CN104873502A

CN104873502A - Therapeutic combinations comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid fir treating cancer

Info

Publication number: CN104873502A
Application number: CN201510179121.1A
Authority: CN
Inventors: 丹尼尔·C·阿德尔曼; 杰弗里·A·西佛曼; 迈克尔·阿金; 詹尼弗·海德; 邓肯·沃克; 贾斯迈·莱特
Original assignee: Sunesis Pharmaceuticals Inc
Current assignee: Viracta Therapeutics Inc
Priority date: 2005-09-02
Filing date: 2006-09-05
Publication date: 2015-09-02

Abstract

The present invention relates to therapeutic combinations comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid fir treating cancer. The invention also provides treatment methods which combine the therapeutic combinations and chemotherapy, radiotherapy, hormonotherapy, biotherapy or immunotherapy. The invention also discloses medical composition and a single unit dosage form which are applicable to the method.

Description

Use the method for (+)-Isosorbide-5-Nitrae-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid Therapeutic cancer

The division that the application is the applying date is on 09 05th, 2006, application number is 200680039484.4, name is called the patent application of " using (+)-1; method of 4-dihydro-7-[(3s; 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid Therapeutic cancer ".

This application claims the U.S. Patent 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 number 60/789 of application on April 3rd, 2006,093 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 are incorporated herein by reference all 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 also called SNS-595 or AG-7352 to treat, prevents or control to comprise the method for specific leukemic cancer.Additionally provide the dosage of SNS-595 and administration thereof, dosage regimen and consumption.

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 is known due to its active anticancer.Mention available SNS-595 in 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 (i.e. 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, such as, see U.S. Patent Application Publication No. 2005-0203120,2005-0215583 and 2006-0025437, all above-mentioned open all full text is incorporated herein by reference.

Still safe and effective consumption and dosage regimen is needed when treating, prevent or control the kinds cancer comprising leukemia with SNS-595 administration.

3. summary of the invention

SNS-595 is a kind of known cytotoxic agent having anticancer efficacy.Present invention discusses and comprise the specific leukemic novel method for the treatment of of treatment.In addition, unique dosage range, dosage regimen and drug dose is also described.

Present specification describes the dosage treatment by SNS-595, its pharmaceutical composition and uniqueness, prevention or control cancer.Usually, the cancer types that available method provided by the present invention is treated, prevents or controlled 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 (i.e. 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 have toleration to conventional therapy.

In certain embodiments, described cancer comprises malignant hematologic disease, includes but not limited to leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin (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 drug resistance.In certain embodiments, this malignant hematologic disease is promyelocytic leukemia, T-chronic myeloid leukemia or Lymphocytic leukemia.

Invention further provides the method by giving SNS-595 in some way to treat, preventing or control cancer.In certain embodiments, the method comprises that to give dosage according to body surface area to mammal be 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, the method comprises and gives dosage according to body surface area to mammal and be about 15g/m ², 25g/m ²or 50mg/m ²sNS-595.Other dosage and dosage regimen are hereafter having more detailed description.

Present invention also offers the dosage for solid tumor and dosage regimen.The dosage of SNS-595 can pass through single dose, the such as IV of 10-15 minute injects and sends (such as single bolus injection), or within a period of time, such as 24 hours periods (such as continuous infusion or in time gradation bolus injection) send and repeatedly, such as until patient experiences stable disease or recovery, or until conditions of patients gets along with or produces unacceptable toxicity.

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

In another embodiment, by SNS-595 and another kind of medicine (" the second active agent ") or another kind is used for the treatment of, prevent or control the conventional therapy conbined usage of cancer, 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 for the treatment of, prevention and corntrol solid tumor.In other embodiments, the invention provides treatment, prevention and corntrol leukemia and lymphadenomatous associating.

Present invention also offers and comprise SNS-595, and second or the pharmaceutical composition of other active agent, single unit dosage forms and dosage regimen.Second active agent comprises particular combination or " the cocktail mixing " of medicine or treatment, or both.

4, accompanying drawing explanation

Fig. 1 describes with the SNS-595 blood drug level in different patient's groups of qwk × 3 administration over time;

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

Fig. 3 describes by measuring focus fluorescence intensity that to carry out focus quantitative;

Fig. 4 shows focus and is formed and dosage and the dependency relationships of time;

The cell being greater than 2 focuses is shown as the function of time and SNS-595 concentration by Fig. 5;

Fig. 6 show have and without the condition of caffeine (it is ATM and ATR inhibitor) under the DNA damage of being induced by SNS-595 and etoposide;

Fig. 7 shows DNA-PK (MO59K cell) and without the DNA damage of being induced by SNS-595 and etoposide under the condition of DNA-PK (MO59J cell);

Fig. 8 a-c show by SNS-595 and differential cytotoxicity preparation to HCT 116 colon cancer cell drug combination collaborative/additive effect;

Fig. 8 d show by SNS-595 and differential cytotoxicity preparation to H460 lung carcinoma cell drug combination collaborative/additive effect;

Fig. 9 shows Combination index when simultaneously using SNS-595 and the DNA damage agent of selecting and antimetabolite to the SKOV3 ovarian cancer cell line of expressing p53 (+/+) and not expressing p53 (-/-), represents respectively with black and gray diamonds;

Figure 10 a-d shows SNS-595 and differential cytotoxicity preparation the effect of HCT 116 colon cancer cell drug combination;

Figure 11 provides and gives three weekly dose (qwk × 3 to patients with advanced solid tumors; Circular=first week; Triangle=second week) and every three weeks dose (q3wk; Rhombus) the dose linear relation of SNS-595;

The anti-tumor activity that Figure 12 provides SNS-595, etoposide, doxorubicin and irinotecan in CCRF-CEM heteroplastic transplantation model compares;

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

Figure 14 shows the marrow cellularity of the female CD-1 mice of SNS-595 initial injection after 6 days.SNS-595 gives the 0th day and the 4th day.All Nonlinear magnify 10 times display;

Figure 15 provides and reacts the neutrophil cell of SNS-595 dosage;

Figure 16 provides the neutrophil count of under different SNS-595 dosage the 8th day;

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

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

Figure 19 provides the body weight change percentage ratio giving different time interval after SNS-595; With

Bone marrow at the 12nd day after Figure 20 shows the SNS-595 giving 20mg/kg rebounds.

5. define

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

Optically pure (+)-1 in 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 is not substantially containing (-)-1,4-dihydro-7-[(3s, 4s)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid (i.e. 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 not containing this compound of " (-) " form, is thus the enantiomeric excess for " (-) " form substantially.Term " optically pure " or " pure enantiomer " to represent containing percentage by weight more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, the compound of the enantiomer of 97%.

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

Except as otherwise noted, term " treatment " used in the present invention refers to the seriousness alleviating or reduce the symptom relevant with institute's disease therapy or situation.

Term " prevention " comprises the symptom suppressing specified disease or disease.In some embodiments, the patient of cancer family history is had 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, the term " control " used in the present invention comprises the recurrence that this disease or disease in the patient of specified disease or disease were once suffered from prevention, extend the time that the patient suffering from this disease or disease is in relieved state, reduce the mortality rate of patient, and/or the seriousness of the symptom relevant with treated disease or situation is maintained reduction level or avoids this symptom.

" individuality " that use in the present invention is animal, is generally mammal, comprises the mankind, as patient.

The term " cancer " used in the present invention includes but not limited to solid tumor and blood-born tumor.Term " cancer " refers to skin histology, organ, blood and angiopathy, includes but not limited to: bladder cancer, osteocarcinoma or leukemia, the brain cancer, breast carcinoma, cervical cancer, chest cancer, colon cancer, carcinoma of endometrium (endrometrium), the esophageal carcinoma, cancer eye, head cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, oral cancer, cervical region cancer, ovarian cancer, cancer of pancreas, carcinoma of prostate, rectal cancer, gastric cancer, carcinoma of testis, laryngeal carcinoma and uterus carcinoma.

" malignant hematologic disease " that use in the present invention refers to that health blood forms system and immune system-bone marrow and adenoid cancer.This cancer comprises leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin (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 have toleration to conventional therapy.

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

" acute lymphoblastic leukemia (ALL) " that use in the present invention, refers to by early stage agranular leukocyte or the thin born of the same parents' misgrowth of lymph also referred to as " Acute Lymphoblastic Leukemia " and grows the malignant disease caused.

" the T cell leukemia " that use in the present invention refers to that some cell lymphoid being wherein called T lymphocyte or T cell is pernicious disease.T cell is usually can challenge virus infection cell, foreign cell, cancerous cell produce the leukocyte of material of immunity moderation response.

Term " recurrence " refers to by treating its cancerous cell of patient that rear cancer has been eased situation repeatedly again.

Term " intractable or have toleration ", even if refer to after intensive treatment, still has the situation of residual cancer cell in patient body.

The IC used in the present invention ₅₀refer to reach the amount of the concrete test compounds of 50% maximum depression effect, concentration or dosage in the test detecting described effect.

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

Except as otherwise noted, the term " pharmaceutically acceptable salt " used in the present invention includes but not limited to be present in the salt of acidity in compound provided by the present invention or basic group.Under some acid condition, described compound can form various salt with multiple inorganic and organic acid.The acid that can be used to the pharmaceutically acceptable salt preparing this alkali compounds refers to that those form the acid of the salt containing pharmaceutically acceptable anion, includes but not limited to: acetic acid, benzenesulfonic acid, benzoic acid, heavy carbonic, acid tartrate 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 flutter acid.Under some alkali condition, described 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, the term " hydrate " used in the present invention refers to compound or its salt provided by the present invention, it also comprises the stoichiometry combined with Non-covalent molecular intermolecular forces or the water of non-stoichiometry amount.

Except as otherwise noted, the term " solvate " used in the present invention refers to that one or more solvent molecules are combined formed a kind of solvate with compound provided by the present invention.Term " solvate " comprises hydrate (such as monohydrate, dihydrate, trihydrate, tetrahydrate etc.).

Term " altogether administration " and " associating " comprise side by side, concurrently or one after the other give two kinds when no standard time restriction and treat reagent (such as SNS-595 and another kind of anticarcinogen or the second reagent).In one embodiment, two kinds of reagent are present in cell or in patient body simultaneously, or play biological or therapeutic effect simultaneously.In one embodiment, two kinds for the treatment of reagent are in same compositions or unit dosage forms.In another embodiment, reagent is treated in the compositions of separating or unit dosage forms for two kinds.

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

6. the detailed description of invention

6.1SNS-595

In the Treatment and composition for that we are bright, compound used is 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 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 method and composition of the present invention.

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

6.2 using method

The four-stage of proliferative cell experience cell cycle: G ₁, S, G ₂and M.The cell observing division these stages are first by carrying out DNA synthesis (it is called as synthesis phase or the S phase of cell cycle) and mitosis (being also referred to as the mitotic stages of cell cycle or M stage or S phase) during at cell is determined.Synthesizing at DNA the time slot being accomplished between mitosis and observe between mitosis to next DNA synthesis cycle is G respectively ₁stage and G ₂stage.The non-proliferative cell of multiplication capacity is under optimum conditions kept to be in dormancy or G ₀state, its typical characteristic has departed from cell cycle.

SNS-595 is a kind of cell cycle inhibitor, can at G ₂stage catches cell.Not by concrete theoretical restriction, SNS-595 mediation finally causes the activation in the DNA-PK path of apoptotic cell death.These events are specific to S phase, and namely they only betide the S phase of cell cycle.Not by concrete theoretical restriction, treating with SNS-595 the double-strand DNA cleavage number causing S phase to be formed increases, and this damage hinders the ability of cell synthetic DNA, and extends the time that cell is in S phase.Once DNA damage in cell be detected, apoptosis markers occurs rapidly.Seemingly p73 is dependent in the rapid generation of apoptosis, because with compared with p73 cell, in p73 null cell, the sensitivity of SNS-595 decrease beyond 11 times.

As shown in Figure 7, the formation of double-strand break activates the cell mechanism of DNA-PK mediation reparation and apoptosis with dosage-dependent manner, include but not limited to: i) DNA-PK expresses; Ii) H2AX phosphorylation; Iii) c-Abl phosphorylation; Iv) p 53 phosphorylation; V) p73 phosphorylation; Vi) p21 expresses; Vii) Caspase (Caspases)-9 activates; And viii) Caspase (Caspases)-3 activation.If DNA damage is very serious, to such an extent as to when can not repair double-strand break by non-homogeneous end connection (NHEJ), cell enters apoptosis rapidly.Some cells can arrive G ₂stage, but these cells can not enter M stage and be captured (being mediated by cdc2/ cell periodic protein B) due to damage, and final apoptosis.By concrete theoretical restriction, because SNS-595 has S-multi-stage selective, be nonfatal to the poisonous SNS-595 dosage of proliferative cell (therefore just experiencing the cell cycle comprising S phase) for non-proliferative cell.

6.2.1 solid tumor

Therefore, the invention provides treatment, control or the method for prophylaxis of cancer, the mammal that the method comprises 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, the method comprises treatment, prevention or controls tumor, liposarcoma, melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, renal carcinoma, salivary gland carcinoma, small cell lung cancer or carcinoma sarcomatodes in colon cancer, cancer of pancreas, breast carcinoma, mesothelioma, cancer of biliary duct, 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 controls acute leukemia, such as AML, includes but not limited to undifferentiated AML (M0), myeloblastic leukemia (Ml), 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 coming from haematogonium (B-cell), thymocyte cell (T-cell) and lymph node.According to method-U.S.-English (FAB) morphological classification table, acute lymphoblastic leukemia can be divided into immature and pleomorphism (various shape) lymphoblast (T-cell or front-B-cell) of L1-mature form lymphoblast (T-cell or front-B-cell), L2-and L3-lymphoblast (B-cell; Burkitt cell).

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

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

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

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

In one embodiment, acute myeloid leukaemia is myelomonocytic leukemia (M4 or 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, the L1 type that acute lymphoblastic leukemia is is feature with mature form lymphoblast (T-cell or front-B-cell).

In one embodiment, the L2 type that acute lymphoblastic leukemia is is feature with immature and pleomorphism (various shape) lymphoblast (T-cell or front-B-cell).

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

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

In some embodiments, SNS-595 is used to the leukemia for the treatment of drug resistance, as chronic myelogenous leukemia (CML).Thus, can select for those provide a kind of to the patient that other Therapeutic Method does not respond with SNS-595 treatment.In some embodiments, these other Therapeutic Method comprise use treat.In some embodiments, the method for the treatment of Philadelphia chromosome positive chronic myelogenous leukemia (Ph+CML) is provided.In some embodiments, treatment is provided right there is the method for the Philadelphia Chromosome Positive chronic myelogenous leukemia (Ph+CML) of drug resistance.

Method provided by the present invention comprises having accepted treatment of cancer before but to the responseless patient of standard care, and the patient not accepting before to treat treats.Although some diseases or disease commonplace in certain age group, present invention also offers the method for the treatment patient without the need to considering patient age.Further, additionally provide carrying out performing the operation with the method for the treatment of the disease of tissue or the patient that treats of situation and the patient that do not carry out above-mentioned treatment.Have different clinical manifestations due to cancer patient and produce different clinical effectiveness, the Therapeutic Method therefore giving patient can be different according to his/her prognosis.Without the need to too much test, experienced clinician can determine easily to can be used to the concrete second class grade chemical of Therapeutic cancer individual patient effectively, type of surgery, not based on the type of the standard care of medicine.

The dosage of SNS-595 can pass through single dose, the such as IV of 10-15 minute injects and sends (such as single bolus injection), or within a period of time, such as 24 hours periods (such as continuous infusion or in time gradation bolus injection) send and repeatedly, such as until patient experiences stable disease or recovery, or until conditions of patients gets along with or produces unacceptable toxicity.Such as, solid tumor stable disease is often referred to the perpendicular diameter can measuring focus and measured increase than last time and be no more than 25%, see, ResponseEvaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the NationalCancer Institute 92 (3): 205-216 (2000).Stable disease or instability judge by known method, and as patients symptomatic's assessment, physical examination, use X-ray, CAT, PET or MRI scanning imagery make tumor visual, and other evaluation methodology generally adopted.

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

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

In other embodiments, SNS-595 and another medicine (" the second active agent ") or another treat, control or the method conbined usage of prophylaxis of cancer.Second active agent comprises micromolecule and macromole (i.e. protein and antibody), and its example provides in the present invention, and stem cell or umbilical blood.The current surgical operation, immunotherapy, biotherapy, X-ray therapy and other non-drug therapy that are used for the treatment of, prevent or control cancer can be included but not limited to the method for SNS-595 conbined usage or Therapeutic Method.Present invention discusses the individually dosed and/or different dosing regimes in therapeutic alliance of SNS-595.

Present invention also offers the pharmaceutical composition (i.e. single unit dosage forms) of method used in the present invention, especially comprise the pharmaceutical composition of SNS-595 and the second active agent.

6.3 dosage and dosage regimen

In one embodiment, the present invention's treatment, prevention or control the method for cancer and comprise and give dosage according to patient skin surface area and be about 1mg/m ²to 150mg/m ²sNS-595.In another embodiment, the method comprises that to give dosage be about 1mg/m ²to 100mg/m ²sNS-595.In another embodiment, the method comprises to dosage is about 1mg/m ²to 75mg/m ²sNS-595.In another embodiment, the method comprises that to give to dosage be about 1mg/m ²to 60mg/m ²sNS-595.In another embodiment, the method comprises that to give dosage be about 1mg/m ²to 50mg/m ²sNS-595.In another embodiment, the method comprises to dosage is about 1mg/m ²to 48mg/m ²sNS-595.In another embodiment, the method comprises that to give dosage be about 1mg/m ²to 24mg/m ²sNS-595.In another embodiment, the method to comprise according to body surface area to giving dosage is about 3mg/m ²to 27mg/m ²sNS-595.In another embodiment, the method comprises that to give to dosage according to body surface area be about 3mg/m ²to 24mg/m ²sNS-595.In another embodiment, the method to comprise according to body surface area to giving dosage is about 10mg/m ²to 90mg/m ²sNS-595.In another embodiment, the method to comprise according to body surface area to giving dosage is about 15mg/m ²to 80mg/m ²sNS-595.Body surface area can calculate, such as, calculate according to 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 ².In another embodiment, this dosage is the 3mg/m based on body surface area ²to 18mg/m ².In another embodiment, this dosage is 3mg/m ²to 15mg/m ².In 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 ²or 65mg/m ².In 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 ²or 50mg/m ².

In one embodiment, described dosage is the 15mg/m based on body surface area ².In another embodiment, this dosage is the 25mg/m based on body surface area ².In another embodiment, this dosage is the 30mg/m based on body surface area ².In 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 ².In another embodiment, this dosage is the 15mg/m based on body surface area ²to 75mg/m ².In another embodiment, this dosage is 30mg/m ²to 50mg/m ².In 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 use mg/m ²outside measurement unit represent.Such as, available mg/kg represents dosage.Those of ordinary skill in the art easily can realize mg/m according to the height of the individuality provided or body weight or height and body weight ²to the conversion (see http: ///www.fda.gov/cder/cancer/animalframe.htm) of mg/kg.Such as, 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, the such as IV of 10-15 minute injects and sends (such as single bolus injection), or within a period of time, such as 24 hours periods (such as continuous infusion or in time gradation bolus injection) send and repeatedly, such as until stable disease or recovery, or until conditions of patients gets along with or produces unacceptable toxicity.Such as, stable disease or instability are judged by known method, such as patients symptomatic's assessment, physical examination and other generally accepted assessment mode.

The amount of the pharmaceutical composition that method of the present invention gives depend on be treated mammal, the order of severity of symptom of disease or disease, administering mode, administration frequency and prescribing doctor judgement.

In some embodiments, administration frequency is arrive about once a day about monthly.In certain embodiments, administration is once a day, once, biweekly, once in a week, biweekly every other day, three weeks once or surrounding once.In one embodiment, pharmaceutical composition provided by the present invention is given weekly.

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

Therefore, in one embodiment, SNS-595 gives with single dose or the dosage that separates weekly in the cycle of three weeks to 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 one week, two weeks, three weeks, surrounding, five weeks 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 waiting period.In some embodiments, be 28 days waiting period.In one embodiment, be until there is enough bone marrow to recover waiting period.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 treatment cycle more more than typical regimen.

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

Such as, in one embodiment, in certain leukemic method for the treatment of, 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 sky, do not give SNS-595 to this mammal during this period; Iii) give another dosage to this mammal and be about 10mg/m ²-150mg/m ²sNS-595; With, iv) repeat step I i)-iii) repeatedly.In another embodiment, the 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 patient is about 1mg/m ²-75mg/m ²sNS-595; Ii) wait at least one sky, do not give SNS-595 to this mammal during this period; And iii) to give another dosage to this patient be 1mg/m ²-75mg/m ²sNS-595.In one embodiment, step I i)-iii) repeatedly.

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

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

In another embodiment, described method is included in step I) and iii) in give about 3mg/m ²to 24mg/m ²dosage.And in another embodiment, the method is included in step I) and iii) in give about 15mg/m ²dosage.In another embodiment, the 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 ²or about 3mg/m ²to 24mg/m ²dosage.

In another embodiment, described method is included in step I) and iii) in give about 15mg/m ²to 80mg/m ²dosage.And in another embodiment, the method is included in step I) and iii) in give about 15mg/m ²to 75mg/m ²dosage.And in another embodiment, the method is included in step I) and iii) in give about 20mg/m ²to 65mg/m ², about 30mg/m ²to 50mg/m ², about 35mg/m ², about 40mg/m ²or about 45mg/m ²dosage.

In the above-mentioned methods, for example, if waiting period be 6 days, so gave the SNS-595 (step I) of predose at the 1st day; Waiting period be 6 days (step I i); The SNS-595 (step I ii) of subsequent dose is given at the 8th day.Other typical period comprises 2 days, 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, 2 days are at least waiting period and step I i) to iii) at least in triplicate.In another embodiment, 3 days are at least waiting period and step I i) to iii) at least repeat five times.In another embodiment, 3 days are at least waiting period and step I i) to iii) at least in triplicate.In another embodiment, 3 days are at least waiting period and step I i) to iii) at least repeat five times.In another embodiment, 6 days are at least waiting period and step I i) to iii) at least in triplicate.In another embodiment, 6 days are at least waiting period and step I i) to iii) at least repeat five times.In another embodiment, 14 days are at least waiting period and step I i) to iii) at least in triplicate.In another embodiment, 20 days are at least waiting period and step I i) to iii) at least in triplicate.In another embodiment, 20 days are at least waiting period and step I i) to iii) at least repeat five times.In another embodiment, 28 days are at least waiting period and step I i) to iii) at least in triplicate.In another embodiment, 27 days are at least waiting period and step I i) to iii) at least repeat five times.In another embodiment, 28 days are at least waiting period and step I i) to iii) at least repeat five times.

In another embodiment, described medication comprises and gives weekly twice SNS-595 (administration in the 1st, 4,8 and 11 day) to mammal.In another embodiment, this medication comprises and gives weekly a SNS-595 to mammal.In another embodiment, this medication comprises every two circumferential mammals and gives a SNS-595.In another embodiment, this medication comprises every three circumferential mammals and gives a SNS-595.In another embodiment, medication comprises every four circumferential mammals and gives a SNS-595.

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

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, continue three weeks; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 1mg/m ²to 100mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-iii) 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, continue three weeks; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 1mg/m ²to 75mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-iii) repeatedly.

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

In another embodiment, the method provided comprises: i) give dosage once in a week to this mammal and be about 1mg/m ²to 50mg/m ²sNS-595, continue three weeks; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 1mg/m ²to 50mg/m ²sNS-595, continue three weeks; And iv) repeat step I i)-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, continue three weeks; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 1mg/m ²to 48mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-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 24mg/m ²sNS-595; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 1mg/m ²to 24mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-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 2mg/m ²to 40mg/m ²sNS-595, continue three weeks; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 2mg/m ²to 40mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-iii) 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; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 3mg/m ²to 24mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-iii) 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 (namely administration in the 1st, 8 and 15 day); Ii) wait at least 28 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 3mg/m ²to 24mg/m ²sNS-595, continue three weeks.In one embodiment, step I i)-iii) repeatedly.

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

In another embodiment, method provided by the present invention comprises: i) give weekly dosage 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, during this period, do not give any SNS-595 to this mammal; And iii) give weekly dosage 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) 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 3 weeks; Ii) wait for 14 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 15mg/m ²to 80mg/m ²sNS-595, continue 3 weeks.In one embodiment, step I i)-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 15mg/m ²to 80mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day); Ii) wait at least 28 days, during this period, do not give any SNS-595 to this mammal; And iii) give dosage once in a week to this mammal again and be about 15mg/m ²to 80mg/m ²sNS-595, continue 3 weeks.In one embodiment, step I i)-iii) repeatedly.

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

In another embodiment, method provided by the present invention comprises: i) give weekly dosage 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, during this period, do not give any SNS-595 to this mammal; And iii) give weekly dosage 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) repeatedly.

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

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

In some embodiments, described method comprises and gives dosage once in a week to patient and be about 1mg/m ²to 40mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon at least 28 days waiting period.In some embodiments, the method comprises and gives weekly dosage for twice to patient and be about 1mg/m ²to 40mg/m ²sNS-595 (administration in the 1st, 4,8 and 11 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon at least 28 days waiting period.In some embodiments, the method comprises and gives dosage once in a week to patient and be about 1mg/m ²to 40mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon 28 days waiting period.In some embodiments, the method comprises and gives weekly dosage for twice to patient and be about 1mg/m ²to 40mg/m ²sNS-595 (administration in the 1st, 4,8 and 11 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon 28 days waiting period.

In some embodiments, described method comprises and gives dosage once in a week to patient and be about 3mg/m ²to 24mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon at least 28 days waiting period.In some embodiments, the method comprises and gives weekly dosage for twice to patient and be about 3mg/m ²to 24mg/m ²sNS-595 (administration in the 1st, 4,8 and 11 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon at least 28 days waiting period.In some embodiments, the method comprises and gives dosage once in a week to patient and be about 3mg/m ²to 24mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon 28 days waiting period.In some embodiments, the method comprises and gives weekly dosage for twice to patient and be about 3mg/m ²to 24mg/m ²sNS-595 (administration in the 1st, 4,8 and 11 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon 28 days waiting period.

In some embodiments, described method comprises and gives dosage once in a week to patient and be about 15mg/m ²to 80mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon at least 28 days waiting period.In some embodiments, the method comprises and gives weekly dosage for twice to patient and be about 15mg/m ²to 80mg/m ²sNS-595 (namely administration in the 1st, 4,8 and 11 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon at least 28 days waiting period.In some embodiments, the method comprises and gives dosage once in a week to patient and be about 15mg/m ²to 80mg/m ²sNS-595 (namely administration in the 1st, 8 and 15 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon 28 days waiting period.In some embodiments, the method comprises and gives weekly dosage for twice to patient and be about 15mg/m ²to 80mg/m ²sNS-595 (administration in the 1st, 4,8 and 11 day), wherein comprise treatment cycle during this week and this cycle repeats at least three times, be thereupon 28 days waiting period.

In another embodiment, described method comprises and gives dosage once in a week to mammal and be about 1mg/m ²-50mg/m ²sNS-595, wherein comprise treatment cycle during this week and this cycle repeats at least twice.In another embodiment, described dosage is about 2mg/m ²-40mg/m ².In another embodiment, described dosage is about 3mg/m ²-24mg/m ².In another embodiment, described dosage is about 4mg/m ²-20mg/m ².

6.4 Exemplary dosing schedules

The following provide the Exemplary dosing schedules that particular cancers is relevant.These dosage regimens aim to provide explanation, are not exclusive.

On the one hand, the method for the treatment of solid tumor is provided.The method comprises:

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

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

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

Iv) iv) repeat step I i)-iii) repeatedly.

On the other hand, treat the method for solid tumor to comprise and give dosage once in a week to patient and be about 1mg/m ²to 75mg/m ²sNS-595, wherein comprise a treatment cycle during this week and this treatment cycle repeats at least twice.In another embodiment, described dosage is about 15mg/m ²to 80mg/m ².In another embodiment, described dosage is about 3mg/m ²to 24mg/m ².

On the other hand, treat the method for solid tumor to comprise and give dosage once in a week to patient and be about 15mg/m ²to 40mg/m ²sNS-595, continue three weeks, then at least two weeks did not give SNS-595 to described individuality, and wherein this treatment cycle is repeatedly.In another embodiment, described dosage is about 15mg/m ²to 35mg/m ².In another embodiment, described dosage is about 20mg/m ²to 30mg/m ².In another embodiment, described dosage is about 20mg/m ²to 25mg/m ².

On the other hand, once giving patient dose in during the method for the treatment of solid tumor is included in three weeks is 35mg/m ²to 80mg/m ²sNS-595, wherein this comprises treatment cycle during three weeks and this cycle repeats at least twice.

On the other hand, the invention provides the method for the treatment of malignant hematologic disease.In certain embodiments, the method comprises and gives dosage to patient and be about 20mg/m ²to 60mg/m ²sNS-595.

Those are considered to the patient (" severe pretreat patient ") of severe pretreat, giving patient's dose in during described method is included in three weeks is 35mg/m ²to 60mg/m ²sNS-595, wherein this comprises treatment cycle during three weeks and this treatment cycle at least repeats twice.In another embodiment, the Therapeutic Method of severe pretreat patient is comprised give 40mg/m ²to 50mg/m ²dosage.In another embodiment, the Therapeutic Method of severe pretreat patient is comprised give 45mg/m ²to 50mg/m ²dosage.The definition of severe pretreat patient is if Tolcher etc. is described by J.Clin.Oncol.19:2937-2947 (2001), refer to the chemotherapy regimen containing alkylating reagent once accepted more than six courses for the treatment of, more than carboplatin or the ametycin of two courses for the treatment of, any early stage nitroso ureas scheme, the radiotherapy of 25% bone marrow area, need the high-dose chemotherapy that hematopoietic stem cell feeds back, or the patient of large area Bone tumour.

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

On the other hand, treatment neoplastic hematologic disorder is provided as leukemia and lymphadenomatous method.The method comprises:

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

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

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

Iv) step I i is repeated)-iii) repeatedly.

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

In one embodiment, treat the method for malignant hematologic disease and comprise that to give patient dose be once in a week about 20mg/m ², 22mg/m ², 25mg/m ², 27mg/m or 30mg/m ²sNS-595, wherein this week comprise treatment cycle and this treatment cycle at least repeats twice.In one embodiment, treat the method for malignant hematologic disease to comprise and give patient dose once in a week and be about 25mg/m ²sNS-595, wherein this week comprise treatment cycle and this treatment cycle at least repeats twice.

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

In one embodiment, treat the method for malignant hematologic disease to comprise every two circumferential patients and give dose and be about 40mg/m ², 45mg/m ², 50mg/m ², 55mg/m ²or 60mg/m ²sNS-595, wherein this comprised treatment cycle during two weeks.In one embodiment, treat the method for malignant hematologic disease to comprise every two circumferential patients and give dose and be about 50mg/m ²sNS-595, wherein this comprised treatment cycle during two weeks.

6.5 therapeutic alliance

In method and composition provided by the invention, SNS-595 can with other pharmaceutically active compounds (" the second active agent ") conbined usage.Believe that the cancer that some is combined treating 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 the second active agent

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

The example of Large molecule active agents includes but not limited to: hemopoietic growth factor, cytokine, and monoclonal and polyclonal antibody, the especially therapeutic antibodies of cancer antigen.Typical Large molecule active agents is biomolecule, as natural or artificial protein.In the inventive method and compositions, useful especially protein comprises those and hemopoietic CFU-GM and immunocompetence can produce the protein of cell (poieticcells) survival and/or propagation in vitro or in body.Other oroteins in vitro or the directed CFU-E division of body internal stimulus and differentiation.Concrete protein includes but not limited to: interleukin class, as IL-2 (comprising restructuring IL-II (" rIL2 ") and canary rash (canarypox) IL-2), IL-10, IL-12 and IL-18; Interferons, as Intederon Alpha-2a, Interferon Alpha-2b, interferon alfa-n1, Alferon N, interferon beta-I a and interferon gamma-I b; 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 the filgrastim (Amgen, Thousand Oaks, CA) sold and its derivant, include but not limited to Pegfilgrastim; In the U.S. with trade name the Sargramostim ((Immunex, Seattle, WA) sold; In the U.S. with trade name the recombinant epo (Amgen, Thousand Oaks, CA) sold; Epoetin Alfa and A Fadabeiting.

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

Present invention also offers and the native protein of SNS-595 conbined usage and recombinant protein.The present invention comprise further can show in vivo its based on the mutant of native protein of pharmacologically active at least partially of described protein and derivant (such as modified forms).The example of mutant includes but not limited to the protein with one or more amino acid residue different from the corresponding residue in native protein.Term " mutant " also comprises the protein (i.e. nonglycosylated form) lacking the carbohydrate group be usually present in native protein.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 interested protein active partial fusion being formed.See, Penichet, M.L. and Morrison, S.L., J.Immunol.Methods248:91-101 (2001).

Monoclonal and polyclonal antibody can be comprised with the antibody of SNS-595 conbined usage.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 Victibix combines or conbined usage.

Large molecule active agents can be used as anti-cancer vaccine and uses.Such as, can secrete or cause the vaccine of secrete cytokines as IL-2, G-CSF and GM-CSF to can be used in method provided by the present invention and drug component.See, L.A., etc., Curr.Opinion Mol Ther.3 (l): 77-84 (2001).

Make additive properties or the maximized universal law of concertedness on the contrary (see Page from selecting the medicine of the different mechanism of action, and Takimoto R., C, " Principles of Chemotherapy ", CancerManagement:A Multidisciplinary Approach (2001), p.23), the compositions of the second active agent comprising SNS-595 and DNA also can be stoped to synthesize is found to have additivity or cooperative effect.

In the present invention, when reagent directly or indirectly affects the ability of cell synthetic DNA or DNA plerosis damage, which prevent DNA synthesis.This reagent can directly interact with DNA (be such as combined or insert) or combine with the DNA-associated proteins that participation DNA synthesizes or DNA repairs.Usually, the reagent of DNA synthesis is stoped to have activity in S phase but do not need to possess S phase specificity.

Because SNS-595 affects DNA-PK path, the second reagent can be can mediate its Cytotoxic reagent by DNA-PK path.An example suppresses the reagent of non-homologous end joining reparation as DNA-PK inhibitor.Except as otherwise noted, " DNA-PK inhibitor " used herein refers to the reagent of the signal path that can suppress or disturb DNA-PK to mediate.Can be directly (such as the catalytic inhibitor of DNA-PK itself) or indirectly (reagent that such as interferon activity DNA-PK complex (DNA-PK, Ku70 and Ku80) is formed) to the suppression of DNA-PK activity.Other example includes but not limited to: ligase IV inhibitor and apoptosis dose, 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 caused by SNS-595.But, just as some macromole, believe that many micromolecule second active agents also can produce cooperative effect during (before, afterwards or) administration together with SNS-595 simultaneously.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 (urea of such as folacin, purine analogue, neplanocin, pyrimidine analogue and replacement), platinum coordination complex, Topoisomerase II inhibitors and radiation.

Concrete antitumor and anticancer agent includes but not limited to: acivicin, aclarubicin, hydrochloric acid acodazole, acronine, adozelesin, aldesleukin, altretamine, ambomycin, 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, methanesulfonic acid crisnatol, cyclophosphamide, cytosine arabinoside, dacarbazine, actinomycetes D, daunorubicin hydrochloride, decitabine, dexormaplatin, Dezaguanine, 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, EMP sodium, etanidazole, etoposide, etoposide phosphate, 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, 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, hydrochloric acid piroxantrone, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, Safingol, 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, phosphinothioylidynetrisaziridine, formamido thiazole, tirapazamine, FC-1157a, trestolone acetate, phosphoric acid triciribine, trimetrexate, husky glucuronic acid front three is bent, triptorelin, tubulozole hydrochloride, NSC-34462, uredepa, vapreotide, Verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, sulphuric acid vinepidine, sulphuric acid vinglycinate, sulphuric acid vinleurosine, vinorelbine tartrate, sulphuric acid vinrosidine, sulphuric acid vinzolidine, vorozole, zeniplatin, zinostatin, and zorubicin hydrochloride.

Other antitumor and anticancer agent includes, but are not limited to: 20-epi-l, 25 dihydroxyvitamin D3s, 5-ethinyluracil, abiraterone, aclarubicin, acyl group fulvene, gland cyclopentanol, adozelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox (2,4-Dichlorophenoxyaceticacid 2,4 dichlorphenoxyacetic acid), 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, aphidicolin glycine, apoptosis gene is modified, apoptosis instrumentality, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, Azalomvcin, azatyrosine, baccatin III derivative, balanol, batimastat, BCR/ABL antagonist, benzochlorins, benzoylstaurosporine, beta-lactam derivant, beta-alethine, betaclamycinB, belulinic acid Betulinic acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistratene A, bizelesin, breflate, bropirimine, budotitane, BSO, 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, nefrosulfin 1,4-Benzodiazine, cicaprost, along porphyrin, cladribine, clomifene analog, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analog, conagenin, crambescidin 816, crisnatol, cryptophycin 8, cryptophycin A derivant, curacin A, cyclopentanthraquinones, cycloplatam, cypemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dacliximab, decitabine, APL, deslorelin, dexamethasone, right ifosfamide, dexrazoxane, dexverapamil, diaziquone, didemnun B, didox, diethylnorspermine, dihydro-5-azacytidine, dihydro paclitaxel, 9-, two oxymycins, hexichol spiromustine, docetaxel, tadenan, dolasetron, doxifluridine, doxorubicin, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analog, estrogen agonist, estrogen antagonist, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloric acid, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, Ganite (Fujisawa)., galocitabine, ganirelix, gelatinase inhibitor, gemcitabine, glutathion inhibitor, hepsulfam, heregulin, HMBA, hypericin, ibandronic acid, idarubicin, idoxifene, Idramantone, ilmofosine, Ilomastat, imatinib (as ), imiquimod, peptide immunostimulant, the individual inhibitor of para-insulin growth factor-1, 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, sulphuric acid lentinan, leptolstatin, letrozole, leukaemia inhibitory factor, leukocyte interferon-alpha, leuprorelin acetate+estrogen+Progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogues, lipophilic two glycopeptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, earthworm Yin phospholipid, lometrexol, lonidamine, losoxantrone, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, dissolve peptide, maitansine, mannostatin A, Marimastat, masoprocol, maspin, matrilysin inhibitor, matrix metallo-proteinase inhibitor, menogaril, merbarone, meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, mitomycin analogs, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofarotene, molgramostim, Erbitux, human chorionic gonadotropin, MPLA+myobacterium cell wall sk, mopidamol, mustard anticarcinogen, Indian Ocean sponge B, Mycobacterial cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamide, nafarelin, nagrestip, naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin, Nemorubicin, neridronic acid, nilutamide, nisamycin, nitrogen oxide is modified, 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, panaxytiol, panomifene, parabactin, pazelliptine, pegaspargase, peldesine, Pentosan Polysulfate Sodium, pentostatin, pentrozole, perflubron, perfosfamide, perilla alcohol, phenazinomycin, phenylacetate, inhibitors of phosphatases, Picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, placetin A, placetin B, Plasminogen Activator inhibitor, platinum complex, platinum compounds, platinum three amine complex, porfimer sodium, porfiromycin, prednisone, propyl group two acridone, prostaglandin J2, proteasome inhibitor, a-protein base imnlune modulator, inhibitors of protein kinase C, inhibitors of protein kinase C class, microalgae, protein tyrosine phosphatase inhibitor, purine nucleoside phosphorylase inhibitor, alizarinopurpurin, pyrazoloacridine, pyridoxylated Hemoglobin Polyoxyethylene conjugate, raf antagonist, Raltitrexed, ramosetron, ras farnesyl protein transferase inhibitor, ras inhibitor, ras-GAP inhibitor, demethylation retelliptine, rhenium Re 186 diphosphate, rhizomycin, ribozyme, RII VAAE, rohitukine, romurtide, Roquinimex, rubiginone B1, ruboxyl, Safingol, saintopin, SarCNU, sarcophytol A, Sargramostim, Sdi 1 analogies, semustine, old and feeble derivatives inhibitors 1, there is MODN, signal transduction inhibitor, sizofiran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin associated proteins, sonermin, sparfosic acid, spicamycin D, spiromustine, spleen pentapeptide, spongistatin 1, Squalamine, stipiamide, stromelysin inhibitors, sulfinosine, potent vasoactive intestinal peptide antagonists, suradista, suramin, (.+-.)-Swainsonine, tallimustine, methiodide tamoxifen, tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase 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, UBC inhibitor, ubenimex, urogenital sinus derives growth inhibiting factor, 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, phosphinothioylidynetrisaziridine, 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, EMP 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 supportive care reagent.The example of supportive care reagent is antiemetic.Concrete antiemetic includes but not limited to: phenothiazines, butyrophenones, benzodiazepine, corticosteroid, serotonin antagonist class, Cannabinoids and NK ₁receptor 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 treated concrete indication, the age of patient and the order of severity of situation and ill effect, and correspondingly can be regulated by those skilled in the art.Such as, can with reference to the dosage in ThePhysician ' s Desk Reference and dosage regimen.

6.5.2 the typical method of therapeutic alliance

In certain embodiments, method provided by the invention comprises combines SNS-595 with one or more second active agents, and/or with radiotherapy or surgical operation conbined usage.SNS-595 and the second active agent is given by identical or different route of administration simultaneously or carry out successively to patient.The disease that can the well-formedness for the concrete route of administration of concrete active agent will depend on active agent itself (such as orally give and not decompose before entering blood flow) and be treated.The route of administration of the second active agent recommended is that prior art is known, see 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 1,000mg, about 5mg to about 500mg, about 10mg to about 375mg or about 50mg to about 200mg.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 be 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, treatment provided by the present invention, prevention and/or control the method for malignant hematologic disease, the method comprises and being combined with conventional treatments by SNS-595 (such as, period or afterwards) uses, and conventional treatments includes but not limited to be used for the treatment of at present, to prevent or to control the surgical operation of cancer, immunotherapy, biotherapy, X-ray therapy or its non-drug therapy.Not by concrete theoretical restriction, when using with conventional therapy simultaneously, SNS-595 can provide and add and or synergy.

In certain embodiments, described second active agent and SNS-595 use simultaneously or postpone to use for 1-50 hour.In certain embodiments, first SNS-595 uses, and then uses the second active agent in delay after 1-50 hour.In other embodiments, first use the second active agent, then use SNS-595 in delay after 1-50 hour.In some embodiments, time delay is 24 hours.

In one embodiment, before conventional therapy, period or afterwards, SNS-595 can separately or with the second active agent conbined usage disclosed in this invention, SNS-595 dosage used 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) give to treat the supportive care reagent of effective dose to patient.

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

In another embodiment, described alkylating reagent is chlormethine and the cancer for the treatment of is bladder cancer, breast carcinoma, Hodgkin, leukemia, pulmonary carcinoma, melanoma, ovarian cancer or carcinoma of testis.In another embodiment, this chlormethine is chlorambucil.In another embodiment, this chlormethine is chlorambucil and treatment effective dose is at least 0.1mg/kg.In another embodiment, this chlormethine is chlorambucil and treatment effective dose is the oral dose being about 0.1mg/kg to about 0.2mg/kg every day, continues for three to six weeks.In another embodiment, this chlormethine is chlorambucil and treats the dosage that effective dose is every three to surrounding 0.4mg/kg.In another embodiment, this chlormethine is cyclophosphamide.In another embodiment, this chlormethine is cyclophosphamide and treats the intravenously administrable dosage that effective dose is at least 10mg/kg.In another embodiment, this chlormethine is cyclophosphamide and treats the intravenously administrable dosage that effective dose is every seven to ten days about 10mg/kg to about 15mg/kg.In another embodiment, this chlormethine is cyclophosphamide and treats effective dose is the oral dose being about 1mg/kg to 5mg/kg every day.In another embodiment, this chlormethine is melphalan.In another embodiment, this chlormethine is melphalan and treats effective dose is at least 2mg oral dose every day.In another embodiment, this chlormethine is melphalan and treats the oral dose that effective dose is 6mg two weeks to three week every days, is about 2mg to about 4mg oral dose again every day after inactive two to surrounding melphalan.In another embodiment, chlormethine be melphalan and treatment effective dose be every four weeks to the 10mg/m day every day of four in six weeks ²oral dose.

In another embodiment, described alkylating reagent is nitroso ureas and the cancer for the treatment of is the cerebral tumor, rectal cancer, Hodgkin, hepatocarcinoma, pulmonary carcinoma, lymphatic cancer or melanoma.In another embodiment, this nitroso ureas is carmustine.In another embodiment, this nitroso ureas is carmustine and treatment effective dose is at least 150mg/m ².In another embodiment, this nitroso ureas is carmustine and treats effective dose is about 150mg/m of every six to eight weeks ²to 200mg/m ²intravenously administrable dosage.

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

In another embodiment, described second reagent is for antitumor antibiotics and the cancer for the treatment of is 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 bleomycin.In another embodiment, this antibiotic is bleomycin and treats effective dose is at least 10 units/m ².In another embodiment, this antibiotic is bleomycin and treatment effective dose is once in a week or weekly twice 10 units/m ²to 20 units/m ²vein, subcutaneous or intramuscular dose.In another embodiment, this antibiotic is actinomycin D.In another embodiment, this antibiotic is actinomycin D and treatment effective dose is at least 0.01mg/kg.In another embodiment, this antibiotic is actinomycin D and treatment effective dose is the intravenously administrable dosage being about 0.010mg/kg to about 0.015mg/kg five day every day in every three weeks.In another embodiment, this antibiotic is actinomycin D and treats effective dose is every three weeks or surrounding 2mg/m ²intravenously administrable dosage.In another embodiment, this antibiotic is daunorubicin.In another embodiment, this antibiotic is daunorubicin and treatment effective dose is at least 30mg/m ².In another embodiment, this antibiotic is daunorubicin and treats effective dose is be about 30mg/m every day ²to about 45mg/m ²intravenously administrable dosage, continue three days.In another embodiment, this antibiotic is liposomal daunorubicin and treats effective dose is every two weeks 40mg/m ²intravenously administrable dosage.In another embodiment, this antibiotic is doxorubicin.In another embodiment, this antibiotic is doxorubicin and treatment effective dose is at least 15mg/m ².In another embodiment, this antibiotic is doxorubicin and treats effective dose is every three weeks about 60mg/m ²to about 90mg/m ²intravenously administrable dosage.In another embodiment, this antibiotic is doxorubicin and treats effective dose is weekly about 15mg/m ²to about 20mg/m ²intravenously administrable dosage.In another embodiment, this antibiotic is doxorubicin and treatment effective dose is one-period, comprises 30mg/m weekly ²intravenously administrable dosage, continues two weeks, subsequently inactive doxorubicin two weeks.

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

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

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

In another embodiment, described antimetabolite is pyrimidine analogue, and the cancer for the treatment of 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 cytosine arabinoside.In another embodiment, this pyrimidine analogue is cytosine arabinoside, and treatment effective dose is at least 100mg/m ².In another embodiment, this pyrimidine analogue is cytosine arabinoside, and treatment effective dose is 100mg/m every day ²intravenously administrable dosage, continue seven days.In another embodiment, this pyrimidine analogue is capecitabine.In another embodiment, this pyrimidine analogue is capecitabine, and treatment effective dose is at least 2000mg/m ²daily dose.In another embodiment, this pyrimidine analogue is capecitabine, and treatment effective dose is about 1200mg/m twice daily ²to about 1300mg/m ²oral dose, continues 14 days.In another embodiment, this pyrimidine analogue is capecitabine, and treatment effective dose is cycle of three weeks, wherein 1250mg/m twice daily ²dosage, continue 14 days, drug withdrawal subsequently a week.In another embodiment, this pyrimidine analogue is fluorouracil.In another embodiment, this pyrimidine analogue is fluorouracil, and treatment effective dose is at least 10mg/kg.In another embodiment, this pyrimidine analogue is fluorouracil, and treatment effective dose is be about 300mg/m every day ²to about 500mg/m ²intravenously administrable dosage, continue at least three days.In another example, this pyrimidine analogue is fluorouracil, and treatment effective dose is the intravenously administrable dosage being about 12mg/kg every day, continues 3 to 5 days.In another embodiment, this pyrimidine analogue is fluorouracil and treats the intravenously administrable dosage that effective dose is weekly about 10mg/kg to about 15mg/kg.

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

In another embodiment, described second reagent is platinum coordination complex, and the cancer for the treatment of 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 carboplatin.In another embodiment, this platinum coordination complex is carboplatin, and treatment effective dose is at least 300mg/m ².In another embodiment, this platinum coordination complex is carboplatin, and treatment effective dose is every surrounding at least 300mg/m ²dosage.In another embodiment, this platinum coordination complex is carboplatin, and treatment effective dose is every surrounding 300mg/m ²dosage.In another embodiment, this platinum coordination complex is carboplatin, and treatment effective dose is every surrounding at least 360mg/m ²dosage.In another embodiment, this platinum coordination complex is cisplatin.In another embodiment, this platinum coordination complex is cisplatin, and treatment effective dose is at least 20mg/m ².In another embodiment, this platinum coordination complex is cisplatin, and treatment effective dose be in every three to four to five in surrounding day every day 20mg/m ²intravenously administrable dosage.In another embodiment, this platinum coordination complex is cisplatin, and treatment effective dose is every three weeks 50mg/m ²intravenously administrable dosage.In another embodiment, this platinum coordination complex is oxaliplatin.In another embodiment, this platinum coordination complex is oxaliplatin, and treatment effective dose is at least 75mg/m ².In another embodiment, this platinum coordination complex is oxaliplatin, and treatment effective dose is about 50mg/m ²to about 100mg/m ².In another embodiment, this platinum coordination complex is oxaliplatin, and treatment effective dose is every two weeks about 50mg/m ²to about 100mg/m ²iV amount of infusion.In another embodiment, this platinum coordination complex is oxaliplatin, and treatment effective dose is every two weeks about 80mg/m ²to about 90mg/m ²iV amount of infusion.In another embodiment, this platinum coordination complex is oxaliplatin, and treatment effective dose is the 85mg/m of every two weeks two hours ²iV amount of infusion.

In another embodiment, described second reagent is Topoisomerase II inhibitors, and the cancer for the treatment of is Hodgkin, leukemia, small cell lung cancer, sarcoma or carcinoma of testis.In another embodiment, this Topoisomerase II inhibitors is etoposide.In another embodiment, this Topoisomerase II inhibitors is etoposide, and treatment effective dose is at least 35mg/m ².In another embodiment, this Topoisomerase II inhibitors is etoposide, and treatment effective dose is about 50mg/m ²to about 100mg/m ².In another embodiment, this Topoisomerase II inhibitors is etoposide, and treatment effective dose be in every three weeks or surrounding five days at least three every days be about 35mg/m ²to about 50mg/m ²intravenously administrable dosage.In another embodiment, this Topoisomerase II inhibitors is etoposide, and treatment effective dose be in every three weeks or surrounding five days at least three every days be about 50mg/m ²to about 100mg/m ²intravenously administrable dosage.In another embodiment, this Topoisomerase II inhibitors is etoposide, and treatment effective dose be in every three weeks or surrounding five days at least three every days be about 100mg/m ²oral dose.In another embodiment, this Topoisomerase II inhibitors is teniposide.In another embodiment, this Topoisomerase II inhibitors is teniposide, and treatment effective dose is at least 20mg/m ².In another embodiment, this Topoisomerase II inhibitors is teniposide, and treatment effective dose is weekly 100mg/m ².In another embodiment, this Topoisomerase II inhibitors is teniposide, and treatment effective dose is weekly twice 100mg/m ²dosage.In another embodiment, this Topoisomerase II inhibitors is teniposide, and treatment effective dose is be about 20mg/m every day ²to about 60mg/m ², continue five days.In another embodiment, this Topoisomerase II inhibitors is teniposide, and treatment effective dose is be about 80mg/m every day ²to about 90mg/m ², continue five days.

6.6 pharmaceutical compositions and dosage form

Make pharmaceutical composition in method provided by the present invention, this pharmaceutical composition contains SNS-595 and pharmaceutically acceptable carrier, as diluent or adjuvant, or the SNS-595 combined as another kind of anticarcinogen with other active ingredient.In clinical practice, SNS-595, by any conventional route administration, includes but not limited to oral, parenteral, rectum or by sucking (such as with aerosol form) approach.In some embodiments, the compositions in the present invention is acidic composition (such as pH<4).Not by concrete theoretical restriction, this acidic composition can provide suitable balance between the property of medicine of the dissolubility and needs that increase SNS-595 (such as improving the comfort of patient by reducing the stimulation of sending site).

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

Described compositions can also be aerosol.In order to use with liquid aerosols, said composition can be stable sterile solution or the solid composite dissolving in apyrogeneity sterilized water, normal saline or other acceptable carrier any in use.In order to directly suck with Dry aerosol form, meticulous for effective ingredient separation is combined with water-soluble solid diluent or carrier (such as dextran, mannitol, lactose).

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 active ingredients.Selectable second or the example of additional active ingredients have open in the present invention.

In certain embodiments, compositions provided by the invention is pharmaceutical composition or single unit dosage forms.The SNS-595 of prevention or treatment effective dose is contained at this pharmaceutical composition provided and single unit dosage forms, and one or more typical pharmaceutically acceptable carrier or excipient.Term " carrier " refers to the diluent, adjuvant (i.e. Freund ' s adjuvant (completely with incomplete)), excipient or the carrier that use together with medicine.These pharmaceutical carriers can be sterile liquids, such as, comprise oil, animal, plant or synthesize the water or oil of originating, as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Oleum sesami etc.In certain embodiments, when this pharmaceutical composition is by intravenously administrable, water is as carrier.Normal saline and D/W and glycerol also can be used as fluidity carrier, especially for Injectable solution.Being described in " Remington ' s Pharmaceutical Sciences " of 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 pharmaceutical arts, 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 etc.Whether concrete excipient is applicable to being combined with a kind of pharmaceutical composition or dosage form depending on a various factors well known in the art, includes but not limited to that dosage form gives the concrete active component in individual mode and dosage form.If needed, described compositions or single unit dosage forms can also comprise wetting agent or the emulsifying agent of trace, or pH buffer reagent.

The present invention further provides the pharmaceutical composition and the dosage form that reduce the compound of active ingredient breaks down rate containing one or more.This 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 the forms such as solution, suspension, emulsion, powder.This compositions and dosage form contain preventive or the therapeutic agent of prevention or treatment effective dose, in certain embodiments, with purified form, and appropriate carrier, to provide the form be suitable for individual administration.Described dosage form should match with administering mode.In one embodiment, this pharmaceutical composition or single unit dosage forms are aseptic and are suitable for individuality, as the form of animal individual or mammalian subject and individual human administration.

Pharmaceutical composition provided by the present invention is formulated into compatible with the administering mode expected.The example of administering mode includes but not limited to parenteral, as in intravenous, Intradermal, subcutaneous, intramuscular, subcutaneous, suction, intranasal, transdermal, locally, in mucosa, tumor, synovial fluid administration and rectally.In a particular embodiment, 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 prepared with the usual manner be suitable for people's subcutaneous administration.Typically, the compositions for intravenously administrable is sterile isotonic aqueous buffer solution.If needed, 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 forms carrying out parenteral to individuality; With can be reconstructed into the sterile solid (as crystallization or amorphous solid) being suitable for carrying out the liquid forms of parenteral to individuality.

The composition of dosage form provided by the present invention, shape and type will be different according to its purposes.Such as, the dosage form for the treatment of first for disease compares one or more active components that this dosage form that the dosage form for same disease maintaining treatment can comprise more multiple dose comprises.Similarly, non-bowel dosage form compares one or more active components that the peroral dosage form that is used for the treatment of same disease or disease can comprise containing this dosage form of less dosage.In the present invention, between particular dosage form, difference that is above-mentioned or other side it will be apparent to those skilled in the art that.See: 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, such as, be placed in the hermetically sealed container (as ampoule or bag) of display amount of active agent dry freeze powder or without aqueous concentrate.When said composition is used for infusion administration, its available infusion bottle containing aseptic medicinal water or normal saline disperses.When said composition is used for drug administration by injection, an ampoule injection sterilized water or normal saline can be provided to mix before administration to make described composition.

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

6.6.1 parenteral dosage forms

Parenteral dosage forms, includes but not limited to patient's administration by various approach: in subcutaneous, intravenous (comprising bolus injection), intramuscular and intraarterial delivery.Because their administration can avoid the natural protection of patient to pollutant usually, therefore parenteral dosage forms is preferably aseptic or can carry out sterilizing before patient's administration.The example of parenteral dosage forms includes but not limited to: injection solution, solubilized or the dry products, injection suspension and the emulsion that are suspended in the pharmaceutically acceptable carrier of injection.

The carrier being suitable for parenteral dosage forms is well known to those skilled in the art.Example includes but not limited to: USP water for injection; Aqueous carriers, such as but not limited to sodium chloride injection, ringer's injection, glucose injection, dextrose & sodium chloride injection and Lactated Ringers Injection; Water miscible property carrier, such as but not limited to ethanol, Polyethylene Glycol and polypropylene glycol; And non-aqueous carriers, 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 compounds that can improve one or more active component disclosed in this invention also can be incorporated in described parenteral dosage forms.Such as, cyclodextrin and its derivant can be used for the dissolubility increasing active component.See 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 in the present invention, topical and mucosal drug delivery dosage form include but not limited to: the dosage form that ophthalmic solution, spray, aerosol, emulsifiable paste, lotion, ointment, gel, solution, emulsion, suspension or other any prior art are known.See, Remington ' s Pharmaceutical Sciences, the 20th edition, Mack Publishing, Easton PA (2000); With Introduction to Pharmaceutical DosageForms, the 4th edition, Lea & Febiger, Philadelphia (1985).The dosage form being applicable to treat mucous membrane tissue in oral cavity can be made into collutory or buccal cavity gel.Further, transdermal dosage form comprises " reservoir formula " or " substrate formula " paster, and it can be used for skin and keeps a period of time to permeate to allow required dosage active component.

Being applicable to the excipient (such as carrier and diluent) of Topical dosage forms in the present invention and mucosa delivery dosage form and other material for pharmaceutical arts knows, and depends on the concrete tissue that given pharmaceutical composition or dosage form are used.In fact, typical excipient includes but not limited to: water, acetone, ethanol, ethylene glycol, propylene glycol, l, 3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil and its mixture, for the formation of aseptic and pharmaceutically acceptable solution, emulsion or gel.If needed, wetting agent or wetting agent also can add in pharmaceutical composition and dosage form.The example of above-mentioned supplementary element is known prior art, see Remington ' s Pharmaceutical Sciences, and 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 tensile are sent to improve.Also can add in pharmaceutical composition or dosage form if the compound of stearates is advantageously to change hydrophilic or the lipophile of one or more active component, thus raising is sent.In this, stearate can be used as the lipid carriers of described preparation, emulsifying agent or surfactant, and as delivery enhancer or penetration enhancers.The different salt of described active component, hydrate or solvate can be used for the character regulating final composition further.

7. embodiment

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

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

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

The clinical testing data of embodiment 2:SNS-595 late in solid tumor cancer patient

Safety and the curative effect of SNS-595 are investigated in the research of being risen gradually by two groups of dosage.As described below, the Refractory solid tumor of SNS-595 to patient has good safety and active anticancer.

In more than 10 minutes, SNS-595 is given to patients with advanced solid tumors IV transfusion by 2 kinds of schemes.In the first scheme (A), give SNS-595 weekly, continue three weeks, then drug withdrawal at least 7 days (qwkx3).In first scheme (B), within every three weeks, give SNS-595 once (q3wk).

In two schemes, the predose of SNS-595 is 3mg/m ², and dosage increases gradually with continuous print 3 groups (sequential cohorts of 3).Dosage doubles until relevant adverse events meets or exceeds 2 grades or occur abnormal laboratory values first first, and then dosage increases gradually with the Fibonacci sequence pattern of improvement.

In 42 days of research, do not use other to treat, if do not used Mitomycin-C, BCNU, nitroso ureas medicine or MAb therapy.

In research A, 21 patients (male 9, women 12) are divided into 6 groups and carry out treating (dosage range 3-24mg/m ²/ wk).In research B, 41 patients (male 25, women 16) are divided into 9 groups and carry out treating (dosage range 3-75mg/m ²/ wk).Median age is 61 years old (research A) and 59 years old (research B), sex 12 female/9 man (research A), 16 female/25 men (research B), all patients have European tumor cooperative association function status scoring (ECOG PS) 0-2 level.Selected patient has Refractory 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 list for the treatment of 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
				Müllerian ducts 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 the patient according to option A administration, within the 1st day and the 15th day in treatment, gather PK sample and analyze by non-compartment analysis method.SNS-595 blood drug level adopts confirmatory LC-MS/MS analysis to determine.AUC (area under curve) is with dosage and average AUC _infproportional increase, 3 to 24mg/m ²during dosage level, correspondingly change within the scope of 1.7 to 15 μ g*hr/ml.T1/2 is about 19 hours.The drug dependence that medication three Zhou Houwei observes pharmacokinetic parameter sexually revises.Fig. 1 describes SNS-595 blood drug level in different patient's group over time.Table 3 provides the patient's pharmacokinetic parameter according to option A administration.

Table 3: the 1st week and the 3rd week mean serum pharmacokinetic parameter

To the patient treated according to option b, at single dose administration 3 to 75mg/m ²the later evaluation kinetic parameter of 36 patients (21 severe pretreat patients and 15 slight pretreat patients).Until 48mg/m ²the clearance rate (CL) of all patients, 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).Until dosage rises to 48mg/m ², severe pretreat patient is similar with the drug exposure of slight pretreat patient and increase with dose linear.60mg/m is reached at dosage ²during dosage level, slight pretreat patient presents the drug exposure larger than dose linear AUC (area under curve).Table 4 shows the patient's pharmacokinetic parameter according to option b administration.

Table 4: the 3rd week pharmacokinetic parameter

In research A, carry out pharmcokinetic evaluation (first time and for the third time administration after) the 1st day and the 15th day, as shown in table 5, SNS-595 shows variability between high repeatability pharmacokinetics and low patient.Do not observe pharmacokinetic parameter accumulation after repeat administration or change.Linearly increase at 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 not change from the 1st day to the 15th day.

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

Table 5 provides the mean serum pharmacokinetic parameter of two groups of researchs

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

Figure 11 shows the dose linear relation in research A and B.

Table 6 provides the hematology observed in research affects data.

Table 6: hematology affects

N=queue patient populations

* absolute neutrophil count (cell/μ L)≤500 continues to be greater than 7 days

In this manual, term " maximum tolerated dose " or " MTD " refer to lower than having in 6 patients >=2 dosage levels occurring the SNS-595 dosage of dose-limiting toxicity (DLT).The alkylating reagent of the >6 course for the treatment of, chemotherapy or the platinum of >2 course for the treatment of, Mitomycin-C or any nitroso ureas has been received before term " severe pretreat " or " HP " patient refer to, or the patient of the XRT of >25% bone.Term " slight pretreat " or " MP " patient refer to that the patient not reaching HP definition is (see Tolcher etc., JCO 2001; 19:2937-2947).

Dose-limiting toxicity (DLT) refers to that absolute neutrophil count (ANC)≤500 is more than or equal to 7 days or febrile neutropenia or platelet nadir <25000 or hemorrhage or non-blood untoward reaction (AE) >=3 grade (illustrating as described in (CTCAE v3.0) in Common Terminology Criteria for Adverse Events version 3 .0) herein, and wherein untoward reaction needs the Dose delays of >14 days.

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

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

* patient's number/all grade patient numbers of grading system >=3

Table 8: hematology affects

Table 9: serious adverse reaction (SAE) that may be relevant to drugs

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

In research A, MTD is 15mg/m ²; Be 48mg/m to severe pretreat patient (HP) MTD in research B ², slight pretreat patient (MP) is 60mg/m ².

Two patients are had to have fourth stage thrombocytopenia respectively in two groups of researchs; Non-blood toxicity is mostly grade 1/2, does not have dose-limiting 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 a patient part and alleviates (PR) and six patient experiences stable disease SD (scope 16-24 week).To research B, optimum curative effect comprises PR and 11 SD (scope 18-58 week).Table 11 provides the detailed data that in two groups of researchs, partial rcsponse/trace is alleviated.

Table 10: clinical activity

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

Obviously, SNS-595 shows clinical activity to patients with advanced solid tumors, interior two patient part reaction and 17 patient experiences stable disease during being included in more than 16 weeks.

As can be seen from data, good to SNS-595 toleration, the scheme that Per-Hop behavior is administered once for once with three weeks all demonstrates clinical activity.Dose-limiting toxicity is non-accumulation neutropenia.SNS-595 shows expected pharmacokinetics, has the low variability in patient and between patient.Do not observe pharmacokinetic parameter after repeat administration to change.

Describe according to the present embodiment, every three weeks 48mg/m are comprised to the dose therapeutically effective of patients with solid tumor ²15mg/m weekly ².

Embodiment 3: High content screening and microscopy

Cell is closely to converge group's bed board and to grow 36 hours.Then cell is with the compound treatment of given concentration given time.Cell is fixed with 4% formaldehyde and is used the triton of 0.1% thoroughly to change.Cell is exposed to 1 hour (anti-pATM-Chemicon, anti-gH2AX-Cell Signaling Technology) in the 1:100 diluent of first antibody in 10%FBS/PBS at 25 DEG C.Cell to be exposed in the 1:100 diluent in 10%FBS/PBS of second antibody 1 hour at 25 DEG C.In 10%FBS/PBS, Hoechst dyeing is carried out under 500ng/ml concentration.High content screening utilizes some probe algorithm Cellomics Arrayscan instrument to analyze.

Fig. 2 shows and gives various compound the HCT116 cell of 6 hours.Then by fixing for cell also analysing protein phosphorylation state (gH2AX image is obtained by fluorescence microscope, and pATM image is obtained by ArrayScan VTi).As seen from the figure, SNS-595 treatment result in core focus (nuclear foci) formation.

Fig. 3-5 describes core focus and is formed and dosage and the dependency relationships of time.Then fixed cell carries out phosphorylation-ATM and analyzes.Cellomics Arrayscan software is used for determining focus (Fig. 3, orange point).Focus is quantitatively by carrying out focus fluorescence intensity (Fig. 4) or the mensuration that is greater than the cell of 2 focuses and the functional relationship (Fig. 5) of time and SNS-595 concentration.

Embodiment 4:MTT colorimetry and sensitization process

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

Sensitization is undertaken by number of chemical process.Cell chemical sensitizer pretreatment 16 hours, (concentration is as follows: caffeine, 2mM then to add medicine; DNAPK inhibitor II (self-control), l0uM; And wortmannin, 100nM).Data provide in form 12.EC is determined by MTT colorimetry ₅₀cytotoxic multiple reduces determines sensitization.

Data show that SNS-595 shows unique PIKK dependency.Although all activated with ATM/ATR and DNAPK after SNS-595 process, only have DNAPK to be required for DNA repairs and if only if when DNAPKcs activity reduces cell just responsive to SNS-595.ATM/ATR mediates the G2-outpost of the tax office and catches.The G2-outpost of the tax office is lost and cell then can not be made responsive to SNS-595.Contrary with SNS-595, other DSB derivants all of test all utilize ATM/ATR to repair, and demonstrate sensitivity when ATM or DNAPK activity inhibited.

Embodiment 5: DNA plerosis damage under shortage DNA-damages sensitive kinase ATM and ATR

Having under 2mM caffeine or caffeine-free condition with 10mM SNS-595 or 10mM etoposide process HCT-116 cell 6 hours.Then remove compound and make cellular-restoring 16 hours.GH2AX focus before and after medicine is cleaned in difference analysis of cells.As shown in Figure 6, the DNA damage of SNS-595 induction can be repaired easily in without ATM and ATR situation.On the contrary, other medicines (such as etoposide), need to utilize ATM and ATR to carry out DNA reparation.Caffeine process inhibits the activity of ATM and ATR, causes the defect of homologous recombination, Nucleotide Sequence Analysis, mispairing reparation aspect.

Embodiment 6: DNA plerosis damage under shortage DNA-damages sensitive kinase DNA-PK

MO59K (wt) and MO59J (DNAPKcs (-/-)) cell 10mM SNS-595 or 10mM etoposide process 6 hours.Then remove compound and make cellular-restoring 16 hours.GH2AX focus before and after medicine is cleaned in difference analysis of cells.As shown in Figure 7, in shortage DNA-PK situation, SNS-595 damage is not effectively repaired.By contrast, the damage that other medicines (such as etoposide) are induced can be repaired easily.

The combination research of embodiment 7:SNS-595

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

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

Dead cell proportion=1-[sample aperture absolute value-acellular matched group absolute value

Meansigma methods]/[only have the meansigma methods-nothing of DMSO matched group absolute value thin

The meansigma methods of born of the same parents' matched group absolute value]

Project study: when when compound is to comprise the administration of cleaning step, the fresh warm culture medium of cell l00 μ l cleans 30 minutes, carries out another again and take turns cleaning after 90 minutes.

Statistical analysis: Combination index value when data (dead cell proportion) carry out analyzing with Calculsyn.V2 (Biosoft) and are expressed as influenced part proportion (Fa)=0.5 at this.All data error line indicate the confidence interval of its meansigma methods 95%.

If obtain the Combination index of 0.85-1.2, then this share and is considered to additivity.If obtain the Combination index being less than 0.85, then this share and is considered to collaborative.If obtain the Combination index being greater than 1.2, this share and is considered to antagonism.See Fig. 8-10.

Visible in Fig. 8 a-8d, give to HCT116 colon carcinoma cell line (8a, 8b and 8c) and H460 lung cancer cell line 8 (d) Combination index showing when SNS-595 and various kinds of cell toxin and significantly work in coordination with or be at least addition simultaneously.Visible in fig .9, give SNS-595 and some DNA damage agent and antimetabolite simultaneously, express or do not have and have no obvious Combination index in the SKOV3 ovarian cancer cell line that p53 expresses and change having p53.

As shown in figures 10 a-10d, when to HCT116 colon cancer cell SNS-595 and docetaxel (see Figure 10 a and 10c) and gemcitabine (see Figure 10 b and 10d) administration altogether, or when SNS-595 postpones administration in 24 hours, SNS-595 may be antagonism.Relative to first other reagent of administration (see Figure 10 a and 10b, administration and 24 hours altogether), first administration SNS-595 (see 10c and 10d, administration and 24 hours altogether) its antagonism may reduce.When cell so can obtain additivity or possible concertedness with time the second agent treated (see Figure 10 a-d, cleaning in 2 hours and cleaning in 24 hours) with the first agent treated, cleaning.

Embodiment 8:MTT cell viability detection-leukaemia:

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

Cell is plated on 96 orifice plates with 3000 cells/well and cultivates 16 hours.Diluted chemical compound liquid to be diluted in DMSO with 3 times from 10mM and to make.Carry out 1:100 in the medium and dilute titration to obtain finalization compound concentration.96 orifice plates are ventilated and adds the diluted chemical compound liquid (100ml/ hole) be dissolved in culture medium.Cultivate at 37 DEG C after 72 hours and carry out MTT analysis.Briefly, the MTT solution of 20ml is added in each hole.Cell cultivates 1-2 hour at 37 DEG C.The cell lysis buffer solution adding 100ml/ hole is carried out lysis and spends the night to MTT solubilising under 37 DEG C of conditions.Flat board spectromax instrument reads at 570nm place absorbance method.IC ₅₀(data are provided in table 13) is calculated with regression analysis in GraphPad Prism.As shown in table 13, SNS-595 shows effective antiproliferative activity to test blood cell system.

Table 13: the IC of different cell line ₅₀value

Embodiment 9: heteroplastic transplantation model

LM3-Jck human malignant's lymphom tumor top (2-3 square millimeter) is transplanted to nude mice by subcutaneous.Allow tumor to grow to diameter and be approximately 7-14mm.Mus pairing is grouped into without treatment group, irinotecan group (100mg/kg, IV, q4d × 3), doxorubicin treatment group (12mg/kg, IV, single-dose), etoposide treatment group ((12mg/kg, IV, q1d × 5)) and SNS-595 treatment group (25 and 20mg/kg, IV, q7d × 5).The average group body weights situation of dead at the most that to decline in 30% or less and every 6 treatment animals is defined as acceptable toxicity.The active anticancer of medicine plays assessment in the 21st day at initial administration.

Nude mice by subcutaneous is transplanted to the acute lymphoblastic leukemia tumor top of 2-3 square millimeter.Allow tumor to grow to diameter and be approximately 8-20mm.Mus pairing is grouped into without treatment group, irinotecan group (100mg/kg, IV, q4d × 3), doxorubicin treatment group (12mg/kg, IV, q7d × 3), etoposide treatment group ((12mg/kg, IV _,q1d × 5)) and SNS-595 treatment group (25 and 20mg/kg, IV, q7d × 5).The average group body weights situation of dead at the most that to decline in 30% or less and every 6 treatment animals is defined as acceptable toxicity.The active anticancer of medicine plays the 20th or assessment in 21 days at initial administration.Table 14 provides the data of survival rate in tumor suppression (TI) and CCRF-CEM and LM3-Jck heteroplastic transplantation model.

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

Data from table 14, with completed tumor regression when 20 and 25mg/kg dosed administration, SNS-595 shows very strong active anticancer to LM-3Jck malignant lymphoma.In CCRF-CEM and LM3-Jck xenograft model, the tumor control rate (IR) of SNS-595 is suitable with irinotecan, but is better than etoposide and doxorubicin.

Embodiment 10: bone marrow/cytological analysis

Give to female CD-1 Mus vein the SNS-595 that dosage is 5,10,15 or 20mg/kg the 0th day and the 4th day.After initial injection, analysis of Hematology Changes is carried out in blood drawing in the 6th, 8 and 12 day.Got femur at the 6th day and be fixed on Streck, and before medullary cell analysis, carrying out H & E dye.Again giving SNS-595 two days later, from femur, isolated bone marrow shows the dose dependent that cellularity reduces.When dosage is 20mg/kg, cellularity reduces to 7.5%, and the neutrophil cell that circulates dropped to minimum point 51 ± 24cells/mL blood at the 8th day from 1244 ± 55 cells before medication/mL blood.Absolute neutrophils number rebounds subsequently and returns to normal level very soon.At the 8th day, total WBCs also touched the bottom, but also returned to normal level.Hematopoietic marrow cellularity dose dependent reduces expression in fig. 14.The figure illustrates the cellularity in the 6th day bone marrow after the SNS-595 of initial injection various dose.

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

Figure 18 display is injected at the 8th day for SNS-595 slight platelet response.After Figure 19 shows administration SNS-595, the percent weight of different time changes.After Figure 20 shows the SNS-595 of injection 20mg/kg, the bone marrow of the 12nd day rebounds.

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

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

Totally 21 patients (male 9 and women 12; Median age=64 year old, scope 21-80 year) be divided into five groups and treat with two schemes.In first scheme (A), give weekly SNS-595 once, continue three weeks, then drug withdrawal 7 days (qwk × 3).In first scheme (B), give weekly SNS-595 twice, continue two weeks (biwk × 2).It is 28 days that the cycle duration of two schemes comprises withdrawal time.In option A, each cycle is total to administration 3 times, and in option b, each cycle is total to administration 4 times.If patient experiences stable disease or better also can increase treatment cycle.Predose in option A is 18mg/m ², the predose in option b is 9mg/m ², and dosage progressively increases according to group.Its dosage of the group of 3-6 name patient is increased by the Fibonacci sequence pattern of improvement.

Pharmacokinetic analysis is carried out to the plasma sample collected in the cycle 1.Table 15 provides some pharmacokinetic parameters in research.

Table 15: pharmacokinetic parameter

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

SNS-595 blood drug level is analyzed by confirmatory LC-MS/MS and is determined.Before in each scheme, the blood amount of two doses level linearly increases, at 9-27mg/m ²during dosage, AUC is 4.3-17.8 μ ghr/mL.CL, Vss and t1/2 and patients with solid tumor similar, meansigma methods is respectively ~ 2L/hr/m ², 58L/m ²with 23 hours.Table 15 shows six patients periphery blast cell (blast) after treatment cycle 1 be distributed in all dosage groups and has been reduced beyond 50%.

Until 27mg/m in the scheme of qwk × 3 ²or until 13.5mg/m in the scheme of biwk × 2 ²all do not observe dose-limiting toxicity (DLT).The restricted toxicity of dose comprises nausea/vomiting, diarrhoea and mucositis.Only observe an example 4 grades of heat generation leukopenias.

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

Table 16: serious adverse reaction (SAE) that may be relevant to drugs

The effective dosage regimen for the treatment of malignant hematologic disease can be give weekly about 50mg/m ²to about 80mg/m ², continue three weeks, effective dosage regimen of another treatment malignant hematologic disease is for give about 55mg/m weekly ²to about 75mg/m ², continue 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, continue three weeks.

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

In the present invention, above-mentioned embodiment is only exemplary, and those skilled in the art should be known or can be determined the equivalent of numerous particular compound, material and step by routine test.All these equivalents to be all considered in protection scope of the present invention and to comprise in detail in the claims.

Claims

1. treat the method for acute myeloid leukaemia, it comprises, and to give dosage to the people suffering from acute myeloid leukaemia be 50-90mg/m ²optically pure (+)-l, 4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid.

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

3. the process of claim 1 wherein described leukemia be recurrence, intractable or to be selected from surgical operation, chemotherapy, X-ray therapy, hormonotherapy, biotherapy, immunotherapy, blood transfusion and combination thereof therapy there is toleration.

4. the process of claim 1 wherein that described dosage is 50mg/m ²to 80mg/m ², give weekly once, at least continue two weeks.

5. the method 4 of claim, wherein said dosage is 55mg/m ²to 75mg/m ².

6. the method 5 of claim, wherein said dosage is 60mg/m ².

7. the method 5 of claim, wherein said dosage is 65mg/m ².

8. the method 5 of claim, wherein said dosage is 70mg/m ².

9. the method 5 of claim, wherein said dosage is 75mg/m ².

10. the process of claim 1 wherein that described dosage gives weekly once, at least continue three weeks.

11. the process of claim 1 wherein that described dosage gives twice weekly.

The method of 12. claim 11, wherein said dosage is 80mg/m ²to 90mg/m ².

The method of 13. claim 11, wherein said dosage is 65mg/m ²to 75mg/m ².

The method of 14. claim 11, wherein said dosage is given two weeks.

The method of 15. claim 1, wherein said optically pure (+)-l, 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 IV injection.

16. the process of claim 1 wherein that described dosage is injected with 10-15 minute IV gives.

The method of 17. treatment acute myeloid leukaemias, it comprises, and to give dosage to the people suffering from acute myeloid leukaemia be 85-95mg/m ²optically pure (+)-l, 4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid.

The method of 18. treatment acute myeloid leukaemias, it comprises, and to give dosage to the people suffering from acute myeloid leukaemia be 90-100mg/m ²optically pure (+)-l, 4-dihydro-7-[(3S, 4S)-3-methoxyl group-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines-3-carboxylic acid.

The method of 19. claim 17 or 18, wherein said acute myeloid leukaemia is myeloblastic leukemia or promyelocytic leukemia.

The method of 20. claim 17 or 18, wherein said leukemia be recurrence, intractable or to be selected from surgical operation, chemotherapy, X-ray therapy, hormonotherapy, biotherapy, immunotherapy, blood transfusion and combination thereof therapy there is toleration.

The method of 21. claim 17 or 18, wherein said dosage gives weekly once, continues three weeks.

The method of 22. claim 17 or 18, wherein said dosage gives twice weekly.

The method of 23. claim 17 or 18, wherein said optically pure (+)-l, 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 IV injection.

The method of 24. claim 17 or 18, wherein said dosage is injected with 10-15 minute IV and is given.