CN1313764A - New use of taxoid derivatives - Google Patents
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- CN1313764A CN1313764A CN99809900A CN99809900A CN1313764A CN 1313764 A CN1313764 A CN 1313764A CN 99809900 A CN99809900 A CN 99809900A CN 99809900 A CN99809900 A CN 99809900A CN 1313764 A CN1313764 A CN 1313764A
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- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The present invention relates a new use of taxoid derivatives. It relates more precisely to a method for treating abnormal cell proliferation of different resistant cell lines expressing multidrug resistance P-glycoprotein. This type of cells are representative of colon cancer cells. The products of the present invention are also usable to treat the colon cancer of mammals including men. The preferred compound is 4 alpha -acetoxy-2 alpha -benzoyloxy-5 beta , 20-epoxy-1 beta -hydroxy-7 beta -dimethoxy-9-oxo-11-taxen-13 alpha -yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate.
Description
The present invention relates to the new purposes of taxoid (taxoid) derivant.Or rather, it relates to a kind of method for the treatment of the abnormal cell proliferation of the different resistant cell lines of expressing multidrug resistance P-glycoprotein.This class cell is the representative of colon cancer cell.The present invention relates to express the treatment of the different resistant cell line abnormal cell proliferations of multidrug resistance P-glycoprotein, also relate to the treatment of the different resistant cell line abnormal cell proliferations of expressing multidrug resistance P-glycoprotein, also relate to chemical compound by using logical formula I or its pharmaceutically acceptable salt or its solvate and treat the mammal colon tumor of (comprising the people):
Wherein:
Z represents the base of hydrogen atom or following general formula:
Wherein:
R
1Expression
It is optional that described atom or base are selected from halogen atom and contain the alkyl of 1～4 carbon atom, the alkoxyl that contains 1～4 carbon atom or trifluoromethyl by the one or more identical or different atoms or the benzoyl of base replacement,
Thenoyl or furanylcarbonyl or
Base R
2-O-CO-, wherein, R
2Expression:
-contain the alkyl of 1～8 carbon atom,
-contain the thiazolinyl of 2～8 carbon atoms,
-contain the alkynyl of 3～8 carbon atoms,
-contain the cycloalkyl of 3～6 carbon atoms,
-contain 4～6 carbon atoms cycloalkenyl group or
-contain the bicyclic alkyl of 7～10 carbon atoms, these bases are optional to be selected from following substituent group and to replace by one or more: halogen atom and hydroxyl, the alkoxyl that contains 1～4 carbon atom, dialkyl amido (wherein, each moieties contains 1～4 carbon atom), piperidino or morpholino base, 1-piperazinyl (choose wantonly at 4 alkyl that contained 1～4 carbon atom and replace or replaced) by the phenylalkyl that moieties wherein contains 1～4 carbon atom, the cycloalkyl that contains 3～6 carbon atoms, the cycloalkenyl group that contains 4～6 carbon atoms, phenyl (optional be selected from following atom or base replaces: halogen atom and contain the alkyl of 1～4 carbon atom or contain the alkoxyl of 1～4 carbon atom) by one or more, cyano group or carboxyl or alkoxy carbonyl are (wherein, moieties contains 1～4 carbon atom)
-optional by one or more phenyl that following atom or base replace or α-or betanaphthyls that are selected from: halogen atom and contain the alkyl of 1～4 carbon atom or contain the alkoxyl of 1～4 carbon atom, perhaps
-5 yuan of aromatic heterocyclics are preferably selected from furyl and thienyl,
-or contain the saturated heterocyclyl of 4～6 carbon atoms, optionally replaced by one or more alkyl that contain 1～4 carbon atom,
R
3Expression
The alkyl that contains the unbranched or side chain of 1～8 carbon atom,
The thiazolinyl that contains the unbranched or side chain of 2～8 carbon atoms,
The alkynyl that contains the unbranched or side chain of 2～8 carbon atoms,
The cycloalkyl that contains 3～6 carbon atoms,
Optional by one or more phenyl that following atom or base replace or α-or betanaphthyls that are selected from: halogen atom and alkyl, thiazolinyl, alkynyl, aryl, aralkyl, alkoxyl, alkylthio group, aryloxy group, arylthio, hydroxyl, hydroxyalkyl, sulfydryl, formyl, acyl group, acylamino-, aromatic acylamino, alkoxy carbonyl amino, amino, alkyl amino, dialkyl amido, carboxyl, alkoxy carbonyl group, carbamyl, alkyl carbamyl, dialkyl group carbamyl, cyano group, nitro and trifluoromethyl
Perhaps 5 yuan of fragrant heterocycles; this virtue heterocycle comprises one or more identical or different hetero atoms that are selected from nitrogen-atoms, oxygen atom and sulphur atom; and optional be selected from following identical or different substituent group and replace: halogen atom and alkyl, aryl, amino, alkyl amino, dialkyl amido, alkoxy carbonyl amino, acyl group, aryl carbonyl, cyano group, carboxyl, carbamyl, alkyl carbamyl, dialkyl group carbamyl or alkoxy carbonyl group by one or more
Condition is: phenyl, α-or the substituent group of betanaphthyl and aromatic heterocyclic in, alkyl and other basic moieties comprise 1～4 carbon atom, and thiazolinyl and alkynyl comprise 2～8 carbon atoms, and aryl is phenyl or α-or betanaphthyl,
R
4Expression
The alkoxyl that in unbranched or side chain, contains 1～6 carbon atom,
The alkene oxygen base that in unbranched or side chain, contains 3～6 carbon atoms,
The alkynyloxy group that in unbranched or side chain, contains 3～6 carbon atoms,
Contain 3～6 carbon atoms cycloalkyloxy or
The cyclenes oxygen base that contains 4～6 carbon atoms,
These bases are optional to be replaced by one or more halogen atoms or by following base: the alkoxyl that contains 1～4 carbon atom, the alkylthio group or the carboxyl that contain 1～4 carbon atom, alkoxy carbonyl group (wherein, moieties contains 1～4 carbon atom), cyano group or carbamoyl group or N-alkyl carbamoyl group or N, N-dialkyl group carbamoyl group (wherein, each moieties contains 1～4 carbon atom); Or the nitrogen-atoms that is connected with it forms saturated 5 yuan or 6 yuan of heterocyclic radicals, this heterocyclic radical is optional to contain second hetero atom that is selected from oxygen, sulfur or nitrogen-atoms, and optional quilt contains the alkyl of 1～4 carbon atom, and perhaps phenyl or phenylalkyl are (wherein, moieties contains 1～4 carbon atom) replace
R
5Expression
The alkoxyl that in unbranched or side chain, contains 1～6 carbon atom,
The alkene oxygen base that contains 3～6 carbon atoms,
The alkynyloxy group that contains 3～6 carbon atoms,
Contain 3～6 carbon atoms cycloalkyloxy or
The cyclenes oxygen base that contains 3～6 carbon atoms,
These bases are optional to be replaced by one or more halogen atoms or by following base: the alkoxyl that contains 1～4 carbon atom, the alkylthio group or the carboxyl that contain 2～4 carbon atoms, alkoxy carbonyl group (wherein, moieties contains 1～4 carbon atom), cyano group or carbamoyl group or N-alkyl carbamoyl group or N, N-dialkyl group carbamoyl group (wherein, each moieties contains 1～4 carbon atom); Or the nitrogen-atoms that is connected with it forms saturated 5 yuan or 6 yuan of heterocyclic radicals, optional second hetero atom that is selected from oxygen, sulfur or nitrogen-atoms that contain of this heterocyclic radical, optional quilt contains the alkyl of 1～4 carbon atom, and perhaps phenyl or phenylalkyl (wherein, moieties contains 1～4 carbon atom) replace.
Preferably, can be by R
3The aryl of expression is the optional selected phenyl that replaces from following one or more atoms or base or α-or betanaphthyl: halogen atom (fluorine; chlorine; bromine; iodine) and alkyl; thiazolinyl; alkynyl; aryl; aralkyl; alkoxyl; alkylthio group; aryloxy group; arylthio; hydroxyl; hydroxyalkyl; sulfydryl; formyl; acyl group; acylamino-; aromatic acylamino; alkoxy carbonyl amino; amino; alkyl amino; dialkyl amido; carboxyl; alkoxy carbonyl group; carbamyl; the dialkyl group carbamyl; cyano group; nitro and trifluoromethyl; condition is: alkyl and other basic moieties comprise 1～4 carbon atom; thiazolinyl and alkynyl comprise 2～8 carbon atoms, and aryl is phenyl or α-or betanaphthyl.
Preferably, can be by R
3The heterocyclic radical of expression is to comprise one or more nitrogen that are selected from; 5 yuan of aromatic heterocyclics of the identical or different atom of oxygen and sulphur atom; this aromatic heterocyclic is optional to be selected from following identical or different substituent group and to replace by one or more: halogen atom (fluorine; chlorine; bromine; iodine) and contain the alkyl of 1～4 carbon atom; the aryl that contains 6～10 carbon atoms; the alkoxyl that contains 1～4 carbon atom; the aryloxy group that contains 6～10 carbon atoms; amino; the alkyl amino that contains 1～4 carbon atom; dialkyl amido (wherein; each moieties contains 1～4 carbon atom); acylamino-(wherein; acyl moiety contains 1～4 carbon atom); the alkoxy carbonyl amino that contains 1～4 carbon atom; the acyl group that contains 1～4 carbon atom; aryl carbonyl (wherein; aryl moiety contains 6～10 carbon atoms); cyano group; carboxyl or carbamoyl group; the alkyl carbamoyl group (wherein; moieties contains 1～4 carbon atom); the dialkyl group carbamoyl group (wherein; each moieties contains 1～4 carbon atom) or alkoxy carbonyl group (wherein, alkoxyl partly contains 1～4 carbon atom).
Preferably, basic R
4And R
5(they may be identical or different) expression contains the unbranched or branched alkoxy of 1～6 carbon atom, optional by following base replacement: methoxyl group, ethyoxyl, ethylmercapto group, carboxyl, methoxycarbonyl group, carbethoxyl group, cyano group, carbamyl, N-methyl carbamyl, N-ethyl carbamyl, N, N-dimethyl methyl aminoacyl, N, N-diethyl carbamyl, N-pyrrolidine carbonyl or N-piperidino carbonyl.
More particularly, the present invention relates to the product of logical formula I, wherein, Z represents the base of hydrogen atom or logical formula II, wherein, and R
1Expression benzoyl or basic R
2-O-CO-, wherein, R
2The expression tert-butyl group, and, R
3Expression contains the alkyl of 1～6 carbon atom, the thiazolinyl that contains 2～6 carbon atoms, the cycloalkyl that contains 3～6 carbon atoms, optional by one or more phenyl that are selected from following identical or different atom or base replacement: halogen atom (fluorine, chlorine) and alkyl (methyl), alkoxyl (methoxyl group), dialkyl amido (dimethylamino), acylamino-(acetylamino), alkoxy carbonyl amino (tert butoxy carbonyl amino) or trifluoromethyl; Perhaps 2-or 3-furyl, 2-or 3-thienyl or 2-, 4-or 5-thiazolyl, and R
4And R
5(they may be identical or different) expression separately contains the unbranched or branched alkoxy of 1～6 carbon atom.
More particularly, the present invention relates to the product of logical formula I, wherein, Z represents the base of hydrogen atom or logical formula II, wherein, and R
1Expression benzoyl or basic R
2-O-CO-, wherein, R
2The expression tert-butyl group, and, R
3Expression isobutyl group, isobutenyl, cyclobutenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, and R
4And R
5(they may be identical or different) represents methoxyl group, ethyoxyl or propoxyl group separately.
Even the more special product of logical formula I meaningfully, wherein, R
3Expression phenyl, and R
1The expression tertbutyloxycarbonyl, R
4And R
5(they may be identical or different) expression methoxyl group, ethyoxyl or propoxyl group.
On further higher meaning, the present invention relates to formula (I 4 α-acetate-2 α-benzoxy-5 β a), 20-epoxy-1 beta-hydroxy-7 β, 10 β-dimethoxy-9-oxo-11-Ramulus et folium taxi cuspidatae alkene-13 α-Ji (11-taxen-13 α-and yl) (2R, 3S)-3-tert butoxy carbonyl amino-2-hydroxyl-3-phenylpropionic acid ester.
Prepare derivant of the present invention from patent W096/30355 is known by two processes.By first multistep process, from the 10-deacetylation baccatin III of following formula:
Optionally protect it at 7 and 13, for example be the form of silicyl diether, then, the effect of the product by following general formula:
R-X (IV) wherein, R represents as defined above base, X represents active ester residue (for example sulfuric ester or sulphonic acid ester residue) or halogen atom, has unit-OR and at 7 and 13 products with silicyl thereby be given in 10.Then, substitute the silicyl protecting group with hydrogen atom and be given in 10 and still have base-OR and at 7 and 13 chemical compounds with OH base.The derivant of back by with the derivatives reaction of formula IV 7 quilts optionally etherificate provide the derivant (wherein, Z equals hydrogen) of formula I.
Last step comprises: by original known method 13 bit esterified formulas (I derivant (wherein, Z represents hydrogen) a), that is, in the presence of beta-lactam, for example, by patent EP617, the method for describing in 018; Perhaps the Zai oxazolidine in the presence of, for example, as described in above-mentioned patent WO96/30355.After 7 and 10 s' protecting group is gone protection, acquisition formula (I ester (wherein, Z is not a hydrogen, and R represents hydrogen) a).Next step comprises: the reagent that forms on the spot by sulfoxide and acetic anhydride from formula (V) act on 7 and 10 reactions (reaction of Pummerer type) simultaneously,
R-SO-R (V) wherein, R has above-mentioned identical implication, forms alkylthio group alcoxyl fundamental mode intermediate 7 and 10.
(it can obtain required formula (I is chemical compound a)) is to carry out on the midbody compound that obtains previously by acting on of active Raney nickel to last step.
Usually, the effect of the reagent that forms on the spot from the sulfoxide (being preferably dimethyl sulfoxine) and the acetic anhydride of general formula (V) is in the presence of acetic acid or acetogenin (for example halogenated acetic acids), carries out under the temperature between 0 and 50 ℃.
Usually, active Raney nickel is to carry out under the temperature between-10 and 60 ℃ in the effect in the presence of aliphatic alcohol or the ether.
In the FR97-14442 application, another method has been described.This invention can in a step, realize 10-deacetylation baccatin or its on 7 and 10 of 13 bit esterified formula VI derivants two hydroxyl-functional bases directly, optionally with the alkylation of while
Wherein, A represent hydrogen or following formula (II side chain a):
Wherein, G represents the protecting group of hydroxyl-functional, R
1And R
3Have with formula II in identical implication or formula (I d) De oxazolidine unit:
Wherein, R
1And R
3Have with formula II in identical implication, R
aAnd R
b(they may be identical or different) expression hydrogen or alkyl, aryl, halogen, alkoxyl, aralkyl, alkoxy aromatic yl, haloalkyl, halogenated aryl, these substituent groups might be chosen wantonly and form 4 yuan to 7 yuan rings.
Advantageous applications 10-deacetylation baccatin [that is, the product of formula III] is made raw material, and it can make the expense of remarkable save operation method, in addition, avoids intermediate protection necessary in the aging method and goes to protect step.
At protection (among the basic G of II hydroxyl-functional a), usually preferred all protecting groups of selecting to be described in for example following monograph: Greene and Wuts, " protecting group in the organic synthesis " (Protective Groups in Organic Synthesis), 1991, John Wiley ﹠amp; Sons; and MacOmie; " protecting group in the organic chemistry " (Protective Groups inOrganic Chemistry); 1975; Plenum Press; they are gone protection under the condition of the seldom degraded or the other parts of the molecule of not degrading; for example ● ether; preferably for example following ether: methoxy ether; 1-ethoxyethyl group ether; benzyloxymethyl ether; right-methoxyl group benzyloxy ylmethyl ether; optional by one or more bases (methoxyl group for example; chlorine; nitro) benzylic ether of Qu Daiing; 1-methyl isophthalic acid-methoxy ethyl ether; 2-(trimethyl silyl) ethoxyl methyl ether; THP trtrahydropyranyl ether and silyl ether (for example trialkylsilyl ethers), ● carbonic ester (for example trichlorine ethyl carbonate ester).
More particularly, the basic R of general formula (II b)
aAnd R
bBe selected from those that describe among the patent WO94/07878, and described derivant those (wherein, R especially more preferably
aBe hydrogen, R
bBe right-methoxyphenyl).
Described alkylating agent is selected from: ● alkyl halide is preferably selected from alkyl iodide (RI) ● alkyl sulfate (for example dimethyl sulfate) ● oxygen, for example trialkyl oxygen borate, particularly trimethyl oxygen tetrafluoroborate (Me
3OBF
4).
The advantageous applications methyl iodide.
In the presence of anion reagent (for example one or more highly basic), in anhydrous medium, use alkylating agent.
In the alkali that can use in anhydrous medium, following alkali is worth mentioning: ● alkali metal hydride, for example sodium hydride or hydrofining ● alkali metal alcoholates, for example potassium tert-butoxide ● silver oxide Ag
2O ● 1, two (dimethylamino) naphthalenes of 8-a ● metal base or two metal base mixture, those that describe in for example following publication: P.Caubere, chemistry comment (Chem.Rev.), 1993,93,2317～2334 or M.Schlosser, modern synthetic method (Mod.Synth.Methods) (1992), 6,227～271; Especially lithium alkylide/tert-butyl alcohol alkali metal salt or alkali amide/tert-butyl alcohol alkali metal salt combination is preferred.One of these two kinds of alkali can " on the spot " generate.
In the whole possible combination of alkylating agent and anion reagent, preferably in the presence of hydrofining, use methyl iodide.
Reaction is preferably carried out in organic media (it is inertia under reaction condition).In solvent, advantageous applications: ● ether, for example oxolane or dimethoxy-ethane ● when using silver oxide, advantageous applications polar non-solute (for example dimethyl formamide), perhaps arsol (for example toluene) ● when using 1, during 8-pair of (dimethylamino) naphthalene, advantageous applications Arrcostab (for example ethyl acetate).
In order to implement the present invention better, advantageous applications is greater than 2, more preferably use the anion reagent between 2 and 20 and the mol ratio of substrate.
Also advantageous applications is greater than 2, more preferably use the alkylating agent between 2 and 40 and the mol ratio of substrate.
Reaction temperature between advantageous applications-30 ℃ and 80 ℃.
Response time, advantageously in the scope of a few hours and 48 hours, this depended on selected reagent.
After alkylation step, when the latter is when carrying out on the 10-deacetylation baccatin, this operation forwards esterif iotacation step to by known way then, for example by above-mentioned patent EP617,018 or WO96/30355 in the method described.
For example; according to first kind of 3 footwork; this operation at first starts from the dialkyl groupization of 10-deacetylation baccatin; promptly; in the presence of highly basic, use alkylating agent and carry out alkylation; in second step, in the presence of the activator that is selected from tertiary amine and metal base (they guarantee to form alkoxide at 13), 13 beta-lactam couplings with 7 and 10 two etherfied 10-deacetylation baccatins and due care.Then, realize the protection of going of side chain by mineral acid or organic acid effect.
For example, according to second kind of 3 footwork, this operation at first starts from the dialkyl groupization of 10-deacetylation baccatin, promptly, in the presence of highly basic, use alkylating agent and carry out alkylation, in second step, in the presence of activator (for example dialkyl amino yl pyridines), in the presence of coupling agent (for example imidodicarbonic diamide), at 13 with 7 and 10 two etherfied 10-deacetylation baccatins and oxazolidine coupling.By splitting of mineral acid or organic acid effect Shi Xian oxazolidine.
According to the third method, this operation starts from 13 bit esterified at the Tetraol of 7 and 10 due cares, that is, react with beta-lactam Huo oxazolidine in the presence of coupling agent and/or activator described in above-mentioned two kinds of methods.7 and 10 go protection after, in the presence of highly basic, carry out 7 and 10 s' two etherificates by alkylating agent.Then, realize the protection of going of side chain by mineral acid or organic acid effect.
The product of logical formula I has significant biological nature.
In vivo, the product that has confirmed logical formula I shows active (under the dosage at 1～30mg/kg) in transplanting has the mice of adenocarcinoma of colon C51 or C38, and shows active to other liquid tumor or solid tumor.
The chemical compound of formula I has the antitumor characteristic, more particularly, has the activity of antitumor (they anti-Taxol and Taxotere ).Such tumor for example comprises: colon tumor, their a large amounts are expressed multidrug resistance P-glycoprotein." multidrug resistance " is a common term, and it relates to the resistance of tumor to all cpds with different structure and mechanism of action.Common known taxoid is tested tumor (for example P388/DOX) level identification, and P388/DOX is at the selected P388 murine leukemia cell line of amycin (DOX) resistance, its express P-glycoprotein.Chemical compound of the present invention is still less discerned by P388/DOX.More particularly, described chemical compound than the littler degree of Taxotere be identified.
The chemical compound of formula I is mainly used in the medicine that preparation is used for treating the abnormal cell proliferation of the cell line of expressing multidrug resistance P-glycoprotein.The chemical compound of formula I mainly is used to prepare the medicine for the treatment of colon cancer.
Described chemical compound mainly is chemical compound (wherein, the R of formula I
4And R
5Each methoxyl group naturally) has the high characteristic of other known taxoid chemical compound of specific activity (for example Taxol or Taxotere are used for the treatment of the cancerous cell line of expressing multidrug resistance P-glycoprotein).It also has the activity of anti-(anti-amycin or anti-vincristine) tumor cell.
The product of formula I can be handled simultaneously with other treatment at least and use.More preferably combine application: antineoplastic agent, monoclonal antibody, immunotherapy, X-ray therapy or biological response instrumentality with comprising following treatment processing.
The product of formula I preferably is applied by parenteral dispenser method (for example intravenous, intraperitoneal, intramuscular or subcutaneous dispenser).
(I product a) is an effective anticancer agent in the preclinical models to embodiment 1. foreword formulas.The external antiproliferative properties of antagonism cell line
Found that Docetaxel has cross tolerance (RIGEL I. and HORWITZ S.B. to the cell line of expressing multidrug resistance P-glycoprotein, " about the research of RP56976 " (Studies withRP56976)) [the semi-synthetic analog of Taxotere : Taxol, state-run cancer institute magazine (J.Natl.Cancer Inst.), 83,288～291,1991].
The application standard method, the docetaxel after 4 days compares with continuous exposure, has detected the cytotoxicity of product I a to the different resistant cell lines of expression multidrug resistance P-glycoprotein.
By the IC that will obtain about resisting cell
50Value is divided by the IC that obtains about sensitive cells
50Value has been calculated resistance factor.
The product of finding formula I a is bigger than docetaxel activity to whole resistance tumor cell lines of having been estimated.What is interesting is, the product of finding formula I a has the minimum resistance of reporting to the leadship after accomplishing a task (resistance factor: 1.8～4.3) in P388/TXT, P388/VCR, HL60/TAX and Calc18/TXT cell line, described cell line is the moderate resistance of reporting to the leadship after accomplishing a task (resistance factor: 4.8～23.5) to docetaxel, so they can more can represent clinical setting.
In addition, the product of finding formula I a two kinds the cell line KB V1 of the most anti-docetaxel and P388/DOX (resistance factor: the resistance of reporting to the leadship after accomplishing a task 59 and 50) has sharply reduced (resistance factor: 7.6 and 10).
Also Mus P388/CPT5 cell line (having obtained the resistance to camptothecine, not express P-glycoprotein) has been estimated the product of formula I a.Find that (resistance factor: 286) compare, the resistance of reporting to the leadship after accomplishing a task of the product of formula I a and docetaxel has sharply reduced (resistance factor: 4.8 and 10.5) with camptothecine.The product that this result enlightens formula I a is obtaining the potential application aspect the oncotherapy of the resistance of camptothecin derivative.Table 0.1: the product of formula I a and docetaxel are to the relevant antagonism of the resistant cell line of express P-glycoprotein
* should choose the mdr1 gene as the relative expression of probe from RNA trace test acquisition.CaCo2
| Resistant cell line | Resistance factor to following material | Mdr1 mRNA level * | |
| docetaxel | The product of formula I a | ||
| ?P388/DOX ?P388/TXT ?P388/VCR ?HL60/TAX ?Calc18/TXT ?KB?V1 | ????50.7 ????4.8 ????5.8 ????8.1 ????23.5 ????59.0 | ????10.0 ????1.8 ????1.8 ????2.5 ????4.3 ????7.6 | ????+++ ????++ ????++ ????++ ????++ ????++++ |
Human colon adenocarcinoma CaCo-2 cell line (ATCC HTB37) (having confirmed the expression foundation level of its performance by the P-glycoprotein of mdr1 gene code) product of formula I a and the antiproliferative properties of docetaxel have been detected.Used methodology, that is, 96 orifice plates, the time of contact of medicine, (96 hours) and the dimethyl diaminophenazine chloride of living cells were painted.With the IC50 ecbatic, be summarized in the following table.The product of formula I a and docetaxel suppress effect to the growth in vitro of CaCo-2 cell line
* the value in the bracket: experiment number
| Cell | Medicine | ????IC 50(μg/ml) * |
| ????CaCo-2 | The product of docetaxel formula I a | ????108±17(3) ????22±3(3) |
The product of formula I a is cytotoxicity to the CaCo-2 cell, IC
50Value is included in the scope of describing about other human cell line [that is, HL60, Calc18 and KB (joint sees before)] who tests.Otherwise the IC50 that docetaxel is higher to CaCo-2 cell performance is equivalent to 4.9 times about the observed value of product of formula I a.Therefore, to discern the ability of docetaxel lower than docetaxel to the higher antiproliferative activity of CaCo-2 cell and energy the force rate of the P-glycoprotein identification formula I a product of expressing by this cell line itself be consistent to the product of formula I a.
The anti-tumor in vivo activity
The product of using formula I a is at ethanol: (50: 50, standard recipe carried out pesticide application in vivo plan and antitumor effect research to polyoxyethylene sorbitan monoleate before clinical in v/v).After the dilution, ultimate density is 5% ethanol, 5% Polysorbate, and 90% glucose-5% is in water.
Then, design clinical formulation, wherein, the product of formula I a has been dissolved in polyoxyethylene sorbitan monoleate.After the dilution, final polyoxyethylene sorbitan monoleate concentration is 5%.In conclusion subsequently, unless otherwise indicated, all standard recipe has carried out research in the body before the applying clinical.
Use the product of formula I a by intravenous route (i.v.).Test and data analysis have been carried out by standard scheme.
The active terminal point that is used to evaluate the solid tumor of subcutaneous implantation is :-tumor growth suppresses (T/C), and wherein, T and C are respectively processed group and contrast groups average tumor
Weight (representing) with mg.Press the NCI standard, T/C＞42% ,-, be inactive, T/C≤42% ,+, be active floor level.T/C＜10%, ++, be considered to the high anti-tumor activity level, its proof has further progress (DN-2 level).
Under the situation of high anti-tumor activity, also used following two terminal points :-tumor growth delay, T-C, wherein, T and C are that processed group and contrast groups tumor reach preliminary dimension (750～1500mg) required average times (representing with the sky).-log (cell that kills and wounds), it is the logarithm of the total cellular score of killing and wounding by processing.Can this value be changed into the activity of artificial evaluation by Southern Research Institute (SRI): log (total cellular score of killing and wounding)＜0.7=-torpescence; 0.7～1.2=+; 1.3～1.9=++; 2.0～2.8=+++;＞2.8=++++ is highly active.
As for late tumor, disappearing can be (tumor quality alleviates more than 50%) or completely of part.Disappear fully and to be included in part and to disappear.
The active terminal point that is used for estimating the leukemia of implanting at intraperitoneal is the percent (%ILS) (with respect to the average natural law calculating of death) that increases in host's life-span.
As follows about active NCI criterion :-P388: highly active, ++ 〉=75%ILS; Vivaciously ,+27～74%ILS; Torpescence ,-＜27%ILS.
Toxicity is based on drug fatality (〉=10%) or loss in weight minimum point＞20%.
When needing, docetaxel is used for contrast test.Colon tumor colon 51
Product at the 4th, 6,8 day intravenous injection formula I a.Under HNTD (9.3mg/kg/ injection), find highly active, 0%T/C and 2.6 log (cell that kills and wounds).Lower dosage provides 2.2 log (cell that kills and wounds).Find that also docetaxel is highly active, 3.1 log (cell that kills and wounds).Evaluation is to the effect of BALB/c female mice intravenous injection formula I a product resistive connection enteraden cancer C51
Tumor reaches average time=15.1 day of 750mg in the contrast groups.The abbreviation of using: the highest non-toxic of HNTD=, bwl=body weight loss, DD=drug fatality, bwl=body weight loss.Late period, colon 38
| Agent (in batches) | Dosage (per injection mg/kg) | Scheme (my god) | T/C (the 18th day %) | T-C (my god) | Log (total cellular score of killing and wounding) | Remarks |
| The product of formula I a | ????24.2 ????15.0 ????9.3 ????5.8 | ?4,6,8 | ????- ????- ????0 ????0 | ?- ?- ?25.8 ?21.9 | ????- ????- ????2.6 ????2.2 | HNTD is active for toxicity (5/5DD) toxicity (1/5DD) |
| Docetaxel | ????24.2 ????15.0 ????9.3 ????5.8 | ?4,6,8 | ????- ????0 ????0 ????4 | ?31.1 ?22.4 ?8.9 | ????- ????3.1 ????2.2 ????0.9 | Toxicity 22.8%bwl HNTD is highly active active |
Product to injection formula I a in the mouse vein with 200～400mg tumor.Under HNTD (20mg/kg/ injection), find highly vivaciously, produce 5/5 and disappear fully, all mices all became tumor free survivor at the 139th day.Lower dosage (12.4mg/kg/ injection) causes identical disappear fully number and 80% tumor free survivor.By contrast, in identical test, docetaxel only produces 40% part and disappears under HNTD.Evaluation is to the effect of B6D2F1 female mice intravenous injection formula I a product adenocarcinoma of colon C38 in anti-late period
Tumor reaches average time=18.5 day of 1000mg in the contrast groups.The abbreviation of using: the highest non-toxic of HNTD=, bwl=body weight loss, DD=drug fatality, the 139th day observed no tumor survival person of TFS=.
| Agent (in batches) | Dosage (per injection mg/kg) | Scheme (my god) | T-C (my god) | Log (total cellular score of killing and wounding) | Disappear fully | Remarks |
| The product of formula I a | ????32.2 ????20.0 ????12.4 ????7.7 | ?14,17,20 | ??- ??- ??- ?25.0 | ????- ????- ????- ????2.7 | ????- ????5/5 ????5/5 ????2/5 | Toxicity (1/5DD) HNTD highly active (5/5TFS) highly active (4/5TFS) is active |
| DOcetaxel | ????32.2 ????20.0 ????12.4 ????7.7 | ?14,17,20 | ?- ?29.1 ?6.1 ?2.5 | ????- ????3.1 ????0.7 ????0.3 | ????- ????0/5 ????0/5 ????0/5 | The highly active critical active torpescence of toxicity 20.6%bwl HNTD |
Claims (9)
1. the chemical compound of formula I is used for the treatment of application in the medicine of the cell line abnormal cell proliferation of expressing multidrug resistance P-glycoprotein in preparation, and described application comprises: chemical compound or pharmaceutically acceptable salt or the solvate of giving administration effective dose formula I
Wherein:
Z represents the base of hydrogen atom or following general formula:
Wherein:
R
1Expression
It is optional that described atom or base are selected from halogen atom and contain the alkyl of 1～4 carbon atom, the alkoxyl that contains 1～4 carbon atom or trifluoromethyl by the one or more identical or different atoms or the benzoyl of base replacement,
Thenoyl or furanylcarbonyl or
Base R
2-O-CO-, wherein, R
2Expression:
The alkyl that contains 1～8 carbon atom,
The thiazolinyl that contains 2～8 carbon atoms,
The alkynyl that contains 3～8 carbon atoms,
The cycloalkyl that contains 3～6 carbon atoms,
Contain 4～6 carbon atoms cycloalkenyl group or
The bicyclic alkyl that contains 7～10 carbon atoms,
These bases are optional to be selected from following substituent group and to replace by one or more: halogen atom and hydroxyl, the alkoxyl that contains 1～4 carbon atom, wherein each moieties contains the dialkyl amido of 1～4 carbon atom, piperidino or morpholino base, 1-piperazinyl (choose wantonly at 4 alkyl that contained 1～4 carbon atom and replace or replaced) by the phenylalkyl that moieties wherein contains 1～4 carbon atom, the cycloalkyl that contains 3～6 carbon atoms, the cycloalkenyl group that contains 4～6 carbon atoms, phenyl (optional be selected from following atom or base replaces: halogen atom and contain the alkyl of 1～4 carbon atom or contain the alkoxyl of 1～4 carbon atom) by one or more, cyano group or carboxyl or wherein moieties contain the alkoxy carbonyl of 1～4 carbon atom
-optional by one or more phenyl that following atom or base replace or α-or betanaphthyls that are selected from: halogen atom and contain the alkyl of 1～4 carbon atom or contain the alkoxyl of 1～4 carbon atom, perhaps
-5 yuan of aromatic heterocyclics are preferably selected from furyl and thienyl,
-or contain the saturated heterocyclyl of 4～6 carbon atoms, optionally replaced by one or more alkyl that contain 1～4 carbon atom,
R
3Expression
The alkyl that contains the unbranched or side chain of 1～8 carbon atom,
The thiazolinyl that contains the unbranched or side chain of 2～8 carbon atoms,
The alkynyl that contains the unbranched or side chain of 2～8 carbon atoms,
The cycloalkyl that contains 3～6 carbon atoms,
Optional by one or more phenyl that following atom or base replace or α-or betanaphthyls that are selected from: halogen atom and alkyl, thiazolinyl, alkynyl, aryl, aralkyl, alkoxyl, alkylthio group, aryloxy group, arylthio, hydroxyl, hydroxyalkyl, sulfydryl, formyl, acyl group, acylamino-, aromatic acylamino, alkoxycarbonyl amino, amino, alkyl amino, dialkyl amido, carboxyl, alkoxy carbonyl group, carbamyl, alkyl carbamyl, dialkyl group carbamyl, cyano group, nitro and trifluoromethyl
Perhaps 5 yuan of fragrant heterocycles; this virtue heterocycle comprises one or more identical or different hetero atoms that are selected from nitrogen, oxygen and sulphur atom; and optional be selected from following identical or different substituent group and replace: halogen atom and alkyl, aryl, amino, alkyl amino, dialkyl amido, alkoxycarbonyl amino, acyl group, aryl carbonyl, cyano group, carboxyl, carbamyl, alkyl carbamyl, dialkyl group carbamyl or alkoxy carbonyl group by one or more
Condition is: phenyl, α-or the substituent group of betanaphthyl and aromatic heterocyclic in, alkyl and other basic moieties comprise 1～4 carbon atom, and thiazolinyl and alkynyl comprise 2～8 carbon atoms, and aryl is phenyl or I-or 9-naphthyl,
R
4Expression
The alkoxyl that in unbranched or side chain, contains 1～6 carbon atom,
The alkene oxygen base that in unbranched or side chain, contains 3～6 carbon atoms,
The alkynyloxy group that in unbranched or side chain, contains 3～6 carbon atoms,
Contain 3～6 carbon atoms cycloalkyloxy or
The cyclenes oxygen base that contains 4～6 carbon atoms,
These bases are optional to be replaced by one or more halogen atoms or by following base: the alkoxyl that contains 1～4 carbon atom, the alkylthio group or the carboxyl that contain 1～4 carbon atom, wherein moieties contains the alkoxy carbonyl group of 1～4 carbon atom, cyano group or carbamoyl group or N-alkyl carbamoyl group or wherein each moieties contain the N of 1～4 carbon atom, N-dialkyl group carbamoyl group; The nitrogen-atoms that perhaps is connected with it forms saturated 5 yuan or 6 yuan of heterocyclic radicals, optional second hetero atom that is selected from oxygen, sulfur or nitrogen-atoms that contain of this heterocyclic radical, optional quilt contains the alkyl of 1～4 carbon atom, perhaps phenyl or wherein the moieties phenylalkyl that contains 1～4 carbon atom replace
R5 represents
The alkoxyl that in unbranched or side chain, contains 1～6 carbon atom,
The alkene oxygen base that contains 3～6 carbon atoms,
The alkynyloxy group that contains 3～6 carbon atoms,
Contain 3～6 carbon atoms cycloalkyloxy or
The cyclenes oxygen base that contains 3～6 carbon atoms,
These bases are optional to be replaced by one or more halogen atoms or by following base: the alkoxyl that contains 1～4 carbon atom; the alkylthio group or the carboxyl that contain 2～4 carbon atoms; wherein moieties contains the alkoxy carbonyl group of 1～4 carbon atom; cyano group or carbamoyl group or N-alkyl carbamoyl group or wherein each moieties contain the N of 1～4 carbon atom; N-dialkyl group carbamoyl group; the nitrogen-atoms that perhaps is connected with it forms saturated 5 yuan or 6 yuan of heterocyclic radicals; this heterocyclic radical is selected from oxygen optional containing; second hetero atom of sulfur or nitrogen-atoms; optional quilt contains the alkyl of 1～4 carbon atom, perhaps phenyl or wherein the moieties phenylalkyl that contains 1～4 carbon atom replace.
2. the application of compound of claim 1, wherein, Z represents the base of hydrogen atom or logical formula II, wherein, R
1Expression benzoyl or basic R
2-O-CO-, wherein, R
2The expression tert-butyl group, and, R
3Expression contains the alkyl of 1～6 carbon atom, the thiazolinyl that contains 2～6 carbon atoms, the cycloalkyl that contains 3～6 carbon atoms, optional by one or more phenyl that are selected from following identical or different atom or base replacement: halogen atom and alkyl, alkoxyl, dialkyl amido, acylamino-, alkoxycarbonyl amino or trifluoromethyl; Perhaps 2-or 3-furyl, 2-or 3-thienyl or 2-, 4-or 5-thiazolyl, and R
4And R
5, they may be identical or different, and expression contains the unbranched or branched alkoxy of 1～6 carbon atom separately.
3. the application of compound of claim 2, wherein, Z represents the base of hydrogen atom or logical formula II, wherein, R
1Expression benzoyl or basic R
2-O-CO-, wherein, R
2The expression tert-butyl group, and, R
3Expression isobutyl group, isobutenyl, cyclobutenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, and R
4And R
5, they may be identical or different, represents methoxyl group, ethyoxyl or propoxyl group separately.
4.4 α-acetate-2 α-benzoxy-5 β, 20-epoxy-1 beta-hydroxy-7 β, 10 β-dimethoxy-9-oxo-11-Ramulus et folium taxi cuspidatae alkene-13 α-Ji (2R, 3S)-3-tert-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid ester is used for the treatment of application in the medicine of abnormal cell proliferation of the cell line of expressing multidrug resistance P-glycoprotein in preparation.
5. the chemical compound of claim 1～4 can be used for treating application in the medicine of colon cancer in preparation.
6. the application of compound of claim 5, wherein, this application is handled with other treatment at least and is carried out simultaneously.
7. the application of compound of claim 6, wherein, other treatment is handled and is comprised: antineoplastic agent, monoclonal antibody, immunotherapy, X-ray therapy or biological response instrumentality.
8. the application of compound of claim 1, wherein, described medicine is applied by parenteral dispenser method.
9. each application of compound of claim 1～8, wherein, the chemical compound of formula I is applied by intravenous, intraperitoneal, intramuscular or subcutaneous dispenser method.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98115650.8 | 1998-08-20 | ||
| EP98115650A EP0982028A1 (en) | 1998-08-20 | 1998-08-20 | New use of taxoid derivatives |
| US12384399P | 1999-03-11 | 1999-03-11 | |
| US60/123,843 | 1999-03-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1313764A true CN1313764A (en) | 2001-09-19 |
Family
ID=26149552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99809900A Pending CN1313764A (en) | 1998-08-20 | 1999-08-18 | New use of taxoid derivatives |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1105119A2 (en) |
| JP (1) | JP2002523364A (en) |
| KR (1) | KR20010079665A (en) |
| CN (1) | CN1313764A (en) |
| AU (1) | AU5742099A (en) |
| BG (1) | BG105273A (en) |
| CA (1) | CA2341191A1 (en) |
| EE (1) | EE200100082A (en) |
| HU (1) | HUP0104000A3 (en) |
| IL (1) | IL141231A0 (en) |
| MX (1) | MXPA01001721A (en) |
| NO (1) | NO20010655D0 (en) |
| SK (1) | SK2352001A3 (en) |
| TR (1) | TR200100575T2 (en) |
| WO (1) | WO2000010547A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2922107B1 (en) * | 2007-10-10 | 2010-02-26 | Aventis Pharma Sa | NEW TAXOID COMPOSITIONS |
| PT2493466T (en) | 2009-10-29 | 2021-03-29 | Sanofi Mature Ip | Novel antitumoral use of cabazitaxel |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2697522B1 (en) * | 1992-10-30 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
| MA23823A1 (en) * | 1995-03-27 | 1996-10-01 | Aventis Pharma Sa | NEW TAXOIDS, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM |
| FR2732968B1 (en) * | 1995-04-14 | 1997-05-16 | Rhone Poulenc Rorer Sa | NOVEL TAXOIDS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1999
- 1999-08-18 JP JP2000565869A patent/JP2002523364A/en active Pending
- 1999-08-18 IL IL14123199A patent/IL141231A0/en unknown
- 1999-08-18 SK SK235-2001A patent/SK2352001A3/en unknown
- 1999-08-18 MX MXPA01001721A patent/MXPA01001721A/en unknown
- 1999-08-18 KR KR1020017002136A patent/KR20010079665A/en not_active Application Discontinuation
- 1999-08-18 EE EEP200100082A patent/EE200100082A/en unknown
- 1999-08-18 TR TR2001/00575T patent/TR200100575T2/en unknown
- 1999-08-18 AU AU57420/99A patent/AU5742099A/en not_active Abandoned
- 1999-08-18 EP EP99944532A patent/EP1105119A2/en not_active Withdrawn
- 1999-08-18 CN CN99809900A patent/CN1313764A/en active Pending
- 1999-08-18 HU HU0104000A patent/HUP0104000A3/en unknown
- 1999-08-18 CA CA002341191A patent/CA2341191A1/en not_active Abandoned
- 1999-08-18 WO PCT/EP1999/006292 patent/WO2000010547A2/en not_active Application Discontinuation
-
2001
- 2001-02-07 NO NO20010655A patent/NO20010655D0/en unknown
- 2001-02-20 BG BG105273A patent/BG105273A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EE200100082A (en) | 2002-06-17 |
| SK2352001A3 (en) | 2001-07-10 |
| HUP0104000A2 (en) | 2002-04-29 |
| MXPA01001721A (en) | 2005-06-03 |
| NO20010655L (en) | 2001-02-07 |
| JP2002523364A (en) | 2002-07-30 |
| BG105273A (en) | 2001-11-30 |
| HUP0104000A3 (en) | 2003-01-28 |
| CA2341191A1 (en) | 2000-03-02 |
| TR200100575T2 (en) | 2001-07-23 |
| WO2000010547A3 (en) | 2000-06-29 |
| AU5742099A (en) | 2000-03-14 |
| NO20010655D0 (en) | 2001-02-07 |
| WO2000010547A2 (en) | 2000-03-02 |
| EP1105119A2 (en) | 2001-06-13 |
| IL141231A0 (en) | 2002-03-10 |
| KR20010079665A (en) | 2001-08-22 |
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