CN1391484A - Method of potentiating chemotherapy and treating solid tumors - Google Patents
Method of potentiating chemotherapy and treating solid tumors Download PDFInfo
- Publication number
- CN1391484A CN1391484A CN00812921A CN00812921A CN1391484A CN 1391484 A CN1391484 A CN 1391484A CN 00812921 A CN00812921 A CN 00812921A CN 00812921 A CN00812921 A CN 00812921A CN 1391484 A CN1391484 A CN 1391484A
- Authority
- CN
- China
- Prior art keywords
- replacement
- alkyl
- unsubstituted
- aralkyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention provides a method of treating solid tumors which comprises administering an effective amount of a combination of (1) a bioresponse modifier and (2) a chemotherapeutic agent. This invention also provides a method of potentiating the effects of a chemotherapeutic regimen in a mammal in need of treatment with such regimen which comprises administering a bioresponse modifier in addition to a chemotherapeutic regimen.
Description
The present invention relates to the application that is combined in chemotherapeutic sensitivity and treatment solid tumor aspect of a kind of biological response modifier and a kind of chemotherapeutics.
The cancer chemotherapy classical way that is used for solid tumor uses cytotoxic drug emphatically, and this medicine is at analytic metabolism process (antimetabolite) or disturbs the general toxin (alkylating agent) of multiple metabolic process.Antibiotics (amycin, mitoxantrone, ametycin etc.) is directed to duplicating or integrating of nucleic acid, and therefore, in general, pair cell is toxic.Similarly, microtubule reactive compound (taxanes, vinca) also shows the toxicity of pair cell at the basic structure composition of cell.
Trend in recent years is the medicine that combination has the different mechanisms of action, and biological respinse rate and survival rate that this has improved some solid tumors comprise breast carcinoma, carcinoma of prostate and small cell lung cancer.Yet most of solid tumors have shown low biological respinse rate, to the no obvious shadow of existence.This carcinoid comprises nonsmall-cell lung cancer, head and neck cancer, gastric cancer, cancer of pancreas, cervical cancer, melanoma, adrenocortical tumor and soft tissue sarcoma etc.Particularly, need new Therapeutic Method for these solid tumors and general solid tumor.
United States Patent (USP) 5,312,831 (and EP 652228) disclose urethanes and carbamide class medicine that the inducing cell factor produces, be used for chemotherapy, radiotherapy, the bone marrow transplantation of cancer or infect back recovery neutrophil cell, with treatment cancer, AIDS, aplastic anemia, myelodysplastic syndromes, infectious disease, and be used for the enhance immunity reaction.
United States Patent (USP) 4,666,890 disclose a kind of synthetic tripeptides, have reported the effect of immunomodulator, are better than as the chemotherapy adjuvant as antitumor agent.Cell wall constituent of being reported and synthetic analogues thereof are D-glutamic acid (D-Glu) part that will be connected in lysine (Lys) or meso diaminopimelic acid (A2pm) through q-and other main peptide chain or the side peptide that the fatty acyl group at two ends merges into a single whole that joins.
Summary of the invention
The invention provides a kind of method for the treatment of solid tumor, this method comprises with (1) a kind of biological response modifier of effective dose and (2) a kind of chemotherapeutant and making up.The present invention also provides the synergisting method that need is carried out the mammiferous embolic chemotherapy of this treatment, and this method also comprises with a kind of biological response modifier except embolic chemotherapy carries out administration.Term used herein biological response modifier and chemotherapeutics comprise with one or more biological response modifier and chemotherapeutics and carry out administration, can comprise with two kinds of chemotherapeutics as the term chemotherapeutics and carry out administration.
The definition of treatment is that the solid tumor of being treated is provided the treatment of mitigate the disease or suppresses its growth, or radical cure.
For reaching the purpose of the institute of the present invention range of definition, biological response modifier is to swash the in vivo material of natural immune system, typically comprises cytokine induction agent and immunological adjuvant.The cytokine induction agent is the material that the inducing cell factor produces, and comprises cytokine such as IL-1, TNF; Natural product is as muramyldipeptide, liopopolysaccharides and beta glucan; Synthetic cytokine induction agent, as be disclosed in United States Patent (USP) 5,312, the material in 831 and 4,666,890, this open report is by reference citation as a reference.The cytokine induction agent is the preferred biological response modifier of the present invention.
Particularly preferred cytokine induction agent is to be disclosed in United States Patent (USP) 5,312, the formula I of 831 (EP652228), and structure is:
Wherein,
R
1Be selected from hydrogen, replacement or do not replace (C
1-C
20) alkyl, replacement or unsubstituted ring alkyl, replacement or unsubstituted ring alkyl-alkyl, vinyl, acetenyl, replacement or not substituted-amino, replacement or do not replace acylamino-, replacement or unsubstituting aromatic yl, replacement or unsubstituting aromatic alkyl, replacement or unsubstituted aryloxy, replacement or unsubstituting alkoxy aryl, replacement or not substituted alcoxyl aralkyl and replacement or the unsubstituted 1-4 of containing heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen atom;
R
aAnd R
3Be selected from hydrogen, replacement or unsubstituted (C respectively
1-C
6) alkyl, replacement or unsubstituted alkoxyalkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkyl-alkyl, replacement or unsubstituted aryl, replacement or unsubstituted aralkyl, replacement or unsubstituted alcoxyl aralkyl, vinyl, acetenyl and replacement or unsubstituted 1-4 heteroatomic monocycle or the bicyclic heterocyclic radical of containing, hetero atom is selected from nitrogen, sulfur and oxygen atom, for R
3, in described heterocycle hetero atom directly with-CH-X-part-the CH-base key closes;
R
2, R
bAnd R
cBeing selected from carboxyl or quilt is respectively protected carboxyl, carboxyl or is protected carboxyl low-grade alkyl and Carboxylamide;
X is oxygen or nitrogen;
R
4Be H or amino protecting group; Wherein, the alkyl of above-mentioned replacement, cycloalkyl, cycloalkyl-alkyl, amino, acylamino-, aryl, aralkyl, aryloxy group, alkoxy aromatic yl, the substituent group of alcoxyl aralkyl and heterocyclic radical is selected from halogen, hydroxyl, low alkyl group, lower alkoxy, aryloxy group, aralkoxy, amino, single-or two-lower alkyl amino, virtue is amino, arylalkylamino, carboxyl, formoxyl, elementary alkoxy carbonyl, aryloxycarbonyl, aromatic alkoxy carbonyl, low-grade alkyl thio group, the aryl thio group, the aralkyl thio group, the aryl sulfinyl, the aryl sulfinyl, the aralkyl sulfinyl, the low alkyl group sulfonyl, aryl sulfonyl, aralkyl sulfonyl and contain 1-4 heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen;
Or the acceptable salt of its medicine.
The preparation method of substituent definition and formula I chemical compound is seen United States Patent (USP) 5,312,831 and EP652228.The agent of formula I cytokine induction may contain one or more asymmetric carbon atoms; In the case, formula I chemical compound comprises various diastereomers, racemic modification and various R thereof and S isomer (entantiomers).
The example of the various concrete definition of above-claimed cpd and these definition (selecting from EP652228B) as follows: a) (C
1-C
20) alkyl can be the straight or branched low alkyl group of a kind of 1-20 of having carbon atom, as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, neopentyl, isopentyl, hexyl, isohesyl etc.B) cycloalkyl can be the cycloalkyl of a kind of 3-6 of having carbon atom, as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.C) cycloalkyl-alkyl can be the cycloalkyl-alkyl of a kind of 4-12 of having carbon atom, as cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, 1-cyclopropyl ethyl, 2-cyclopropyl ethyl, 2-cyclopropyl ethyl, 1-cyclobutyl ethyl, 2-cyclobutyl ethyl, 1-cyclopenta ethyl, 2-cyclopenta ethyl, 1-cyclohexyl ethyl, 3-cyclohexyl propyl group, 3-cyclopenta propyl group, 4-cyclohexyl butyl, 4-cyclopenta butyl, 4-cyclopenta amyl group or 4-amyl group cyclohexyl.D) acylamino-can be that acyl moiety is from a kind of acid, as organic carboxylic acid or the deutero-acylamino-of carbonic acid.Comprise fat-based, aryl and/or heterocyclic radical in each acylamino-molecule.These fatty acyl groups with acyl group are derived from fatty acid; comprise: alkanoyl (as formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, valeryl, caproyl, α-ethyl-caproyl, heptanoyl group, lauroyl, stearyl, docosane acyl group), one group of chemical formula: CH
3(CH
2)
31CO, [CH
3(CH
2)
21]
2CHCO, [CH
3(CH
2)
15]
2CHCO, CH
3(CH
2)
41CO etc.); Elementary alkoxy carbonyl (as methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl, uncle's penta oxygen carbonyl etc.) etc.Acyl moiety also can be an aroyl, and acyl group is derived by the acid of a kind of replacement or unsubstituting aromatic yl, and wherein, aryl can comprise phenyl, tolyl, xylyl, naphthyl etc.Its suitable examples is as follows: aroyl (as benzoyl group, toluyl, dimethylbenzene acyl group, naphthoyl base, phthalyl etc.); Aromatic alkoxy carbonyl (as benzyloxycarbonyl group, diphenyl methoxy carbonyl, triphenyl methoxycarbonyl group, Alpha-Naphthyl-methoxycarbonyl group etc.) etc.Acyl moiety also can be a heterocyclic acyl; wherein acyl group is had heterocyclic acid and is derived by a kind of; comprise: the heterocycle carbonyl; wherein heterocyclic moiety is to contain a heteroatomic 5-6 element heterocycle at least; it contains at least one to four hetero atoms, and hetero atom is selected from nitrogen, oxygen and sulfur (as thiophene acyl group, furanylcarbonyl, pyrrolylcarbonyl, 5-oxygen-2-pyrrolidine carbonyl, nicotinoyl etc.) etc.E) aryl can be the aryl of a kind of 6-15 of having carbon atom, as phenyl, xenyl, 1-naphthyl or 2-naphthyl.F) aralkyl can be the aralkyl of a kind of 7-15 of having carbon atom, as benzyl, 1-naphthyl methyl, 2-naphthyl methyl, 5,6,7, and 8-tetrahydrochysene-1-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl, phenethyl, 3-phenyl propyl or 4-phenyl butyl.G) aryloxy group can be the aryloxy group of a kind of 6-15 of having carbon atom, as phenoxy group, biphenylyloxy, 1-naphthoxy or 2-naphthoxy.H) alkoxy aromatic yl or alkoxy aromatic alkyl can be the alkoxy aromatic yl or the alkoxy aromatic alkyl of a kind of 6-21 of having carbon atom, as benzoyl group, or the alkoxy benzene methyl.I) contain 1-4 heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen atom, it can be the heterocyclic radical of a kind of 4-15 of having carbon atom, as pyrrole radicals, furyl, thienyl, pyridine radicals, phonetic azoles base, pyrazolyl, thiazolyl, isothiazolyl isoxazolyl oxazolyl, pyrazinyl, pyrimidine radicals, pyridazinyl, indyl, quinolyl, isoquinolyl, 2, the 3-phthalazinyl, the naphthidinyl base, quinoxalinyl, quinazolyl, 1,4-benzodioxan base, 1,3-benzodioxan base, 1,2, the 3-triazolyl, 1,3, the 4-triazolyl, 1,3, the 4-thiadiazolyl group, 1,2, the 3-thiadiazolyl group, tetrazole radical, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, imidazolidinyl, the 2-imidazole radicals, the morpholino base, piperizine N-oxide-base, piperazine N-oxide-base, morpholine N-oxide-base, low alkyl group morpholino base such as N-methylmorpholine are for base, N-ethylmorpholine is for base or N-propyl group morpholino base, piperazinyl, piperidino, piperidyl, thiomorpholine is for base or thio-morpholinyl.
Aforesaid substituent group (a)-(i) can be a halogen atom, as chlorine atom, fluorine atom or bromine atoms, hydroxyl; Low alkyl group is as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group; Lower alkoxy is as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy; Aryloxy group is as phenoxy group, 1-naphthoxy or 2-naphthoxy; Aralkoxy is as benzyloxy, benzene ethyoxyl, 1-naphthyl methoxyl group or 2-naphthyl methoxyl group; Amino; Single-or two-lower alkyl amino, as methylamino, ethylamino, third amino, isopropylamino, fourth amino, Zhong Ding amino, isobutyl amino, uncle's fourth amino, dimethylamino or lignocaine; Virtue is amino, as phenylamino, 1-naphthylamino or 2-naphthylamino; Arylalkylamino is as benzyl amino, benzene ethylamino, 1-naphthyl methylamino or 2-naphthyl methylamino; Carboxyl; Formoxyl; Elementary alkoxy carbonyl, as methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, secondary butoxy carbonyl, isobutyl boc or tertbutyloxycarbonyl; Aryloxycarbonyl is as carbobenzoxy, 1-naphthalene oxygen carbonyl or 2-naphthalene oxygen carbonyl; Aromatic alkoxy carbonyl is as benzyloxycarbonyl group, benzene carbethoxyl group, 1-naphthyl methoxycarbonyl group or 2-naphthyl methoxycarbonyl group; Sulfydryl; Low alkyl group sulfenyl such as methyl mercapto, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, secondary butylthio, isobutyl sulfenyl or uncle's butylthio; Arylthio such as thiophenyl, 1-naphthalene sulfenyl or 2-naphthalene sulfenyl; Aromatic alkylthio such as benzylthio, benzene ethylmercapto group, 1-naphthyl methyl mercapto or 2-naphthyl methyl mercapto; The aryl sulfinyl is as phenyl sulfinyl, 1-naphthyl sulfinyl or 2-naphthyl first sulfonyl; The aralkyl sulfinyl is as benzyl sulfinyl, phenethyl sulfinyl, 1-naphthyl methyl sulfinyl or 2-naphthyl methyl sulfinyl; The low alkyl group sulfonyl, as mesyl, ethylsulfonyl, sulfonyl propyl base, isopropyl sulfonyl, butyl sulfonyl, isobutyl group sulfonyl, sec-butyl sulfonyl or tert-butyl group sulfonyl; Aryl sulfonyl is as phenyl sulfonyl, 1-naphthalene sulfonyl base or 2-naphthalene sulfonyl base; The aralkyl sulfonyl is as benzyl sulfonyl, phenethyl sulfonyl, 1-naphthyl methyl sulfonyl or 2-naphthyl methyl sulfonyl; Or 4-15 carbon atom and heteroatomic monocycle of 1-4 or bicyclic heterocycle arranged, hetero atom is selected from oxygen, nitrogen and sulfur, as pyrrole radicals, furyl, thienyl, pyridine radicals, pyrimidine radicals, pyrazolyl, thiazolyl, isothiazolyl isoxazolyl oxazolyl, pyrazinyl, pyrimidine radicals, pyridazinyl, indyl, quinolyl, isoquinolyl, 2, the 3-phthalazinyl, the naphthidinyl base, quinoxalinyl, quinazolyl, 1,4-benzodioxan base, 1,3-benzodioxan base, 1,2, the 3-triazolyl, 1,3, the 4-triazolyl, 1,3, the 4-thiadiazolyl group, 1,2, the 3-thiadiazolyl group, tetrazole radical, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, imidazolidinyl, the 2-imidazole radicals, morpholinyl, the morpholino base, morpholine N-oxide-base, low alkyl group morpholinyl such as N-methylmorpholine are for base, and N-ethylmorpholine is for base or N-propyl group morpholino base, piperazinyl, piperidino, piperidyl, thiomorpholine is for base or thio-morpholinyl.
Ring low alkyl group used herein " refer to C
1-C
6Alkyl.
The protecting group of being protected carboxyl or being protected carboxyl low-grade alkyl comprises that those skilled in the art's routine is used for the carboxyl-protecting group commonly used of peptide and chemistry of amino acids; as T.Green: " Protecting Groups in Organic Synthesis "; J Wiley and Sons, the protecting group of mentioning in 1981..They comprise monosilane ester, fat hydrocarbon ester and aromatic ester such as trimethyl silyl ester, t-butyldimethylsilyl ester, acetonyl ester, benzoyl ester etc.
Protected amino protecting group and comprised that those skilled in the art's routine is used for the amino protecting group commonly used of peptide and chemistry of amino acids, as T.Green, the protecting group of mentioning in the supra 218-287 page or leaf.The selection of suitable protecting group is the condition of removing protecting group, and is harmonious with other construction features of this chemical compound.Suitable protecting group comprises acyl group, as tertbutyloxycarbonyl or benzyloxycarbonyl group etc.
With respect to above-mentioned general the description, preferred formula I chemical compound is wherein:
R
1Be selected from and replace or do not replace (C
1-C
20) alkyl, replacement or unsubstituted ring alkyl, replacement or unsubstituted ring alkyl-alkyl, replacement or unsubstituting aromatic yl, replacement or unsubstituting aromatic alkyl, replacement or unsubstituted aryloxy, replace or the unsubstituting alkoxy aryl, and replace or unsubstituted alkoxy aromatic alkyl.Wherein, aforementioned aryl is selected from and replaces or unsubstituted phenyl;
R
aAnd R
3Be selected from hydrogen, replacement or unsubstituted (C respectively
1-C
6) alkyl;
R
2, R
bAnd R
cBeing selected from carboxyl or quilt is respectively protected carboxyl, carboxyl or is protected carboxyl low-grade alkyl and carboxylic amides;
X is oxygen or nitrogen;
R
4Be H or amino protecting group.
In addition, most preferred formula I chemical compound is those formulas I chemical compound that following group is wherein arranged among the present invention
R
1Be selected from (C
4-C
14) alkyl, cycloalkyl, (C
2-C
8) the alkyl cycloalkyl, phenyl, the benzyl, (C that replace
4-C
8) alkyl phenyl and (C
1-C
6) alkyl or alkoxyl-benzyl;
R
aAnd R
3Be independently selected from hydrogen and (C
1-C
6) alkyl;
R
2, R
bAnd R
cBeing independently selected from carboxyl or quilt is protected carboxyl, carboxyl or is protected carboxyl low-grade alkyl and carboxylic amides;
X is oxygen or nitrogen;
R
4Be H or amino protecting group.
Particularly preferred formula I chemical compound is those formulas I chemical compound that following group is wherein arranged:
R
1Be selected from n-hexyl, 4-n-pentyl cyclohexyl;
R
1And R
3Be independently selected from hydrogen or methyl;
R
2, R
bAnd R
cIt is carboxyl;
X is oxygen or nitrogen;
R
4Be H.
Preferred those have the formula I chemical compound of following D-isothreonine configuration especially:
Wherein, R
3Be methyl, R
1And R
2As defined above.
Those chemical compounds that also partly have following stereochemical structure particularly preferably in the diaminourea basic alanine in heptan two of molecule:
Wherein, R
1Be methyl, R
b, R
cAnd R
4Definition as described above.
Aspect stereochemical structure, following formula I chemical compound is most preferred:
Wherein, R
3And R
1Be methyl, X is an oxygen, R
b, R
c, R
1, R
2, R
4As defined above.
Particularly preferred cytokine induction agent is [R-(R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-] alanine or the acceptable salt of its medicine (formula I chemical compound), this chemical compound has been disclosed in United States Patent (USP) 5,312, among 831 embodiment 28.
United States Patent (USP) 5,312,831 disclose several standard pharmacological test procedures, and whether this test procedure can make those skilled in the art estimate out chemical compound is biological response modifier.Test procedure as the 16-17 hurdle has been estimated IL-6, the inducing action that CSF and G-CSF produce.
Preferred chemotherapeutics is microtubule agent or macrophage activation agent.The microtubule reactive compound is to make the microtubule unstable compounds, or the polymerization (as vincristine) by preventing tubulin or make the microtubule instability by the depolymerization (as taxanes) that prevents tubulin.The assembling of microtubule with separate that to join be a dynamic process, be subjected to the influence (kinases) of the conjugated protein and protein phosphorylation of tubulin.The microtubule reactive compound comprises the taxanes class, as paclitaxel or docetaxel, vincristine, vinblastine, Vinorelbine etc.But the macrophage activation agent active chemical compound that is activating macrophage is as amycin, doxirubicin and similarly amerantrone class and anthracycline drug, cisplatin, carboplatin, ametycin, bleomycin etc.Preferred chemotherapeutics is paclitaxel or carboplatin, or both compositionss.Microtubule agent of the present invention or macrophage activation agent or can obtain from commercial channels, the standard fabrication method preparation in the perhaps available published document.
Biological response modifier is estimated in the standard pharmacological test procedure in vivo to the potentiation of chemotherapeutics, in this program people's non-small cell type pulmonary carcinoma (NSCLC) cell line is moved into the nude mice flank portion that immunodeficiency is arranged.Below briefly introduce the used test procedure and the result that obtains.[R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine is used as representational biological response modifier and paclitaxel is used as representational chemotherapeutics.
Obtain 6-8 Balb-c nu/nu female mice in age in week from Charles Rive laboratory, 8-10 mice in age in week is used in experiment.People's non-small cell type pulmonary carcinoma (NSCLC) cell line H-157 from U.S. tissue culture preservation institute (ATCC) (Bethesda, MD).The cell RPMI culture medium culturing that 10% hyclone is arranged.
The mice percutaneous is injection 7.5 * 10 down
6H-157 NSCLC oncocyte.Tumor grows into 80-150mg when big, measures the length (l) and width (w) of tumor with slide gauge.With formula l * w
2/ 2 calculate the volume of tumor.With mm
3The volume of meter can directly transfer the unit intensity milligram of supposition to.Inject after 7 days, with mice at random (injection day be the 0th) be divided into 10 groups, average tumor weight is 100mg.The treatment group is at injection paclitaxel (30mg/kg) on the 0th and in the 1st day and injectable drug solvent (vehicle) on the 8th or [R (R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine (100 μ g/kg).
On the 7th and 14, accept paclitaxel and add [R (R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-animal of alanine group, its tumor speed of growth is compared with without the matched group of medication or the group of only accepting paclitaxel treatment obvious inhibitory action being arranged.Recorded on 7th separately and suppress tumor growing state (through student ' s t check, p≤0.05), adding usefulness [R-(R*, R*)]-N-[(R)-6-carboxy-N with paclitaxel after one day with the paclitaxel group
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine, the inhibition degree obviously strengthens.On 14th, there is not significant difference with paclitaxel group inhibition degree and matched group separately; And accepted paclitaxel on 0th and in injection on the the 1st and the 8th [R-(R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-group of alanine, compared with not making the matched group of treatment or only using the group of paclitaxel, still have obvious inhibitory action.Gained the results are shown in Table 1.In following table, [R (R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-code name of alanine is CI.
Table 1 CI adds the inhibitory action of paclitaxel to the growth of tumour cell of bare mouse different species transplanting
aData are from 5 independent evaluations (mean+SD), when estimating at every turn, and every group of 10 mices.The treatment group was accepted paclitaxel (30mg/kg) on 0th, at injection solvent on the the 1st and the 8th or CI (100 μ g/kg).
bP≤0.05 and blank group or only compare (Student ' s t check) with the paclitaxel group.
cP≤0.05 is compared with the blank group.
| The treatment group | ? aTumor heavy (mg) the 7th day | The % suppression ratio | Tumor heavy (mg) the 14th day | The % suppression ratio |
| The blank group | ??410±99 | ????- | ??1234±354 | ????- |
| The paclitaxel group | ? c289±108 | ????30 | ??866±348 | ????30 |
| Paclitaxel+CI group | ? b182±69 | ????56 | ? b491±151 | ????60 |
Only used on the 1st and the 8th [R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-evaluation test of the tumor-bearing mice of alanine (100 μ g/kg) carried out several times (data are not shown); do not have and once only to demonstrate and use [R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine itself has inhibitory action to the growth of tumour cell of nude mice.[R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine can not directly suppress tumor cell in vitro grows, and can not strengthen paclitaxel inhibitory action to growth of tumour cell in cell culture.
The clinical research evaluation has also been carried out in effect to biological response modifier and chemotherapeutics.[R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine is as representational biological response modifier, and paclitaxel and carboplatin are as representational chemotherapeutics.In this research, gave [R-(R*, R*)]-N-[(R)-6-carboxy-N on the 7th in first round chemotherapy (carboplatin and paclitaxel) precontract to patient with advanced cancer
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine (0 takes turns).The patient after carried out second in about 21 days and take turns chemotherapy, and gave [R-(R*, R*)]-N-[(R)-6-carboxy-N after taking turns chemotherapy in the 1st day and the 8th day second
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-] alanine, dosage is as shown in the table.69% patient is clinical effectively, tumor or complete obiteration, and perhaps part reduces, or makes stable disease.Controlled among the patient at 16, intended being diagnosed as NSCLC for 6.In this group, there are 3 people to reply fully, 1 people partly replys, and 1 people's stable disease has only 1 people's PD.The complete response rate of expection that carries out chemotherapy with standard chemotherapy regimen (paclitaxel and carboplatin) only has an appointment 5%, 6 to be controlled to be had 3 people to demonstrate to reply fully to be all beyond one's expectations among the patient.In this therapeutic scheme, dose of paclitaxel is 175-200mg/m
2, the area under curve of carboplatin (AUC) dosage is 6mg/ml * min.Clinical test results is summarized in following table.In following table, [R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-] alanine represents with CI.
Table 2 paclitaxel, carboplatin and CI combination are to the therapeutic outcome of patient with advanced cancer
aFully: do not have obvious disease
| ??? aThe tumor response reaction | ||||||
| # is controlled the patient | Dosage (μ g/kg) b | Fully | Part | Stable | Development | |
| ????3 | ????0.1 | ????2 | ????1 | |||
| ????6 | ????0.2 | ????1 | ????2 | ????3 | ||
| ????4 | ????0.266 | ????1 | ????1 | ????1 | ????1 | |
| ????3 | ????0.4 | ????1 | ????1 | ????1 | ||
| Add up to | ????16 | ????4 | ????3 | ????4 | ????5 | |
Part: tumor reduces 〉=50%
Stable: the state of an illness does not further develop
Development: the state of an illness has development
bThe dosage of CI
The result who carries out body internal standard pharmacology test and clinical trial with representational biological response modifier and chemotherapeutics shows that the combination of biological response modifier and chemotherapeutics can be used to strengthen the curative effect of standard chemotherapy, is used for the treatment to solid tumor.Especially, compositions of the present invention can be used for treating non-small cell type pulmonary carcinoma, glioma, ovarian cancer, breast carcinoma, carcinoma of prostate, head and neck cancer, renal carcinoma, cancer of pancreas, hepatocarcinoma, colon cancer and soft tissue sarcoma etc.
Combination treatment used among the present invention can carry out simultaneously, or staggered carrying out.Carrying out chemotherapeutic period, biological response modifier can be in the different time administration.Therefore, the term combination does not also mean that administration simultaneously, or make as a whole medicament.For example a kind of typical useful therapeutic scheme in clinical research is the patient before accepting first of chemotherapy course of treatment, accepts the biological response modifier treatment earlier.Typical embolic chemotherapy be after chemotherapy repeat several weeks, in this case, how in the future biological response modifier can be in the second chemotherapy administration course of treatment one day or administration.This staggered administration is sustainable in the whole treatment phase.
For the while administration, the composition of combination can be mixed with single dosage form, but the composition of combination all preparation in advance become the gradation form of administration.
The prescription of special chemotherapeutics is well-known on the art technology (and most of used be commercially available or preparing of having used in clinical trial), and these chemotherapeutics can be with typical vein or oral administration; But different with every kind of medicament and patient, the also available non-intestinal injection of chemotherapeutics, rectum, vagina, percutaneous, subcutaneous, local, the direct infusion of nose administration or canceration position.
Biological response modifier of the present invention also can be oral, vein, non-intestinal, rectum, vagina, percutaneous, subcutaneous, local, the direct infusion of nose administration or canceration position.Biological response modifier can be prepared according to the normative document methodology.For example formula I chemical compound and [R-(R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-] prescription of alanine is referring to United States Patent (USP) 5,312,831.
Biological response modifier that is not commercially available or can not obtains in clinical trial and chemotherapeutics (or resulting being not suitable for used) can be prepared separately, or with the acceptable carrier that is used for administration of one or more medicines for example, solvent, diluent etc. are together prepared.Can tablet, oral medication such as capsule, dispersion powder, granule, suspending agent form, as content is the suspending agent of 0.05%-5%, as contain the syrup of 10%-50% sugar, as contain the alcoholic acid elixir of 20%-50% etc., or parenteral aseptic injectable solution or contain the suspension of 0.05%-5% in waiting Zhang Jiezhi.This pharmaceutical preparation can contain 0.05% to 90% active component and carrier combinations.Usually content mostly is 5% to 60% (weight).
The prescription that is used for tablet and capsule administration can have solid carrier, comprise starch, lactose, dicalcium phosphate, microcrystalline Cellulose, sucrose and Kaolin, liquid-carrier can comprise sterilized water, Polyethylene Glycol, non-ionic surface active agent and edible oil, as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami, as long as be suitable for the character of active component and the particular dosage form of required administration.Usually can be flavoring agent, coloring agent, antiseptic and antioxidant with the adjuvant that is prepared in the pharmaceutical composition, as vitamin E, vitamin C, BHT and BHA.
These compositions in the combination can drug administration by injection or intraperitoneal administration.These active component can free alkali or the form of the acceptable salt of medicine in water with suitable surfactant, mix as hydroxypropyl cellulose, be prepared into solution or suspension.Available glycerol, aqueous Polyethylene Glycol or the two mixture in oil prepare dispersant.Under common storage and service condition, these preparations contain a kind of antiseptic, in case microbial growth.
The pharmaceutical dosage form that is suitable for injection comprises aseptic aqueous solution or dispersant and is used for preparing the sterilized powder of sterile solution or dispersant temporarily.Various injection types all must be aseptic, and certain fluidity must be arranged, and make it be easy to be positioned in the syringe.Make and storage requirement under, preparation must be stablized, and necessary can antimicrobial, as the pollution of antibacterial, mycete.Carrier must be a kind of solvent or disperse medium, as moisture, pure, polyhydric alcohol (as glycerol, propylene glycol and liquid macrogol) and suitable mixture and vegetable oil thereof.
Expectation should be adjusted the dosage of used chemotherapeutics and biological response modifier according to the patient to treatment with to the inherent toxic reaction of standard embolic chemotherapy in therapeutic process.Such as situation, reduce the consumption of chemotherapeutics according to bone marrow depression or liver function reduction.The initial dose of estimating chemotherapeutics is the initial amount that does not have biological response modifier to exist.Such as for using paclitaxel, carboplatin and [R-(R*, R*)]-N-[(R)-6-carboxy-N '-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-therapy of alanine combination, estimate that the amount of paclitaxel is 135-225mg/m
2, preferred dose is 175-200mg/m
2, the area under curve of carboplatin (AUC) dosage is 5-7mg/ml * min, preferred amounts is 6mg/ml * min.The biological response modifier dosage of design changes with the intensity of its induction of immunity system.For the cytokine induction agent, then the ability that produces according to the inducing cell factor changes.For [R-(R*, R*)]-N-[(R)-the 6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine, estimate the predose scope at 0.005-2 μ g/kg, preferred dose is 0.01-1 μ g/kg.
Claims (22)
1. method for the treatment of the mammal solid tumor, this method comprises carries out administration to described mammal with a kind of biological response modifier of effective dose and a kind of combination of chemotherapeutant.
2. a biological response modifier and a kind of chemotherapeutics are preparing the purposes for the treatment of in the mammal solid tumor medicament.
3. claim 1 or 2 described method or purposes, wherein biological response modifier is the cytokine induction agent.
4. described method of claim 3 or purposes, wherein the cytokine induction agent is a formula I chemical compound, its structure is:
Wherein,
R
1Be selected from hydrogen, replacement or do not replace (C
1-C
20) alkyl, replacement or unsubstituted ring alkyl, replacement or unsubstituted ring alkyl-alkyl, vinyl, acetenyl, replacement or not substituted-amino, replacement or do not replace acylamino-, replacement or unsubstituting aromatic yl, replacement or unsubstituting aromatic alkyl, replacement or unsubstituted aryloxy, replacement or unsubstituting alkoxy aryl, replacement or not substituted alcoxyl aralkyl and replacement or the unsubstituted 1-4 of containing heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen atom;
R
aAnd R
3Be independently selected from hydrogen, replacement or unsubstituted (C
1-C
6) alkyl, replacement or unsubstituted alkoxyalkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkyl-alkyl, replacement or unsubstituted aryl, replacement or unsubstituted aralkyl, replacement or unsubstituted alcoxyl aralkyl, vinyl, acetenyl and replacement or unsubstituted 1-4 heteroatomic monocycle or the bicyclic heterocyclic radical of containing, hetero atom is selected from nitrogen, sulfur and oxygen atom, for R
3, in described heterocycle hetero atom directly with-CH-X-part-the CH-base key closes;
R
2, R
bAnd R
cBeing independently selected from carboxyl or quilt is protected carboxyl, carboxyl or is protected carboxyl low-grade alkyl and Carboxylamide;
X is oxygen or nitrogen;
R
4Be H or amino protecting group; Wherein, the alkyl of above-mentioned replacement, cycloalkyl, cycloalkyl-alkyl, amino, acylamino-, aryl, aralkyl, aryloxy group, alkoxy aromatic yl, the substituent group of alcoxyl aralkyl and heterocyclic radical is selected from halogen, hydroxyl, low alkyl group, lower alkoxy, aryloxy group, aralkoxy, amino, single-or two-lower alkyl amino, virtue is amino, arylalkylamino, carboxyl, formoxyl, elementary alkoxy carbonyl, aryloxycarbonyl, aromatic alkoxy carbonyl, low-grade alkyl thio group, the aryl thio group, the aralkyl thio group, the aryl sulfinyl, the aryl sulfinyl, the aralkyl sulfinyl, the low alkyl group sulfonyl, aryl sulfonyl, aralkyl sulfonyl and contain 1-4 and be selected from nitrogen, the hetero atom monocycle or the bicyclic heterocyclic radical of sulfur and oxygen; Or the acceptable salt of its medicine.
5. described method of claim 4 or purposes, its Chinese style I chemical compound are [R-(R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine or the acceptable salt of its medicine.
6. each method or purposes among the claim 1-5, wherein said chemotherapeutics is microtubule agent or macrophage activation agent.
7. described method of claim 6 or purposes, wherein, microtubule agent or macrophage activation agent are selected from paclitaxel, docetaxel, vincristine, vinblastine, Vinorelbine, amycin, doxirubicin, cisplatin, carboplatin, ametycin and bleomycin.
8. described method of claim 7 or purposes, wherein microtubule agent or macrophage activation agent are paclitaxel and carboplatin.
9. one kind is carried out the method for the mammiferous chemotherapeutic sensitivity of chemotherapy to needs, and this method also comprises with a kind of biological response modifier except embolic chemotherapy carries out administration.
10. the described method of claim 9, biological response modifier wherein is the cytokine induction agent.
11. the described method of claim 10, wherein the cytokine induction agent is a formula I chemical compound, and structure is:
Wherein,
R
1Be selected from hydrogen, replacement or do not replace (C
1-C
20) alkyl, replacement or unsubstituted ring alkyl, replacement or unsubstituted ring alkyl-alkyl, vinyl, acetenyl, replacement or not substituted-amino, replacement or do not replace acylamino-, replacement or unsubstituting aromatic yl, replacement or unsubstituting aromatic alkyl, replacement or unsubstituted aryloxy, replacement or unsubstituting alkoxy aryl, replacement or not substituted alcoxyl aralkyl and replacement or the unsubstituted 1-4 of containing heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen atom;
R
aAnd R
3Be independently selected from hydrogen, replacement or unsubstituted (C
1-C
6) alkyl, replacement or unsubstituted alkoxyalkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkyl-alkyl, replacement or unsubstituted aryl, replacement or unsubstituted aralkyl, replacement or unsubstituted alcoxyl aralkyl, vinyl, acetenyl and replacement or unsubstituted 1-4 heteroatomic monocycle or the bicyclic heterocyclic radical of containing, hetero atom is selected from nitrogen, sulfur and oxygen atom, for R
3, in described heterocycle hetero atom directly with-CH-X-part-the CH-base key closes;
R
2, R
bAnd R
cBeing independently selected from carboxyl or quilt is protected carboxyl, carboxyl or is protected carboxyl low-grade alkyl and Carboxylamide;
X is oxygen or nitrogen;
R
4Be H or amino protecting group; Wherein, the alkyl of above-mentioned replacement, cycloalkyl, cycloalkyl-alkyl, amino, acylamino-, aryl, aralkyl, aryloxy group, alkoxy aromatic yl, the substituent group of alcoxyl aralkyl and heterocyclic radical is selected from halogen, hydroxyl, low alkyl group, lower alkoxy, aryloxy group, aralkoxy, amino, single-or two-lower alkyl amino, virtue is amino, arylalkylamino, carboxyl, formoxyl, elementary alkoxy carbonyl, aryloxycarbonyl, aromatic alkoxy carbonyl, low-grade alkyl thio group, the aryl thio group, the aralkyl thio group, the aryl sulfinyl, the aryl sulfinyl, the aralkyl sulfinyl, the low alkyl group sulfonyl, aryl sulfonyl, aralkyl sulfonyl and contain 1-4 and be selected from nitrogen, the heteroatomic monocycle or the bicyclic heterocyclic radical of sulfur and oxygen; Or the acceptable salt of its medicine.
12. the described method of claim 11, its Chinese style I chemical compound are [R-(R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen-heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine or the acceptable salt of its medicine.
13. each method among the claim 9-12, wherein chemotherapeutics is microtubule agent or macrophage activation agent.
14. the described method of claim 13, wherein microtubule agent or macrophage activation agent are selected from paclitaxel, docetaxel, vincristine, vinblastine, Vinorelbine, amycin, doxirubicin, cisplatin, carboplatin, ametycin and bleomycin.
15. the described method of claim 14, wherein microtubule agent or macrophage activation agent are paclitaxel and carboplatin.
16. one kind be used for simultaneously, respectively or the order administration contain biological response modifier and chemotherapeutics as the application of the product of compound formulation at the treatment solid tumor.
17. the described product of claim 16, wherein biological response modifier is the cytokine induction agent.
18. the described product of claim 17, wherein the cytokine induction agent is a formula I chemical compound, and structure is:
Wherein,
R
1Be selected from hydrogen, replacement or do not replace (C
1-C
20) alkyl, replacement or unsubstituted ring alkyl, replacement or unsubstituted ring alkyl-alkyl, vinyl, acetenyl, replacement or not substituted-amino, replacement or do not replace acylamino-, replacement or unsubstituting aromatic yl, replacement or unsubstituting aromatic alkyl, replacement or unsubstituted aryloxy, replacement or unsubstituting alkoxy aryl, replacement or not substituted alcoxyl aralkyl and replacement or the unsubstituted 1-4 of containing heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen atom;
R
aAnd R
3Be independently selected from hydrogen, replacement or unsubstituted (C
1-C
6) alkyl, replacement or unsubstituted alkoxyalkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkyl-alkyl, replacement or unsubstituted aryl, replacement or unsubstituted aralkyl, replacement or unsubstituted alcoxyl aralkyl, vinyl, acetenyl and replacement or unsubstituted 1-4 heteroatomic monocycle or the bicyclic heterocyclic radical of containing, hetero atom is selected from nitrogen, sulfur and oxygen atom, for R
3, in described heterocycle hetero atom directly with-CH-X-part-the CH-base key closes;
R
2, R
bAnd R
cIndependently being selected from carboxyl or quilt is protected carboxyl, carboxyl or is protected carboxyl low-grade alkyl and Carboxylamide;
X is oxygen or nitrogen;
R
4Be H or amino protecting group; Wherein, the alkyl of above-mentioned replacement, cycloalkyl, cycloalkyl-alkyl, amino, acylamino-, aryl, aralkyl, aryloxy group, alkoxy aromatic yl, the substituent group of alcoxyl aralkyl and heterocyclic radical is selected from halogen, hydroxyl, low alkyl group, lower alkoxy, aryloxy group, aralkoxy, amino, single-or two-lower alkyl amino, virtue is amino, arylalkylamino, carboxyl, formoxyl, elementary alkoxy carbonyl, aryloxycarbonyl, aromatic alkoxy carbonyl, low-grade alkyl thio group, the aryl thio group, the aralkyl thio group, the aryl sulfinyl, the aryl sulfinyl, the aralkyl sulfinyl, the low alkyl group sulfonyl, aryl sulfonyl, aralkyl sulfonyl and contain 1-4 heteroatomic monocycle or bicyclic heterocyclic radical, hetero atom is selected from nitrogen, sulfur and oxygen; Or the acceptable salt of its medicine.
19. the described product of claim 18, its Chinese style I chemical compound are [R-(R*, R*)]-N-[(R)-6-carboxy-N
2-[[2-carboxyl-1-methyl-2-[(1-oxygen heptyl) amino] ethyoxyl] carbonyl]-the L-lysyl-]-alanine or the acceptable salt of its medicine.
20. the described product of claim 16-19, wherein chemotherapeutics is microtubule agent or macrophage activation agent.
21. the described product of claim 20, wherein microtubule agent or macrophage activation agent are selected from paclitaxel, docetaxel, vincristine, vinblastine, Vinorelbine, amycin, doxirubicin, cisplatin, carboplatin, ametycin and bleomycin.
22. the described product of claim 20, wherein microtubule agent or macrophage activation agent are paclitaxel and carboplatin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39605199A | 1999-09-15 | 1999-09-15 | |
| US09/396,051 | 1999-09-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1391484A true CN1391484A (en) | 2003-01-15 |
Family
ID=23565645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00812921A Pending CN1391484A (en) | 1999-09-15 | 2000-09-12 | Method of potentiating chemotherapy and treating solid tumors |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1214092A2 (en) |
| JP (1) | JP2003509383A (en) |
| CN (1) | CN1391484A (en) |
| AR (1) | AR025659A1 (en) |
| AU (1) | AU7373600A (en) |
| BR (1) | BR0014001A (en) |
| CA (1) | CA2381078A1 (en) |
| WO (1) | WO2001019399A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60219617T2 (en) * | 2001-05-16 | 2008-01-03 | Novartis Ag | COMBINATION OF N-5- 4- (4-METHYL-PIPERAZINO-METHYL) -BENZOYLAMIDO -2-METHYLPHENYL -4- (3-PYRIDIL) -2-PYRIMIDINE AMINE WITH A BIPHOSPHONATE |
| CN109601739B (en) * | 2019-01-17 | 2022-10-14 | 河南湾流生物科技有限公司 | Compound amino acid feed additive and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1059919A1 (en) * | 1998-02-24 | 2000-12-20 | Dovetail Technologies, Inc. | Small molecules that increase the conversion of food to body weight gain |
| IL143901A0 (en) * | 1998-12-23 | 2002-04-21 | Searle & Co | Use of cyclooxygenase-2- inhibitor, a matrix metallaproteinase inhibitor, an antineoplastic agent and optionally radiation as a combination treatment of neoplasia |
-
2000
- 2000-09-12 CA CA002381078A patent/CA2381078A1/en not_active Abandoned
- 2000-09-12 CN CN00812921A patent/CN1391484A/en active Pending
- 2000-09-12 BR BR0014001-5A patent/BR0014001A/en not_active Application Discontinuation
- 2000-09-12 JP JP2001523030A patent/JP2003509383A/en active Pending
- 2000-09-12 WO PCT/US2000/025008 patent/WO2001019399A2/en not_active Application Discontinuation
- 2000-09-12 EP EP00961841A patent/EP1214092A2/en not_active Withdrawn
- 2000-09-12 AU AU73736/00A patent/AU7373600A/en not_active Abandoned
- 2000-09-14 AR ARP000104818A patent/AR025659A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1214092A2 (en) | 2002-06-19 |
| WO2001019399A3 (en) | 2001-12-13 |
| JP2003509383A (en) | 2003-03-11 |
| BR0014001A (en) | 2002-05-21 |
| WO2001019399A2 (en) | 2001-03-22 |
| CA2381078A1 (en) | 2001-03-22 |
| AU7373600A (en) | 2001-04-17 |
| AR025659A1 (en) | 2002-12-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3974938B2 (en) | Antitumor composition containing taxane derivative | |
| CN1222294C (en) | Combined preparations comprising morpholine anthracyclines and anticancer agent | |
| EP1718322B1 (en) | Synergistic compositions with fk-228 | |
| JP2010270124A (en) | Anti-cancer combination | |
| CN1536995A (en) | Antitumor compositions containing taxane derivatives | |
| EA008302B1 (en) | Use of antitumor indolopyrrolocarbazole derivatives and other anticancer agent in combination | |
| US5795871A (en) | Pharmaceutical composition for treatment of non-small cell lung cancer | |
| KR20120028868A (en) | A polysaccharide liposome, the preparation method and use of it | |
| JP5336466B2 (en) | Combined use of cholestanol derivatives | |
| KR101572529B1 (en) | Tetraarsenic oxide combination therapy for cancer treatment | |
| CN1391484A (en) | Method of potentiating chemotherapy and treating solid tumors | |
| AU2018348892B2 (en) | Formulation containing A-decarbonized-5a androstane compound for increasing white blood cell and use thereof | |
| RU2240793C1 (en) | Anti-tumor agent | |
| CN1200712C (en) | A combination comprising camptothecin and a stilbene derivative for the treatment of cancer | |
| US7863255B2 (en) | Methods of administering antitumor agent comprising deoxycytidine derivative | |
| CN106928298B (en) | Structural composition of cyclic dinucleotide cGAMP derivative, preparation method and application of cyclic dinucleotide cGAMP derivative in tumor resistance | |
| WO2023050297A1 (en) | Topical pharmaceutical composition, application, and kit | |
| DE60210329T2 (en) | COMBINED TUMOR THERAPY BASED ON SUBSTITUTED ACRYLOYL DISTAMYCIN DERIVATIVES AND PROTEIN KINASE (SERIN / THREONINE-KINASE) INHIBITORS | |
| EP3829586A1 (en) | Combination therapy for treating cancer | |
| CN105193810B (en) | 5 fluorouracil compositions and its application in antitumor injection is prepared | |
| RU2270682C2 (en) | Method for enhancing of cyclophosphan antitumor and antimetastatic activity in experiment | |
| US4600573A (en) | Compositions and method for alleviating the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea | |
| US7465754B1 (en) | Method of potentiating chemotherapy and treating solid tumors | |
| JPH02235813A (en) | Antitumor agent | |
| CN111603470A (en) | Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |