CN100500213C - Anti-tumour medicinal composition containing blood vessel inhibitor - Google Patents

Anti-tumour medicinal composition containing blood vessel inhibitor Download PDF

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CN100500213C
CN100500213C CNB2005100422644A CN200510042264A CN100500213C CN 100500213 C CN100500213 C CN 100500213C CN B2005100422644 A CNB2005100422644 A CN B2005100422644A CN 200510042264 A CN200510042264 A CN 200510042264A CN 100500213 C CN100500213 C CN 100500213C
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dihydroindole ketone
methylene
tumor
indole
dihydro
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CN1686546A (en
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孔庆忠
孙娟
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DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD.
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

A composite medicine containing the vascular inhibitor for treating solid tumor by locally putting it in the tumor is composed of the active anticancer component chosen from tyrosine kinase inhibitor and the combination of tyrosine kinase inhibitor and anticancer nitrosourea, and the medicinal auxiliary (biocompatible and biodegradable high-molecular polymer).

Description

The entity-tumor-resistant medicine composition that contains vasoinhibitor
(1) technical field
The present invention relates to a kind of entity-tumor-resistant medicine composition, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.Therefore wherein operative treatment not only can not be known the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and.
The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., J Surg Oncol.1997 Oct; 64:268-273).Also can be referring to referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, consequently treatment failure.
Therefore, the present invention is directed to the deficiencies in the prior art, a kind of entity-tumor-resistant medicine composition is provided, this pharmaceutical composition can suppress or destroy the blood vessel of tumor effectively and can suppress the new vessels of tumor, simultaneously can suppress tumor cell, thereby can better treat tumor, reduce recurrence.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of entity-tumor-resistant medicine composition is provided.Decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.
Entity-tumor-resistant medicine composition of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is the combination of vasoinhibitor or vasoinhibitor and nitrosourea cancer therapy drug, and described vasoinhibitor is a Tyrosine kinase inhibitor.
The formation that blood vessel suppresses to suppress or to destroy the blood vessel of tumor effectively and can suppress the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also promoted chemotherapeutics around tumor, to reach infiltration and the diffusion in the tumor tissues.
Above-mentioned Tyrosine kinase inhibitor is selected from one of following or combination:
Imatinib mesylate (Imatinib mesylate has another name called imatinib mesylate, Glivec),
4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate (4-((Methyl-1-piperazinyl) methyl)-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate, ST I571, CGP-57148B, STI-571A, CGP57148)
5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide (5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylicAcid (2-Diethylaminoethyl) amide, Sutent, SU11248, SU011248)
3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (3,3-Dichloro-5-(4-methylpiperidinosulfonyl)-2-indolinone, DCM),
3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone (3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one, SU9516, SU9518)
1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-4-methyl (SU6663, SU-5402,1H-Pyrrole-3-propanoic acid, 2-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-4-methyl);
2H-indole-2-dihydroindole ketone (2H-Indol-2-one);
3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS] (3-((4,5-dimethyl-1H-pyrrol-2-yl) methylene)-1,3-dihydro-[CAS], SU5614, semaxanib, SU-011271, SU-011606, SU-11612);
Pyrroles's lactone dihydroindole ketone (pyrrolyllactone indolinones, SU6577);
The lactams dihydroindole ketone (pyrrolyllactam indolinones, SU6597);
3-(4-dimethylamino-naphthal-1-methylene)-1, and 3-dihydro-indole-2-dihydroindole ketone (3-(4-Dimethylamino-naphthalen-l-ylmethylene)-l, 3-dihydro-indol-2-one, MAZ51);
1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indol-2-indolinone, RPI-1);
3-[5-methyl-2-(2-oxygen-1,2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid (3-[5-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-proprionic acid, SU10944);
5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides (5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-N-[2-(diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, SU11652);
5-[(Z)-(5-fluoro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides (5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide), SU11654);
5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides ((5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide), SU11655);
3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl) TGA] hydrazono-]-the 1H-2-dihydroindole ketone (3-[[(3-phenyl-4 (3H)-quinazolinone-2-yl) mercaptoacetyl] hydrazono]-1H-2-indolinones, SU1165);
3-two (4-anisyl) methylene-2-dihydroindole ketone (3-bis (4-methoxyphenyl) methylene-2-indolinone, TAS-301);
3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone (3-[4-(1-formylpiperazin-4yl)-benzylidenyl]-2-indolinone, SU4984);
3-([5-imidazoles] 2,1-methylene thiazole)-2-dihydroindole ketone (3-(5-imidazo) 2,1-blthiazolylmethylene)-2-indolinone, IBMI);
3-1 (2, the 6-methylimidazole [2, the methylene-5-methoxyl group-2-dihydroindole ketone of 1-Bj-thiazole-5-yl) (3-1 (2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl) methylenel-5-methoxy-2-indolinone, DMMI, SU9518];
Imidazoles [2,1-b] methylene thiazole-2-dihydroindole ketone (Imidazo[2,1-b] thiazolylmethylene-2-indolinones, ITI);
Methylene indole-2-dihydroindole ketone (indolylmethylene-2-indolinones, IMI);
(2-chloro-indole) methylene-2-dihydroindole ketone (2-chloroindolyl) methylene-2-indolinone, CMI);
Arlydene 2-dihydroindole ketone (arylidene 2-indolinone, AI);
1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indol-2-one), Cpd 1 for 2H-indole-2-dihydroindole ketone);
3-(4-dimethylamino-benzal)-2-dihydroindole ketone (3-(4-dimethylamino-benzylidenyl)-2-indolinone, DMBI);
5-chloro-3-methylene pyridine-2-dihydroindole ketone (5-chloro-3-pyridylmethylene-2-indolinone, CPMI);
3, and 3-lutidines-1-phenyl-2-dihydroindole ketone (3,3-dipyridylmethyl-1-phenyl-2-indolinone, DPMPI);
E-3-(2-chloro-3-methylene indole) 1, and 3-indoline-2-dihydroindole ketone (E-3-(2-chloro-3-indolylmethylene) 1,3-dihydroindol-2-indolinone, CIDI);
Gefitinib (Gefitinib, claim 4-quinazoline oxazolone amine again, N-(3-chloro-4-fluoro phenyl)-7-methoxyl group-6-[3-4-morpholine) propoxyl group], 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin] propoxy];
Erlotinib (4-quinazoline oxazolone amine, N-(3-acetenyl)-6,7-two (2-methoxy ethyl)--hydrochloride 4-Quinazolinamine, N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)-monohydrochloride, Tarceva, OSI-774, erlotinib, CP-358774, OSI-774, R-1415);
(phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-yl) (Phenol, 4-(4-(((1R)-1-phenylethyl) amino)-1H-pyrrolo (2,3-d) pyrimidine-6-yl)-, PKI-166, CGP-59326, CGP-59326B, CGP-62706, CGP-74321, CGP-75166, CGP-76627);
Lapatinib (4-quinazoline oxazolone amine, N-[3-chloro-4-[(3-fluoro) methoxy ethyl]-the 6-[5-[[2-[sulfidomethyl] ethyl] furan-2-yl]] two (4-tolyl sulfate) single hydrate], 4-Quinazol inamine, N-[3-chloro-4-[(3-fluorobenzyl) methoxyphenyl]-6-[5-[[[2-[methylsulfonyl] ethyl] amino] methyl] furan-2-yl]] bis (4-methylbenzenesulfonate) monohydrate, lapatinibditosylate, GW-2016, GW-572016, GW-572016F);
Votaranib (N-(4-chlorphenyl)-4-(pyridine-4-methyl) faces phenylenedimethylidyne-1-amine (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl) phtalazin-1-amine, vatalanib, PTK-787, PTK/ZK, Schering VEGF-TK1, Schering AG, ZK-222584));
WAY-EKB 569 ((2E)-N-[4-[(3-chloro-4-fluoro phenyl) amine]-3-cyanogen-7-ethoxyquin-6-yl]-4-(dimethylamino) also-the 2-amide ((2E)-N-[4-[(3-chloro-4-fluorophenyl) amino]-3-cyano-7-ethoxyquinol in-6-yl]-4-(dimethy lamino) but-2-enamide, EKB-569, pelitinib).
Above Tyrosine kinase inhibitor also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above-mentioned Tyrosine kinase inhibitor is with imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM); 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; the 2H-indol-2-one; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569 are preferred.
Tyrosine kinase inhibitor can be used separately; when using separately; can select imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone; 3-[5-methyl-2-(2-oxygen-1; 2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl) TGA] hydrazono-]-1H-2-dihydroindole ketone (SU1165); 3-two (4-anisyl) methylene-2-dihydroindole ketone; the 3-[4-formyl piperazine-4yl)-benzal]-the 2-dihydroindole ketone; 3-([5-imidazoles] 2; 1-methylene thiazole)-the 2-dihydroindole ketone; 3-1 (2; 6-methylimidazole [2; methylene-5-methoxyl group-2-the dihydroindole ketone of 1-Bj-thiazole-5-yl); imidazoles [2; 1-b] methylene thiazole-2-dihydroindole ketone; methylene indole-2-dihydroindole ketone; (2-chloro-indole) methylene-2-dihydroindole ketone; arlydene 2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone; 3-(4-dimethylamino-benzal)-2-dihydroindole ketone; 5-chloro-3-methylene pyridine-2-dihydroindole ketone; 3; 3-lutidines-1-phenyl-2-dihydroindole ketone or E-3-(2-chloro-3-methylene indole) 1, a kind of in 3-indoline-2-dihydroindole ketone or several.
Entity-tumor-resistant medicine composition anticancer effective component of the present invention is preferably as follows:
Imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone or 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569.
Tyrosine kinase inhibitor also can share with cancer therapy drug except that independent application, and cancer therapy drug can be has the medicine that suppresses growth of tumour cell, is mainly nitrosourea medicament, is selected from one of following or combination:
Streptozocin (streptozotocin; STZ); alestramustine (Alestramustine); atrimustine (Atrimustine); ambamustine (Ambamustine); nimustine (ACNU; Nimustine); bendamustine (Bendamustine); ditiomustine (Ditiomustine); bofumustine (Bofumustine); carmustine (carmustine; BCNU; carmustine); elmustine (Elmustine); ecomustine (Ecomustine); galamustine (Galamustine; GCNU); fotemustine (Fotemustine); estramustine (Estramustine); hemustine heCNU He (hemustine; heCNU); pentamustine (Pentamustine; Neptamustine); mannomustine (Mannomustine; MCNU); lomustine (lomustine; CCNU; lomustine; chlorethyl cyclohexyl nitrosourea); semustine (Semustine; CH3-CCNU; Me-CCNU; methyl lomustine; methyl-CCNU)); Ranimustine (Ranimustine); prednimustine (Prednimustine); uracil mustard (Uramustine, Uracil Mustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tallimustine) or spiromustine (Spiromustine).
Above nitrosourea medicament also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
The preferred atrimustine of above-mentioned nitrosourea medicament, ambamustine, nimustine, bendamustine, carmustine, elmustine, fotemustine, estramustine, mannomustine, lomustine, semustine, Ranimustine, prednimustine, uracil mustard, Sarmustine SarCNU, tauromustine, streptozocin, tallimustine or spiromustine.
Therefore, preferred a kind of or several Tyrosine kinase inhibitor and alestramustines of the anticancer effective one-tenth of entity-tumor-resistant medicine composition of the present invention; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; the combination of tallimustine or spiromustine.
Entity-tumor-resistant medicine composition anticancer effective component of the present invention is preferably atrimustine; ambamustine; nimustine; bendamustine; carmustine; elmustine; fotemustine; estramustine; mannomustine; lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; tallimustine or spiromustine and imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; the combination of ZK-222584 or WAY-EKB 569.
Vasoinhibitor percentage by weight concrete condition and deciding in compositions can be good with 1%-70% from 0.01%-99%, is the best with 2%-40%.When vasoinhibitor and nitrosourea cancer therapy drug use in conjunction, the weight ratio of the two can be 1:9 to 9:1.The nitrosourea cancer therapy drug is percentage by weight 0-50% in compositions.
Entity-tumor-resistant medicine composition anticancer effective component of the present invention is preferably as follows:
(a) imatinib mesylate of 0.1-50%, 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide, 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone, 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone, 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl, 2H-indole-2-dihydroindole ketone or 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS], gefitinib, Erlotinib, phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base, Lapatinib, ZK-222584 or WAY-EKB 569; Or (b) imatinib mesylate of 0.1-50%; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(3H-imidazoles 4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone or 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; the atrimustine of ZK-222584 or WAY-EKB 569 and 5-25%; ambamustine; nimustine; bendamustine; carmustine; elmustine; fotemustine; estramustine; mannomustine; lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; the combination of tallimustine or spiromustine.Below all be weight percentage.
Pharmaceutic adjuvant of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded, comprise one of following or its combination: (1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to, polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), polypeptide (polypeptides), polyactide (polylactides) is as polylactic acid (polylactic acid), polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid, SA), polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP)) with certain herbaceous plants with big flowers diacid (SA), liposome, Polyethylene Glycol (polyglycolide) (polymer of hydroxyacetic acid and lactic acid), carboxylic acids (carboxyl ic acids), fatty acid (fatty acids), phospholipid (phosphol ipids), nucleic acid (nucleic
Acids), polyamino acid (polyamino acids), aminoacid such as phenylalanine (phenylalanine), tyrosine (tyrosine), different bright (isoleucine), polynucleotide (polynucleotides); Natural polymer as, but be not limited to, protein and polysaccharide (polysaccharides) comprise hyaluronic acid (hyaluronic acid), chondroitin sulfate (chondroitin sulfate), collagen protein, gelatin, albumin etc.Wherein, preferred polymer is polifeprosan, polyactide, Polyethylene Glycol or polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid).
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the lactic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid.Above polyhydroxy acid can singly select or multiselect, and when singly selecting, the molecular weight of polylactic acid (PLA) can be, but is not limited to, 5000-100, and 000, but with 10,000-50,000 is preferred, with 10,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50,000 is preferred, with 10,000-20,000 for most preferably; The molecular weight of the copolymer of glycolic and lactic acid (PLGA) can be, but is not limited to, 1000-100, and 000, but with 10,000-50,000 is preferred; With 10,000-20,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.When PLA and PGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.Compositions can discharge effective ingredient by the mode of direct diffusion and/or degraded.Above molecular weight peak value scope is mainly GPC and records.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: polyethylene propylene (polyvinyl propylene), polyvinylpyrrolidone (polyvinylpyrrolidone, PVP), organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes), silicone (silicone) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change entity-tumor-resistant medicine composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt or sodium salt etc.
The used pharmaceutic adjuvant of entity-tumor-resistant medicine composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40:50-90, preferably weight ratio 15-30:65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of entity-tumor-resistant medicine composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of composition for treating solid tumor also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Because entity-tumor-resistant medicine composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
When share with above-mentioned non-operative treatment, entity-tumor-resistant medicine composition of the present invention can be used simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.Vasoinhibitor has potentiation significantly to act on to the nitrosourea cancer therapy drug, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
Route of administration
Entity-tumor-resistant medicine composition of the present invention can be used through various approach, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperi toneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as with in selective arterial, the tumor, tumor week injection or be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump and slow releasing capsule or sustained release profile in vivo test implant as selecting for use.
When the effective ingredient of entity-tumor-resistant medicine composition is vasoinhibitor, this entity-tumor-resistant medicine composition is based on topical, as with in selective arterial, the tumor, tumor week injection or be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, as slow releasing agent, implant or sustained-release implant.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is to reduce the repair ability of tumor cell to DNA, increases the action effect of therapies such as chemotherapy.The effective dose of vasoinhibitor is 1-800 milligram/kg body weight, is ideal with 10-500 milligram/kg body weight, with 20-200 milligram/kg body weight for the most desirable.Vasoinhibitor shared ratio in compositions is decided because of concrete condition, is good with 1%-70%, is the best with 2%-40%.
When used the part, its blood level maintained reduced levels, and concentration maintains higher level in the tumor.
When vasoinhibitor and nitrosourea cancer therapy drug use in conjunction, the ratio of the two can be 1:9 to 9:1, and the effective dose of nitrosourea cancer therapy drug is 0.01-200 milligram/kg body weight, is ideal with 1-30 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable.
Entity-tumor-resistant medicine composition of the present invention can be used for the treatment of the people and animal can be planted tumor, comprise entity tumor, blood and lymph tumor etc., but mainly treat the medicine of people's various entity tumors, comprise and originate from brain with preparation, the central nervous system, kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, former or cancer or sarcoma or the carcinosarcoma that shifts of rectum.
Entity-tumor-resistant medicine composition of the present invention also can be used for the treatment of the medicine of the various entity tumors of house pet and animal, when being used for the treatment of the various entity tumor of house pet and animal, the material of species specificity is preferably selected in the active ingredient of entity-tumor-resistant medicine composition of the present invention for use.
Also can add other medicinal ingredient in the entity-tumor-resistant medicine composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can with topical, wherein be released to the best with local slow again as injection in selective arterial injection and the direct tumor body for good through various administrations.When used the part, composition for treating solid tumor of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Entity-tumor-resistant medicine composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
Entity-tumor-resistant medicine composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, implant, implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on agent for slow releasing in the body.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Picking dosage form of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method.Wherein dissolution method can be used for the manufacturing of microsphere, and its method is arbitrarily, and entity-tumor-resistant medicine composition also can be packed in the liposome.
The characteristics of entity-tumor-resistant medicine composition technology of preparing of the present invention be with vasoinhibitor and nitrosourea cancer therapy drug separately or packaged in combination in pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, wait to fill part mixing after the universe dry.Treat that the universe is shaped immediately after dry and sterilizes packing.
Above vasoinhibitor can be in various degree inhibition or reduce the activity of tumor cell revascularization, experiment in vivo and vitro of the present invention is found the notable synergistic effect of vasoinhibitor to the nitrosourea cancer therapy drug.When the two associating topical application, especially local the placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
By following test and embodiment the technology side of composition for treating solid tumor of the present invention is further described:
Tumor-inhibiting action in the body of test one, vasoinhibitor and nitrosourea cancer therapy drug.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is imatinib mesylate (IMTN), and the 3rd to 6 group is respectively BCNU, ACNU, CCNU and estramustine.The the 7th to 10 group is respectively IMTN and BCNU, ACNU, CCNU and the female not associating of department.Except that IMTN placed in tumor, BCNU, ACNU, CCNU and estramustine were intraperitoneal administration.Dosage measuring is 5mg/kg except that IMTI is 100mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 60±16cm 3
2(6) IMTI 42±10cm 3 <0.05
3(6) ACNU 41±12cm 3 <0.01
4(6) BCNU 44±10cm 3 <0.01
5(6) CCNU 38±10cm 3 <0.01
6(6) Estramustine 41±8cm 3 <0.01
7(6) IMTN+ACNU 24±6cm 3 <0.001
8(6) IMTN+BCNU 22±46cm 3 <0.001
9(6) IMTN+CCNU 22±6cm 3 <0.001
10(6) The IMTN+ estramustine 18±3.2cm 3 <0.001
Annotate: imatinib mesylate (IMTN) is a vasoinhibitor, and BCNU, ACNU, CCNU and estramustine are the nitrosourea cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and nitrosourea cancer therapy drug (the 3rd to 6 group) application separately all have obvious tumor-inhibiting action (P＜0.05).And use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test two, vasoinhibitor and nitrosourea cancer therapy drug.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 2).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor SU11248; The the 3rd to 6 group is respectively the nitrosourea cancer therapy drug.The the 7th to 10 group of associating that is respectively vasoinhibitor SU11248 and different nitrosourea cancer therapy drugs.Except that blood vessel inhibitor SU11248 placed in tumor, BCNU, ACNU, CCNU and estramustine were intraperitoneal administration.Dosage measuring vasoinhibitor SU11248 is that 200mg/kg is 5mg/kg outward.。The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.
Table 2
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 75±23cm 3
2(6) SU11248 62±5.0cm 3 <0.05
3(6) Fotemustine 43±2.3cm 3 <0.01
4(6) Semustine 42±3.6cm 3 <0.01
5(6) Tauromustine 44±3.4cm 3 <0.01
6(6) Spiromustine 44±3.8cm 3 <0.01
7(6) The SU11248+ fotemustine 24±3.6cm 3 <0.001
8(6) The SU11248+ semustine 22±3.4cm 3 <0.001
9(6) The SU11248+ tauromustine 20±3.2cm 3 <0.001
10(6) The SU11248+ spiromustine 18±3.0cm 3 <0.001
Annotate: 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide (SU11248) is a vasoinhibitor, and fotemustine, semustine, tauromustine and spiromustine are the nitrosourea cancer therapy drug.
Test three, topical application vasoinhibitor are to the potentiation of nitrosourea cancer therapy drug.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM), and the 3rd to 6 group is respectively BCNU, ACNU, CCNU and estramustine.The the 7th to 10 group is respectively DCM and BCNU, ACNU, CCNU and the female not associating of department.BCNU, ACNU, CCNU and estramustine.All medicines are placed in being tumor, and metering all is 5mg/kg except that blood vessel inhibitor DCM the 100mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th day.
Table 3
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 60±14cm 3
2(6) DCM 44±10cm 3 <0.05
3(6) ACNU 40±12cm 3 <0.01
4(6) BCNU 33±8cm 3 <0.01
5(6) CCNU 34±8cm 3 <0.01
6(6) Estramustine 32±8cm 3 <0.01
7(6) DCM+ACNU 26±4.6cm 3 <0.001
8(6) LNM+BCNU 24±4.4cm 3 <0.001
9(6) LNM+CCNU 22±4cm 3 <0.001
10(6) The LNM+ estramustine 18±3.8cm 3 <0.001
Annotate: 3, (4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM) is a vasoinhibitor to 3-two chloro-5-, and BCNU, ACNU, CCNU and estramustine are the nitrosourea cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and nitrosourea cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test four, vasoinhibitor and nitrosourea cancer therapy drug.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).First group is contrast, the the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor 3-[1-(3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone (SU9516), the 3rd to 6 group is respectively BCNU, ACNU, CCNU and estramustine.The the 7th to 10 group is respectively SU9516 and BCNU, ACNU, CCNU and the female not associating of department.Except that SU9516 placed in tumor, BCNU, ACNU, CCNU and estramustine were intraperitoneal administration.Dosage measuring is 5mg/kg except that SU9516 is 100mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.
Table 4
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 60±16cm 3
2(6) SU9516 40±9cm 3 <0.05
3(6) ACNU 41±12cm 3 <0.01
4(6) BCNU 44±10cm 3 <0.01
5(6) CCNU 38±10cm 3 <0.01
6(6) Estramustine 41±8cm 3 <0.01
7(6) SU9516+ACNU 28±6cm 3 <0.001
8(6) SU9516+BCNU 26±46cm 3 <0.001
9(6) SU9516+CCNU 24±6cm 3 <0.001
10(6) The SU9516+ estramustine 20±3.2cm 3 <0.001
Annotate: SU9516 is that (3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-the 2-dihydroindole ketone is a vasoinhibitor to 3-[1-, and BCNU, ACNU, CCNU and estramustine are the nitrosourea cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and nitrosourea cancer therapy drug (the 3rd to 6 group) application separately all have obvious tumor-inhibiting action (P＜0.05).And use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test five, vasoinhibitor and nitrosourea cancer therapy drug.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 5).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-4-methyl (SU6663); The the 3rd to 6 group is respectively the nitrosourea cancer therapy drug.The the 7th to 10 group of associating that is respectively vasoinhibitor SU6663 and different nitrosourea cancer therapy drugs.Except that blood vessel inhibitor SU6663 placed in tumor, BCNU, ACNU, CCNU and estramustine were intraperitoneal administration.Dosage measuring vasoinhibitor SU6663 is that 200mg/kg is 5mg/kg outward.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 30th day.
Table 5
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 75±23cm 3
2(6) SU6663 64±5.2cm 3 <0.05
3(6) Fotemustine 43±2.3cm 3 <0.01
4(6) Semustine 42±3.6cm 3 <0.01
5(6) Tauromustine 44±3.4cm 3 <0.01
6(6) Spiromustine 44±3.8cm 3 <0.01
7(6) The SU6663+ fotemustine 28±3.6cm 3 <0.001
8(6) The SU6663+ semustine 24±3.4cm 3 <0.001
9(6) The SU6663+ tauromustine 22±3.2cm 3 <0.001
10(6) The SU6663+ spiromustine 16±3.0cm 3 <0.001
Annotate: 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-4-methyl (SU6663) is a vasoinhibitor, and fotemustine, semustine, tauromustine and spiromustine are the nitrosourea cancer therapy drug.
Tumor-inhibiting action in the body of test six, vasoinhibitor and nitrosourea cancer therapy drug.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 6).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor 2H-indole-2-dihydroindole ketone or 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1, and 3-dihydro-[CAS] (SU5614); The the 3rd to 6 group is respectively the nitrosourea cancer therapy drug.The the 7th to 10 group of associating that is respectively vasoinhibitor SU5614 and different nitrosourea cancer therapy drugs.Except that blood vessel inhibitor SU5614 placed in tumor, BCNU, ACNU, CCNU and estramustine were intraperitoneal administration.Dosage measuring vasoinhibitor SU5614 is that 200mg/kg is 5mg/kg outward.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 30th day.
Table 6
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 75±23cm 3
2(6) SU5614 60±5.0cm 3 <0.05
3(6) Fotemustine 43±2.3cm 3 <0.01
4(6) Semustine 42±3.6cm 3 <0.01
5(6) Tauromustine 44±3.4cm 3 <0.01
6(6) Spiromustine 44±3.8cm 3 <0.01
7(6) The SU5614+ fotemustine 26±3.6cm 3 <0.001
8(6) The SU5614+ semustine 22±3.4cm 3 <0.001
9(6) The SU5614+ tauromustine 20±3.2cm 3 <0.001
10(6) The SU5614+ spiromustine 18±3.0cm 3 <0.001
Annotate: 2H-indole-2-dihydroindole ketone or 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS] is vasoinhibitor (SU5614), and fotemustine, semustine, tauromustine and spiromustine are the nitrosourea cancer therapy drug.
Similar potentiation also sees the associating of other vasoinhibitor and other nitrosourea cancer therapy drug.With multiple other tumor cell (comprising the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma, cancer of pancreas, renal carcinoma and the esophageal carcinoma etc.) is that subjects draws similar results.
In a word, experimental result shows that vasoinhibitor among the present invention is to the potentiation of listed nitrosourea cancer therapy drug.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of any one (or multiple) vasoinhibitor and any one (or multiple) nitrosourea cancer therapy drug or packs separately.The entity-tumor-resistant medicine composition that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type.
The preparation method of entity-tumor-resistant medicine composition of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
3. removal organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment 1.
With 90mg molecular weight peak value is that the polylactic acid (PLGA) of 10000-20000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 10mg imatinib, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10% imatinib.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 14-21 days, is 25-45 days at the subcutaneous drug release time of mice.
Embodiment 2. is as described in the embodiment 1, and anticancer effective component that different is is one of following:
Percentage by weight is the imatinib mesylate of 1-60%; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone; 3-[5-methyl-2-(2-oxygen-1; 2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(the 2-pyrrolidinyl-1-ylethyl)-1H-pyrroles-3-carboxylic acid amides; 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl) TGA] hydrazono-]-the 1H-2-dihydroindole ketone; 3-two (4-anisyl) methylene-2-dihydroindole ketone; the 3-[4-formyl piperazine-4y1)-benzal]-the 2-dihydroindole ketone; 3-([5-imidazoles] 2; 1-methylene thiazole)-the 2-dihydroindole ketone; 3-1 (2; 6-methylimidazole [2; methylene-5-methoxyl group-2-the dihydroindole ketone of 1-Bj-thiazole-5-yl); imidazoles [2; 1-b] methylene thiazole-2-dihydroindole ketone; methylene indole-2-dihydroindole ketone; (2-chloro-indole) methylene-2-dihydroindole ketone; arlydene 2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone; 3-(4-dimethylamino-benzal)-2-dihydroindole ketone; 5-chloro-3-methylene pyridine-2-dihydroindole ketone; 3; 3-lutidines-1-phenyl-2-dihydroindole ketone; E-3-(2-chloro-3-methylene indole) 1; 3-indoline-2-dihydroindole ketone; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569.
Embodiment 3.
With 70mg molecular weight peak value is that the polylactic acid (PLGA) of 20000-30000 is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20mg5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide (SU11248) and 10 milligrams of carmustines (BCNU) shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 20%SU11248 and 10% carmustine entity-tumor-resistant medicine composition.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4. is as described in the embodiment 3, and different is that contained anticancer effective component is:
(a) imatinib mesylate of 1-50% or 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2, the alestramustine of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide and 1-30%, atrimustine, ambamustine, nimustine, bendamustine, ditiomustine, bofumustine, carmustine, elmustine, ecomustine, CNCC, galamustine, fotemustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, semustine, Ranimustine, prednimustine, uracil mustard, Sarmustine SarCNU, tauromustine, streptozocin, the combination of tallimustine or spiromustine; Perhaps
(b) 3 of 1-50%, 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone or 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1, the alestramustine of 3-dihydro-indole-2-dihydroindole ketone and 1-30%, atrimustine, ambamustine, nimustine, bendamustine, ditiomustine, bofumustine, carmustine, elmustine, ecomustine, CNCC, galamustine, fotemustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, semustine, Ranimustine, prednimustine, uracil mustard, Sarmustine SarCNU, tauromustine, streptozocin, the combination of tallimustine or spiromustine; Perhaps
(c) the 1H-pyrroles of 1-50%-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone or 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; the alestramustine of ZK-222584 or WAY-EKB 569 and 1-30%; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; the combination of tallimustine or spiromustine.
Below all be weight percentage.
Embodiment 5.
50mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 80:20) copolymer is put into container; after adding 100 milliliters of dichloromethane dissolving mixings; add 50mg3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM) shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the 50%DCM entity-tumor-resistant medicine composition.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6. is as described in the embodiment 5, and different is that anticancer effective component is:
The imatinib mesylate of percentage by weight 1-50%; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569.
Embodiment 7.
60mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 80:20) copolymer is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 30mg imatinib mesylate and 10 milligrams of carmustines, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 30% imatinib mesylate and 10% carmustine entity-tumor-resistant medicine composition.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 8. is as described in the embodiment 7, and different is that anticancer effective component is:
The imatinib mesylate of 1-50%; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; the alestramustine of ZK-222584 or WAY-EKB 569 and 1-30%; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; the combination of tallimustine or spiromustine.
Below all be weight percentage.
Embodiment 9.
(EVAc) puts into container with the 60mg ethylene vinyl acetate copolymer, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 40mg imatinib mesylate, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 40% percentage by weight imatinib mesylate.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 10. is as described in embodiment 1,2 or 3, and different is, and that used pharmaceutic adjuvant is respectively is one of following:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the glycolic of 5000-15000,10000-20000,20000-35000 or 30000-50000 and the copolymer of lactic acid (PLGA);
C) ethylene vinyl acetate;
D) weight ratio 10:90,20:80,30:70,40:60,50:50 or 60:40 to carboxy phenyl propane: certain herbaceous plants with big flowers diacid copolymer (polifeprosan); With
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, protein, polysaccharide, hyaluronic acid, chondroitin sulfate, collagen protein, gelatin or albumin.
Embodiment 11. is as described in embodiment 1 or 3, and different is to contain anticancer effective component to be:
(a) 10-30% imatinib mesylate;
(b) combination of 10-30% imatinib mesylate and 20% nimustine;
(c) combination of 10-30% imatinib mesylate and 20% carmustine;
(d) combination of 10-30% imatinib mesylate and 20% estramustine;
(e) combination of 10-30% imatinib mesylate and 20% lomustine;
(f) combination of 10-30% imatinib mesylate and 20% Bestrabucil;
(g) combination of 10-30% imatinib mesylate and 20% fotemustine;
(h) combination of 10-30% imatinib mesylate and 20% atrimustine;
(i) combination of 10-30% imatinib mesylate and 20% semustine; Or
(j) 10-30% imatinib mesylate and 20% Sarmustine SarCNU.
Below all be weight percentage.
Embodiment 12. is as described in embodiment 1 or 3, and different is to contain anticancer effective component to be:
(a) combination of the gefitinib of 10-30% carmustine and 10-30%;
(b) combination of the Erlotinib of 10-30% carmustine and 10-30%;
(c) combination of the Lapatinib of 10-30% carmustine and 10-30%;
(d) combination of the ZK-222584 of 10-30% carmustine and 10-30%;
(e) combination of the WAY-EKB 569 of 10-30% carmustine and 10-30%; Or
(f) phenol of 10-30% carmustine and 10-30%, and 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2, the 3-d) combination of pyrimidine-6-base.Below all be weight percentage.
Test seven, composition for treating solid tumor are to tumor vascular inhibitory action
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection treats that in its hypochondrium tumor growth was divided into 10 groups with it after 14 days.First group is contrast, and the 2nd to 9 group is the treatment group, 10 kinds of tumors pharmaceutical combinations accepting respectively to mention among the embodiment 11.All medicines are placed in being tumor, and the amount of pharmaceutical composition is 0.25mg.The treatment back was taken out tumor on the 10th day, observed blood vessel through H.E. dyeing and suppressed situation, and calculate tumor vascular suppression ratio (%).
The result shows that the different pharmaceutical that tries has the obvious suppression effect to tumor vessel, and suppression ratio is between 44%-80%.Show that the used tumor vessel inhibitor of the present invention is of universal significance.Therefore, the tumor vessel selection of inhibitors in the composition for treating solid tumor of the present invention is for arbitrarily.Equally, the associating of nitrosourea cancer therapy drug and tumor vessel inhibitor also is arbitrarily.
Composition for treating solid tumor can be made various dosage forms with existing method.Above embodiment only is used for explanation, and is not limitation application of the present invention.

Claims (5)

1. entity-tumor-resistant medicine composition, comprise anticancer effective component and medicinal slow-release auxiliary material, it is characterized in that this entity-tumor-resistant medicine composition is the implantation slow release agent, anticancer effective component is the combination of vasoinhibitor or vasoinhibitor and nitrosourea cancer therapy drug, and described vasoinhibitor is a Tyrosine kinase inhibitor;
Described Tyrosine kinase inhibitor is selected from one of following or combination:
Imatinib mesylate, 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide, 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone, 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone, 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl, 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS], pyrroles's lactone dihydroindole ketone, the lactams dihydroindole ketone, 3-(4-dimethylamino-naphthal-1-methylene)-1,3-dihydro-indole-2-dihydroindole ketone, 1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone, 3-[5-methyl-2-(2-oxygen-1,2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid, 5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides, 5-[(Z)-(5-fluoro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides, 5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides, 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl) TGA] hydrazono-]-the 1H-2-dihydroindole ketone, 3-two (4-anisyl) methylene-2-dihydroindole ketone, 3-[4-formyl piperazine-4-yl-benzal]-the 2-dihydroindole ketone, 3-([5-imidazoles] 2,1-methylene thiazole)-the 2-dihydroindole ketone, 3-1 (2,6-methylimidazole [2, methylene-5-methoxyl group-2-the dihydroindole ketone of 1-Bj-thiazole-5-yl), imidazoles [2,1-b] methylene thiazole-2-dihydroindole ketone, methylene indole-2-dihydroindole ketone, (2-chloro-indole) methylene-2-dihydroindole ketone, arlydene 2-dihydroindole ketone, 1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone, 3-(4-dimethylamino-benzal)-2-dihydroindole ketone, 5-chloro-3-methylene pyridine-2-dihydroindole ketone, 3,3-lutidines-1-phenyl-2-dihydroindole ketone, E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone, gefitinib, Erlotinib, phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base, Lapatinib, ZK-222584 or WAY-EKB 569;
Described nitrosourea cancer therapy drug is selected from alestramustine, atrimustine, ambamustine, nimustine, bendamustine, ditiomustine, bofumustine, carmustine, elmustine, ecomustine, CNCC, galamustine, fotemustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, methyl lomustine, semustine, Ranimustine, prednimustine, uracil mustard, Sarmustine SarCNU, tauromustine, streptozocin, in tallimustine or the spiromustine one or more;
Described medicinal slow-release auxiliary material is one of following component:
A) molecular weight is the polylactic acid of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the glycolic of 5000-15000,10000-20000,20000-35000 or 30000-50000 and the copolymer of lactic acid;
C) ethylene vinyl acetate;
D) weight ratio 10:90,20:80,30:70,40:60,50:50 or 60:40 to carboxy phenyl propane: the decanedioic acid copolymer; Or
E) xylitol, oligosaccharide, chitin, protein, polysaccharide, hyaluronic acid, chondroitin sulfate, collagen protein, gelatin or albumin.
2. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that anticancer effective component is:
Imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569 and alestramustine; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; the combination of tallimustine or spiromustine.
3. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that anticancer effective component is:
(a) 10-30% imatinib mesylate,
(b) combination of 10-30% imatinib mesylate and 20% nimustine,
(c) combination of 10-30% imatinib mesylate and 20% carmustine,
(d) combination of 10-30% imatinib mesylate and 20% estramustine,
(e) combination of 10-30% imatinib mesylate and 20% lomustine,
(f) combination of 10-30% imatinib mesylate and 20% Bestrabucil,
(g) combination of 10-30% imatinib mesylate and 20% fotemustine,
(h) combination of 10-30% imatinib mesylate and 20% atrimustine,
(i) combination of 10-30% imatinib mesylate and 20% semustine, or
(j) combination of 10-30% imatinib mesylate and 20% Sarmustine SarCNU;
Below all be weight percentage.
4. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that this anti-cancer composition effective ingredient is:
(a) combination of the gefitinib of 10-30% carmustine and 10-30%,
(b) combination of the Erlotinib of 10-30% carmustine and 10-30%,
(c) combination of the Lapatinib of 10-30% carmustine and 10-30%,
(d) combination of the ZK-222584 of 10-30% carmustine and 10-30%,
(e) combination of the WAY-EKB 569 of 10-30% carmustine and 10-30%, or
(f) phenol of 10-30% carmustine and 10-30%, and 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2, the 3-d) combination of pyrimidine-6-base;
Below all be weight percentage.
5. the application of the described entity-tumor-resistant medicine composition of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum former or secondary.
CNB2005100422644A 2005-04-06 2005-04-06 Anti-tumour medicinal composition containing blood vessel inhibitor Expired - Fee Related CN100500213C (en)

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