, leukemia, small cell lung cancer, sarcoma or carcinoma of testis.In another embodiment, this topoisomerase II inhibitor is an etoposide.In another embodiment, this topoisomerase II inhibitor is an etoposide, and the treatment effective dose is 35mg/m at least ²In another embodiment, this topoisomerase II inhibitor is an etoposide, and the treatment effective dose is about 50mg/m ²To about 100mg/m ²In another embodiment, this topoisomerase II inhibitor is an etoposide, and the treatment effective dose be per three the week or all around in five days at least three times every day about 35mg/m ²To about 50mg/m ²Intravenously administrable dosage.In another embodiment, this topoisomerase II inhibitor is an etoposide, and the treatment effective dose be per three the week or all around in five days at least three times every day about 50mg/m ²To about 100mg/m ²Intravenously administrable dosage.In another embodiment, this topoisomerase II inhibitor is an etoposide, and the treatment effective dose be per three the week or all around in five days at least three times every day about 100mg/m ²Oral dose.In another embodiment, this topoisomerase II inhibitor is a teniposide.In another embodiment, this topoisomerase II inhibitor is a teniposide, and the treatment effective dose is 20mg/m at least ²In another embodiment, this topoisomerase II inhibitor is a teniposide, and the treatment effective dose is 100mg/m weekly ²In another embodiment, this topoisomerase II inhibitor is a teniposide, and the treatment effective dose is twice 100mg/m weekly ²Dosage.In another embodiment, this topoisomerase II inhibitor is a teniposide, and the treatment effective dose is about 20mg/m every day ²To about 60mg/m ², continue five days.In another embodiment, this topoisomerase II inhibitor is a teniposide, and the treatment effective dose is about 80mg/m every day ²To about 90mg/m ², continue five days.

6.6 pharmaceutical composition and dosage form

Make pharmaceutical composition in the method provided by the present invention, this pharmaceutical composition contains SNS-595 and pharmaceutically acceptable carrier, as diluent or adjuvant, or with the SNS-595 of other active ingredient such as another kind of anticarcinogen combination.In clinical practice, SNS-595 can be by any conventional route administration, includes but not limited to oral, parenteral, rectum or by sucking (for example with aerosol form) approach.In some embodiments, the compositions among the present invention is acidic composition (for example pH＜4).Be not subjected to concrete one theory, this acidic composition can provide suitable balance between the dissolubility that increases SNS-595 and the property of medicine that needs (stimulation of for example sending the site by minimizing improves patient's comfort).

In one embodiment, SNS-595 is by the IV drug administration by injection.The compositions that is used for parenteral can be Emulsion or sterile solution.Can use propylene glycol, Polyethylene Glycol, vegetable oil (especially olive oil) or injectable organic ester (as ethyl oleate) as solvent or carrier during use.These compositionss also can comprise adjuvant, especially wetting agent, isotonic agent (isotonizing), emulsifying agent, dispersant and stabilizing agent.Sterilization can be carried out in several ways, as using bacteriology's filter, radiation or heating.They also can be made into the aseptic solid composite form, and it can dissolve in sterilized water or any other injectable sterile media when using.

Described compositions can also be an aerosol.In order to use with the liquid aerosol form, said composition can be stable sterile solution or the solid composite that dissolves in apyrogeneity sterilized water, normal saline or any other medicinal carrier in use.In order directly to suck, make up with the meticulous separation of effective ingredient and with water-soluble solid diluent or carrier (for example dextran, mannitol, lactose) with the dry gas solation.

Pharmaceutical composition can be prepared into separately, single unit dosage forms.Pharmaceutical composition and dosage form comprise SNS-595 and one or more excipient.

Pharmaceutical composition and dosage form also can comprise one or more additional activity compositions.Selectable second or the example of additional activity composition have open in the present invention.

In certain embodiments, compositions provided by the invention is pharmaceutical composition or single unit dosage forms.Contain SNS-595 and one or more typical pharmaceutically acceptable carrier or the excipient that prevents or treat effective dose at this pharmaceutical composition that provides and single unit dosage forms.Term " carrier " refers to the diluent, adjuvant (being Freund ' s adjuvant (completely with incomplete)), excipient or the carrier that use with medicine.These pharmaceutical carriers can be sterile liquids, for example comprise the water or the oil in oil, animal, plant or synthetic source, as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Oleum sesami or the like.In certain embodiments, when this pharmaceutical composition passed through intravenously administrable, water was as carrier.Normal saline and D/W and glycerol also can be used as the fluidity carrier, especially at Injectable solution.In " Remington ' s Pharmaceutical Sciences " that be described in E.W.Martin of the example of suitable pharmaceutical carriers.

Typical pharmaceutical composition and dosage form contain one or more excipient.Suitable excipient is known by the pharmaceutical field technical staff, and its nonrestrictive example comprises: starch, glucose, lactose, sucrose, gel, maltose, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, Talcum, sodium chloride, drying defatted milk powder, glycerol, propylene, ethylene glycol, water, ethanol or the like.Whether suitable the combination with a kind of pharmaceutical composition or dosage form depended on various factors well known in the art to a kind of concrete excipient, includes but not limited to that dosage form gives individual mode and the concrete active component in the dosage form.If desired, described compositions or single unit dosage forms can also comprise the wetting agent or the emulsifying agent of trace, or the pH buffer reagent.

The present invention further provides and has contained pharmaceutical composition and the dosage form that one or more reduce the chemical compound of active component resolution ratio.This chemical compound is called " stabilizing agent " herein, includes but not limited to: antioxidant (as ascorbic acid), pH buffer agent or salt buffer agent.

Described pharmaceutical composition and single unit dosage forms can be forms such as solution, suspension, emulsion, powder.This compositions and dosage form contain the preventive or the therapeutic agent of prevention or treatment effective dose, in certain embodiments, and with purified form and an amount of carrier, so that the form that is suitable for to individual administration to be provided.Described dosage form should be complementary with administering mode.In one embodiment, this pharmaceutical composition or single unit dosage forms are aseptic and are suitable for to individuality, as the form of animal individual or mammalian subject and individual human administration.

It is compatible with the administering mode of expecting that pharmaceutical composition provided by the present invention is formulated into.The example of administering mode includes but not limited to parenteral, as in intravenous, Intradermal, subcutaneous, the intramuscular, in subcutaneous, the suction, intranasal, transdermal, part, mucosa, tumor, synovial fluid administration and rectally.In specific embodiments, said composition is to be suitable for the usual manner preparation of administration in people's intravenously administrable, subcutaneous administration, intramuscular, intranasal administration or topical.In embodiments, pharmaceutical composition is to be suitable for the usual manner preparation of administration under fell.Typically, the compositions that is used for intravenously administrable is a sterile isotonic aqueous buffer solution.If desired, said composition also can comprise solubilizing agent and alleviate the local anesthetic (as lignocaine) of injection position pain.

The example of dosage form includes but not limited to: be applicable to the liquid dosage form of carrying out parenteral to individuality; With can be reconstructed into the sterile solid (as crystallization or amorphous solid) that is suitable for carrying out the liquid dosage form of parenteral to individuality.

The composition of dosage form provided by the present invention, shape and type will be according to its purposes and are different.For example, being used for dosage form that disease treats first compares and is used for same disease and keeps the dosage form of treatment and can comprise more one or more active components that this dosage form comprised of multiple dose.Similarly, non-parenteral dosage forms is compared the peroral dosage form that is used for the treatment of same disease or disease and can be contained still less one or more active components that this dosage form comprised of dosage.Among the present invention between the particular dosage form differences above-mentioned or others it will be apparent to those skilled in the art that.Referring to: Remington ' s Pharmaceutical Sciences, the 20th edition, MackPublishing, Easton PA (2000).

The composition of compositions provided by the present invention usually separately or be mixed into unit dosage forms and provide for example, places the dry freeze powder of the hermetically sealed container (as ampoule or bag) that shows amount of active agent or does not have aqueous concentrate.When said composition was used to infuse administration, its available infusion bottle that contains aseptic medicinal water or normal saline disperseed.When said composition is used for drug administration by injection, can provide ampoule injection sterilized water or normal saline before administration so that described composition mixed.

Exemplary dosage form provided by the present invention contains consumption per day or the about 1mg/m of all consumptions ²To about 75mg/m ²SNS-595, take with food as morning every day single-dose or gradation.Concrete dosage form provided by the present invention contains has an appointment 1,3,6,9,12,15,18,21,24,27 or 30mg/m ²SNS-595.

6.6.1 parenteral dosage forms

Parenteral dosage forms can include but not limited to by all means to patient's administration: in subcutaneous, intravenous (comprising bolus injection), the intramuscular and the intra-arterial administration.Because their administration can be avoided the natural defence of patient to pollutant usually, thus parenteral dosage forms preferably aseptic or before patient's administration, can sterilize.The example of parenteral dosage forms includes but not limited to: injection solution, solubilized or be suspended in dry products, injection suspension and the emulsion that can accept on the injection pharmacy in the carrier.

The carrier that is suitable for parenteral dosage forms is well known to those skilled in the art.Example includes but not limited to: USP water for injection; The aqueous carrier is such as but not limited to sodium chloride injection, ringer's injection, glucose injection, dextrose ﹠ sodium chloride injection and lactic acid ringer's injection; But water compatibility carrier is such as but not limited to ethanol, Polyethylene Glycol and polypropylene glycol; With non-aqueous carrier, such as but not limited to: Semen Maydis oil, cotton seed oil, Oleum Arachidis hypogaeae semen, Oleum sesami, ethyl oleate, isopropyl myristate and benzyl benzoate.

Those deliquescent chemical compounds that can improve one or more active component disclosed in this invention also can be incorporated in the described parenteral dosage forms.For example, cyclodextrin and its derivant can be used for increasing the dissolubility of active component.Referring to U.S. Patent number 5,134,127, it is incorporated herein by reference.

6.6.2 topical and mucosal drug delivery dosage form

In certain embodiments, provided by the present invention percutaneous drug delivery, topical and mucosal drug delivery dosage form.Percutaneous drug delivery among the present invention, topical and mucosal drug delivery dosage form include but not limited to: ophthalmic solution, spray, aerosol, emulsifiable paste, lotion, ointment, gel, solution, emulsion, suspension or the known dosage form of other any prior art.Referring to, Remington ' s Pharmaceutical Sciences, the 20th edition, Mack Publishing, Easton PA (2000); With Introduction to Pharmaceutical DosageForms, the 4th edition, Lea ﹠amp; Febiger, Philadelphia (1985).The dosage form that is applicable to mucous membrane tissue in the treatment oral cavity can be made into collutory or buccal cavity gel.Further, the transdermal dosage form comprises " reservoir formula " or " substrate formula " paster, and it can be used for skin and keeps a period of time to allow the infiltration of required dosage active component.

Be applicable to that topical dosage form among the present invention and excipient (for example carrier and diluent) and other material of mucosa delivery dosage form know for the pharmaceutical field technical staff, and depend on the concrete tissue that the pharmaceutical composition given or dosage form are used.In fact, typical excipient includes but not limited to: water, acetone, ethanol, ethylene glycol, propylene glycol, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil and its mixture are used to form aseptic and pharmaceutically acceptable solution, emulsion or gel.If desired, wetting agent or wetting agent also can add in pharmaceutical composition and the dosage form.Above-mentioned examples of additional ingredients is known prior art, referring to Remington ' s Pharmaceutical Sciences, the 20th edition, MackPublishing, Easton PA (2000).

Also the pH value of scalable pharmaceutical composition or dosage form is to increase sending of one or more active component.Similarly, the polarity of scalable solvent carrier, ionic strength or opening property are sent with raising.Also can in pharmaceutical composition or dosage form, add hydrophilic or the lipophile of chemical compound, send thereby improve advantageously to change one or more active component as stearates.In this, stearate can be used as lipid carrier, emulsifying agent or the surfactant of described preparation, and as delivery enhancer or penetration enhancers.Different salt, hydrate or the solvate of described active component can be used for further regulating the character of final composition.

7. embodiment

Some embodiment provided by the present invention describes by following non-limiting example.

Embodiment 1: the pharmaceutical composition that is applicable to injection or venous transfusion

Acidic composition (＜pH 4) can provide suitable balance (for example by to the comfort of administration position stimulation still less with the increase patient) aspect dissolubility that increases SNS-595 and the required pharmaceutical properties.The illustrative example of suitable compositions comprises: contain 10mg SNS-595 in every milliliter is adjusted to pH 2.5 with methanesulfonic acid 4.5% the sorbitol aqueous solution.A scheme for preparing above-mentioned solution is an example to be prepared as follows 100mg/10mL: the SNS-595 and the 450mg D-sorbitol that add 100mg in the distilled water; Be settled to 10mL; The pH value of final solution is adjusted to 2.5 with methanesulfonic acid.But also lyophilization of the compositions that obtains.This lyophilization dosage form can be dissolved in the concentration that sterilized water obtains being suitable for before use.

Embodiment 2:SNS-595 is the clinical testing data among the solid tumor cancer patient late

Safety and the curative effect of SNS-595 investigated in the research of rising gradually by two groups of dosage.As described below, SNS-595 has good safety and active anticancer to patient's intractable solid tumor.

In surpassing 10 minutes, give SNS-595 with 2 kinds of schemes to advanced solid tumor patient IV transfusion.In first kind of scheme (A), give SNS-595 weekly, continue three weeks, drug withdrawal at least 7 days (qwkx3) then.In second kind of scheme (B), give SNS-595 once (q3wk) per three weeks.

In two schemes, the predose of SNS-595 is 3mg/m ², and dosage increases gradually with successive 3 groups (sequential cohorts of3).Dosage doubles to meet or exceed 2 grades or occur unusual experiment value first up to relevant adverse events first, and dosage increases gradually with the Fibonacci sequence pattern of improvement then.

In 42 days of research, do not use other treatment, as not using Mitomycin-C, BCNU, nitroso ureas medicine or MAb therapy.

In research A, 21 patients (9 of male, 12 of women) are divided into 6 groups and treat (dosage range 3-24mg/m ²/ wk).In research B, 41 patients (25 of male, 16 of women) are divided into 9 groups and treat (dosage range 3-75mg/m ²/ wk).Median age is 61 years old (research A) and 59 years old (research B), and sex 12 woman/9 men (research A), 16 woman/25 men (research B), all patients have European tumor cooperative association function status (ECOG PS) the 0-2 level of marking.Selected patient has intractable solid tumor and good organ dysfunction.Table 1 provides the demographics of patient in two groups of researchs.

Table 1: patient demographics situation

Table 2 is the tabulation of treatment tumor type in two groups of researchs.

Table 2: treatment tumor type

	qwk×3	q3wk	Sum
				N (# treatment)	21	41	62
Ovarian cancer	1	9	10
				Colon cancer	3	6	9
NSCLC	0	6	6
				Cancer of pancreas	3	2	5
Renal carcinoma	1	4	5
				Melanoma	1	3	4
Adenocarcinoma (etiology unknown)	0	3	3
				Breast carcinoma	2	0	2
Sarcoma	0	3	3
				Cancer of biliary duct	1	1	2
Mesothelioma	2	0	2
				Neuroendocrine carcinoma	1	1	2
Bladder cancer	0	1	1
				Leiomyosarcoma	1	1	2
Liposarcoma	1	0	1
				Miao Le manages cancer	0	1	1
Nasopharyngeal carcinoma	1	0	1
				Salivary gland carcinoma	1	0	1
Small cell lung cancer	1	0	1
				Carcinoma sarcomatodes	1	0	1

To patient, gathered the PK sample at the 1st day that treats and the 15th day and also analyze with non-compartment analysis method according to the option A administration.It is definite that SNS-595 blood drug level adopts checking property LC-MS/MS to analyze.AUC (area under curve) is with dosage and average AUC _InfProportional increase is 3 to 24mg/m ²During dosage level, correspondingly in 1.7 to 15 μ g*hr/ml scopes, change.T1/2 is about 19 hours.The drug dependence that medication three Zhou Houwei observe pharmacokinetic parameter sexually revises.Fig. 1 described in the different patients group SNS-595 blood drug level over time.Table 3 provides the patient's pharmacokinetic parameter according to the option A administration.

Table 3: the 1st week and the 3rd week be pharmacokinetic parameter on average

Dosage (mg/m 2)	N (the 1st week, the 3rd week)	T 1/2hr	C max μg/ml	AUC inf μg·hr/ml	Cl obs L/hrm 2	V asobs L/m 2
							3	7(4，3)	23.3±7.2	0.577±0.795	1.71±0.20	1.77±0.23	52.7±18.2
6	6(3，3)	13.5±2.2	0.531±0.28	2.09±0.53	3.05±0.84	51.0±8.22
							12	6(3，3)	19.9±5.3	1.84±2.7	6.81±1.68	1.87±0.53	44.6±8.53
15	10(5，5)	26.4±15.2	0.865±0.318	10.8±4.7	1.59±0.56	43.8±7.90
							18	6(4，2)	15.8±4.2	1.69±0.83	8.50±2.86	2.36±0.88	47.19±8.06
24	1(1，0)	24.2	0.6	15.2	1.58	50.0
							Meansigma methods		18.5±4.6	--	--	2.22±0.58	47.6±10.7
Scope		10-33	0.6-1.8	2-15	1.4-4.3	30-75

To patient, at single dose administration 3 to 75mg/m according to the option b treatment ²After assessed 36 patients' kinetic parameter (21 severe pretreat patients and 15 slight pretreat patients).Up to 48mg/m ²All patients' clearance rate (CL), distribution volume, t1/2 (T _1/2) remain unchanged.In slight pretreat patient, until 75mg/m ²Its PK parameter remains unchanged.CL is 2.2L/hr/m ²(scope 1.0-3.8L/hr/m ²), distribution volume is 53L/m ²(scope 31-76L/m ²), and T _1/2Be about 21 hours (scope 13-49 hour).Rise to 48mg/m up to dosage ², severe pretreat patient is similar with slight pretreat patient's drug exposure and increase with dosage is linear.Reach 60mg/m at dosage ²During dosage level, slight pretreat patient presents the bigger drug exposure than the linear AUC (area under curve) of dosage.Table 4 has shown the patient's pharmacokinetic parameter according to the option b administration.

Table 4: the 3rd all pharmacokinetic parameters

Dosage (mg/m 2)	n	T 1/2hr	C max μg/ml	AUC inf μg·hr/ml	Cl obs L/hrm 2	V asobs L/m 2
							3	3	16.4±4.8	0.139±0.08	1.14±0.26	2.72±0.58	57.7±8.7

6	2	22.2±1.9	0.347±0.22	3.04±0.32	1.98±0.21	59.8±0.5
							12	3	18.0±4.1	2.25±1.07	6.32±0.22	1.90±0.07	45.2±8.9
24	3	15.7±3.2	2.70±2.57	12.63±0.86	1.91±0.13	40.7±8.8
							36	6	22.5±4.2	3.38±1.92	18.05±0.73	2.00±0.08	61.4±12.8
48	10	26.4±13.1	3.08±1.92	29.41±11.34	1.92±0.91	58.8±14.5
							60	8	25.0±17.9	3.86±1.68	40.71±23.67	1.88±0.88	48.0±7.3
75	4	25.0±4.9	5.05±1.72	46.09±6.12	1.65±0.22	56.3±9.4
							Meansigma methods		21.3±5.3	--	--	2.0±0.4	53.2±4.1
Scope		13-56	0.1-5	1-46	1-3.8	31-76

In research A, carried out pharmacokinetics assessment (after the first time and the administration for the third time) at the 1st day and the 15th day, as shown in table 5, SNS-595 has shown variability between high repeatability pharmacokinetics and low patient.Do not observe pharmacokinetic parameter accumulation or change behind the repeat administration.At the linear increase of 8 multiple dose scopes (1.6-15 μ g-hr/mL) Chinese medicine exposed amount, clearance rate (CL), distribution volume (Vss) and T _1/2Meansigma methods be respectively 2L/hr/m ², 48L/m ², 19 hours, and do not change from the 1st day to the 15th day.

In research B, first day assessment pharmacokinetic parameter after the administration first time; At linear (1.1-46 μ ghr/mL), CL, Vss and the T of increasing of 24 multiple dose scope Chinese medicine exposed amounts _1/2Meansigma methods be respectively 2L/hr/m ², 53L/m ², and 21 hours.

Table 5 provides the average pharmacokinetic parameter of two groups of researchs

Table 5:wk 1 and wk 3 pharmacokinetic parameter meansigma methodss

	Qwk * 3 the 1st weeks	Qwk * 3 the 3rd weeks	q3wk
				N	20	16	39
Dosage range (mg/m 2)	3-24	3-18	3-75
				AUCinf scope (μ ghr/mL)	2-15	2-7	1-46
T 1/2(hr)±SD	22±11	19±8	21±5
				CL obs(L/hr/m 2)±SD	1.9±0.7	2.2±0.9	2.0±0.4
Vss(L/m 2)±SD	48±12	47±8	53±4

Figure 11 has shown the dosage linear relationship among research A and the B.

Observed hematology influenced data during table 6 provided and studied.

Table 6: hematology's influence

# # dosage n ANC≤500 heat generation neutrophil cell 3mg/m 2 qwk×3 4 0 06mg/m 2 qwk×3 3 0 012mg/m 2 qwk×3 3 0 015mg/m 2 qwk×3 6 0 018mg/m 2 qwk×3 4 0 024mg/m 2 qwk×3 1 0 03mg/m 2 q3wk 3 0 06mg/m 2 q3wk 3 0 012mg/m 2 q3wk 3 0 024mg/m 2 q3wk 3 0 036mg/m 2 q3wk 6 0 048mg/m 2 q3wk 6 1 048mg/m 2(HP) q3wk 5 2 060mg/m 2 q3wk 8 3 175mg/m 2 q3wk 4 0 0

N=formation patient quantity

^*Neutrophil cell absolute counting (cell/μ L)≤500 continued greater than 7 days

In this manual, term " maximum tolerated dose " or " MTD " refer to be lower than among 6 patients has 〉=2 dosage levels that the SNS-595 dosage of dose-limiting toxicity (DLT) occurs.Term " severe pretreat " or " HP " patient accepted before referring to＞alkylating reagents of 6 courses of treatment, chemotherapy or＞platinum, Mitomycin-C or any nitroso ureas of 2 courses of treatment, perhaps＞25% patient of the XRT of bone.Term " slight pretreat " or " MP " patient refer to not reach the patient of HP definition, and (referring to Tolcher etc., JCO 2001; 19:2937-2947).

Dose-limiting toxicity (DLT) refers to that neutrophil cell absolute counting (ANC)≤500 reduces disease or the hemorrhage or non-hematology's untoward reaction in platelet minimum point＜25000 (AE) 〉=3 grade (as describing explanation in (CTCAE v3.0) among the Common Terminology Criteria for Adverse Events version 3 .0) more than or equal to 7 days or heat generation neutrophil cell herein, and wherein the untoward reaction dosage that needs＞14 days postpones.

Table 7-9 provides the data of safety of two groups of researchs.

Table 7: common (＞10% patient) untoward reaction

^*Patient's number of grading system 〉=3/all grade patient numbers

Table 8: hematology's influence

Table 9: may with research medicine relevant serious adverse reaction (SAE)

As can be seen, neutropenia is two groups of dose-limiting toxicities (DLT) in the research from data.In research A, be 24mg/m at dosage level ²The time, the dose-limiting toxicity (DLT) of neutropenia appears in the first patient.Then 5 patients are used 18mg/m ²Dosage treatment, 2 DLT that develop into neutropenia wherein.In research B, for severe pretreat patient, observing at dosage is 60mg/m ²The time, observe fourth stage neutropenia dose-limiting toxicity (DLT) above 7 days.For slight pretreat patient, it is 75mg/m that dose-limiting toxicity appears at dosage ²The time.

MTD is 15mg/m among the research A ²Among the research B is 48mg/m to severe pretreat patient (HP) MTD ², slight pretreat patient (MP) is 60mg/m ²

There are two patients that fourth stage thrombocytopenia is arranged respectively in two groups of researchs; Non-haematics toxicity mostly is grade 1/2 greatly, does not have dose limitation gastrointestinal toxicity or neurotoxicity.

Table 10 provides the clinical activity of SNS-595 in two groups of researchs.To research A, optimum curative effect comprises that a patient is partly alleviated (PR) and six conditions of patients are stablized SD (scope 16-24 week).To research B, optimum curative effect comprises a PR and 11 SD (scope 18-58 week).Table 11 provides the detailed data of part alleviations/trace alleviation in two groups of researchs.

Table 10: clinical activity

Table 11: partly/micro-reaction (PR/MR) detailed data

Obviously, SNS-595 has shown clinical activity to the advanced solid tumor patient, is included in stable above interior two patient's partial reactions during 16 weeks and 17 conditions of patients.

As can be seen, good to the SNS-595 toleration from data, the scheme that is administered once weekly and was administered once in three weeks all demonstrates clinical activity.Dose-limiting toxicity is non-accumulation neutropenia.SNS-595 has shown expected pharmacokinetics, has in the patient and the low variability between the patient.Not observing pharmacokinetic parameter behind the repeat administration changes.

Describe according to the present embodiment, the dose therapeutically effective of patients with solid tumor is comprised per three all 48mg/m ²15mg/m weekly ²

Embodiment 3: high intension screening and microscopy

Cell is closely to converge group's bed board and to grow 36 hours.Cell is with the given time of the compound treatment of given concentration then.Cell is changed thoroughly with 4% formaldehyde fixed and with 0.1% triton.Cell is exposed to 1 hour (anti--pATM-Chemicon, anti--gH2AX-Cell Signaling Technology) in 1: 100 diluent of first antibody in 10%FBS/PBS at 25 ℃.Cell in 25 ℃ of 1: 100 diluents in 10%FBS/PBS that are exposed to second antibody 1 hour.Under 500ng/ml concentration, in 10%FBS/PBS, carry out Hoechst dyeing.High intension screening utilizes the some probe algorithm to analyze with Cellomics Arrayscan instrument.

Fig. 2 has shown and gives all cpds 6 hours HCT116 cell.Then with cell fixation and analysing protein phosphorylation state (the gH2AX image obtains by fluorescence microscope, and the pATM image obtains by ArrayScan VTi).As seen from the figure, the SNS-595 treatment has caused nuclear focus (nuclear foci) to form.

Fig. 3-5 has illustrated nuclear focus formation and the dependency relationships of dosage and time.Fixed cell carries out phosphorylation-ATM analysis then.Cellomics Arrayscan software is used for determining focus (Fig. 3, orange point).Focus quantitatively can be by carrying out to focus fluorescence intensity (Fig. 4) or greater than the mensuration of the functional relationship (Fig. 5) of the cell of 2 focuses and time and SNS-595 concentration.

Embodiment 4:MTT colorimetry and sensitization are handled

Cell is plated in 96 orifice plates with 4000 cells/well, cultivates and uses compound treatment 72 hours after 24 hours.Cultivated 1-2 hour and cytolysis with 5%MTT then.At wavelength is that 570nm carries out the MTT colorimetric analysis and determines EC with linear regression analysis ₅₀

Sensitization is handled by number of chemical and is carried out.Cell is used chemical sensitizer pretreatment 16 hours, and (concentration is as follows: caffeine, 2mM to add medicine then; DNAPK inhibitor II (self-control), 10uM; And wortmannin, 100nM).Data provide in form 12.Determine EC by the MTT colorimetry ₅₀Cytotoxic multiple reduces to determine sensitization.

Data show that SNS-595 has shown unique PIKK dependency.Although handle back ATM/ATR and DNAPK is activated with SNS-595, have only DNAPK be DNA repair needed and if only if DNAPKcs is active when reducing cell just to the SNS-595 sensitivity.ATM/ATR mediation G2-catches at the outpost of the tax office.The forfeiture of the G2-outpost of the tax office then can not make cell to the SNS-595 sensitivity.Opposite with SNS-595, other DSB derivant of all of test all utilizes ATM/ATR to repair, and demonstrates sensitivity when ATM or DNAPK activity inhibited.

Embodiment 5: damage DNA plerosis damage under responsive kinases ATM and the ATR at shortage DNA-

Handled the HCT-116 cell 6 hours having under 2mM caffeine or the caffeine-free condition with 10mM SNS-595 or 10mM etoposide.Remove chemical compound then and made cellular-restoring 16 hours.The gH2AX focus in the analysis of cells respectively before medicine is cleaned and afterwards.As shown in Figure 6, the inductive DNA damage of SNS-595 can be repaired under no ATM and ATR situation easily.On the contrary, other medicines (for example etoposide) need utilize ATM and ATR to carry out DNA and repair.Caffeine is handled the activity that has suppressed ATM and ATR, causes the defective of homologous recombination, nucleotide excision reparation, mispairing reparation aspect.

Embodiment 6: damage DNA plerosis damage under the responsive kinases DNA-PK at shortage DNA-

MO59K (wt) and MO59J (DNAPKcs (/-)) cell handled 6 hours with 10mM SNS-595 or 10mM etoposide.Remove chemical compound then and made cellular-restoring 16 hours.The gH2AX focus in the analysis of cells respectively before medicine is cleaned and afterwards.As shown in Figure 7, the SNS-595 damage is not effectively repaired under shortage DNA-PK situation.By contrast, the inductive damage of other medicines (for example etoposide) can be repaired easily.

The combination research of embodiment 7:SNS-595

Cell line and cell culture: HCTl116 and NCI-H460 cell line obtain by ATCC.SKOV3 (p53-/-) and SKOV3 (p53+ /+) obtain from George doctor's Stark of Cleveland medical centre Alan Jay Lerner institute (LernerInstitute of the Cleveland Clinic) laboratory.All cells ties up in the RPMI culture medium of having added 10%FBS 1% sodium bicarbonate solution and 1% antibiotic solution (Cellgro) and cultivates.

The MTT colorimetry: with cell in 96 orifice plates with 4000 cells/well bed boards (remove SKOV3 (p53-/-), it is with 8000 cells/well bed boards), cultivate and used compound treatment in 24 hours then.Compound treatment continues 72 hours.Cell was handled 1-2 hour with 5%MTT then, cytolysis.At wavelength is that the 570nm place carries out colorimetric analysis.Dead cell proportion is determined by following formula:

Dead cell proportion=1-[sample aperture absolute value-acellular matched group average absolute]/[DMSO matched group average absolute-acellular matched group average absolute is only arranged]

Project study: when at chemical compound when comprising the scheme administration of cleaning step, cell cleaned 30 minutes with the fresh warm culture medium of 100 μ l, carried out another after 90 minutes again and took turns cleaning.

Statistical analysis: data (dead cell proportion) are analyzed with Calculsyn.V2 (Biosoft) and are expressed as the exponential quantity of share of influenced part proportion (Fa)=0.5 o'clock at this.All data are indicated the confidence interval of its meansigma methods 95% with error line.

If obtain the index that share of 0.85-1.2, then this share and is considered to additivity.If obtain the index that share less than 0.85, then this share and is considered to work in coordination with.If obtain the index that share greater than 1.2, this share and is considered to antagonism.Referring to Fig. 8-10.

In Fig. 8 a-8d, as seen, shown obvious synergistic when giving SNS-595 and various kinds of cell toxin simultaneously or be at least the index that share of addition HCT116 colon carcinoma cell line (8a, 8b and 8c) and H460 lung cancer cell line 8 (d).In Fig. 9, as seen, give SNS-595 and some DNA damage agent and antimetabolite simultaneously, express or do not have in the SKOV3 ovarian cancer cell line that p53 expresses and do not see that significantly share index changes having p53.

Shown in Figure 10 a-10d, when to the HCT116 colon cancer cell with SNS-595 and docetaxel (referring to Figure 10 a and 10c) and the common administration of gemcitabine (referring to Figure 10 b and 10d), perhaps during SNS-595 delay administration in 24 hours, what SNS-595 may be for antagonism.With respect to other reagent of administration at first (referring to Figure 10 a and 10b, administration and 24 hours) altogether, at first its antagonism of administration SNS-595 (referring to 10c and 10d, administration and 24 hours) altogether may reduce.When cell with first agent treated, clean and so can obtain additivity or possible concertedness during with second agent treated (, cleaning in 2 hours and cleaning in 24 hours) referring to Figure 10 a-d.

Embodiment 8:MTT cell viability detection-leukaemia:

Following cell line is used for this detection: HL-60 (promyelocytic leukemia); Jurkat (T chronic myeloid leukemia); CCRF-CEM (Lymphocytic leukemia); CEM/C2 (the camptothecine resistance derivant of CCRF-CEM).

Cell is plated on 96 orifice plates with 3000 cells/well and cultivated 16 hours.Diluted chemical compound liquid is diluted in the DMSO with 3 times from 10mM and makes.In culture medium, carry out dilution titration in 1: 100 to obtain final compound concentration.To 96 orifice plates ventilations and add the diluted chemical compound liquid (100ml/ hole) that is dissolved in the culture medium.Carrying out MTT after cultivating 72 hours under 37 ℃ analyzes.Briefly, the MTT solution that adds 20ml in each hole.Cell was cultivated 1-2 hour down at 37 ℃.The cell lysis buffer solution in adding 100ml/ hole is carried out lysis and under 37 ℃ of conditions the MTT solubilising is spent the night.Flat board reads with the absorbance method at the 570nm place with the spectromax instrument.IC ₅₀In GraphPad Prism, calculate (data are provided in the table 13) with regression analysis.As shown in table 13, SNS-595 has shown effective antiproliferative activity to test blood cell system.

Table 13: the IC of different cell lines ₅₀Value

Embodiment 9: heteroplastic transplantation model

To nude mice subcutaneous transplantation LM3-Jck human malignant lymphoma tumor top (2-3 square millimeter).Allow tumor length to be approximately 7-14mm to diameter.The Mus pairing is grouped into no treatment group, irinotecan group (100mg/kg, IV, q4d * 3), doxorubicin treatment group (12mg/kg, IV, single-dose), etoposide treatment group ((12mg/kg, IV, and SNS-595 treatment group (25 and 20mg/kg, IV, q7d * 5) q1d * 5)).Average group weight loss 30% or still less and per 6 the treatment animals in dead at the most one situation be defined as acceptable toxicity.The active anticancer of medicine plays assessment in the 21st day in initial administration.

Acute lymphoblastic leukemia tumor top to nude mice subcutaneous transplantation 2-3 square millimeter.Allow tumor length to be approximately 8-20mm to diameter.The Mus pairing is grouped into no treatment group, irinotecan group (100mg/kg, IV, q4d * 3), doxorubicin treatment group (12mg/kg, IV, q7d * 3), etoposide treatment group ((12mg/kg, IV, and SNS-595 treatment group (25 and 20mg/kg, IV, q7d * 5) q1d * 5)).Average group weight loss 30% or still less and per 6 the treatment animals in dead at the most one situation be defined as acceptable toxicity.The active anticancer of medicine plays assessment in the 20th or 21 day in initial administration.Table 14 provides the data of survival rate in tumor suppression (TI) and CCRF-CEM and the LM3-Jck heteroplastic transplantation model.

Table 14:SNS-595 and other cancer therapy drug active anticancer are relatively

Data from table 14 as seen, with 20 and during the 25mg/kg dosed administration tumor disappear fully, SNS-595 has shown very strong active anticancer to the LM-3Jck malignant lymphoma.In CCRF-CEM and LM3-Jck heteroplastic transplantation model, the tumor control rate of SNS-595 (IR) is suitable with irinotecan, but is better than etoposide and doxorubicin.

Embodiment 10: bone marrow/cytological analysis

Giving dosage the 0th day and the 4th day to female CD-1 Mus vein is 5,10,15 or the SNS-595 of 20mg/kg.Carry out analysis of Hematology Changes in the blood drawing in the 6th, 8 and 12 day of initial injection back.Get femur at the 6th day and be fixed on the Streck, and before the medullary cell analysis, carry out H﹠amp; E dyeing.Giving SNS-595 once more two days later, isolated bone marrow has shown the dose dependent that cellularity reduces from femur.When dosage was 20mg/kg, cellularity reduced to 7.5%, and the circulation neutrophil cell drops to minimum point 51 ± 24cells/mL blood at the 8th day 1244 ± 55 cells/mL blood before the medication.Absolute neutrophil cell number rebounds subsequently and returns to normal level very soon.Total WBCs also touched the bottom at the 8th day, but also returned to normal level.The minimizing of hemopoietic medullary cell structure dose dependent is illustrated among Figure 14.The figure illustrates behind the SNS-595 of initial injection various dose the 6th day cellularity in the bone marrow.

Figure 15 has shown the 4th, 6,8 and 12 day the neutrophil cell number in initial injection back.As can be seen from Fig. 16, all SNS-595 dosage groups all obviously descend at the 8th day periphery neutrophil cell.As can be seen from Fig. 17, the animal of accepting 20mg/kg SNS-595 injection was less than 50 cells/ml at the 8th day.

Figure 18 shows that being injected at the 8th day for SNS-595 has slight platelet response.Figure 19 shows that the body weight percentage ratio of different time behind the administration SNS-595 changes.Figure 20 has shown behind the SNS-595 of injection 20mg/kg the 12nd day bone marrow bounce-back.

Embodiment 11: the clinical testing data of patients with malignant hematological diseases SNS-595

To late period or the slow IV of acute leukemia patient injecting SNS-595.Diagnosis comprises AML (19 patients) and ALL (2 patients).All patients all suffer to be had the disease of toleration or is the disease recurrence (intermediate value is 3 (scope 1-6) before the scheme) after the treatment before treatment before.

Totally 21 patients (male 9 and women 12; Median age=64 years old, scope 21-80 year) is divided into five groups with two kinds of schemes treatments.In first scheme (A), give SNS-595 weekly once, continue three weeks, drug withdrawal 7 days (qwk * 3) then.In second kind of scheme (B), give SNS-595 twice weekly, continue two weeks (biwk * 2).The persistent period in cycle of two kinds of schemes comprises that withdrawal time is 28 days.Altogether administration 3 times of phase weekly in the option A, phase administration 4 times altogether weekly in option b.If conditions of patients is stable or better also can increase treatment cycle.Predose in the option A is 18mg/m ², the predose in the option b is 9mg/m ², and dosage progressively increases according to group.Its dosage of 3-6 name patient's group increases by the Fibonacci sequence pattern of improvement.

The plasma sample of collecting in cycle 1 is carried out pharmacokinetic analysis.Table 15 provides some pharmacokinetic parameters in the research.

Table 15: pharmacokinetic parameter

Dosage (mg/m 2)	Scheme	T 1/2 Hr	AUC inf μg·hr/ml	Cl obs L/hrm 2	V asobs L/m 2
						18	qwk×3	24±4	8.0±1.4	2.3±0.4	72±21
27	qwk×3	22±10	17.8±5	1.6±0.4	47±21
						9 *	biwk×2	24±5	4.3±1.3	2.3±0.7	65±2
13.5 *	biwk×2	21±7	5.9±2.9	2.5±1.2	61±6

^*4th, 8 with administration in 11 days after similar PK

SNS-595 blood drug level is analyzed by checking property LC-MS/MS and is determined.The blood amount of two doses level is linear before in each scheme increases, at 9-27mg/m ²AUC is 4.3-17.8 μ ghr/mL during dosage.CL, Vss and t1/2 and patients with solid tumor are similar, and meansigma methods is respectively～2L/hr/m ², 58L/m ²With 23 hours.Table 15 shows that six patients that are distributed in all dosage groups reduce to have surpassed 50% through treatment cycle 1 back periphery blast cell (blast).

In qwk * 3 schemes until 27mg/m ²Or in biwk * 2 schemes until 13.5mg/m ²All do not observe dose-limiting toxicity (DLT).The restricted toxicity of dose comprises nausea, diarrhoea and mucositis.Only observe 4 grades of heat generation leukopenias of an example.

In the option A (qwk * 3), other patient organizes dosage and is respectively 38mg/m ²And 50mg/m ²And in the option b (biwk * 2), other patient organizes dosage and is respectively 19mg/m ²And 25mg/m ²Data of safety is shown in table 16.

Table 16: may with research medicine relevant serious adverse reaction (SAE)

The effective dosage regimen of treatment malignant hematologic disease can be weekly about 50mg/m ²To about 80mg/m ², continuing for three weeks, effective dosage regimen of another treatment malignant hematologic disease is about 55mg/m weekly ²To about 75mg/m ², continued for three weeks.Effective dosage regimen of other treatment malignant hematologic disease comprises and gives 60mg/m weekly ², 65mg/m ², 70mg/m ²Or 75mg/m ², continued for three weeks.

Effective dosage regimen of other treatment malignant hematologic disease can comprise weekly about 25mg/m ²To about 50mg/m ²Twice, continued for two weeks.The effective dose of another treatment malignant hematologic disease is about 30mg/m weekly ²To about 45mg/m ²Twice, continued for two weeks.Effective dose of other treatment malignant hematologic disease comprises and gives 30,35,40 or 45mg/m weekly ²Twice, continued for two weeks.

Above-mentioned embodiment only is exemplary among the present invention, and those skilled in the art should know or can determine by routine test the equivalent of numerous particular compound, material and step.All these equivalents all are considered in protection scope of the present invention and are included in claims.

Claims (51)

1. treat leukemic method, this method comprises optically pure (+)-1 for the treatment of effective dose to mammal, 4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid, wherein said leukemia are chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia or acute myeloid leukaemia.

2. the process of claim 1 wherein that described leukemia is an acute lymphoblastic leukemia.

3. the method for claim 2, wherein said acute lymphoblastic leukemia originates from haematogonium, thymus or lymph node.

4. the method for claim 3, wherein said acute lymphoblastic leukemia is the T-chronic myeloid leukemia.

5. the method for claim 4, wherein said T-chronic myeloid leukemia is peripheral t-chronic myeloid leukemia, T-cell lymphocyte leukemia, skin T-chronic myeloid leukemia or adult T cell leukemia.

6. the process of claim 1 wherein that described leukemia is an acute myeloid leukaemia.

7. the process of claim 1 wherein that described acute myeloid leukaemia is myeloblastic leukemia or promyelocytic leukemia.

8. each method among the claim 1-7, wherein said leukemia are for recurrence, intractable or conventional therapy toleration.

9. each method among the claim 1-8, wherein said optically pure (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid is with about 1 to about 150mg/m ²Dosed administration.

10. the method for claim 9, wherein said dosage are about 1 to about 75mg/m ²

11. the method for claim 9, wherein said dosage are about 15 to about 80mg/m ²

12. each method among the claim 9-11, wherein said dosage is about 50mg/m ²To about 80mg/m ², give once weekly.

13. the method for claim 12, wherein said dosage is about 55mg/m ²To about 75mg/m ²

14. the method for claim 12, wherein said dosage is about 60mg/m ²

15. the method for claim 12, wherein said dosage is about 65mg/m ²

16. the method for claim 12, wherein said dosage is about 70mg/m ²

17. the method for claim 12, wherein said dosage is about 75mg/m ²

18. the method for claim 12-17, wherein said dosage gives weekly once, continues for three weeks.

19. each method among the claim 9-11, wherein said dosage is about 25mg/m ²To about 50mg/m ², give weekly twice.

20. the method for claim 19, wherein said dosage is about 30mg/m ²To about 45mg/m ²

21. the method for claim 19, wherein said dosage is about 30mg/m ²

22. the method for claim 19, wherein said dosage is about 35mg/m ²

23. the method for claim 19, wherein said dosage is about 40mg/m ²

24. the method for claim 19, wherein said dosage is about 45mg/m ²

25. the method for claim 19-24, wherein said dosage continued to give 2 weeks.

26. each method among the claim 1-12, wherein said optically pure (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid gives as the IV injection.

27. the method for claim 26, wherein said dosage are injected with 10-15 minute IV and are given.

28, treatment method for cancer, this method comprises that giving dosage to the mammal that these needs are arranged is about 1mg/m ²To 75mg/m ²Optically pure (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid.

29. the method for claim 28, wherein said cancer comprise that solid tumor and described dosage are about 3mg/m ²To 24mg/m ²

30. the method for claim 28 or 29, wherein said dosage is about 15mg/m ²

31. the method for claim 29 or 30, wherein said method comprises to mammal and gives optically pure (+)-1 once in a week, 4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid wherein comprises treatment cycle between this one-period and this treatment cycle repeats at least twice.

32. the method for claim 31, wherein said dosage are 15mg/m ²

33. treatment method for cancer, this method comprise that giving dosage to the mammal that these needs are arranged is about 15mg/m ²To 80mg/m ²Optically pure (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid.

34. the method for claim 28, wherein said cancer comprise that solid tumor and described dosage are about 6mg/m ²To about 75mg/m ²

35. the method for claim 34, wherein single dose is injected with 10-15 minute IV and is given and people patient that described mammal crosses for severe pretreat.

36. the method for claim 35, wherein said dosage is about 45mg/m ²To about 55mg/m ²

37. the method for claim 35, wherein said dosage are 48mg/m ²

38. the method for claim 33, wherein said method comprise that giving dosage once in a week to mammal is 15mg/m ²-80mg/m ²Optically pure (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid wherein comprises treatment cycle between this one-period and this treatment cycle repeats at least twice.

39. the method for claim 33, wherein said dosage are 60mg/m ²

40. the method for claim 39, wherein said dosage be for to inject the single dose that gives with 10-15 minute IV, and described mammal is the slight people patient that crosses of pretreat.

41. each method among the claim 28-38, wherein said cancer are bladder cancer, breast carcinoma, cervical cancer, CNS cancer, colon cancer, the esophageal carcinoma, head and cervical region cancer, hepatocarcinoma, pulmonary carcinoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, salivary gland carcinoma, small cell lung cancer, skin carcinoma, gastric cancer, carcinoma of testis, thyroid carcinoma, uterus carcinoma or malignant hematologic disease.

42. each method among the claim 28-41, wherein said cancer are melanoma, myeloma, neuroblastoma, sarcoma, mesothelioma, cancer of biliary duct, leiomyosarcoma, liposarcoma or carcinoma sarcomatodes.

43. each method among the claim 1-42, it also comprises second reagent for the treatment of effective dose.

44. the method for claim 43, wherein said second active agent are the antigenic therapeutic antibodies of cancer, hemopoietic growth factor, cytokine, antitumor and anticancer agent, antibiotic, cox-2 inhibitor, immunomodulator, immunosuppressant, glucocorticoid or its pharmacological activity mutant or derivatives thereof.

45. the method for claim 44, wherein said antibody are anti-EGFR-antibodies.

46. the method for claim 45, wherein said antibody are Erbitux or handkerchief Buddhist nun monoclonal antibody.

47. the method for claim 43, wherein said second active agent are alkylating reagent, antitumor antibiotics, antimetabolite, platinum coordination complex, topoisomerase II inhibitor or radiation.

48. the method for claim 43, wherein said second active agent are etoposide, daunorubicin, actinomycin D, ametycin, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-Fu, wet casual penicillin, geldanamycin, gemcitabine or its combination.

49. the method for claim 43, wherein said second active agent are docetaxel, doxorubicin, daunorubicin, irinotecan, gefitinib, erlotinib or its combination.

50. be used for the treatment of leukemic optically pure (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid, wherein said leukemia are chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia or acute myeloid leukaemia.

Optically pure 51. (+)-1,4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1, the application of 8-naphthyridines-3-carboxylic acid in the leukemic medicine of preparation treatment, wherein said leukemia is chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia or acute myeloid leukaemia.

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