TWI282793B - C10 ester substituted taxanes - Google Patents

Abstract

Taxanes having an ester substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and side chain substituents.

Description

1282793 A7 B7 V. INSTRUCTIONS OF THE INVENTION (1 Background of the invention, often:: for novel yew compounds, "there are heterogeneous anti-tumor agents = sylvestris group, in which polyglycomycin π] and paclitaxel are In biology and chemistry, it is already quite salty. (The title of the purple material itself is used as a cancer chemotherapeutic agent, and has a wide range of tumor suppressing activity. Paclitaxel, and the following structural formula: heart

(Please read the notes on the back and fill out this page) Order! Where Ac is an ethyl group. Colm et al., U.S. Patent 4,814,47, discloses that certain paclitaxel analogs are significantly greater than paclitaxel. One of these analogues, often referred to as ^docetel, has the following structural formula: Ma Xi-Line. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

OH t巳u〇C〇Nd 〇 c6hv

Although paclitaxel and doxalazine are useful chemotherapeutic agents, # π 1 is limited in its effectiveness, including limited efficacy against certain cancer types and - 4 - the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793

V. INSTRUCTIONS (2) Toxicity to patients when administered at various doses. Therefore, there is still a need for other chemotherapeutic agents with improved efficacy and lower toxicity. Disclosure of the Invention Accordingly, in the object of the present invention, it is advantageous to provide a taxane, which is effective as an antitumor agent and in terms of toxicity, in comparison with paclitaxel and docetaxel. In general, such taxanes have an ester substituent other than ruthenium formate, acetate and hetero-substituted acetate at C_l, a hydroxy substituent at C-7, and a range of C-3, substituents. Thus, in brief, the present invention is directed to a taxane composition itself, a pharmaceutical composition comprising a taxane and a pharmaceutically acceptable carrier, and a method of administration. Other objects and features of the present invention will be apparent, and a portion will be pointed out hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT In the specific embodiment of the present invention, the yew compound of the present invention corresponds to the structure (1): c Please read the notes on the back and then fill in the page) - 丨 line - The Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, printed R2 as a decyloxy group;

(1) 5- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed jade, invention description (3) R7 is the basis; I R9 is a keto group, a hydroxyl group or a decyloxy group; R10 is R10aCOO-; R1 〇a is a hydrocarbon group, a substituted hydrocarbon group or a heterocyclic group, wherein the hydrocarbon group or the substituted hydrocarbon group contains a carbon atom, and is a substituent with respect to *RiQa thereof At the α and /5 positions of carbon; R1 4 is a hydrogen or light group; X3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclic group, wherein the alkyl group contains at least two a carbon atom; x5 is -COXi 〇, -COOXi 0 or -CONHXi 〇; Xi 〇 is a hydrocarbon group, a substituted hydrocarbon group or a heterocyclic group; Ac is an ethyl group; and 々 Stereochemical configuration. In a particular embodiment, r2 is ester (R2aq0)a), carbamate (R2aR2bNc(o)o_), carbonated (R2a〇c(0)0.) or thiourethane. (3⁄4 a sc(o)o-), wherein r2 a and r2 b are independently hydrogen, a hydrocarbyl group, a substituted hydrocarbyl group or a heterocyclic group. In a preferred embodiment, the % is an ester (R2aC(0)0-)' wherein the Han 2 a is an aryl or heteroaromatic group. In another preferred embodiment, R2 is vinegar (R2aC(0)0-) wherein R2a is substituted or unsubstituted phenyl, furyl, thienyl or pyridyl. In a particularly preferred embodiment, r2 is benzhydryloxy. Although in a specific embodiment of the present invention, it is a ketone group, in other cases of bone-bearing travel, % may have a stereochemical configuration of α or ,, preferably a stereochemical configuration, and may be, for example,... Or /5-hydroxy or heart or /?-decyloxy. Example paper size τ'® National Standard (CNS) A4 χ 2·$) -~- ' (Please read the back note and then fill out this page) Raise. Order - Line ' 1282793 A7 B7 V. Invention Description (4) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Finance, for example, when R9 is a decyloxy group, it may be an ester (R9aC(0)0-) or a urethane (R^R^bNCCOP-). a carbonate (11^0(:(0)0-) or a thiocarbamate (R9aSC(〇)0-), wherein 11^ and the heart "stand up as hydrogen, a hydrocarbyl group, a substituted hydrocarbyl group or Heterocyclic group. If R9 is an ester (R9aC(0)0-), it is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group or a A substituted or unsubstituted heteroaromatic group is more preferably an ester (R9aC(0)0-) wherein is a substituted or unsubstituted phenyl group, a substituted or unsubstituted furyl group, substituted or Unsubstituted thienyl or substituted or unsubstituted pyridyl. In a particular embodiment, & is (R^QOX)-), wherein is fluorenyl, ethyl, propyl (linear, Branched or cyclic), butyl (straight chain, branched or cyclic), pent a radical (straight, branched or cyclic) or a hexyl (linear, branched or cyclic). In another specific embodiment, Rg is (R9aC(〇)〇_), which is substituted a methyl group, a substituted ethyl group, a substituted propyl group (straight chain, branched or cyclic), a substituted butyl group (straight chain, branched or cyclic), substituted pentyl group ( a linear, branched or cyclic) or substituted hexyl (straight, branched or cyclic) wherein the substituent is selected from the group consisting of heterocyclyl, alkoxy, decyloxy, alkynyloxy, Aryloxy, hydroxy, protected hydroxy, keto, decyloxy, nitro, amine, amine, thiol, ketal, acetal, ester and ether moiety, but not phosphorus In a particular embodiment, R10 is R10aCOO-, wherein R1〇a is (i) substituted or unsubstituted C:2 to cs alkyl (straight, branched or cyclic), For example, ethyl, propyl, butyl, pentyl or hexyl; (ii) substituted or unsubstituted A to q alkenyl (linear, branched or cyclic), such as vinyl, propionate Chinese National Standard (CNS A4 size (210 X 297 mm) 1282793 A7 V. Description of invention (5) Π. Mercapto: pentamidine or hexyl group '(10) substituted or unsubstituted c, to 〇8 alkynyl (straight Chain or branched), such as ethyl, propyl, butyl, decynyl or hexynyl; (iv) substituted or unsubstituted phenyl; or (7) substituted or unsubstituted Heteroaromatic such as fluorenyl, b-sequenyl or (10). The substituent may be a hydrocarbyl group or any heteroatom-containing substituent identified elsewhere for a substituted hydrocarbyl group. In a preferred embodiment, R10a, ethyl, linear, branched or cyclic propyl, straight chain, branched or cyclic butyl, straight chain, branched or cyclic pentyl, straight bond, branched or cyclic hexyl, Linear or branched propylene, isobutenyl, furyl or thienyl. In another specific embodiment, R1〇a is substituted ethyl, substituted propyl (linear, branched or cyclic), substituted propylene (linear or branched), Substituted fluorenyl, substituted thiol or substituted thiophene' wherein the substituent is selected from the group consisting of heterocyclyl, alkoxy, decyloxy, alkynyloxy, aryloxy, hydroxy, Protects the hydroxyl, keto, oxiranyl, nitro, amine, amine, thiol, ketal, condensation, ester and ether moiety, but not the phosphorus containing moiety. Exemplary x3 substituents include substituted or unsubstituted c2 to c8 alkyl, substituted or unsubstituted c'2 to C8 alkenyl, substituted or unsubstituted c2 to C8 alkynyl, substituted or Unsubstituted heteroaromatic compound containing 5 or 6 ring atoms and substituted or unsubstituted phenyl group. Exemplary preferred X3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, fluorenyl and pyridyl groups. Exemplary X5 substituents include -CO% oxime, -COOXi(R) or -CONHXi0, wherein Xi is a substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic group. 8 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) %-------Book ------ ---line! Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282793 A7 _______B7______ V. Description of invention (6) The preferred x5 substituents include -COX! 0, -COOXi 〇 or -CONHX! 〇, where χι 〇 is (i) Substituted or unsubstituted C! to C8 alkyl, such as substituted or unsubstituted methyl, ethyl, propyl (linear, branched or cyclic), butyl (linear, branched) Or cyclic), pentyl (straight, branched or cyclic) or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C2 to C8 alkenyl Substituted or unsubstituted ethyl hydrazino, propyl fluorenyl (linear, branched or cyclic), butenyl (linear, branched or cyclic), pentenyl (linear, branched) Or cyclic) or hexyl (linear, branched or cyclic), (iii) substituted or unsubstituted c2 to c8 alkynyl, such as substituted or unsubstituted ethynyl, propyne Base (straight or branched), butynyl (straight or branched), pentynyl (straight or branched) or hexynyl (straight or branched); (iv) Replace or not a substituted phenyl group, or (v) a substituted or unsubstituted heteroaromatic group, such as a furyl group, a thienyl group or a pyridyl group, wherein the substituent is selected from the group consisting of a heterocyclic group, an alkoxy group, an alkenyloxy group, and an alkyne group. Oxyl, aryloxy, light, protected hydroxy, keto, decyloxy, nitro, amine, decyl, thiol, ketal, acetal, ester and ether moiety, but Not a phosphorus-containing partial group. In a preferred embodiment of the present invention, the yew compound of the present invention corresponds to the structure (2): (Please read the note on the back and then fill in the page). Order - 丨 line · Ministry of Economics Property Bureau employee consumption cooperative printing

(2) -9 Paper Chinese National Standard (CNS) A4 specification (210 X 297 public) 1282793 Α7 Β7 V. Invention description (7) where two r7 are hydroxyl groups;

Rj 〇 is R 〇 a C00-; X 3 is a substituted or unsubstituted alkyl, alkenyl, block or heterocyclic group wherein the alkyl group contains at least two carbon atoms; X5 is -COXi 0, -C00&amp ; 0 or -CONH&〇; and Xl 〇 is a hydrocarbyl group, a substituted hydrocarbyl group or a heterocyclic group;

Ri 0 a is a hydrocarbon group, a substituted hydrocarbon group or a heterocyclic group, wherein the hydrocarbon group or the substituted hydrocarbon group contains a carbon atom at a position of α and /? relative to a carbon in which 10 a is a substituent; hydrazine is benzoic acid Base; and Ac is an ethyl group. For example, in this preferred embodiment, wherein the taxane compound corresponds to structure (2), R! 0a may be substituted or unsubstituted ethyl, propyl or butyl, more preferably substituted. Or an unsubstituted ethyl or propyl group, more preferably a substituted or unsubstituted ethyl group, and more preferably an unsubstituted ethyl group. When R1 0 a is selected from them, in a particular embodiment, X3 is selected from substituted or unsubstituted alkyl, decyl, phenyl or heterocyclic groups, more preferably substituted or unsubstituted. The alkenyl group, the phenyl group or the heterocyclic group is more preferably a substituted or unsubstituted phenyl or heterocyclic group, and more preferably a heterocyclic group such as a furyl group, a hexenyl group or a batch group. When R10a and X3 are selected from the group, in a specific embodiment, X5 is selected from -C〇Xi 0 ' wherein X10 is a phenyl group, an alkyl group or a heterocyclic group, more preferably a phenyl group. Or 'when R1 〇a and X3 are selected from it, in a specific embodiment 'X5 is selected from -C〇X1 〇' where X1 〇 is phenyl, burning -10- This paper scale applies to Chinese national standards (CNS) A4 specification (21() x 297 Μ} (Read the back of the weeping matter and fill out this page) Order. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282793 A7 ____B7_ V. Invention description (8) Or a heterocyclic group, more preferably phenyl hydrazine or x5 is -COOXi oxime, wherein Xi 〇 is an alkyl group, preferably a third-butyl group. Therefore, in a more specific embodiment, it corresponds to structure 2 The yew compound, wherein (i) χ5 is -COOX! 0, wherein Xi 〇 is a third-butyl group, or χ 5 is -COXi 〇, wherein Xi 〇 is a phenyl group, and (ii) x 3 is substituted or not Substituted cycloalkyl, alkenyl, phenyl or heterocyclic group, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl or pyridyl, more preferably unsubstituted Butyryl, sulphonyl, P-sequenyl or pyridyl, and (iii) R7a is an unsubstituted ethyl or propyl group, more preferably an ethyl group. Corresponding to a preferred embodiment of structure 1 or 2, wherein R10 is R10aCOOv, R10a may be substituted or unsubstituted ethyl or propyl, and more preferably unsubstituted ethyl or propyl. When 〇a is selected from them, in a particular embodiment, X3 is selected from substituted or unsubstituted cycloalkyl, phenyl or heterocyclic groups, more preferably substituted or unsubstituted naphthenes. a phenyl group, a furyl group, a pyrenyl group or a pyridyl group. When Ri Pa and X 3 are selected from the group, in a specific embodiment, the X 5 group is selected from the group consisting of COOXi oxime, wherein X10 is a third-butyl group, a third-pentyl group, an isobutyl group, an isopropyl group or a substituted or unsubstituted cycloalkyl group. R2, R9 and Ri 4 are as defined in structures 1 and 2, and preferably are individually benzoyl. a decyloxy group, a keto group and a hydrogen group. Therefore, in a more specific embodiment, it is a yew compound corresponding to structure 2, wherein (1) X5 is -COOXi 〇, wherein Χίο is a third-butyl group, a third group. A pentyl, isobutyl, isopropyl or unsubstituted cycloalkyl group, and more preferably a third-butyl group (ii) Χ3 is a substituted or unsubstituted cycloalkyl group, a phenyl group, a furan group a group, 17-thenyl or pyridyl, and more preferably an unsubstituted cycloalkyl, phenyl, decyl, thienyl or pyridyl group, and (iii) Ri 〇a is an unsubstituted ethyl or propyl group Based on _____11_ _____ This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) I -------- Order -- ------- 丨 丨 丨 丨 丨 智慧 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 128 Each has a three-dimensional chemical configuration, ~ and Rl can each have a π-body chemical configuration, and the heart can have a "stereochemical configuration, while at the same time Ri 〇 has a 乂 化学 chemical configuration, or & Chemical configuration, while & 〇 has a beta stereo chemical configuration. l / /, therefore, in a preferred embodiment, is a purple compound corresponding to structure 丨 or 2, wherein R1 〇 is R1〇aCOO_, wherein R1〇a is ethyl. In this specific embodiment, X3 is preferably a cycloalkyl 'isobutyl decyl group or a heterocyclic group, more preferably a % group, more preferably a furyl group, a porphinyl group or a pyridyl group; and \ is preferably stupid. A mercapto group, an alkoxycarbonyl group or a heterocyclic carbonyl group is more preferably a benzamidine group, a third-butoxycarbonyl group or a third-pentyloxycarbonyl group. In an alternative embodiment of this embodiment, X3 is a heterobasic group; X5 is a benzamyl 'alkoxycarbonyl or a heterocyclic carbonyl group, more preferably a benzamidine group, a third-butoxycarbonyl group or a third group. More preferably, the pentyloxycarbonyl group is more preferably a third-butoxycarbonyl group; the group is a benzylidene group, the % is a ketone group, and the palpitbrane is a hydrogen group. In another alternative embodiment of this embodiment, the & is a heterocyclic ring. Substituent; = 5 is a benzoic acid group, a pyrocarbonyl group or a heterocyclic carbonyl group, more preferably a benzoyl group, a third-butoxycarbonyl group or a third: pentyloxycarbonyl group, and more preferably a third-butoxy group R2 is a benzoyl ketone group and Ri4 is a hydrogen group. In another alternative embodiment of this embodiment, χ3 is a heterocyclic group; X5 is a benzamidine group, an oxocarbonyl group or a heterocyclic carbonyl group, more preferably a benzamidine group or a third butyloxycarbonyl group. Further, a mono-pentyloxycarbonyl group is more preferably a third butoxym group; R2 is a benzoyl group: a ketone group and a heart 4 is a hydroxyl group. Another alternative in this embodiment = 'x3 is a heterocyclic group; x5 is a benzoyl group, a burned oxygen or a heterocyclic carbon group' is preferably a benzamidine group, a third-butoxycarbonyl group or a third - Μ礼规卷,更更好-12 This paper size applies to China National Standard (CNS) A4 specification (21〇X 297 mm) (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printed nnnnnn I.^JI nn In el·- n nv an II ϋ_Β- ϋ i^— ϋ— ^1· ^_-ϋ i^i 1282793 A7 B7 V. Invention Description (1 〇 罘 丁虱 carbonyl; R is benzene ~. In this JLr per m turbidity and Ru is a hydroxyl group in this one of the other examples (please read the back of the note before you fill in this page) for benzamidine, dry oxygen In the formula, X3 is a heterocyclic group; X5 is a 'carbonyl or a heterocyclic carbonyl group, more preferably a benzamidine group, a second-butan rolled carbonyl group or a third-pentylene group, and /々r2 is a benzamidine group. Base, h is a sonono and its _3rd - butoxycarbonyl; another alternative, horse gas base. In this particular example, 3 horses 4% base; Χ5 is benzylidene, alkoxycarbonyl Or more pleasing, better, better horsebenzyl, third-butoxycarbonyl or third_two = more preferably a third-butoxy group; R2 is a benzamidine group, _ In another alternative embodiment of this embodiment, the soil, Xs benzylidene, alkoxycarbonyl or heterocyclic carbonyl, more benzylidene, and third butyloxycarbonyl Oxycarbonyl, and more preferably, the diterpene; the R2 is a benzoyl group, the % is a methoxy group, and the chlorine line is J. In each of the alternatives of the specific embodiment, when the yew compound has In the structure, R7 and Rl can each have a point stereo chemical configuration, R#Rl〇 can each have an alpha stereochemical configuration, and can have a "stereochemical configuration, while at the same time have /? stereo chemical configuration, or R7 can have a three-dimensional chemical configuration, and at the same time, Ri 〇 has an alpha stereochemical configuration. The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing is also in the preferred embodiment, corresponding to structure 1 or 2 The yew compound ' wherein Han 10 is Ri〇aCOO_, wherein Ri〇a is a propyl group. In this embodiment, & preferably is cycloalkyl, isobutyl decyl, benzene a substituted phenyl group such as p-nitrophenyl or a heterocyclic group, more preferably a heterocyclic group, more preferably a furyl group, a thienyl group or a pyridyl group; and Xs is preferably a benzamidine group, An alkoxy fluorenyl or a heterocyclic carbonyl group, more preferably a benzoic acid group, a third-butoxycarbonyl group or a third-pentyloxycarbonyl group. In an alternative embodiment of this embodiment, X3 is a heterocyclic-13-paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of the invention (11 soil is benzoic acid, oxy-reactive or heterocyclic, preferably benzoic) The third butoxycarbonyl group or the third-pentyloxy group is more preferably a third-butoxy R2^Tsi group, and the group is a hydrogen group. In another alternative thereto, χ3 is a heterocyclic group; Χ5 is a benzamidine group, an oxycarbonyl group or a heterocyclic carbonyl group, more preferably a benzamidine group, a third-butoxycarbonyl group or a ruthenium carbonyl group. More preferably, it is a third-butoxycarbonyl group; R2 is a benzamidine group; 1^9 is a ketone group; and 4 is a fluorenyl group. In another alternative form of this embodiment, X3 is a hetero-l' group, χ5 is a benzamidine group, a oxycarbonyl group or a heterocyclic group is preferably a benzene group (tetra), a third oxycarbonyl group or a third pentyloxy group. The base is also a tri-butoxycarbonyl group; R2 is a benzamidine group, a % is a ketone group, and R14 is a Zhao group. In another alternative form of this embodiment, & is a heterocyclic group; = is a benzamidine group, an alkoxycarbonyl group or a heterocyclic carbonyl group, more preferably a benzamidine group, a tris-butoxycarbonyl group or The third-pentyloxycarbonyl group is more preferably a third-butoxycarbonyl group; h is a benzoyl group, the heart is a hydroxyl group, and the heart 4 is a hydroxyl group. In this specific implementation = another alternative, χ3 is a heterocyclic group; & is a benzyl alcohol, an alkoxycarbonyl or a heterocyclic carbonyl group, more preferably a benzamidine group, a third butyloxycarbonyl group or a Further, a pentyloxycarbonyl group is more preferably a third-butoxycarbonyl group; a is a benzamidine group, h is a hydroxyl group, and & 4 is a hydrogen group. In another alternative embodiment of this embodiment + base; x5 is a benzoyl group, a (tetra)carbonyl group or a heterocyclic group, more preferably a benzamidine group, a third butanoxycarbonyl group or a third pentylene group, Preferably, it is a third-butoxycarbonyl group; the % is a benzamidine group; the % is an anthracene oxide; and the & 4 is a fluorenyl group. In another alternative form of this embodiment, & is a heterocyclic group; = is a benzoinyl, alkoxycarbonyl or heterocyclic carbonyl group, more preferably a benzamidine second-butoxycarbonyl group or a second - pentyloxycarbonyl, more preferably third · butoxycarbonyl (please read the back of the note before you fill out this page) Order: 丨 line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing-14 1282793 A7 Γ~~ --^ __ 1-5, description of the invention (12); R2 is a benzamidine group, converted to an oxy group and Ri 4 is a hydrogen group. In each of the alternative embodiments of the specific embodiment, when the yew compound has the structure 1, R7 and R! 〇 each have a/5-dimensional chemical configuration, and R7 and R! 〇 each have an alpha stereochemical configuration, R7 It can have an alpha stereochemical configuration, while the ruler has a point stereo chemical configuration, or R? can have a/5 stereo chemical configuration, while & 〇 has a "stereochemical configuration. The sapphire compound can be treated with an alkoxide having a taxane tetracyclic nucleus and a C-13 metal oxide substituent to form a compound having a /5-decylamine substituent at C-13 ( Obtained by removing the hydroxy protecting group as described in more detail in Holton U.S. Patent No. 5,466,834. This /5-decalamine has the following structural formula (3):

乂5, /PX, "όρ2 (3) where Ρ2 is the protecting group for each group and X3 is as defined above, and the oxide of the household has the structural formula (4): --------- ----- (Please read the notes on the back and fill out this page) Order · --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

MOI

5 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Inventive Note (13) where Μ is metal or ammonium, p7 is hydroxy, protecting group of base, and R1 〇 As defined above. (Please read the precautions on the back and fill out this page.) Alkoxide 4 can be prepared from 10-deacetylated baccatin bismuth (or its derivatives) by selective protection of C(7) hydroxyl groups. The C(10) hydroxyl group is then esterified and then treated with a metal amination. In a particular embodiment of the invention, the c(7) hydroxy group of deacetylated baccatin bacillus is selectively protected with an oxiranyl group, for example as described by Denis et al. (j. Am. Chem) · Soc., 1988, 110, 5917). In general, the alkalylating agent can be used alone or in combination with a catalytic amount of a base such as an alkali metal base. Or the c(io) radical of the zirconia compound can be selectively basalized in the absence of a base, for example, in Holton et al. (Description of the patent application ~ 099/09021. The deuteration agent 'can be used for the selective deuteration of the hydroxyl group C (l〇) hydroxyl group' includes a substituted or unsubstituted alkyl or aryl group. Anhydrides. Although the deuteration of the hydroxyl group C(10) hydroxyl group is carried out at a suitable rate for many deuteration agents, it has been found that the reaction rate can be increased by adding Lewis acid to the reaction mixture. Preferred Lewis acids include zinc chloride, tin chloride, antimony trichloride, cuprous gas, cuprous gas, antimony trioxide, antimony trichloride, and antimony trichloride. Zinc or tri-gasification is particularly good. The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs printed in C(2), C(9) and C(14) with alternative substituents. Raspberry in derivatives and processes for their preparation are known in the art. In the case of c(2) a taxane derivative having an oxime substituent other than benzamidine, for example, Holton et al. Prepared as described in U.S. Patent No. 5,728,725, issued to U.S. Patent No. 6,002,023, issued toK. The yew compound can be applied according to, for example, Hdt〇n et al. US Patent-16- This paper scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 public) 1282793 Five A7 B7, invention description (14) 6 , 〇11,056 or Gunawardana et al., U.S. Patent No. 5,352,8,6. The chelating compound having a hydroxy substituent at C(14) can be prepared from naturally occurring 1' hydroxy-10-deca Acetyl berry gibberellin Ι π. Methods for preparing and resolving this ruthenium starting material are generally known. For example, indoleamine can be used according to Holton's U.S. Patent 5,43,16. And the enzymes described in U.S. Patent No. 5,567, 614 to Patel, or the PCT patents. The liver homogenate described in the application 〇0/4i2〇4 is resolved by stereoselective hydrolysis. In a preferred embodiment, the less endotoxin is cleaved at the c(4) position. Substituted, this less indoleamine can be made as shown in the following reaction scheme: (Please read the notes on the back first) Fill in this page again - - , 〇, , CH〇 NH2 ό I OCHo Step A Benzene 〇

Ac〇/"V I : 〇 .Cl line Step B H3C 〇, toluene

Step C H3c〇, /〇 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

NEU \)Ac (±)9

Step E

/〇HNY ’v〇Ac

K〇H HN- Bovine Liver Analysis

Xx

Step F

Step D

0 CAN, CHXN ’t)Ac (+)9 0

々OH

p-TsOH HN- 0 , 〇Me Ο OMe -17- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1282793 A7 B7 V. Invention Description (15 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed in which Ac is a B-based, NEt, 盏二Γ... f+, τςΠττ a female, CAN is a high-density ammonium nitrate, and a quinone-p-toluene acid. Μ ^ Λ „ π, dry liver analysis can be refined by For example, a palmitic isomerization compound is combined with a bovine liver suspension (for example, by adding a relay == a device, and then adding a _ slow _ to make the liter), and combining them. The compounds are useful for inhibiting growth in mammals, including humans, and are preferably administered in the form of a pharmaceutical composition comprising an anti-tumor compound of the invention in combination with at least one pharmaceutically or pharmaceutically acceptable drug. Carriers. Carriers are also known in the art as excipients, vehicles, adjuvants, adjuvants or diluents which are pharmaceutically inert, imparting appropriate ingredients or forms to the compositions, and will not Any substance that reduces the therapeutic effect of anti-tumor compounds. When administered in an appropriate manner In animal or human, the right carrier does not produce adverse allergic or other unsuitable reactions, it is ', pharmaceutically or pharmacologically acceptable,. The pharmaceutical composition containing the antitumor compound of the present invention can be any The proper formulation is based on the selected route of administration. The composition of the present invention can be formulated for any route of administration, as long as the target tissue can be effectively treated via this route. Suitable routes of administration include but not Limited to oral, parenteral (eg intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or sternal), local (nose, percutaneous, intraocular) ), intravesical, intraspinal, enteral, pulmonary, lymphatic, intracavitary, vaginal, transurethral, intradermal, auricular, intramacular, cheek, local correction, endotracheal, intralesional, percutaneous, endoscopy Check, transmucosal, sublingual and intestinal administration. 18- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill in the form) .) ------- prayer book -

---I β 1282793

V. Description of the Invention (16) The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, Prints R, a pharmaceutically acceptable carrier for use in the composition of the present invention, which is known to those skilled in the art. And based on a number of factors: the particular anti-tumor compound used, as well as its concentration, stability and desired bioavailability, the disease, condition or symptom treated by the composition; the age, size and general symptoms of the patient And the route of administration. The appropriate carrier is easily determined by the artist: (see, for example, JG Naim: Remingt〇n's Medicine to Gennar〇), Mack Publishing Company (Easton, PA), (1985), pp. 1492-1517 The page 'its content is incorporated herein by reference. Preferably, the composition is formulated into tablets, dispersible powders, pills, capsules, gel caps, sachets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, mashes Dosage, lozenge, dragee, lozenge or any other dosage form which can be administered orally. Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 7 i Pharmaceuticals, Chapters 9 and 10 (Editor Banker & Department 0 (1 flavor 1979); Lieberman et al., Pharmacological Forms: Tablets (1981, and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Edition (1976). Compositions of the invention for oral administration, comprising a compound of the invention having an effective anti-tumor amount, In a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms, including sugars, starches, and other conventional materials, including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, flowers Sterol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, soil, alginic acid, gum arabic, corn starch, horse starch, sodium saccharin, magnesium carbonate, scutellaria, microcrystalline cellulose, colloidal Cerium oxide, croscarmellose sodium, talc, magnesium stearate and stearic acid. Furthermore, this solid dosage form -19 - 1 paper size applies to China National Standard (CNS) A4 specification (210 X 297 metric tons ) ' — (please first Note Complete this page and then read it back) - 'Order: - Line 1282793

V. INSTRUCTIONS (17) The horse may be uncoated or may be coated by known techniques; for example, to delay disintegration and absorption. The antitumor compound of the present invention is preferably also formulated for parenteral administration, for example, by intravenous, intraarterial, subcutaneous, intradermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, Intraperitoneal or intrasternal routes of injection. The composition of the present invention for parenteral administration comprises an effective antitumor amount of a tumor compound in a pharmaceutically acceptable carrier. Suitable for parenteral dosage forms, including solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art. Suitable carriers for liquid dosage forms for oral or parenteral administration include non-aqueous, pharmaceutically acceptable polar solvents such as oils, alcohols, siamines, guanidines, bonds, g, homogens, and mixtures thereof, as well as water, saline solution, dextrose solution (eg, DW5), electrolyte solution, or any other aqueous pharmaceutically acceptable liquid. The Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, prints the non-aqueous pharmaceutically acceptable polar solvents of the field, including but not limited to alcohols (eg... glycerol dimethanol formal, heart glycerol dimethanol formal, butyl alcohol with a mosquito) Aliphatic or aromatic alcohols of the atom, such as methanol, ethanol, propanol, isopropanol, butanol, third-butanol, hexanol, octanol, pentene hydrate, decyl alcohol, glycerol, ethylene glycol , hexanediol, methyl hydrogen fluoride methanol, lauryl alcohol, cetyl alcohol or stearyl alcohol, fatty alcohols such as polyalkylene (such as polypropylene: alcohol, polyethylene glycol), phytosan, recommended sugar And fatty acid esters of cholesterol "melamines (such as dimethylacetamide (DMa), benzoic acid vinegar DMA, dimethyl ketoamine, team (money ethyl (a) (penta) amine, Μ # dimethyl ____ —— - 20 - This paper scale applies to China National Standard (CNS) A4 1282793

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperatives. V. Description of the invention (18 oxime, 2-tetrahydropyridinone, -4-methyl-2-tetrahydropyridinone or polyvinyltetramine) Pbi?); esters (eg 1-methyl-2-tetrahydropyrrolidone, 2-tetrahydropyrrolidone, acetates, such as monoacetin, diacetin and triacetin) Aliphatic or aromatic esters, such as ethyl octanoate, alkyl oleate decyl benzoate, benzyl acetate, dimethyl sulfoxide (DMS hydrazine), esters of glycerol, such as # citrate or tartaric acid, Di- or triglyceride, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, phytosan fatty acid esters, fatty acid-derived PEG esters, glyceryl monostearate , glycerides, such as mono-, di- or tri-glycerides, fatty acid esters, such as isopropyl myristate, fatty acid-derived pEG esters, such as pEG-light oleate and PEG-hydroxystearate Acid ester, mercapto tetrahydropyrrolidone, plonic acid 60, polyoxyethylene phthalic acid oleic acid polyester, such as poly(ethoxylated) 3〇-6〇花楸Poly(oleate) 2-4, poly(ethylene oxide) 15_2〇monooleate, poly(ethylene oxide)ΐ5·2〇mono 12_hydroxystearate and poly(ethoxylated)15-2〇 Monocrosinic acid vinegar, polyoxyethylene phthalocyanine phthalocyanine esters, such as polyfluorene ethylene-flower sucrose monooleic acid vinegar, polyethylene oxide-flower sucrose monopalmitate, polyethylene oxide- Monolaurin phytosterol ester, polyoxyethylene acetonitrile-flower sulphate monostearate, and P〇lySorbate® 20, 40, 60 or 80, available from ICI (Wilmington, DE) Mercaptotetrahydrop-pyrrolidone, a sub-alcoholically modified fatty acid ester such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oil (eg Cremophor® EL solution or Cremophor® RH 40 solution) , sugar fatty acid vinegar (meaning that 'monosaccharides (such as vinegar, such as ribose, ribulose, arabinose, xylose, xylose and xylulose, hexoses, such as glucose, fructose, galactose , mannose and sucrose, triose, butyrate, heptose and one zero 21 - scale applicable to China National Standard (CNS) A4 specification (210 X 297 public) "- -- (Please read the notes on the back and fill out this page) Order -· -- Line ' 1282793 A7 , _B7_____ V. Invention description (19 ) (Please read the note on the back and fill out this page) Disaccharides (such as sucrose, maltose, lactose and trehalose) or oligosaccharides or their C4 - C 2 fats (such as saturated fats and acid-like acids such as caprylic acid, tannic acid, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperatives Printing a mixture of lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, oleic acid, cis decenoic acid and linseed oleic acid, Or a condensation product of a steroid ester; a burnt group having 2 to 30 carbon atoms, a square group or a meal acid (for example, acetic acid, tetrahydrofuran, anthraquinone, and a Acid); sugar gnashing acid (tetrachloromethane methanol polyglycol ether) · ketones having 3-30 carbon atoms (such as acetone, methyl ethyl ketone, methyl isobutyl ketone); Aliphatic, cycloaliphatic or aromatic hydrocarbons of 4 to 30 carbon atoms (eg benzene, cyclohexane, dichloromethane, dioxane) Terpenoids, hexane, n-decane, n-dodecane, n-hexane, cyclopentene, tetramethylene sulfone, tetramethylene sulfonium, toluene, dimethyl sulfoxide (DMS oxime) or Minerals, plants, animals, oils of spontaneous or synthetic origin (eg mineral oils such as aliphatic or marine hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons) And refined paraffin oil, vegetable oil, such as linseed, tung, safflower, big dan, ramie, cottonseed, groundnut, colza, coconut, 椋 、, olive, corn, corn germ, sesame, peach and peanut oil, and glycerides Such as monoglycerides, diesters or triesters, animal oils, such as fish, seafood, whale brain, cod liver, soleus liver, squalene, squalane and shark liver oil, oleic oils and polyoxyethylene Baseted castor oil); pit-based or aryl telluride having from 1 to 30 carbon atoms and optionally greater than one halogen substituent; di-methane; monoethanolamine; petroleum ether; trolamine; 3 polyunsaturated fatty acids (such as linolenic acid, decyl pentenoic acid, quinone dicarbonate or bismuth) Carbahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (s〇lut〇1(g) -22 1282793 Α7 Β7 5, invention description (20) <Read the back Precautions Fill in this page again) HS-15, available from BASF (Ludwigshafen, <}ermany)); polyoxyethylene glycerol; sodium laurate; sodium oleate; or phytosan monooleate. Other pharmaceutically acceptable solvents for use in the present invention are well known to those skilled in the art and are identified in the Chemistry Information Book (Williams & Wilkens), Medical Excipient Handbook (US Medicine) Association (Washington, DC) and the British Medical Association (London, UK, 19683⁄4, Modern Pharmacy (G. Banker et al., 3rd edition) (Marcel Dekker, Inc. (New York, New York), 1995), Pharmacology of Therapeutics Fundamentals (published by Goodman & Gilman. McGmw Hill), Medical Dosage Form (edited by H. Lieberman et al.) (Marcel Dekker, Inc. (New York, New York), 1980), Remington's Medal of Medicine (edited by A. Gennaro, 19th Edition) (Mack Publishing (Easton, PA), 1995), United States Pharmacopoeia 24, National Formulary 19 (Philadelphia, PA), AJ, Spiegel et al., and non-aqueous solvents in non-aqueous Uses in Intestinal Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963). Ministry of Economic Affairs, Intellectual Property Office, Staff Consumption Cooperative, Printed a better solvent, including known anti-tumor a stabilizer, such as a triglyceride-rich oil, such as safflower oil, soybean oil or a mixture thereof, and a subalkoxy-modified fatty acid ester such as polyoxyl 40 hydrogenated castor oil, and poly Oxyethylated castor oils (eg Cremophor® EL solution or Cremophor ® RH 40 solution). Commercially available triglycerides, including Intmlipid® emulsified soybean oil (Kabi-Pharmacia (Stockholm, Sweden), Nutralipid® Emulsion (McGaw, Irvine, California), Liposyn® II 20. '〇 emulsion (20 0/〇 fat emulsified solution containing 100 mg of safflower oil, 100 mg of soybean oil, 12 mg of lecithin and 25 mg of glycerol per ml of solution) Abbott Laboratories (Chicago, Illinois)), Liposyn® III 2% emulsion (2°" fat emulsion solution, -23- _ per liter of solution for Chinese National Standard (CNS) A4 specification (210 X 297 mm 1282793 A7 P________B7___ V. Description of invention (21) WO mg safflower oil, 100 mg soybean oil, 12 mg lecithin and 25 mg glycerol; Abbott Laboratories (Chicago, Illinois), natural or combined The glycerol derivative 'containing decyl hexaene fluorenyl group is based on the total fatty acid content at 25 〇/〇 and 100% by weight (Dhasco® (available from Martek Bi〇sciences, Inc., Colombia, MD), DHA Maguro® (available from Daito Corporation (Los Angeles, CA) 'Soyacal® and Travemulsion®. Ethanol is a preferred solvent for dissolving the antitumor substance to form a solution, an emulsion and the like. It is understood that other minor ingredients are added to the compositions of the present invention for a variety of purposes as are known in the pharmaceutical industry. Most of these ingredients will confer some sexual shells, which will strengthen the anti-tumor compound, maintain the stability of the composition, control the pH, and help the anti-tumor compound to be processed into a medical compound. Each of these ingredients is preferably present in less than all of the composition (about 15% by weight, more preferably less than about 5% by weight, and most preferably less than about 5% by weight of the total composition. Some Ingredients, such as fillers or diluents γ, can constitute up to 9% by weight of the total composition. As in the formulation technique, the additive includes a cryoprotectant to prevent the yew structure from being surface active and moisturized. Or an emulsifier (such as egg yolk, polyglycolic acid H Tween® 8 〇, pluronic acid 6 〇, polyoxyethylene stearic acid vinegar), printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (please read the back first) Precautions fill out this page) • Line - ^A 1 (eg p-co-benzoic acid ethyl ester), microbial preservatives (eg sterols: phenol, cresol, chlorobutanol, linalic acid, thimerosal and Hydroxybenzamide\, an agent or buffer for adjusting PH値 (for example, acid, alkali, sodium acetate, lauric acid monolaurate), an agent for adjusting solute (eg glycerol) ), thickeners (such as monostearate, stearic acid, cetyl alcohol) Alcohol, guar gum, methyl cellulose, propyl cellulose, light, _ _ - 24 - (iv) of the present paper size "tW5 ^ CNS) A4 size Kimiyoshi ⑽χ 297) 1282793

V. Description of invention (22) glyceric acid, glycerol, hydrazine, glycerol, poly [diol), I agent, dye, (please read the back of the note before you fill in this page) soil), adhesive, a bulking agent, a flavoring agent, a sweetener, an adsorbent, a filler (for example, a sugar such as lactose, sucrose, mannitol or saponin, cellulose or calcium phosphate), a diluent (eg water, saline, electrolyte) Solution), a binder (such as starch, such as corn starch, wheat starch, rice starch or horseshoe starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, Polyethylene tetrahydropyrrolidone, saccharides, polymers, gum arabic) 'disintegrants (such as starch, such as corn starch, wheat glutinous rice, rice starch, potato starch or methine starch, cross-linked polyethylene Hydropyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, cross-linked gingery methylcellulose or cross-linked povidone, lubricants such as vermiculite, talc, stearic acid or its salts, such as hard Magnesium oleate, or polyethylene glycol), coated a coating (such as a concentrated sugar solution, including gum arabic, talc, poly(vinylidene tetrahydrofuroxone, carbopol gel, polyethylene glycol or titanium dioxide), and an antioxidant (such as sodium metabisulfite, Sodium bisulfite, sodium sulfite, dextrose, phenol and sulfur are self-derived). Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed In a preferred embodiment, the pharmaceutical composition of the present invention comprises at least one non-aqueous pharmaceutically acceptable solvent, and an antitumor compound having solubility in ethanol At least about 1 〇〇, 200, 300, 400, 500, 600, 700 or 800 mg / liter. Although not bound by a particular theory, the ethanol solubility of a salty anti-tumor compound can be directly related to its efficacy. This antitumor compound can also crystallize from solution. In other words, a crystalline antitumor compound, such as compound 1393, is soluble in a solvent to form a solution, and then applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 on a steam-25-sheet scale.

, invention instructions (23 I / granules recrystallize, and will not submerge into any amorphous anti-tumor compounds. (Please read the back of the precautions and then fill out this page) when based on the proposed metrics proposed in the examples Preferably, the anti-tumor compound has an ID50 値 (meaning a drug concentration that produces 50% inhibition of colony formation), which is lower than at least 4, 5, 6, 7, 8, 9 of paclitaxel. Or 1 。. The dosage form administered by such a route may be continuous or intermittent, depending on, for example, the physiological condition of the patient, the purpose of administration is treatment or prevention, and other factors known and evaluable by the skilled practitioner The dosage and the dosage of the pharmaceutical composition of the Ministry of Economic Affairs printed by the Intellectual Property Office of the Ministry of Economic Affairs can be easily determined by the general treatment of cancer patients. It should be understood that the dose of anti-tumor compounds is dependent on The age, sex, health and weight of the recipient, and the type of treatment (if any), the frequency of treatment and the nature of the desired effect, depending on the mode of administration, and the transmitted anti-tumor combination The actual amount, as well as the schedule of medication necessary to achieve the beneficial effects described herein, are also based in part on factors such as the bioavailability of the anti-tumor compound, the condition being treated, the desired therapeutic dose, and Other factors that are familiar to the artist are obvious. For animals, especially humans, the dose administered, in the context of the present invention, should be sufficient to achieve the desired therapeutic response in the animal for a reasonable period of time. Orally, or by another route, the effective amount is preferably any amount which, when administered by the route, causes a desired therapeutic response. The composition for oral administration is preferably produced by one method. To achieve a single dose of one or more oral preparations containing at least 2 mg of anti-tumor e-body per square meter of patient's body surface area or a mother square of at least 5 〇, 10 ,, 2 〇 〇, 300, 400 or 500 mg of anti-tumor compounds, of which the average body surface for humans -26- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 2 97 mm) 1282793

V. Description of invention (24) The printed area of the employee consumption cooperative of the Intellectual Property Office of the Ministry of Economic Affairs is 1.8 square meters. A single dose of the orally administered pharmaceutical composition preferably contains from about 2 to about 6 mg of the antitumor compound per square meter of the patient's body surface area, more preferably from about 25 to about 400 mg/m 2 , more preferably From about 4 to about 300 mg/m2, and more preferably from about 5 to about 2 mg/m2. The parenterally administrable composition is preferably prepared in such a manner that a single dose contains at least gram milligrams of anti-tumor compound per square meter of patient body surface area, or at least 4 Å per square meter of patient body surface area, 5 〇100, 150, 200, 300, 400 or 500 mg of anti-tumor compound. A single dose in one or more parenteral preparations preferably comprises from about 20 to about 500 mg of anti-tumor compound per square meter of patient body surface area, more preferably from about 4 to about 4 mg/m2. And more preferably from about 6 〇 to about 35 〇 mg / square meter. However, this dosage can vary depending on the schedule of administration, which can be adjusted as needed to achieve the desired therapeutic effect. It should be noted that the scope of the political d1 provided herein is not intended to limit the invention, but rather to represent a preferred dosage range. The optimal dose is revised for individual patients and is generally known to those skilled in the art and can be determined without undue experimentation. The concentration of the antitumor compound in the liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per liter of composition, more preferably between about 0.1 and about 7 mg per ml. More preferably, it is between about 5 mg and about 5 mg per ml, and preferably between about 15 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because most of the anti-tumor compounds are dissolved in solution at low concentrations. The concentration of the antitumor compound in the orally administered solid pharmaceutical composition is preferably from about 5% by weight to about 50% by weight based on the total weight of the composition. /. Between the better, about 8 wt% and about 4 〇 _________ - 27 _ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ' (Please read the notes on the back before filling in This page) order · 丨 line.L, 1282793

V. Description of invention (25) Quantity. The P曰1 & optimum is about 10 weight 〇/. With about weight. . between. -i--pray.-丨 (please read the note on the back and fill out this page). In a specific example, 'oral solution is made in the following way' to dissolve the antitumor compound in a soluble form. The compound is in any pharmaceutically acceptable solvent (e.g., ethanol or two gas) to form a solution. A suitable volume of carrier, which is a solution, such as cremopho, EL solution', is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient. If such a solution is to be formulated to contain minimal or no ethanol, it is known in the art that when administered in certain formulations, it may cause adverse physiological effects when administered at certain concentrations. --Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed in another specific example, the powder or tablet for oral administration is made by the following formula, so that the antitumor compound is dissolved in the compound capable of dissolving the compound. Any pharmaceutically acceptable solvent (such as ethanol or di-methane) to form a solution. When the solution is allowed to dry under a hollow, the solvent may be evaporated as appropriate. Another carrier can be added to the solution prior to drying, such as a Cremoph〇r® EL solution. The resulting solution is dried under a hollow to form a glass material. This glass material is then mixed with a binder to form a powder. The powder may be mixed with a filler or other conventional compressed tablet and processed to form a tablet for oral administration to a patient. The powder may also be added to any liquid carrier, as previously described, to form an orally administered solution, emulsion, suspension or the like. The parenteral emulsion can be prepared by dissolving the antitumor compound in any pharmaceutically acceptable solvent (e.g., ethanol or dihalomethane) capable of dissolving the compound to form a solution. Place the appropriate volume of carrier as an emulsion, such as Liposyn® II or Liposyn® III emulsion, add ___ -28-sheet scale to the Chinese National Standard (CNS) A4 specification (210 X 297 mm 1 ' ' - 1282793

'Inventive description (26 = the solution = j while stirring, cut into the drug for parenteral administration of the drug: top: 爻 乳化 < emulsion. If necessary, this emulsion can be adjusted to contain 瑕V or not Ethanol or Crem 〇ph〇r (g) solutions, which are known in the art, when administered in a parenteral formulation, are believed to cause adverse physiological effects when administered under the conditions of a sweetness. The enteral pharmaceutical solution can be prepared by dissolving the antitumor compound in any pharmaceutically acceptable solvent (e.g., ethanol or methyl chloride) capable of dissolving the compound to form a solution. 2, is a solution, Φ such as Crem0ph0r8 solution, added to the solution, while f off, to form a pharmaceutically acceptable solution for parenteral administration to the patient. Right need to adjust this solution to contain the minimum amount Or no ethanol or C_phor® solution, as is known in the art, when administered in a parenteral formulation, it may cause adverse physiological effects when administered under wood; Oral or parenteral emulsion or dissolution The liquid is packaged in an IV bag, vial or other container for f, in a concentrated form, and diluted with any pharmaceutically acceptable liquid, such as saline, to achieve an acceptable concentration of taxane prior to use. As used in the art, the terms "hydrocarbon" and "hydrocarbyl" are used herein to describe an organic compound or group consisting solely of the element carbon and hydrogen. These groups include alkyl groups. , alkenyl, alkynyl and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl and aryl moieties substituted by other aliphatic or cyclic hydrocarbyl groups, such as alkanes. Aryl, alkaryl and alkynyl. Unless otherwise indicated, -29- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill in the form) Page) Order: --Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282793 A7 __ B7_________ V. Description of Invention (27) These components preferably contain 1 to 2 carbon atoms The &quot;substituted hydrocarbyl" moiety described herein is A hydrocarbyl moiety substituted with at least one carbon-free atom, including a moiety in which the carbon chain atom is interrupted by an atom, such as nitrogen, oxygen, helium, phosphorus, sulphur or self-atoms. Such substituents include _ s, heterocyclyl, pit oxygen oxo, alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, fluorenyl, decyloxy, nitro, amine, hydrazine Amine, nitro, cyano, thiol, ketal, acetal, ester and ether. 4 Atom Π - The word means an atom other than carbon and hydrogen. A "partial group" is a methyl group in which a carbon atom is covalently bonded to at least one hetero atom and, as the case may be, hydrogen, such as nitrogen, oxygen, helium, phosphorus, boron, sulfur or a halogen atom. The hetero atom may be substituted by other atoms in order to form a heterocyclic group, an alkoxy group, a decyloxy group, an alkynyloxy group, an aryloxy group, a hydroxyl group, a protected hydroxyl group, an oxy group, a decyloxy group, a nitro group, an amine group. , amidino, thiol, ketal, acetal, ester or ether moiety. The "hetero-substituted acetate" moiety described herein is a group in which a carbon of a methyl group is covalently bonded to at least one hetero atom, and optionally has an acetate group of hydrogen, such as nitrogen, Oxygen, bismuth, phosphorus, boron, sulfur or halogen atoms. The hetero atom may be substituted by other atoms in order to form a heterocyclic group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, a hydroxyl group, a protected hydroxyl group, an oxy group, a decyloxy group, a nitro group, an amine group. , amidino, thiol, ketal, acetal, ester or ether moiety. Unless otherwise indicated, the bases described herein are preferably -30-one paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 meals) (please read the back note first) Matters re-fill this page) Order - Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 1282793 A7 B7 V, invention description (28) (please read the note on the back and then fill out this page) Carbon alkyl, in the main chain Contains one | eight carbon atoms, and up to 20 carbon atoms. It may be a straight chain or a branched chain or a ring, and includes a mercapto group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a hexyl group and the like. Unless otherwise indicated, the sulfhydryl groups described herein are preferably low carbon fluorenyl groups containing from two to eight carbon atoms in the backbone and up to 20 carbon atoms. It may be a straight chain or a branched chain or a ring, and includes an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a hexyl group, and the like. Unless otherwise indicated, alkynyl groups as described herein are preferably a low-hard alkynyl group containing from two to eight carbon atoms in the main chain and up to two carbon atoms in the main chain. It may be a straight or branched chain and includes an ethynyl group, a propynyl group, a butyl group, an isobutyl block group, a hexynyl group and the like. The term ''aryl'' or 'ar' as used herein, alone or as part of another group, denotes optionally substituted homocyclic aromatic oxime, preferably monocyclic or A bicyclic group having 6 to 12 carbons in the ring moiety, such as a phenyl group, a biphenyl group, a fluorenyl group, a substituted phenyl group, a substituted biphenyl group or a substituted fluorenyl group. The phenyl group and the substituted phenyl group are more preferred aryl groups. The term "halogen" or "halo" as used herein, alone or as part of another group, refers to gas, bromine, fluorine, and iodine. The Intellectual Property Intelligence Bureau's employee consumption cooperative is printed in this article. The term ''heterocyclyl" or, heterocyclic, as used herein, alone or as part of another group, is optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic. , an aromatic or non-aromatic group having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The hetero phenyl group has hydrazine or 2 oxygen atoms,丨 or 2 sulfur atoms and / or 1 to 4 nitrogen atoms in the ring, and can be combined by a carbon or hetero atom __ -31 - This paper scale applies to China National Standard 1282793 A7 B7

V. INSTRUCTIONS (29) The remainder of the molecule. The slanted heterocyclic group includes a heteroaromatic group, 嬖 (please read the back of the note and fill out this page) such as furyl, porphinyl, pyridyl, oxazolyl, pyrrolyl, fluorenyl, quinine A phenyl group or an isoquinolyl group or the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, ketone, protected, di, decyl, alkoxy, alkoxy, alkynyl, aryl Oxygen, _ _, 酉 胺 amine amino, nitro, aryl, thiol, condensed, condensed, vinegar and ether. - The term "heteroaromatic" as used herein, alone or as part of another group, refers to an optionally substituted aromatic group having at least one heteroatom in at least one In the ring, and preferably 5 or 6 atoms in each ring. Preferably, the heteroaromatic group has hydrazine or 2 oxygen atoms, hydrazine or 2 sulfur atoms and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule via a carbon or hetero atom. Shaofen. Exemplary heteroaromatic groups include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, porphyrin or isoindyl. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, sulfhydryl, decyloxy, morphoxy, decyloxy, alkynyloxy, aryloxy Base, halogen, guanamine, amine, nitro, cyano, thiol, ketal, condensate, g, and mystery. The term "ng||" used in this article by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, alone or as part of another group, is indicated by the c-H group from the organic carboxylic acid. Removing a portion of a group formed by a hydroxyl group, such as RC(0)_, wherein r is R1, R1 〇_, R1 R2N- or R1 S- ' R1 is a hydrocarbon group, a hetero-substituted hydrocarbon group or a heterocyclic group, and Is a chlorine, a hydrocarbyl group or a substituted hydrocarbyl group. The term "decyloxy" as used herein, alone or as another group - 32 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1282793 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed A7 B7 V. Inventive Note (3Q) is a part of the above-mentioned thiol group that has undergone oxygen chain (-0-) combination, such as RC (0 ) 0-, where R is as defined in relation to the term ",". Unless otherwise indicated, the alkoxycarbonyl moiety described herein includes a lower hydrocarbon or a substituted hydrocarbon or a substituted hydrocarbon moiety. Unless otherwise indicated, the amine mercaptooxy moiety described herein is a derivative of an amine methyl acid wherein one or both of the amine hydrogens are optionally hydrocarbyl, substituted hydrocarbyl or hetero The cyclic group moiety is replaced. As used herein, the terms π hydroxy protecting group and π hydroxy protecting group mean a group capable of protecting a free hydroxy group, a protected hydroxy group π), which can be removed after a protective reaction, without Disrupt the rest of the molecule. For a variety of protecting groups for hydroxyl groups, and their synthesis, see "Protective Groups for Organic Synthesis, W. Greene, John Wiley & Sons, 1981 or Fieser & Fieser. Exemplary hydroxy protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (less trimethyldecyl ethoxy)methyl, tetrahydropyranyl, • 2,2 , 2-trisylethoxycarbonyl, tert-butyl(diphenyl)decyl, trialkyldecyl, trimethylmethoxycarbonyl and 2,2,2-trisethoxymethyl . As used herein, &quot;Acn means ethyl thiol; &quot;Bz&quot; means benzylidene, f'Etn means ethyl; f'Men means methyl; "Ph&quot; means phenyl; "iPr" means isopropyl; ntBu&quot; and nt-Bu&quot; means a third-butyl group; "R" means a lower alkyl group, unless otherwise defined; npyn means pyridine or pyridyl; "TES' , meaning triethylsulfonyl; nTMSn means trimethyl sulfhydryl; ''LAH' means hydrogen hydride; &quot;10-DABn means 10-deacetyl berry gibberellin ΠΙ; "Amine protecting group, including but not limited to urethanes such as 2,2,2-trisyl carbamic acid or tert-butyl carbamic acid; "protected hydroxy" means -0P, wherein p is a hydroxy-protection-33- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) I. Line · 1282793 A7 _B7 V. Invention Description (31) Guard base; "tBu〇C〇&quot; and nB〇Cn means third-butoxycarbonyl; &quot;tAmOCO&quot; means third-pentyloxycarbonyl; &quot;PhCCT means phenylcarbonyl; &quot ;2-FuCC T means 2-furylcarbonyl; n2-ThCO'' means 2-thienylcarbonyl; "2-PyC〇" means 2-leafridinylcarbonyl; &quot;3-PyC〇&quot; means 3-pyridine Carbonyl; "4-PyC〇&quot; means 4-pyridylcarbonyl; MC4H7C〇n means butenylcarbonyl; nEt〇C〇&quot; means ethoxycarbonyl; &quot;ibueCO&quot; means isobutylcarbonyl; iBuC〇n means isobutylcarbonyl; niBu〇C〇&quot; means isobutoxycarbonyl; niPr〇C〇&quot; means isopropoxycarbonyl; &quot;nPr〇C〇&quot; means positive-prop Oxycarbonyl; &quot;nPrCO&quot; means n-propylcarbonyl; &quot;tC3 H5 CO&quot; means trans-propenylcarbonyl&quot;;&quot;ibue&quot; means isobutenyl; &quot;THF means tetrahydrofuran; nDMAPn 4-Dimethylamino pyridine • ' &quot;LHMDS ” means hexamethylene diazide hydride. The following examples illustrate the invention. Example 1 (Please read the back note first and then fill out this page)

CeCI Ί

(A - Λ

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 10-propenyl-10-deacetylated baccatin III. at 0.2 g (0.367 mmol) 10-deacetylated baccatin III and 0.272 A mixture of gram (1.10 mmol) of CeCl3 in 10 ml of hexanes HF was added at 25 ° C to 2.35 ml (18.36 mmol) of propionic anhydride. After 30 minutes, the reaction mixture was diluted with EtOAc EtOAc EtOAc. The organic extract was dried over Na 2 S 〇 4 and concentrated in sputum. Make the crude solid on the tannin-34 paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of the invention (32) Purification by flash column chromatography ^ Use 70 ° / . EtOAc / hexane as a dissolving agent gave 0.199 g (yield: 90%) of 10-propenyl-10-deethionylbaccatin III as a solid.

(Please read the note on the back and then fill out this page) 7-Dimethylphenyl decyl-10-propenyl-10-deacetyl berry gibberellin ΠΙ. At 0.200 g (0.333 mmol) 10-propenyl-10-deacetylated baccatin III In a solution of 12 ml of THF, 0.668 ml (4.00 mmol) of gas-based dimethyl was added dropwise at -10 ° C under a nitrogen atmosphere. Base-phenyl decane with 2.48 ml (30.64 mmol) of pyridine. After 90 minutes, the mixture was diluted with a 1:1 mixture of ethyl acetate and hexanes. The mixture was washed with 20 ml of a saturated aqueous solution of sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with a 1:1 mixture of ethyl acetate and hexanes, and the combined organic extracts were washed with brine, dried over Na 2 S s 4 and concentrated. The crude solid was purified by flash column chromatography on a printed gel of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. Using 50% EtOAc / hexane as the eluent, 0.242 g (99 ° /.) 7 - 2 was obtained. Methylphenyl nonylalkyl-10-propenyl-10-deacetylated baccatin III is a solid.

-35- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 1282793 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Description of Invention (33) 7-Dimethylphenyldecane Base 2,-〇 ditriethyl decyl-3f_dephenylphenenyl)-ιο-propenyl-ίο-deacetylated paclitaxel·at 0 400 g (〇544 mmol) 7- Dimethylphenyl decyl _10-propyl hydrazinyl hydrazide _ deacetyl berry gibberellin ΠΙ in a solution of 5.5 liters of HF, 〇 681 ml was added at -45 ° C and nitrogen atmosphere (0.681 Amol) 1 M solution of LHMDS in THF. After 1 hour, slowly add 0.317 g (0.818 mmol) of cis benzhydryl ternal triethyl decyloxy-4-(2-thienyl)-azinotetraindole-2-one in 3 ml Solution in HF. The mixture was warmed to 0 ° C, and after 3 hours, EtOAc (aq. The combined organic extracts were washed with brine, dried over Na 2 S 〇 4 and concentrated in sputum. The crude product was purified by flash column chromatography on silica gel using 4% EtOAc / hexanes as solvent. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Benzyl-2'-indole-triethyldecyl- 3L dephenyl-3L(2-thienyl)]indole-propionyl]indole-deacetylated paclitaxel is a solid.

3f_dephenylphenyl K2-4 phenyl)-10-propenyl-10·deacetylated paclitaxel·0.521 g (0.464 mmol) 7-dimethylphenyldecane-2-f-indole-three Ethyl nonyl-3*-dephenyl-3'-(2·thienyl)-1〇-propionyl-ίο-deacetylated paclitaxel in 2 ml of CH3CN and 2 ml of pyridine Add 3 〇〇 / 0 HF in Η Ο 〇 5 5 ml solution at 〇 ° C. After 3 hours, add 2 ml of saturated hydrogen carbonate _ -36- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) • ιινίίγ (please read the notes on the back and fill out this page)

A7 1282793 B7 A--------- Jade, invention (34) Aqueous sodium solution, and the mixture was extracted three times with 5 &amp; ml of ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in EtOAc. The crude product was purified by flash column chromatography on silica gel using 70 EtOAc / hexanes as hexanes to afford EtOAc EtOAc EtOAc (2-Mexienyl)-indole-propenyl-10-deacetylated paclitaxel is a solid. Melting point 154-155 ° C; [WD25 = -45.0 (c0.1 in CHC13); analysis of C46H51N014S 値: C, 63.22; H, 5.88; measured 値: C, 62.94; H, 5.97.

3f-dephenyl-3′-(2-antimony)-10-propenyl-10-deacetylated paclitaxel 1 H NMR data (CDC13) (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Proton d (ppm) Pattern J(Hz) A 2, 4.78 dd Η3'(2·1), 2ΌΗ(4·1) 2ΌΗ 3.51 d Η2,(4·1) — 3, 6.07 dd NH(8.6), H2f(2.1) 5, 7.04 dd (3.5), (5.0) 10H 1.68 s 2 5.69 d H3(7.0) 3 3.85 d H2(7.0) 4Ac 2.42 s 5 4.96 ' app d 6 a 2.45-2.60 app m ββ 1.89 ddd Η7(10.9), Η5(2·5), Η6α(14·5) 7 4.42 ddd 70Η(4·2), Η6α(6·8), Η6/?(10· 8) 70Η 2.45-2.60 app m 10 6.32 s 13 6.27 app t Η14 /5(9.0) 14 α 2.40-2.43 app m 14/? 2.34 dd Η14α(15.5), Η13(9·0) Me 16 1.16 s Me 17 1.25 app m -37 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) · 1282793 A7 B7 V. Invention description (35)

Me 18 1.84 _ S Me 19 1.70 S 20 a 4.31 d H20/5(8.5) 20/3 4.22 d H20^(8.5) o-benzoate 8.14-8.16 m o-benzamide 6.72-7.73 m NH 6.88 d H3'(8.6) CH3CH2 1.24 t CH3CH2(7,0) CH3CH2 2.45-2.60 app m Example 2 The procedure described in Example 1 was repeated, but with the other appropriately protected endoamine, replacing Example 3/3 - decylamine to prepare a series of compounds having the formula (13) and combinations of substituents identified in the table below. (Please read the notes on the back and fill out this page) :«

订·- -丨线- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Compound X5 X3 R1 0 0499 tBuOCO- Isobutenyl EtCOO- 0503 tBu〇C〇- 2-p ratio aryl base EtC〇〇- 0517 tBuOCO- 3- p ratio base EtCOO- 0521 tBuOCO- 4-p-pyridyl EtCOO- 0536 tBuOCO-2- 2-furyl EtCOO- 0549 tBuOCO- 3-oxiranyl EtCOO- 0550 tBuOCO-2- 2-thiophene EtCOO- 0562 tBuOCO- 3 -Thienyl EtCOO- 0578 tBuOCO-cyclopropyl EtCOO- 0583 tBuOCO- isopropyl EtCOO- 38- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1282793 A7 B7 V. Description of invention ( 36) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 0596 tBuOCO- butyl EtCOO- 0602 tBuOCO- p-nitrophenyl EtCOO- 0611 tBuOCO- phenyl EtCOO- 0625 PhCO- isobutenyl EtCOO- 0634 PhCO- 2-pyridine Based EtCOO- 0647 PhCO- 3-ί7 than decidyl EtCOO- 0659 PhCO- than decyl-EtCOO- 0663 PhCO- 2-furyl-based EtCOO 0670 PhCO 3-furyl-based EtCOO- 0687 PhCO- 2-thienyl-EtCOO- 0691 PhCO- 3-thienyl EtCOO- 0706 PhCO-cyclopropyl EtCOO- 0719 PhCO- isopropyl EtCOO- 0720 PhCO- Cyclobutyl EtCOO- 0732 PhCO- p-Nitrophenyl EtCOO- 0748 PhCO- Phenyl EtCOO- 0838 tBuOCO- Isobutyl sulfonyl CproCOO- 0843 tBuOCO-2-Pyryl CproCOO- 0854 tBuOCO- 2-Thienyl CproCOO - 0860 tBuOCO-cyclopropyl CproCOO- 0879 tBuOCO- p-nitrogen &gt; phenyl phenyl CproCOO- 0882 tBuOCO- phenyl CproCOO- 0890 PhCO- isobutenyl CproCOO- 0908 PhCO 2- 2-pyranyl CproCOO- 0919 PhCO- ' 2-thienyl CproCOO- 0923 PhCO-cyclopropyl CproCOO- 0937 PhCO- phenyl CproCOO- 0947 tBuOCO-isobutenyl PrCOO- 0951 tBuOCO- 2-ρ ratio decyl PrCOO- 0966 tBuOCO- 3-ρ ratio PrcoO- 0978 tBuOCO- 4-ρ ratio decyl PrCOO- 0983 tBuOCO-2-furanyl PrCOO- 0999 tBuOCO- 3-pyranyl PrCOO- 1003 tBuOCO- 2-thienyl PrCOO-1011 tBuOCO- 3-pyrhenyl PrCOO- 39- (Please read the note on the back and fill out this page) - Set · 丨 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention description (37) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1020 tBuOCO- _ ring C PrCOO-1031 tBuOCO- isopropyl PrCOO-1044 tBuOCO-cyclobutyl PrCOO-1060 tBuOCO-phenylPrCOO- 1879 tBuOCO-isobutenyl 2-ThCOO- 1883 tBuOCO- 2-p ratio aryl 2-ThCOO- 1892 tBuOCO- 2-furyl 2-ThCOO- 1900 tBuOCO- 2-p phenyl-2-ThCOO- 1911 tBuOCO- p-nitrophenyl 2-ThCOO- 1923 tBuOCO-3-furanyl 2-ThCOO- 1939 tBuOCO- 3- Far phenyl 2-ThCOO- 1948 tBuOCO- 3-p ratio bite base 2-ThCOO- 1954 tBuOCO- 4-ρ ratio base 2-ThCOO- 1964 tBuOCO- isopropyl 2-ThCOO- 1970 tBuOCO- cyclobutyl 2 -ThCOO- 1988 tBuOCO-phenyl 2-ThCOO-2101 tBuOCO-isobutenyl 2-FuCOO-2111 tBuOCO- 2-p ratio aryl 2-FuCOO-2124 tBuOCO- 3-p ratio aryl 2-FuCOO-2132 tBuOCO- 4-ρ ratio decyl 2-FuCOO-2142 tBuOCO-2-furanyl 2-FuCOO-2159 tBuOCO-3-sulfanyl 2-FuCOO-2164 tBuOCO-2- 2-oCO- 2173 tBuOCO- 3- Thienyl 2-FuCOO-2181 tBuOCO- ^ isopropyl 2-FuCOG-2199 tBuOCO-cyclobutyl 2-FuCOO-2202 tBuOCO- p-nitrophenyl 2-FuCOO- 2212 tBuOCO- phenyl 2-FuCOO-2226 tBuOCO- Isobutyl hydrazide IPrCOO- 2238 tBuOCO- 2-p ratio Cascade IPrCOO-2242 tBuOCO- 3-p ratio cation base IPrCOO-2255 tBuOCO- 4-ρ ratio aryl IPrCOO-2269 tBuOCO-2- 2-pyranyl IPrCOO-2273 tBuOCO 3- 3-furanyl IPrCOO-2287 tBuOCO- 2-喽 基 IPrCOO- -40- (Please read the note on the back and fill out this page) Order: Line ' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (38) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 2291 tBuOCO- &gt;Thienyl IPrCOO-2306 tBuOCO- Isopropyl IPrCOO- 2319 tBuOCO- Cyclobutyl IPrCOO- 2320 tBuOCO- p-Acidyl Phenyl IPrCOO- 2332 tBuOCO- Isobutyl fluorenyl tc3 h5 COO- 2348 tBuOCO- 2-ρ ratio base tc3 h5 COO- 2353 tBuOCO- 3-p ratio precipitation base tC3 h5 COO- 2366 iBuOCO- 4-ρ ratio precipitation base tc3 h5 coo- 2379 tBuOCO - 2-bityl tc3 h5 coo- 2380 tBuOCO- 3-furyl tc3 h5 coo- 2392 tBuOCO- 2-thienyl tc3 h5 coo- 2408 tBuOCO- 3-thienyl tc3 h5 coo- 2413 tBuOCO- isopropyl tc3 H5 coo- 2424 tBuOCO-cyclobutyl tc3 h5 coo- 2439 tBuOCO- p-nitrophenyl tc3 h5 coo- 2442 tBuOCO - phenyl tc3 h5 coo- 2455 tBuOCO- isobutenyl IbueCOO- 2464 tBuOCO- 2-p ratio aryl IbueCOO-2472 tBuOCO- 4-p ratio aryl IbueCOO-2488 tBuOCO-2- 2-pyranyl IbueCOO- 2499 tBuOCO-3 -furanyl IbueCOO- 2503 tBuOCO- 2-thienyl IbueCOO- 2511 tBuOCO- 3-sulfonyl IbueCOO- 2520 tBuOCO- * phenyl IbueCOO- 2781 tBuOCO 3- 3-furanyl CproCOO- 2794 tBuOCO- 3-ρ seno CproCOO- 2802 tBuOCO- 2-p ratio CproCOO- 2813 tBuOCO- 4-ρ ratio bite base CproCOO-2826 PhCO- 3-furyl CproCOO- 2838 PhCO- 3-nonyl CproCOO- 2844 PhCO- than bite CproCOO - 2855 PhCO- 4-ρ ratio bite base CproCOO- 2869 PhCO- p-nitrophenyl CproCOO- 3053 2-FuCO 2- 2-anthracene EtCOO- -41 - (Please read the back note first and then fill out this page ) Order: _ Line' This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention description (39) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 3071 iPrOCO- cemb Base CproCOO-3096 EtOCO- 2-Thienyl PrCOO-3102 iBuOCO-2- 2-bityl CproCOO-3110 iBuOCO- 2-bito-based PrCOO-3129 iBuOCO- 2-p-saltyl CproCOO- 3132 nPrCO- 2-p-saltyl CproCOO- 3148 nPrCO- 2-thienyl-PrCOO- 3163 iBuOCO- 2-thienyl-EtCOO- 3204 PhCO- 2-Chloropyranto-PrCOO- 3219 nPrCO-2-furyl-EtCOO- 3222 nPrCO-2- 2-pyranyl-PrCOO- 3258 PhCO- 2-pyrimenyl-PrCOO- 3265 iBuOCO-2- 2-indenyl _ PrCOO- 3297 2- FuCO-Secretyl CproCOO-3314 nPrCO- 2-ρ-Senyl-PrCOO- 3352 2-FuCO- 2-Thienyl-PrCOO- 3361 iPrOCO-2- 2-Phenyl-EtCOO- 3370 EtOCO- 2-p-Senyl-EtCOO- 3408 2-ThCO-2-thiophenyl-PrCOO-3417 iPrOCO-2- 2-pyranyl PrCOO-3425 2-ThCO-2-thiophenyl-EtCOO- 3453 2-ThCO-2-pyromyl CproCOO-3482 PhCO-cyclopropyl PrCOO-3494 tC3 H5 CO- 2-ρ thiophene EtCOO- 3513 tC3 H5 CO ' 2-Soul phenyl CproCOO-3522 iPrOCO-2-furanyl EtCOO-3535 EtOCO-2-furanyl EtCOO-3543 C4H7 CO- 2 -Thienyl CproCOO- 3588 C4H7 CO- 2-Thienyl EtCOO- 3595 tC3 H5 CO- 2-Mexenopheno-PrCOO- 3603 C4H7 CO- 2-Thienyl PrCOO- 3644 2-ThCO-2-17-Fanyl EtCOO- 3656 2-ThCO-2- 2-bityl PrCOO- 36 63 2-ThCO 2- 2-Panyl CproCOO- -42 - This paper size is applicable to China National Standard (CNS) A4 specification (2W x 297 mm) # ------* II r 清电闻璜Back t In addition, please fill out this page) i 订· _ line - 1282793 A7 B7 V. Invention description (40) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 3677 EtOCO- _2-biting base CproCOO- 3686 2-FuCO- 2- Furan-based PrCOO-3693 EtOCO-2-furyl-PrCOO-3800 C4H7 CO- 2-furyl-PrCOO- 3818 2-FuCO-2-17-propanyl-EtCOO- 3853 iPrOCO-2-ulanyl CproCOO- 3866 2-FuCO- 2-furyl CproCOO- 3909 iPrOCO 2- 2-thienyl PrCOO- 3938 C4H7 CO- 2-furyl CproCOO- 3945 C4H7 CO-furanyl EtCOO-3957 iBuOCO- fluoropyrano-PrCOO- 3971 tC3 H5 CO- 2-furan Base CproCOO-3982 tC3 H5 CO 2-Chloroyl EtCOO-3994 tC3 H5 CO- 2-furyl PrCOO- 4051 EtOCO-2- 2-nonyl CproCOO- 4062 nPrCO-2-furanyl CproCOO-4112 3-PyCO- 2 -pyrimenyl CproCOO- 4121 3-PyCO- 2-p-saltyl EtCOO- 4190 3-PyCO-2-thiophenyl-PrCOO- 4207 4-PyCO- 2-ρ-saltyl EtCOO- 4329 ibueCO- 2-ρ plug Phenyl CproCOO- 4335 ibueCO-2- 2-thiophene EtCOO- 4344 ibueCO 2- 2-thienyl PrCOO-4665 iBuOCO- ^ 3-furyl CproCOO- 4704 iBuOCO-3-furanyl PrCOO- 4711 iBuOCO- 3-thienyl EtCOO-4720 iBuOCO- Isobutenyl CproCOO- 4799 iBuOCO- Yuba propyl EtCOO-4808 iBuOCO-cyclopropyl NPrCOO- 4834 iBuOCO- 3-thienyl NPrCOO- 4888 tC3 H5 CO- 3- oxiranyl EtCOO- 4919 tC3 H5 CO- 3-bit喃 NPrCOO- 4944 tC3 H5 CO- 3-ρ-fuca-based CproCOO- 5011 iBuOCO- 3-Sercapyl CproCOO- -43- Read the back of the note and fill in the page This paper scale applies to the Chinese national standard (CNS A4 size (210 X 297 mm) 1282793 A7 B7 V. Description of invention (41 5040 tc3 h5 co- J3-pyryl

CproCOO- 5065 iBuOCO- isobutenyl

EtCOO-5144 iBuOCO- isobutenyl

NprCOO-5232 iBuOCO- cyclopropyl

CproCOO-5495 tBuOCO-3-furanyl

EtCOO- 6522 tAmOCO- 2-pyranyl

EtCOO-Example 3 The following specific taxanes of Structural Formula 14 can be prepared according to the methods described in Example 1 and elsewhere herein, wherein 0 is as defined above, including where Rio is Ri〇aC〇〇-, and the heart (^ (1) substituted or unsubstituted 4 to (8 alkyl, such as ethyl, or linear, branched or cyclic propyl, butyl, pentyl or hexyl; (ii) substituted or not Substituted C2 to C8 alkenyl, such as vinyl, or linear, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 Alkynyl, such as ethynyl, or straight or branched propynyl, butynyl, pentynyl or hexyl; (iv) substituted or unsubstituted phenyl, or (7) substituted or unsubstituted Substituted heteroaromatics, such as furyl, thienyl or pyridyl. The substituents may be as defined elsewhere for substituted hydrocarbyl groups. In a particular embodiment, &amp; Q may be R10 a C〇〇- Wherein R10 a is an ethyl group, a linear, branched or cyclic propyl group, a linear or branched propylene group, an isobutyl group, a furyl group or a pyrenyl group. (Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs.

(14) -44 - This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1282793 A7 B7 V. Invention description (42) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed X5 X3 , R1 0 tBuOCO-2-furanyl·RaCOO- tBuOCO-3-furanyl RaCOO- tBuOCO- 2-thienyl RaCOO- tBuOCO- thiophene RaCOO- tBuOCO- 2-ρ ratio aryl base 'RaCOO- tBuOCO- specific precipitation base RaCOO- tBuOCO- 4-pyridyl RaCOO- tBuOCO- • Isobutyl fluorene RaCOO_ tBuOCO- isopropyl RaCOO- tBuOCO-cyclopropyl RaCOO- tBuOCO- cyclobutyl I^COO- tBuOCO-cyclopentyl RaCOO- tBuOCO- phenyl RaCOO- Benzopyridyl 2-furanyl RaCOO-benzimidyl 3-furanyl RaCOO-benzimidyl 2-thienyl R^COO-benzimidyl 3-p-saltyl I^COO-benzimidyl 2-ρ ratio precipitation base RaCOO-benzonitrile-based 3-ρ ratio precipitation RaCOO-benzimidyl 4-ρ ratio precipitation RaCOO-benzimidyl isobutyl fluorene RaCOO-benzimidyl isopropyl RaCOO- Benzopyridylcyclopropyl RaCOO-benzimidylcyclobutyl RaCOO-benzimidylcyclopentyl RaCOO-benzimidylphenylCOO- 2-FuCO-2-pyranyl C OO- 2-FuCO-3-furanyl RaCOO_ 2-FuCO-2- 2-thienyl RaCOO- 2-FuCO-3-0Quinyl RaCOO- 2-FuCO-2-pyridyl R^COO- 2-FuCO-3 - Pyridyl RaCOO- -45- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm (please read the back note first and then fill out this page) 1282793 A7 B7 V. Inventions (43) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed 2-FuCO- 4-p Ratioate RaCOO- 2-FuCO-Isobutenyl Rac〇o-2-FuCO-Isopropyl RaC〇〇- 2-FuCO-cyclopropyl RaCOO- 2-FuCO-cyclobutyl RaCOO- 2-FuCO-cyclopentyl- RaC〇0- 2-FuCO-phenyl COO- 2-ThCO-2-furyl COO- 2-ThCO-furanyl R^ COO- 2-ThCO- 2-thienyl F^COO- 2-ThCO 3- 3-thiophene RaCOO_ 2-ThCO- 2-p ratio aryl group COO- 2-ThCO- 3-ρ ratio aryl group RaCOO 2-ThCO - 4-pyridyl RaC〇0- 2-ThCO-isobutenyl RaCOO- 2-ThCO-isopropyl RaCO〇- 2-ThCO-cyclopropyl RaCOO- 2-ThCO-cyclobutyl RaCOO- 2-ThCO· ring戊-yl R^COO- 2-ThCO-phenyl RaCOO- 2-PyCO-2- 2-pyranyl RaCOO- 2-PyCO- 3-bityl-COO- 2-PyCO- 2-p-thiophene RaCOO- 2-PyCO 3-thiophene RaCOO_ 2-PyCO-2-p ratio decyl RaCOO-2-PyCO-3-0 ratio decidyl RaCO〇 2-PyCO- 4-ρ ratio decyl RaCOO- 2-PyCO- Isobutenyl RaCOO- 2-PyCO- isopropyl RaCOO- 2-PyCO-cyclopropyl RaCOO- 2-PyCO-cyclobutyl R^COO- 2-PyCO- lyophilyl RaCOO- -46- Please read the back Precautions Please fill in the page. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1282793 A7 B7 V. Invention Description (44) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 2-PyCO-Benzene Base, RaCOO- 3-PyCO-2- 2-pyranyl R^COO- 3-PyCO-3-furanyl RaCOO- 3-PyCO-2- 2-thiophenyl-based RaCOO- 3-PyCO 3- 3-thiophenyl-based RaCOO- 3-PyCO - 2-p ratio aryl group 'RaCOO- 3-PyCO- 3-p ratio radix RaC〇0- 3-PyCO- 4-p ratio aryl R^COO 3-PyCO-isobutenyl RaCOO- 3-PyCO- Propyl I^COO- 3-PyCO-cyclopropyl COO- 3-PyCO-cyclobutyl R^COO- 3-PyCO-cyclopentyl RaCOO- 3-PyCO- phenyl R^COO- 4-PyCO-喃基RaCOO- 4-PyCO-3-furanyl RaCOO- 4-PyCO-2-pyrimenyl RaCOO- 4-PyCO-3-thiophenyl R^COO- 4-PyCO-2-p ratio Radical RaCOO- 4-PyCO- 3-p ratio base RaCOO- 4-PyCO- 4-p ratio base RaCOO- 4-PyCO-isobutenyl COO- 4-PyCO-iso-propyl RaCOO- 4-PyCO- ring Propyl R^COO- 4-PyCO-cyclobutyl COO- 4-PyCO-cyclopentyl RaCOO- 4-PyCO-phenyl RaCOO- C4H7CO-2-furanyl RaCOO- c4h7co- 3-pyranyl RaCOO- c4h7 CO 2- 2-Thienyl Racoo- C4 H7CO- 3-ρ thiophene RaCOO· C4 H7CO- 2-p ratio bite-based RaCOO- -47- (Please read the back note first and then fill in this page) This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 1282793 A7 B7 V. Description of Invention (45) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed C4H7CO_ 3-p 比盐棊RaCO〇- c4h7c〇- 4- p ratio of the base RaC〇0- c4h7c〇-isobutenyl RaC〇〇- c4h7c〇-isopropyl RaCOO- c4 h7co-cyclopropyl RaCOO- c4h7c〇-cyclobutyl 'RaCO〇- c4h7co-cyclopentyl COO- C4 H7 CO-phenyl RaCO〇- EtOCO-2-furanyl RaCOO- EtOCO- 3-pyranyl RaCO〇- EtOCO- 2-p thiophene RaCOO- EtOCO- 3-p thiophene R^COO- EtOCO - 2-p ratio radiant base RaCOO- EtOCO- 3-ρ ratio bite-based RaCOO - EtOCO- 4-ρ ratio bite base R^COO- EtOCO- isobutenyl RaCOO- EtOCO- isopropyl RaCOO- EtOCO- cyclopropyl R^COO- EtOCO- cyclobutyl RaCOO- EtOCO- cyclopentyl R^COO - EtOCO- Phenyl RaCOO- iBueCO- 2-bityl RaCOO- iBueCO- 3-furanyl RaCOO- iBueCO-2- 2-thiophene RaCOO- iBueCO- 3- far phenyl COO- iBueCO-2-p ratio RaCOO- iBueCO- 3-ρ ratio base RaCOO- iBueCO- ratio base COO- iBueCO- isobutyl sulfonium RaCOO- iBueCO- isopropyl RaCOO- iBueCO- cyclopropyl RaCOO- iBueCO- cyclobutyl RaCO〇- (please Read the notes on the back and fill in this page) -48- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (46) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed iBueCO- lyophilyl T RaCOO- iBueCO- phenyl RaCOO- iBuCO 2- 2-bityl R^COO- iBuCO 3- 3-furanyl RaCOO- iBuCO 2- 2-nonyl COO- iBuCO- 3-ρ plug吩'R^COO- iBuCO- 2-ρ ratio decidyl group F^COO- iBuCO- 3-ρ ratio aryl group RaCOO- iBuCO- 4-p ratio aryl group RaCOO- iBuCO- isobutenyl RaCOO- iBuCO- isopropyl group R ^COO- iBuCO-cyclopropyl RaCOO- iBuCO-cyclobutyl Rac〇o- iBuCO-cyclopentyl^coo- iBuCO-phenyl R^COO- iBuOCO-2-furanyl RaCOO_ iBuOCO-3-furanyl P^ COO- iBuOCO- 2-喽-based RaCOO- iBuOCO- 3-soul thiophene RaCOO- iBuOCO- 2-ρ ratio aryl group RaCOO- iBuOCO- 3-p ratio aryl group R^COO- iBuOCO- 4-p ratio bite base RaCOO-iBuOCO- Iso: Terpene RaCOO- iBuOCO-Isopropyl RaCOO- iBuOCO- Cyclopropyl RaCOO- iBuOCO- Cyclobutyl RaCOO iBuOCO- Cyclopentyl R^COO- iBuOCO- Phenyl COO- iPrOCO- 2- Furanyl RaCOO- iPrOCO-3-furanyl RaCOO- iPrOCO- 2-pyrimenyl RaCOO- iPrOCO- 3-thienyl R^COO- -49- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Mm) h-------------- (Please read the notes on the back and fill out this page) Order ·· -1282793 A7 B7 V. Inventions (47) Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed iPrOCO- 2-p ratio base RaCOO- iPrOCO- 3-p ratio base RaCOO- iPrOCO- 4-p ratio base RaCOO- iPrOCO-isobutenyl RaCOO- iPrOCO- isopropyl RaC〇0 - iPrOCO-cyclopropyl ' RaCOO- iP rOCO-cyclobutyl RaCOO- iPrOCO-cyclopentyl RaCOO- iPrOCO- phenyl RaCOO- nPrOCO-2-furanyl RaC〇0- nPrOCO- 3-pyranyl RaCOO- nPrOCO-2- 2-indenyl RaCOO- nPrOCO- The thiophene-based RaCOO- nPrOCO- 2-p ratio of the base COO- nPrOCO- 3-p ratio of the base of the RaCOO_ nPrOCO- 4-p ratio of the base P ^ COO- nPrOCO- isobutyl sulfonium RaCOO- nPrOCO- isopropyl R ^ COO - nPrOCO-cyclopropyl RaCOO- nPrOCO-cyclobutyl COO- nPrOCO-cyclopentyl RaCOO- nPrOCO- phenyl RaCOO- nPrCO 2- 2-furanium RaCOO- nPrCO 3- 3-anthranyl RaCOO- nPrCO-2吩-based RaCOO- nPrCO-3 3-soul thiophene RaCOO- nPrCO- 2-p ratio decidyl group I^COO- nPrCO- 3-p ratio aryl group RaCOO- nPrCO- 4-ρ ratio substrate RaCOO- nPrCO-isobutenyl RaCOO - nPrCO- isopropyl RaCOO- nPrCO- lycopene I^COO- (Please read the note on the back and fill out this page) -50- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 PCT) 1282793 A7 B7 V. INSTRUCTIONS (48) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print nPrCO-cyclobutyl i RaCOO- nPrCO-cyclopentyl RaCOO- NPrCO- phenyl RaCOO- tBuOCO- ring Pentyl EtCOO-benzimidylcyclopentyl EtCOO- 2-FuCO-3- 3-thiol 1 EtCOO- 2-FuCO 3- 3-thiophene EtCOO- 2-FuCO 2-peptidyl EtCOO- 2- FuCO- 3-p ratio decyl-EtCOO- 2-FuCO- 4-outer I: bite-based EtCOO- 2-FuCO-isobutenyl EtCOO- 2-FuCO-isopropyl EtCOO- 2-FuCO-cyclopropyl EtCOO- 2 -FuCO-cyclobutyl EtCOO- 2-FuCO-cyclopentyl EtCOO- 2-FuCO-phenyl EtCOO- 2-ThCO-3-furyl-EtCOO- 2-ThCO-3 3-homogenyl EtCOO- 2-ThCO- 2-ί7 than bite-based EtCOO- 2-ThCO- 3-p ratio aryl group EtCOO- 2-ThCO- 4-ρ ratio base EtCOO- 2-ThCO-isobutyl fluorenyl EtCOO- 2-ThCO- isopropyl EtCOO- 2 -ThCO-cyclopropyl EtCOO- 2-ThCO-cyclo Y-based EtCOO- 2-ThCO-cyclopentyl EtCOO- 2-ThCO-phenyl EtCOO 2-PyCO-2-furyl-EtCOO- 2-PyCO-3-furan EtCOO- 2-PyCO-2--»1-senoyl-EtCOO- 2-PyCO- 3-ρ-senoyl-EtCOO- 2-PyCO-2- 2-pyridyl-EtCOO- 2-PyCO- 3-p-salt-based EtCOO- 2-PyCO- 4-ρ ratio aryl group EtCOO- 2-PyCO-isobutenyl EtCOO- -51 - , Buddhism!丨#11 (Read the back of the note first and then fill out this page). The reference paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (49) Ministry of Economics Property Bureau Staff Consumer Cooperative Printed 2-PyCO-Isopropyl i EtCOO- 2-PyCO-cyclopropyl EtCOO- 2-PyCO-cyclobutyl EtCOO- 2-PyCO-cyclopentyl EtCOO- 2-PyCO-phenyl EtCOO- 3-PyCO-2-furyl t EtCOO- 3-PyCO 3- 3-pyranyl EtCOO- 3-PyCO 3- 3-thiophenyl-EtCOO- 3-PyCO-2-p-pyrophilic EtCOO- 3-PyCO- 3-π ratio precipitation EtCOO 3-PyCO- 4-ρ ratio bite base EtCOO 3-PyCO isobutenyl EtCOO 3-PyCO- isopropyl EtCOO 3-PyCO- cyclopropyl EtCOO- 3-PyCO- ring Butyl EtCOO- 3-PyCO-cyclopentyl EtCOO- 3-PyCO-phenyl EtCOO- 4-PyCO-2-furoyl EtCOO- 4-PyCO-3-octyl EtCOO- 4-PyCO-2-thiophenyl EtCOO, 4-PyCO3- 3-thienyl EtCOO- 4-PyCO-2-p ratio base EtCOO- 4-PyCO- 3-p ratio bite base EtCOO- 4-PyCO- 4-p ratio bite base EtCOO- 4- PyCO-isobutenyl EtCOO- 4-PyCO isopropyl EtCOO- 4-PyCO-cyclopropyl EtCOO- 4-PyCO-cyclobutyl EtCOO- 4-P yCO-cyclopentyl EtCOO- 4-PyCO-phenyl EtCOO- C4 H7CO- 3-bityl EtCOO- c4h7 CO- 3-thienyl EtCOO- C4H7CO- 2-ρ ratio decyl-EtCOO- C4 H7 CO-pyridinium Base EtCOO- -52- {Notes on the back of the first reading and then fill out this page) Order: • Line paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (50) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed c4 h7 CO- 4*^ 棊 棊 EtCOO- c4 h7 CO- Isobutenyl EtCOO- C4 H7 CO-Isopropyl EtCOO- C4H7CO- Cyclopropyl EtCOO- c4h7 CO-cyclobutyl EtCOO- C4H7CO-cyclopentyl- EtCOO- c4h7c〇-phenyl EtCOO- EtOCO- 3-furyl-EtCOO- EtOCO- 3-nonyl-based EtCOO- EtOCO- 2-p-denier-based EtCOO- EtOCO - 3-p ratio decyl-EtCOO- EtOCO- 4-ρ ratio decyl-EtCOO- EtOCO-isobutyl hydrazine EtCOO- EtOCO- isopropyl EtCOO- EtOCO- cyclopropyl EtCOO- EtOCO- cyclobutyl EtCOO- EtOCO- cyclopentane EtCOO- EtOCO- phenyl EtCOO- ibueCO-2-furyl EtCOO- ibueCO- 3-furanyl EtCOO- ibueCO-2- 2-thiophene EtCOO- ibueCO- 3-ρ thiophene EtCOO- ib ueCO- 2-p ratio decyl-EtCOO- ibueCO- 3-咕-based EtCOO- ibueCO- 4-ρ ratio decyl-EtCOO- ibueCO- Isobutyl-based EtCOO- ibueCO- isopropyl EtCOO- ibueCO-cyclopropyl EtCOO- ibueCO - Cyclobutyl EtCOO- ibueCO- Cyclopentyl EtCOO- ibueCO- Phenyl EtCOO- iBuCO 2- 2-Chloryl EtCOO- iBuCO 3- 3- yl-EtCOO- iBuCO- 2-p-Senyl-EtCOO--53- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public love (please read the notes on the back and fill out this page)

1282793 A7 B7 V. INSTRUCTIONS (51) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed iBuCO- 3-Mexenophene EtCOO- iBuCO- 2-p Bixian Tomb EtCOO- iBuCO- 3-p diandi-based EtCOO- iBuCO - 4-batch-based EtCOO-iBuCO-isobutenyl EtCOO-iBuCO-isopropyl. EtCOO- iBuCO-cyclopropyl EtCOO- iBuCO-cyclobutyl EtCOO- iBuCO-cyclopentyl EtCOO- iBuCO- phenyl EtCOO- iBuOCO - 2-p ratio decyl-EtCOO-iBuOCO- 3-p ratio aryl group EtCOO-iBuOCO- 4-ρ ratio aryl group EtCOO-iBuOCO-isobutenyl EtCOO-iBuOCO- isopropyl EtCOO- iBuOCO- Cyclobutyl EtCOO- iBuOCO - Cyclopentyl EtCOO-iBuOCO-phenyl EtCOO- iPrOCO- 3-pyranyl EiCOO· iPrOCO- 3-thienyl EtCOO- iPrOCO- 2-p ratio dianthene EtCOO- iPrOCO- 3-p ratio dianthene EtCOO- iPrOCO - 4-p ratio decyl-EtCOO-iPrOCO-isobutyl fluorenyl EtCOO- iPrOCO- isopropyl EtCOO- iPrOCO-cyclopropyl EtCOO· iPrOCO-cyclobutyl EtCOO- iPrOCO-cyclopentyl EtCOO- iPrOCO- phenyl EtCOO- nPrOCO - 2-furyl EtCOO- nPrOCO- 3-pyranyl EtCOO- nPrOCO-2- 2-thiophene EtCOO- nPrOCO 3- 3-thiophene EtCOO- nPrOCO- 2-ρ ratio Physic-based EtCOO- nPrOCO- 3-p than the base EtCOO- -54- irjl· 丨! · i — (Read the following on the back of the page and fill in this page) - • Line · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of invention (52) nPrOCO - 4_pyridinium EtCOO- nPrOCO-isobutenyl EtCOO- nPrOCO- isopropyl EtCOO- nPrOCO-cyclopropyl EtCOO- nPrOCO-cyclobutyl EtCOO- nPrOCO- bad amyl. EtCOO- nPrOCO- phenyl EtCOO- nPrCO- 3-furyl EtCOO- nPrCO-3-. Terbido EtCOO- nPrCO- 2-p ratio bite-based EtCOO- nPrCO- 3-p ratio decyl group EtCOO- nPrCO- 4-p ratio aryl group EtCOO- nPrCO-isobutenyl EtCOO- nPrCO- isopropyl EtCOO- nPrCO- Cyclopropyl EtCOO- nPrCO-cyclobutyl EtCOO- nPrCO-cyclopentyl EtCOO- nPrCO- phenyl EtCOO- Example 4 (Please read the back note first and then fill out this page) _ . Line according to Example 1 and elsewhere in this article In the method described, the following specific taxanes of the formula 15 can be prepared, wherein R7 is a hydroxyl group, and &amp;Q is as defined above in each series (ie, each series of "A" to "κ"), Including C1 to C8 alkyl (straight chain, branched or Cyclic), such as ethyl, propyl Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative printing, butyl, pentyl or hexyl; (Π) substituted or unsubstituted, preferably unsubstituted C2 to C8 olefin a group (straight chain, branched or cyclic) such as vinyl, propenyl, butenyl, pentenyl or hexenyl; (Hi) substituted or unsubstituted And, preferably, unsubstituted &lt;:2 to (8 alkynyl (linear or branched), such as ethynyl, propynyl, butynyl, pentynyl or hexynyl; Substituted or unsubstituted, preferably unsubstituted phenyl; or (v) substituted or unsubstituted -55- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Inventive Note (53), preferably an unsubstituted heteroaromatic group such as a furyl group, a thienyl group or a pyridyl group. In the A" series of compounds, the father is otherwise in this context. Preferably, the heterocyclic group is a substituted or unsubstituted furyl group, a thienyl group or a p-biting group 'Xl Q is a substituted or unsubstituted tert-butyl group, P-senyl group, pyridine a phenyl group or a lower alkyl group (e.g., a tert-butyl group), and each of R7 and ruthenium has a stereochemical configuration. In the "B" series of compounds, ruthenium and R2a are otherwise It is preferred herein that the heterocyclic group is preferably a substituted or unsubstituted furyl group, a phenanthrene group or a p-precipitate group, and Xi 〇 Is a substituted or unsubstituted fluorenyl group, a pyrenyl group, a pyridyl group, a phenyl group or a lower alkyl group (for example, a tert-butyl group), and R 2 a is preferably a substituted or unsubstituted furyl group, Pyrimenyl, pyridyl, phenyl or lower alkyl, and R7 and Ri 〇 each have a stereochemical configuration. In the "Cn series of compounds, Xi 〇 is otherwise defined herein. Preferably, the heterocyclic group is preferably a substituted or unsubstituted furyl group, a pyrimenyl group or a pyridyl group, and Xi 〇 is preferably a substituted or unsubstituted acetonyl group, p-senyl group, P is preferably a substituted or unsubstituted succinyl group, a far phenyl group, a p-specific group, a phenyl group or a low carbon. Alkyl groups, and R7, chemistry and hydrazine each have a stereochemical configuration. In the "D" and "E" series of compounds, Χι 〇 is otherwise defined herein. Preferably, the heterocyclic group is preferably a substituted or unsubstituted furyl group, a thienyl group or a pyridyl group, and Xi 〇 is preferably a substituted or unsubstituted furyl group, a pyrenyl group, a pyridyl group or a benzene group. A base or a lower alkyl group (e.g., a third-butyl group), and R7, R9 (only series D) and &amp; 〇 each have a stereochemical configuration. -56- ________

This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 metric H (please read the note on the back and fill out this page).. Line· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1282793 A7 B7 V. DESCRIPTION OF THE INVENTION (54) In the F series of compounds, 'reagents' % &amp; and Rpa are otherwise defined herein. Preferably, the 'heterocyclic group is preferably a substituted or unsubstituted furanyl group. , thienyl or pyridyl, Xi 〇 is preferably substituted or unsubstituted furyl, 4 phenyl, pyridyl, phenyl or lower alkyl (for example, tert-butyl), & a is preferred Is a substituted or unsubstituted fluorenyl, thienyl, pyridyl, phenyl or lower alkyl group, and each of r7, 1^ and 尺1() has a stereochemical configuration of 0. In the "G" series of compounds Wherein, X 〇 and R 2a are as defined herein in other respects. Preferably, the heterocyclic group is preferably a substituted or unsubstituted furyl, pyrenyl or pyridyl group, and X is preferably Substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg third-butyl) R2 a is preferably a substituted or unsubstituted fluorenyl group, a σ-saltyl group, a pyridyl group, a phenyl group or a lower alkyl group, and each of R7, R9 and &amp; In the oxime series of compounds, 'X〗 〇 is defined in other aspects such as Fengwen. Preferably, the heterocyclic group is preferably a substituted or unsubstituted fluorenyl group, ρ-septenyl group or a bite group. Xl 〇 is preferably substituted or unsubstituted fluorenyl, pyrimenyl, pyridyl, phenyl or lower alkyl (e.g., tert-butyl), and R2a is preferably substituted or unsubstituted. a furanyl, thienyl, pyridyl, phenyl or lower alkyl group, and R7 and R! 0 each have a stereochemical configuration. Among the Τ' series of compounds, 乂10 and R2a are otherwise defined herein. Preferably, the heterocyclic group is preferably a substituted or unsubstituted fluorenyl group, a mulberry phenyl group or a batch, a decyl group, and 乂丨Q is preferably a substituted or unsubstituted fluorenyl group, p a thiophene group, a 17-mercapto group, a phenyl group or a lower carbo group (for example, a tert-butyl group), and R2 a is preferably a substituted or unsubstituted furyl group, a thienyl group, Pyridyl, -57- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public interest) (please read the note on the back and fill out this page) · , Ministry of Industry, Intellectual Property Office, Consumers' Cooperatives 1282793 A7 B7 V. INSTRUCTIONS (55) Phenyl or lower alkyl, and R7 and Rr〇 each have a stereo configuration of 0. In the T series of compounds, Xl is otherwise defined herein. Preferably, the heterocyclic group is preferably a substituted or unsubstituted thiol, porphinyl or pyridyl group, and Xi 〇 is preferably a substituted or unsubstituted thiol group, 57 thiophene group, Pyridyl, phenyl or lower alkyl (for example, tert-butyl), ha is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, and R ?, &amp; and R! 〇 each have a stereo chemical configuration. In the &quot;K&quot; series of compounds, χΐ(), Rh, and others are as defined herein. Preferably, the heterocyclic group is preferably a substituted or unsubstituted furyl, thienyl or pyridyl group, and Xl Q is preferably a substituted or unsubstituted furyl group, a thienyl group, a pyridyl group, a phenyl group. Or a lower alkyl group (for example, a third butyl group) ' R 2 a is preferably a substituted or unsubstituted fluorenyl group, a thiophene group, a pyridyl group, a phenyl group or a lower alkyl group, and R?, R9 And Ri G each have a stereo chemical configuration. Any substituent of each of X3, X5, R2, R? and Rp may be a hydrocarbon group or any substituent containing a hetero atom selected from the group consisting of a heterocyclic group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, and an aryloxy group. a hydroxyl group, a hydroxyl group, a protected hydroxyl group, a ketone group, a decyloxy group, a nitro group, an amine group, a guanamine group, a thiol, a ketal, an acetal, an ester, and an ether moiety, but not a phosphorus-containing moiety Group. (Please read the notes on the back and fill out this page) - Order: -_ Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

(15) -58- The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of invention (56) Printing by the Intellectual Property Bureau of the Ministry of Economic Affairs

Series X5 X3 Pong 1 0 R2 r9 R1 4 A1 -COOX! 〇Heterocyclyl Rj 〇aCOO- c6h5 coo- 〇H A2 -COX! ο Heterocyclyl Ri 0aCOO- c6 h5 coo- 〇H A3 -CONHXi 0 Heterocycle Base Ri 0 a COO- c6h5 coo- 〇H A4 -COOXj Substituted by devaluation (: 2 to c8 alkyl Rio a COO- c6h5coo_ 〇H A5 -COX! Substituted by: (2 to c8 alkane) Base Ri 0 a COO- c6h5 coo- 〇H A6 -CONHXi 〇 之 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 a COO- c6h5 coo- 〇H A8 -COX! Substituted by &lt;:2 to c8 olefin 棊Rio a COO- c6h5 coo- 〇H A9 -CONHX! 0 Depending on the case, 02 to c8 alkenyl 0 a COO- c6h5coo- 〇H A10 -COOX! Substituted for substitution (: 2 to Cg block R1 0 a COO- c6h5 coo- 0 H -59- Read the back of the article; This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Α7 Β7 V. Invention description (57) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing clothing

All -COX! ο Substituted 匸2 to c8 alkynyl RlOaCOO- c6 h5 coo- 0 H A12 -CONHXi 0 Depending on the case, 02 to c8 alkynyl Rio a COO- c6h5 coo- 0 H B1 -COOX 〇Heterocyclic group 0aC〇〇- R2aCO〇- 〇H B2 -COX! ο Heterocyclic group Ri 〇aCOO- R2aCOO- 0 H B3 -CONHXi 0 Heterocyclic group R10aCOO- R2aCOO- 0 H B4 -COOXj Substituted 02 to c8 alkyl Rj 0aCOO- R2aCOO- 〇H B5 COX! Substituted by substitution (: 2 to c8 alkyl R10aCOO- R2aCOO- 0 H B6 -CONHDq 〇 depending on the situation (: 2 to c8 Alkyl R10acoo- R2aCOO- 0 H B7 -COOXi 〇 情 经 经 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : R10aCOO- R2aCOO- 0 H (Please read the note on the back and fill out this page) _-60- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 public) 1282793 A7 B7 V. Invention description ( 58) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

B9 -CONHXi Substituted as a substitute (: 2 to c8 alkenyl RlOaCOO- R2aC〇〇- 〇H B10 -COOX! Substituted by refusal (: 2 to c8 alkynyl Rio a COO- R2aCOO- 〇H B11 -COX! Substituted by devaluation (: 2 to c8 alkynyl 0 a COO- R2aCOO · 〇H B12 -CONHX! 02 之 经 至 02 to c8 alkynyl R1 〇aCO°&quot; R2aCOO- 0 H Ci -COOX! 〇Heterocyclyl R10aC〇O_ C6 h5 COO- R^COO- H C2 -cox! 0 Heterocyclyl R10aCOO- c6h5 COO- a COO- H C3 -CONHXj 〇Heterocyclyl R10aCOO- c6h5 coo- R^ COO- H C4 -COOXj 02 之 至 02 to c8 alkyl R10aCOO- c6h5 coo- R^COO- H C5 -COX! 〇 孓 孓 substituted 02 to c8 alkyl Rj 0aCOO- c6h5 coo- R9 a COO- H C6 -CONHXj 02 to c8 alkyl 0 a COO- c6h5 coo- R9 a COO- H ." 丨! - 丨 丨丨 (please read the notes on the back and fill in this Page) order · - line

-61 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 public tT 1282793 A7 B7 5. Invention description (59) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

C7 -COOX1 has been replaced by devaluation (: 2 to c8 alkenyl Rj0a COO- C6H5COO- R^COO- H C8 -COX! 〇 情况 经 至 至 02 to c8 晞 R1 oa COO- c6h5co〇- R9aC〇 〇- H c9 -CONHX1 0 Substituted 02 to c8 alkenyl Ri oa COO- c6h5coo- R^COO- H CIO -COOX! Substituted by substitution (: 2 to Cg block RlO a COO- c6h5coo - Rg a COO- H Cll -COX! Substituted 02 to block R1 0 a COO- c6h5 coo- a COO- H C12 -CONHXi 02 之 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 C6h5co〇- R^COO- H D1 -COOX! 〇heterocyclic tomb RlO a COO- c6h5 coo- OH H D2 -COX! 〇heterocyclyl RlO a COO- c6h5 coo- OH H D3 -CONHXi 〇heterocyclyl R1 0 a COO- c6h5 coo- OH H D4 -COOXi Substituted by ( (: 2 to c8 alkyl 0 a COO- c6h5 coo- OH H -62- This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) "! rlJIi (please read the note on the back and fill out this page) · . Line - 1282793 A7 B7 V. Invention Description (60 ) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print D5 -COX!Depending on the case, the 02 to c8 alkyl RlOaCOO- c6h5 coo- OH H D6 -CONHX! 02 to c8 fluorenyl Rio a COO- c6h5coo- OH H D8 COXi 〇 之 之 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 Ri 0aCOO- c6h5 coo- OH H D10 -c〇ox10 Depending on the case, 02 to Cg block R1 0 a COO- c6h5 coo- OH H D11 COX! ο Depending on the dragon (: 2 to c8 alkynyl) Rio a COO- c6h5 coo- OH H D12 -CONIDq 02 to c8 alkynyl Rio a COO- c6h5coo- OH H E1 -COOX! 〇heterocyclic group RlO a COO- c6h5 coo- 〇OH E2 - Cox10 ~Ί heterocyclic group R10aC〇〇-1 c6h5co〇- 〇OH -63-

Li"! ! ··! (Please read the notes on the back and fill out this page) I - 丨线- U , This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of invention ( 61) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

E3 -CONHXj 0 Heterocyclyl RlOaCOO- c6 h5 coo- 0 OH E4 -COOX! Substituted 匸2 to c8 alkyl Rio a COO- c6h5 coo- 0 OH E5 -COX! 0:2 to c8 alkyl Rj 0 a COO- c6h5 coo- 0 OH E6 -CONHXi 〇2 to c8 alkyl Rj 0aCOO- c6h5 coo- 0 OH E7 -COOXj 〇 depending on the situation :2 to c8 alkenyl R! 0aCOO- c6h5 coo- 〇OH E8 -COX! C2i c8 sulfhydryl group R! 〇a COO- c6h5 coo- 0 OH E9 -CONHXi disregarded by the situation :2 to 〇8 olefin tomb R10aCOO- c6h5coo- 〇OH E10 -COOX! Substituted by substitution (: 2 to C8 block R10aCOO- c6h5coo- 0 OH E11 -COX! 02 depending on the situation of the 02 to c8 alkyne Base R10aCOO- c6h5 coo- 0 OH (Please read the note on the back and fill out this page) -64- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (62) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

E12 -CONHX! 0 Substituted 匸2 to c8 alkynyl R,! 0 a COO- c6h5 coo- 〇OH F1 -COOXi 0 Heterocyclic Rio a COO- R2aCOO- ^ COO- H F2 -COX! Heterocyclyl R1O a COO- R2aCOO_ R^COO- H F3 -CONHXi 〇Heterocyclyl RlO a COO- R2aCOO- R9aCOO- H F4 -COOXj 0 Depending on the case, &lt;:2 to c8 alkyl Rio a COO- R2aCOO- a COO- H F5 -COX! ο 02 to c8 alkyl as the case may be Rio a COO- R2aCOO- R9aCOO- H F6 -CONHX! 0 Depending on the case, 02 to c8 alkyl Rio a COO- R2aCOO - a COO- H F7 -COOXi Substituted by 夂 (: 2 to c8 alkenyl R1 0 a C0°- R2aCOO- Rg a COO- H F8 -COX! Despise the situation by taking 0:2 to C8 alkenyl R1 0 a COO- R2aCOO_ R^COO- H F9 -CONHXi Substituted &lt;:2 to c8 alkenyl R10aCOO- R2aCOO- R9aCOO- H (Please read the back note first and then fill out this page )

P -• Line · -65- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of invention (63) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

F10 -COOXj 0 optionally substituted c2 to c8 alkynyl group \l 0 a COO- R2aC〇〇- a COO- H F11 -COXi 0 optionally substituted 0:2 to c8 alkynyl Rio a COO- R2aCO〇 - ^ COO- H F12 -CONHX! 0 Substituted as a substitute 0:2 to c8 alkynyl Rio a COO- R2aCO〇- R^COO- H G1 -COOXi 0 Heterocyclyl RlO a COO- R2aCO〇_ OH H G2 -COXi 0 Heterocyclic Rio a COO- R2aCOO- OH H G3 -CONHX! 〇Heterocyclyl RlO a COO- R2aC〇0- OH H G4 -COOXi Derogated 02 to c8 alkyl R1 0 a C0°- R2aCOO- OH H G5 -COX! ο Replace as appropriate (: 2 to c8 alkyl R1 0 a COO- R2aCOO- OH H G6 -CONHX! Despise love core, take &&lt;:2 To c8 alkyl RlO a COO- R2aCOO- OH H G7 -COOX! Substituted by substitution (: 2 to Cg unloading Rl OaC〇〇- R2aCOO- OH H (please read the back note first and then fill out this page ) - ireJ» • Line · -66 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm 1282793 A7 B7 V. Invention description (64) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

G8 COX! Substituted by substitution (: 2 to c8 alkenyl RlOaCOO- R2aCOO- OH H G9 -CONHXl Substituted 02 to c8 alkenyl Rj 〇aCOO- R2aCO〇- OH H G10 -COOX! 〇 Substituted as appropriate (: 2 to c8 alkynyl R1 oa COO- R2aCO〇- OH H G11 -COX! Substituted by devaluation (: 2 to c8 alkynyl Rl 0 a COO- R2aCOO OH H G12 -CONHXi 0 Substituted 匸2 to c8 alkynyl Rl OaCOO- R2aCOO- OH H Hi -COOX! 〇heterocyclyl R1 0 a COO- c6h5 coo- OH OH h2 -COX! 〇heterocyclyl R10aCOO- c6h5 coo- OH OH h3 -CONHXi 〇heterocyclic group R1 0 a COO- c6h5 coo- OH OH h4 -COOXi 〇 情 情 ( (: 2 to c8 alkyl Rj 0aCOO- c6h5 coo- OH OH h5 COX! Substituted (: 2 to c8 alkyl R10aCOO- c6h5 coo- OH OH -67- Note: Read the back δ Note: Please fill out this page. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1282793 A7 B7 V. Description of invention (65) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

H6 -CONHXi Substituted 02 to c8 alkyl RlOaCOO- C6H5 COO- OH OH H7 -COOX! Substituted by: (2 to c8 alkenyl Rio a COO- c6h5 COO- OH OH h8 -COX 〇 情况 之 至 至 至 至 至 至 至 至 至 至 至 CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO -COOXi Substituted as a substitute for 0:2 to c8 alkynyl Rio a COO- c6h5 coo- OH OH Hll -COX! Substituted by substitution (: 2 to c8 fluorenyl R1 0 a COO- c6h5 coo- OH OH H12 -CONHX! 〇X X Substituted & to c8 alkynyl 0aCOO- c6h5 coo- OH OH 11 -COOXi 〇heterocyclyl q aCOO- R2aCOO- 〇OH 12 -COX! 〇heterocyclyl 0 aCOO- R2aCOO- 〇OH 13 -CONHXi 0 Heterocyclic Rj 0aCOO- R2aCOO- 〇OH -68- (Please read the back note and fill out this page) Moderate ruler paper W 99 2 X 10 2 /V 4) AS) N (C standard standard 1282793 A7 B7 V. Invention description (66) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

14 -COOXj Substituted 02 to c8 alkyl \l0aCOO- R2aC〇0- 0 OH 15 -COX! ο Substituted as appropriate (: 2 to c8 alkyl R10aCOO- R2aCOO- 〇OH 16 -CONHXl 〇 Depending on the case, &lt;:2 to c8 alkyl Rio a COO- R2aCOO- 0 OH 17 -COOXi 〇 情况 之 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 The substituted 02 to c8 alkenyl 0 a COO- R2aCO〇- 0 OH 19 -CONHX! The ruthenium substituted 02 to c8 alkenyl OaC〇〇- R2aCOO- 0 OH 110 -COOXj 02 to c8 alkynyl Rj 0aCOO- R2acoo- 0 OH 111 -COX! Deviation to the 02 to Cg block base Rl 0 a COO- R2aCOO- 0 OH (please read the back note before filling in this page) _- 69- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (67) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

112 -CONHX1 Substituted by substitution (: 2 to c8 alkynyl RjOaCOO- R2aC〇〇- 〇OH J1 -COOXj 〇heterocyclic group Rio a COO- R2aC〇0- OH OH J2 -COX! 〇heterocyclic group 0 a COO- R2aCOO- OH OH J3 -CONHXi 〇heterocyclic group Rio a COO- R2aCOO- OH OH J4 -cocoq 0 Depending on the case, 02 to c8 alkyl RlO a COO- R2aCOO OH OH J5 -COX! Substituted 0:2 to c8 alkyl Rj 0aCOO- R2aC〇0- OH OH J6 -CONHXi 0 Substituted as appropriate (: 2 to c8 alkyl RlO a COO- R2aCOO- OH OH J7 -COOX! Substituted 0:2 to c8 fluorenyl R1 0 a COO- R2aCOO- OH OH J8 -COX! Despise the situation, take the Λ (: 2 to c8 alkenyl RlO a COO- R2aCOO- OH OH J9 -CONHXi Substituting c2 to c8 for RkO a COO- R2aCOO- OH OH (Please read the note on the back and fill out this page) -70- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of invention (68) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

J10 -COOX! Substituted 02 to c8 alkynyl RlOaCOO- R2aC〇〇- OH OH J11 COX! 0 Replaced as appropriate (: 2 to c8 block 0 a COO- R2aCOO- OH OH J12 -CONHXj Substituted by 0:2 to c8 alkynyl R10aCOO- R2aCOO_ OH OH K1 -COOX! 〇Heterocyclyl R10aCOO- R2aCOO- R^COO- OH K2 -COX! ο Heterocyclyl Rj 〇aCOO- R2aCOO_ R^ COO- OH K3 -CONHXi 0 Heterocyclyl R10acoo- R2aCOO- R9 a COO- OH K4 -COOX! Substituted 匸2 to c8 alkyl R10aCOO- R2aCOO- R9 a COO- OH K5 -COX! The situation has been replaced (: 2 to c8 alkyl R1 0 a COO- R2aCOO- a COO- OH K6 -CONHX! Deviation of the situation, the recovery of 02 to c8 alkyl Rj 〇a COO- R2acoo- R9 a COO - OH K7 -COOX! Substituted by the situation (: 2 to Cg-based Rj 0aCOO- R2aCOO- R^COO- OH (please read the back of the note first and then fill out this page) Order - • Line-h. - 71 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public 1282793 A7 B7 V. Invention description (69) K8 -COX! Substituting the situation (: 2 to the base %0aC〇〇- a COO- R^CO O- OH K9 -CONHX| q Substituted as appropriate &lt;:2 to Cg-formation RlO a COO- R2aco〇. R^COO- OH K10 -COOXj q Substituted as appropriate (: 2 to c8 alkynyl group 0 a COO- a COO- R^COO- OH K11 -COXj is replaced by the c8 alkynyl group Ri 0aCOO- R2ac〇〇. R9aCOO- OH K12 -CONHX! 〇 depending on the situation (: 2 to c8 alkyne R1 0 a COO- R2aC〇〇. R9aCOO- OH Example 5 (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed with a moderate ruler paper I by cell colony formation test The in vitro cytotoxicity measured will be four hundred cells (HCT11 phantom covered in 2.7 liters of medium (modified McCoy 5a medium containing 1% fetal calf serum and 1 〇〇 unit / ml penicillin and 100 mg / ML streptomycin) 60 mm Petri culture m. The cells were incubated in a C 2 incubator at 37 ° C for 5 hours to attach to the bottom of the Petri dish. The compound confirmed in Example 2 was added to the new medium at ten times the final concentration, and then 0.3 ml of this stock solution was added to the 2.7 ml of the medium in the dish. Next, the cells were incubated with the drug at 37 ° C for 72 hours. At the end of the culture, the drug-containing culture-72-National Standard (CNS) A4 specification (210 297 297 mm) 1282793 A7 B7 V. Invention description (70) (Please read the back note first and then fill out this page The base was decanted, the dish was rinsed with 4 ml of Hank's balanced salt solution (HBSS), 5 ml of new medium was added, and the dish was returned to the incubator for colony formation. After 7 days of culture, colonies were counted using a colony counter. The cell viability was calculated, and the number of ID50 of each test compound (the concentration of the drug which produced 50% inhibition of colony formation) was determined. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -73- This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention Description (71) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed compound living body ID 50 (nm) HCT116 Taxus 2.1 Thanks to others 0.6 0499 &lt;1 0503 &lt;1 ' 0517 &lt;10 0521 &lt;1 0536 &lt;1 0549 &lt;10 0550 &lt;10 0562 &lt;1 0578 &lt;1 0583 &lt;10 0596 &lt;10 0602 &lt;1 0611 &lt;10 0625 &lt;1 0634 &lt;10 0647 12.0 0659 &lt;1 0663 &lt;1 0670 &lt;1 0687 &lt;1 0691 &lt;1 0706 &lt;1 0719 &lt;10 0720 &lt;10 0732 &lt;10 0748 &lt;10 0838 &lt;1 0843 &lt;1 0854 ' &lt;1 0860 &lt;1 0879 &lt;1 0882 &lt;1 0890 &lt;;1 0908 &lt;1 0919 &lt;1 0923 &lt;1 0937 &lt;10 0947 &lt;1 0951 &lt;1 -74- (Please read the back note first and then fill out this page) Order · -- Line · Paper The scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) 1282793 A7 B7 V. Description of invention (72) Ministry of Economic Affairs Intellectual Property Bureau Workers' consumption cooperatives print the standard country's national use I moderate rule sheet paper 0966 &lt;10 0978 &lt;1 0983 &lt;1 0999 &lt;1 1003 &lt;1 1011 &lt;1 1020 &lt;1 ' 1031 &lt;10 1044 &lt;1 1060 &lt;1 1879 &lt;10 1883 &lt;10 1892 &lt;1 1900 &lt;1 1911 &lt;10 1923 &lt;1 1939 &lt;1 1948 &lt;10 1954 &lt;1 1964 &lt;10 1970 &lt;;10 1988 &lt;10 2101 &lt;1 2111 &lt;1 2124 &lt;10 2132 &lt;1 2142 &lt;1 2159 &lt;1 2164 &lt;1 2173 &lt;1 2181 &lt;10 2199 &lt;10 2202 &lt;1 2212 * &lt;10 2226 &lt;1 2238 &lt;1 2242 &lt;10 2255 &lt;1 2269 &lt;1 2273 &lt;1 2287 &lt;1 2291 &lt;1 2306 &lt;10 2319 &lt;10 2320 &lt;1 2332 &lt;1 2348 &lt;1 2353 &lt;10 2366 &lt;1 -75- :―NS)A4 Specification (210 X 297 ^ ) (Please read the note on the back and fill out this page) Order · Line 1282793 A7 B7 V. Description of invention (73) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 2379 &lt;1 2380 &lt;1 2392 &lt;1 2408 &lt;1 2413 &lt;10 2424 &lt;10 2439 &lt;10 . 2442 &lt;1 2455 &lt;10 2464 &lt;1 2472 &lt;1 2488 &lt;1 2499 &lt;1 2503 &lt;1 2511 &lt;1 2520 &lt;10 2781 &lt;1 2794 &lt;1 2802 &lt;1 2813 &lt;1 2826 &lt;1 2838 &lt; 1 2844 &lt;10 2855 &lt;1 2869 &lt;10 3053 &lt;1 3071 &lt;1 3096 &lt;1 3102 &lt;1 3110 &lt;1 3129 &lt;10 3132 &lt;1 3148 &lt;1 3163 . &lt;1 3204 &lt;1 3219 &lt;1 3222 &lt;1 3258 &lt;1 3265 &lt;10 3297 &lt;1 3314 &lt;1 3352 &lt;1 3361 &lt;1 3370 &lt;1 3408 &lt;1 3417 &lt;1 3425 &lt;;1 3453 &lt;1 3482 &lt;1 (Please read the note on the back and fill out this page) Order: --Line-76- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public Ί 1282793 A7 B7 V. Description of invention (74) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 3494 a &lt;1 3513 &lt;1 3522 &lt;1 3535 &lt;1 3543 &lt;10 3588 &lt;10 3595 &lt;1 3603 &lt;10 3644 &lt;1 3656 &lt;1 3663 &lt;1 3677 &lt;1 3686 &lt;1 3693 &lt;1 3800 &lt;1 3818 &lt;1 3853 &lt;1 3866 &lt;1 3909 &lt;1 3938 &lt; 10 3945 &lt;1 3957 &lt;10 3971 &lt;1 3982 &lt;1 3994 &lt;1 4051 &lt;1 4062 &lt;1 4112 &lt;10 4121 &lt;10 4190 &lt;10 4207 &lt;10 4329 &lt;1 4335 &lt;1 4344 &lt;1 4665 &lt;10 4704 &lt;;10 4711 &lt;10 4720 &lt;10 4799 &lt;1 4808 &lt;10 4834 &lt;10 4888 &lt;1 4919 &lt;1 4944 &lt;1 5011 &lt;10 5040 &lt;1 5065 &lt;10 5144 &lt;10 5232 &lt;10 (Please read the note on the back and fill out this page): Line-77 - This paper size applies to China National Standard (CNS) A4 specification (210 x 297 public meal 1282793 A7 B7 5. Invention description (75 5495 &lt;t 6522 &lt;1 (Please read the note on the back and fill out this page) Example 6 Preparation of Oral Administration Solution Solution 1: The antitumor compound 0499 is dissolved in ethanol to form 106 per ml of solution. A solution of this compound in milligrams. An equal volume of CremophoPEL solution was added to the solution while stirring to form a solution containing 53 mg of compound 0499 per ml. This solution was diluted with 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 2: Antitumor compound 0550 was dissolved in ethanol to form a solution containing 140 mg of the compound per ml of solution. An equal volume of CremophoPEL solution was added to the solution while stirring to form a solution containing 70 mg of compound 0550 per ml. This solution was diluted with 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Cooperatives Solution 3: The antitumor compound 0611 was dissolved in ethanol to form a solution containing 150 mg of the compound per ml of solution. An equal volume of CremophopEL solution was added to the solution while stirring to form a solution containing 75 mg of compound 0611 per ml. This solution was diluted with 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 4: Antitumor compound 0748 was dissolved in ethanol to form a solution containing 266 mg of this compound per ml of solution. An equal volume of Cremophor® EL solution was added to the solution while stirring to form a solution containing 133 mg of compound 0748 per ml. This solution was diluted with 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. -78- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 1282793 A7 -----------Β7 _ V. Description of invention (76) Example 7 Oral administration suspension Preparation of Liquid The oral composition of the antitumor compound of the present invention can be prepared by suspending 25 mg of the compound in a fine powder in one milliliter of a carrier containing 1% carboxymethylcellulose in deionized water ( CMC). Example 8 Preparation of Orally Administered Tablets The antitumor compound of the present invention (100 mg) was dissolved in di-methane (2 ml), and Cremophor® EL solution (1 mg) was added. The dioxane can be evaporated under a hollow to form a glassy substance. Microcrystalline cellulose (600 mg) can be added to the glass material and mixed to form a powder which can be processed to form a tablet. Example 9 Preparation of a parenteral pharmaceutical emulsion Emulsion 1: The antitumor compound of the present invention was dissolved in 1 〇〇〇/. In ethanol, a solution containing 4 mg of compound per ml of solution was formed. This solution may be diluted with 19 parts by weight of Liposyn® II (20%) and stirred to form an emulsion containing 2 mg of compound per ml for parenteral administration. Emulsion 2: The antitumor compound of the present invention can be dissolved in 1 〇〇 0 / 〇 ethanol to form a solution containing 40 mg of the compound per ml of the solution. This solution can be diluted with 19 parts by weight of Lip0Syn® III (2%) and agitated to form an emulsion containing 2 mg of compound per ml for parenteral administration. Emulsion 3: The antitumor compound of the present invention can be dissolved in 1 〇〇 0 /. In ethanol, a solution of 40 mg of the compound is formed in the mother's solution. This solution can be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) by the __ -79-____ paper size' — (Please read the back note and then fill out this page) «- • Line · Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed 1282793 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (77) Dilute with 9 parts by weight of Liposyi^III (2%) and stir to form per ml An emulsion containing 4 mg of compound for parenteral administration. Example 10 Preparation of a solution containing a compound for parenteral administration Solution 1: The antitumor compound of the present invention can be dissolved in 100. /. In ethanol, a solution containing 140 mg of compound per ml was formed. This solution may be diluted with an equal volume of Cremophor® EL solution and stirred, and then diluted with 9 parts by weight of a fixed salt solution to form a solution containing 7 mg of the compound per ml of the solution for parenteral administration. Solution 2: The antitumor compound of the present invention was dissolved in 100 ° / 〇 ethanol to form a solution containing 140 mg of the compound per ml of the solution. This solution may be diluted with an equal volume of Cremophor® EL solution and stirred, and then diluted with 4 parts by weight of a fixed salt solution to form a solution containing 11.7 mg of the compound per ml of the solution for parenteral administration. Solution 3: The antitumor compound of the present invention was dissolved in 100% ethanol to form a solution containing 140 mg of the compound per ml of the solution. This solution may be diluted with an equal volume of Cremophor® EL solution and stirred, and then diluted with 2.33 parts by weight of a fixed salt solution to form a solution containing 16.2 mg of the compound per ml of the solution for parenteral administration. Example 11 In Vivo Evaluation of Antitumor Compounds Against Human Lung Cancer Xenografts Antitumor compounds for intravenous administration were formulated and prepared in the following vehicles: 10% ethanol, 10. /〇 Cremophor and 80% isotonic saline. These antitumor compounds were formulated in the manner described in Solution 2 of Example 10. As -80- _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back and fill out this page) Order._ Line 1282793 A7 V. Invention description (78) f ten days?物# &gt; A , ', Paclitaxel (pacicaxel), Bristol Meyers ί Clearly read the back of the note and fill out this page)

Squibb) is obtained from commercially available medicine. The two lung tumor xenografts used in Yuxianxian are SK-MES cancers, which are extremely sensitive to paclitaxel, and NCWil299 (H1299) cancer, which is more resistant to paclitaxel than SK-MBS: tumors. On the first day, the female NCr-hairless old m* with either SK-MES or H1299 tumors (using 1 cubic meter of human lung cancer fragments implanted subcutaneously into the lumbar fossa) will be paired into six The four groups of mice, the average tumor size of the group was 241.244 mg. The treatment group consisted of: vehicle treatment (Group 1); treatment with paclitaxel (Group 2); and treatment with anti-tumor compound 〇5〇3 (Group 3). The Ministry of Economic Affairs, the Intellectual Property Office, and the Staff Consumer Cooperative, which prints paclitaxel and anti-tumor compound 0503, is administered intravenously at a maximum allowable dose (MTD) for each compound, half of which is based on a daily schedule. Give one hour at intervals. The MTD of anti-tumor compound 0503 was calculated from a single dose of data about the intravenous administration of this compound to mice. Paclitaxel itself was administered at a separate intravenous dose of 36 g/kg for the use of two 18 mg/kg doses separated by one hour. Vehicle control animals were administered intravenously twice, with half of the total volume administered one hour apart. The study was terminated on day 60. The results are summarized in Table 1 and include the average number of days of survival (Mds), the number of maternal deaths, the number of survivors, the number of redundant or partial responses, and the number of stable diseases. The average number of days of survival was the number of days after the tumor reached a size of 1.5 grams and the animals were euthanized. If the tumor is not touched at the end of the study, a full response is obtained. If the size of the tumor is reduced to less than -81 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (79) Study the size of the first day, and 1 get a partial response. When this treatment limits the growth of the tumor to a small size, which does not reach 15 g hours at the end of the study, f occurs and the disease is stabilized by π. The Tumor Scoring System is designed to provide a more quantitative level of efficacy (therapeutic potential) in anti-tumor agents that are evaluated against different human solid tumor xenografts. Each mouse in the study was given a score of 1 to 10 at the end of the study. These scores can be summarized as follows: Scoring Description &lt;1 Severe Toxicity 2-3 Tumors reach the cut-off size, but significant tumor growth delays are evident 4-6 Tumor growth is significantly inhibited (Deep disease) 7-9 Partial tumor shrinkage (Partial response) 10 Full response (perfect score) The individual scores for each mouse were averaged to the average score for each treatment group. This tumor scoring system provides a better comparison of different anti-tumor compounds by quantifying treatment outcomes (complete response to partial response). Table 1 Group MDS (5) Toxic death survivors complete response partial response stable disease average score 1 12.2 soil 1.3 (6) 0 0 0 0 0 1+0 2 16 soil 2.0 (6) 0 0 0 0 0 1.3+0.3 3 46_0 ± 0 (2) 0 4 3 0 1 6.5 + 1,6 12-day DDS oxime was calculated from the vehicle-treated control group. Compared with the vehicle control group, paclitaxel (36 mg/kg; Group 2) produced only a modest 30% survival prolongation (MDS = 16.0 days) with no recorded tumor regression. In contrast, the antitumor compound 0503 was highly active. With media or purple shirt-82- (please read the notes on the back and fill out this page) --------Book --------- This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) — 1282793 A7 B7 V. Description of invention (8〇) Compared with the alcohol control group, compound 050$ (72·1 mg/kg; Group 3) produced four and three complete responses. It has a significant prolongation of survival and is recorded in the green treated animals. The antitumor compound 0503 was well tolerated. In the Η1299 experiment, on day 1, mice were paired into groups of six animals, with a mean tumor size range of 229-233 mg. The treatment plan for the Η1299 trial is the same as the sk-mes trial. The 24.5 days of MDS tethering was calculated from the vehicle treatment control group. Paclitaxel (36 mg/kg; Group 2) did not have activity in the Η1299 mode. Compared with vehicle-treated animals, only 1% of the five animals survived prolonged (MDS = 27.〇天 X Statistics Not significant). After paclitaxel treatment, a partial response was found. Table 2 Group MDS(8) Toxic death i live complete response partial response stable disease average score 1 24.5 soil 3.3 (6) 0 0 0 0 0 1.2 soil 0.2 2 27.0 soil 4.6 (5) 0 1 0 0 0 2.7 ± 1.3 3 — 1 5 2 0 3 5.5 + 1.6 Printing by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives (please read the notes on the back and fill out this page) Antitumor Compound 0503 has proven to be effective against Hl299 tumors against paclitaxel. Compound 0503 (72.! mg/kg; Group 3 &lt;) caused two complete responses in the Sm299 assay. Other mice treated with this compound experienced a significantly increased survival time when compared to vehicle treated or paclitaxel treated animals. In the group treated with antitumor compound 0503, one mouse died of toxicity in H1299 4%. Since the dose and timetable are the same as the experiment, no toxic death is found, so the hairless old, the past ones are 83. The paper ruler &amp; Weekly Chinese National Standard (CNS) A4 specification (21〇x 297 Love) ---- 1282793 A7 B7 V. INSTRUCTIONS (81) The effect is probably not due to the toxicity of the system. Based on the extreme reaction of H1299 tumor to antitumor compound 0503, including cancer necrosis and hemorrhage, one explanation is that the compound causes destruction of tumor structure and matrix, and toxic substances are released from the tumor to the host mouse. It is effective when k tumor compound 0503 is administered as a single bolus to resist human lung cancer xenografts in a disadvantageous position (250 mg). Example 12 In Vivo Evaluation of Anti-Tumor Compounds Against HCT116 Human Colon Carcinoma Xenografts Anti-tumor compounds were formulated for intravenous administration and were prepared with the following vehicles: 5% Ethanol, 5% Cremophor, and 90% Isotonic brine. These compounds were formulated in the manner described for Solution 1 of Example 10. Paclitaxel (Breakfast, Bristol Meyers Squibb) was obtained as a commercial medicine. The volume of the drug is 20 grams of the mother, 3 liters. The HCT116 cancer system is representative of human colon tumors and is generally insensitive to chemotherapy drugs. Therefore, such tumors are not clinically treated with paclitaxel. Female NCr-hairless mice with HCT116 tumors (using 1 cubic millimeter of human cancer fragments implanted subcutaneously into the lumbar fossa) were paired on day 1 into groups of five mice, with the average tumor of the group The size ranged from 254 to 26 mg, but the average tumor size of group 3 (the second paclitaxel control group) was 104.8 mg on day 1. The treatment group consisted of: vehicle treatment (group i); intravenous treatment with paclitaxel at the separation dose on day 1 (group 2); paclitaxel peritoneal in 5 doses per day without separation Intracavitary (ip) treatment -84 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm). 丨 丨 ih!丨#·11 (Please read the notes on the back and fill out this page) — ' • Ministry of Industry, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed 1282793 A7 B7 V. Inventions (82), after 1-5 days (Group 3, . . . , and anti-tumor compounds 0503, 0536 , 0663 0670, 0687, 0706, 0908, 0947 OQq (please read the notes on the back and fill out this page), 5丨, 0983, 0999, 1003 and 1011 (individual equine groups 4-16). The treatment groups are summarized in Table 3. The anti-tumor compound is administered in a peri-modal form at a single maximum allowable dose suitable for each compound. The paclitaxel control was administered to each of two =: Group 2 was on Day 1, to separate doses, on a time basis, administered, and Group 3 was administered on an unseparated schedule for five days (every day) ^) tumor compound (MTD, calculated from the earlier single dose data of the old drug for intravenous administration of this compound. All vehicle control animals in the separation drug use method were administered intravenously twice. Wherein, the heart was given half-line interval-hours. The study was terminated on day (9). The results were greened in Table 3, and included the average number of days of survival (MDS), the number of dead mites, and the number of survivors. 'The number of complete or partial responses, and the number of stable diseases. The average number of days of survival is the number of days after the tumor reaches 2 grams and the animal is euthanized. If the tumor cannot be reached at the end of the study, it is completely Respond. If the size of the tumor is reduced to less than the size of the first day of the study, then a response is obtained. When this treatment limits the growth of the Department of Health, the Ministry of Intellectual Property, the employee's consumer cooperative, to a small size, When the study did not reach the size of 20 grams, it occurred, and the disease was stabilized by π. Table 3 Group anti-tumor compound MDS (8) Toxic death survivors Complete response Partial response to stable disease average score 1 Vehicle control 22.2 Soil 2.0 (5 0 0 0 0 0 1 Soil 0 2 Ethyl alcohol (36 mg/kg) 27.5 Soil 1.7 (4) 0 1 0 0 1 2.2 Soil 0.5 -85- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Description of Invention (83) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 3 Ethyl Alcohol (18 mg/kg) 40.8 Soil 3.6 (4) 0 ^ 1 0 1 0 3.6 Earth 1.4 4 No. 0503 (72.6 mg/kg) 0 5 1 4 0 9.2 ± 0.2 5 No. 0536 (49 mg/kg) 0 5 1 4 0 9.2 Soil 0.2 6 No. 0663 (159 mg/kg) 1 4 2 2 0 7.6 Soil 1.9 7 No. 0670 (123 mg/kg) 29.8 ± 0.7 (2) 0 3 2 1 0 6.6 Soil 1.9 8 No. 0687 (159 mg/kg) 0 5 4 1 0 9.6 ± 0.4 9 No. 0706 (108 mg/kg) 0 5 1 4 0 9.2 Soil 0.2 10 No. 0908 (159 mg/kg) 0 5 1 4 0 9.2 Soil 0.2 11 No. 0947 (76.9 mg/kg) 0 5 1 4 0 9.2 Soil 0.2 12 No. 0951 (72.6 mg/kg) 0 5 3 2 0 9.6 Soil 0.2 13 No. 0983 (72.6 mg/kg) 2 3 2 1 0 5.8 Soil 2.4 14 No. 0999 (49 mg / kg) 0 5 1 4 0 9.2 Soil 0.2 -86- (Please read the note on the back and fill out this page) f Order --------- Line ' This paper The scale applies to China National Standard (CNS) A4 specification (2忉x 297 mm) 1282793 V. Description of invention (84) 0 9.4 Soil 0.2 0 9.6 ± 0.2 15 No. 1003 (49 mg / kg) No. 1011 (108 mg kg)

(Please read the notes on the back and fill out this page.) Printed by the Consumers' Cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs, it grows gradually until it reaches the cut-off size of 2.0 grams. For the second calculation, 22.2 days &lt; mds値. In a single dose of % mg/kg (Group 2), 'intravenous administration of paclitaxel produced _ 27.5 days in four mice' and caused a stable disease condition (Table $. Animals in control group 1) The 24, the 24% increase in survival was statistically significant at p - 0.048 (unpaired t test). At a dose of 18 mg/kg, on a daily X 5 schedule ( Group 3), with paclitaxel administered intraperitoneally, caused MDS値 to 40.8 days in four mice, one of which responded partially at the end of the study (12 mg on day 6). In the Dijon group, the 84% survival prolongation was significant 2 = 〇〇〇1; unpaired t test) ° In general, these antitumor compounds were highly active in the hCT116 assay (Table 3). In the study, at the time of the bundle (the 6th day), each mouse experienced a persistent full response or a partial response. In any treated animal, the tumor reached an end point of 2.0 grams, except for the compound 〇67〇.柷 Tumor compound 0670 produced a mixture of tumor shrinkage and tumor reaching a 2 gram cutoff size. Two sputum responses and one partial response were recorded in compound 0670-treated mice (Group 7); the 29-day DDS sputum was calculated for the remaining two animals in this group (with Group 1) Compared with the system, at p = 0.038; unpaired t test) 〇-87- This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Printed A7 B7 V. INSTRUCTIONS (85) On day 60, small tumors in animals that have undergone long-lasting, partial HCT116 reduction (partial response) will be excised and weighed. The actual weight and diameter of these small tumors were compared to the weight of the tumor estimated to be converted to milligrams of tumor weight, which was consistent at the 60th day between the two groups of HCTn6 weight. In Table 3, all the mice referred to as partial responses apparently had a reduction in the size of the tumor from the onset of the third day of the cancer, as evidenced by the actual HCT116 weight on day 6. Eleven of the thirteen antitumor compounds were well tolerated in the study. For the eleven compounds, there was no report of toxic death, and the average weight loss of the group was approximately 8% -12% on day 6. This is well within the acceptable range of side effects of cancer chemotherapeutic drugs set by NCI. As indicated in Table 3, anti-tumor compound 0983 caused two toxic deaths on day 6-1, and the average weight loss of the resulting group was more than 20%. Paclitaxel was well tolerated on both schedules, resulting in only modest weight loss and no death. All of the twelve anti-tumor compounds evaluated against rICTI 16 human colon cancer xenografts demonstrated significant activity against this colon tumor. Each animal treated has a long-lasting, partial or complete reduction in its tumor. The chemotherapeutic drug paclitaxel was included in this study as a positive drug control group. Paclitaxel itself had a prolonged survival rate of 24% higher than that of control mice at a daily schedule without a full response or partial response. Paclitaxel is administered at its most suitable timetable of 5 times a day, which results in 84 compared to the control animals. /. Survival is prolonged and a partial response is generated. Therefore, the efficacy achieved by paclitaxel administration is much lower than that of other Chinese standard (CNS) A4 specifications (210 X 297 mm) for other papers. I---- #·! (Please read the notes on the back and fill out this page) Order · 丨 line · 1282793 A7 B7 V. Invention description (86 )

The person who achieved the tumor compound. X Example 13 (Read the back of the note first and then fill out this page) Anti-tumor compound resistance MX-1 Human breast cancer xenografts in vivo evaluation Thirteen anti-tumor compounds for intravenous administration A single intravenous bolus of the summer time schedule) was prepared in the following vehicle: 5〇. Ethanol, 5% Cremophor and 90% isotonic saline. The compound was formulated in the manner described in the solution 1 of the example (7). Paclitaxel (Breakfast, Bristol Meyers Squibb) used as a control was obtained as a commercially available medicine. The volume of the drug was 0.3 ml per 20 g mouse. MX-1 cancer is a representative of human breast cancer unrelated to estrogen and is sensitive to a variety of chemotherapeutic drugs, including paclitaxel. In fact, paclitaxel can produce tumor shrinkage in mice with MX4 at its most appropriate five-day schedule, but it is far less effective in a daily schedule, as noted in this study. . The Ministry of Economic Affairs’ Intellectual Property Office employee consumption cooperative printed a female NCr-hairless mouse with MX-1 tumors (using 1 cubic millimeter of human-like cancer fragments, implanted subcutaneously into the lumbar fossa) on the third day. Paired into a group of six mice, with an average tumor size ranging from 219.226 mg. Treatment groups included: vehicle treatment (Group 1); paclitaxel treatment (Group 2); and anti-tumor compounds 0503, 0536, 0663, 0670, 0687, 0706, 0908, 0947, 〇951, _3, 0999 , 1003 and 1011 (individually the third group). The treatment group is summarized in Table 4. The anti-tumor compound is administered intravenously at a single maximum tolerated dose (MTD) suitable for each compound. Paclitaxel control is on the first day, -89 - This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Five A7 ^^一__B7 _ Invention description (87) x knife off-dose administration (1 timetable per day). The MTD of the anti-tumor compound was obtained from the earlier single dose data of the intravenously administered mice. All vehicle control animals in the sequestration regimen were administered intravenously twice, with one-half of the total volume administered one hour apart. The research department was terminated on the 60th day. The results are summarized in Table 4 and include the mean number of days of survival (MDS), the number of toxic deaths, the number of survivors, the number of complete or partial responses, and the number of stable disease. The average number of days of survival is the number of days that the tumor reaches 2 grams and the animal is euthanized. A full response is obtained if the tumor does not reach at the end of the study. A partial response was obtained if the tumor size was reduced to less than its size on study day 1. When the treatment limits the growth of the tumor to a small size, it does not reach the size of 2 gram at the end of the study, and occurs, and the disease is stabilized by π. Table 4 (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Group Anti-tumor Compound MDS(8) Toxic Death #活者 redundant response partial response to stable disease average score 1 vehicle control 19.7 ± 3.5 (6) 0 0 0 0 0 1 Soil 0 2 Ethyl alcohol (36 mg/kg) 27.8 (1) 0 1 0 0 1 1.2 Soil 0.8 3 No. 0503 (72.6 mg/kg) 0 6 4 2 0 9.7 Soil 0.2 4 No. 0536 (49 mg/kg) A 2 4 4 0 0 6_7 ± 2_1 5 No. 0663 (159 mg/kg) 28.6(1) 0 5 4 0 1 7.7 Soil 1.5 6 No. 0670 (123 mg / kg) 28·5 士6.1 (4) 0 2 1 1 0 4.3 士1.6 -90- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 B7 V. Invention description (88 No. 0687 (159 mg / kg) 8.3 Soil 1.7 11 12 13 15 No. 0706 (108 mg / kg) No. 0908 (159 mg / kg) No. 0947 (76.9 mg / kg) No. 0951 (72.6 mg / kg) No. 0983 (67.4 mg / kg) No. 0999 (49 mg / kg) No. 1003 (49 mg / kg No. 1011 (108 mg / kg) 8.3 ± 1.7 9.7 ± 0.3 5 · 5 ± 2.1 9.5 ± 0.5 10 ± (please read the notes on the back and fill out this page) 45.3 (1) 29.1 Soil 10.8 (2) 0 6 6 0 8·2 士1·2 7.3 1.7 IO 10 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed All ΜΧ-1 cancer lines were rapidly and progressively grown in all six animals receiving the vehicle (Group 1) . The mds of these mice reaching 2.0 g tumor cut-off point was 19.7 days. Paclitaxel (Group 2) administered intravenously at a single dose of 36 g/kg was not well tolerated in this study; four toxic deaths were recorded. One mouse experienced a stable disease state, while the remaining animals achieved an MDS of 27.8 days (calculated). Therefore, paclitaxel demonstrated moderate antitumor activity in two mice that had not experienced serious side effects. Significant tumor response rates were achieved in this ΜΧ-1 study with thirteen antitumor compounds. Five anti-tumor compounds (0536, 0687, 0706, 0983 and 1011) cause complete and persistent tumor regression in all treated mice (also -91 - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Α7 Β7 V. Description of invention (89) Four toxic deaths occurred). Three other anti-tumor compounds (0503, 0908, 0951) produced a sustained complete response and partial response in 100% treated animals. In all animals, '14 complete responses and 4 Shao responses were generated by the three compounds' without serious toxicity report. The last group of five anti-tumor compounds (0663, 0670, 0947, 0999 and 1003) were a mixed mix of responses, including 16 full response 'two partial responses, one stable disease situation, and nine cases for which Tumors in treated mice reached a 2 gram cut-off, but had MDS 値 greater than those calculated for the vehicle control group. Two mice treated with compound 〇947 died of toxicity. Example 14 Antitumor Compounds Against DU 145 Human Prostate Cancer In Vivo Evaluation of Xenografts Antitumor compounds were in the manner described in Example 1 〇 Solution 1, at 5% Ethanol, 5. /. Made with Cremophor and 90% isotonic saline. Paclitaxel (Pecillinol; Bristol Meyers Squibb) was obtained as a commercial medicine. The volume of the drug was 0.3 ml per 20 g mouse. Male NCr-hairless mice were implanted subcutaneously into the lumbar fossa using 1 cubic millimeter of du 145 prostate cancer fragments and selected for treatment in each of the five mice. The average size of the DU 145 group ranged from 223 to 228 mg. Take the medicine in the first day of the brother: The anti-tumor compound is administered intravenously at a maximum allowable dose (MTD) for each agent as estimated on a daily schedule (single dose of the compound). Intravenous paclitaxel was administered at two separate doses per day (between one hour) at a dose of 12 mg/kg (total dose = 24 mg/kg). Paclitaxel is also used 5 times a day -92- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 public interest) r Qingxian 璜 之 之 之 再 再 再 · · · · · · · · · Employee consumption cooperative printed 1282793 A7 B7 V. Invention description (90) The table was administered intraperitoneally at a daily dose of 18 mg-/kg. The vehicle was administered intravenously to the first group of control mice under a daily schedule. The death was terminated on the 91st day. The treatment groups are detailed in Table 5. Table 5 Group 4 匕 亳 / / kg pathway schedule 1 vehicle --- intravenous once a day 2 paclitaxel 24 intravenous once a day 3 paclitaxel 18 peritoneal cavity 5 times a day 4 0499 77 intravenous daily 1 Time 5 0503 72.6 Intravenous once a day 6 0670 123.1 Intravenous once a day 7 0706 107.6 Intravenous once a day 8 0838 72.6 Intravenous once a day 9 0854 76.9 Intravenous 1 Once a day 10 1011 107.6 Intravenous once a day The results are summarized in Table 6, and include the average number of days of survival (MDS), the drug 丨 丨 丨 丨 丨 — — — — — — — 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 丨丨 清The number of survivors, the number of responses in whole or in part, and the number of stable diseases. The average number of days of survival was the number of days after the tumor reached a height of 1.5 grams and the animals were euthanized. A full response is obtained if the tumor size is reduced to less than the size of its first day of death. When the treatment limits the growth of the tumor to a small size, the π-stable disease occurs when the sample is not reached at the end of the study. -93- This paper scale applies the Chinese National Standard (CNS) A4 specification (21〇X 297 mm). • Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282793 jade, invention description (91: Table 6

(Please read the notes on the back and fill out this page.) The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed DU145 tumor system gradually growing in three of the five mice (group) treated with vehicle; The animals were calculated to be 34. 3 days old. One of the mice in group 1 died on the 40th day and died of unknown cause, while the cancer in the other mouse in group i was slower than the 22 gram of the pair. It slowly degenerates until the tumor is no longer tangible at 71 days. The situation described thereafter is likely to be an example of poor tumor sampling. Two of the five animals receiving paclitaxel at 24 mg/kg (intravenous; once daily) were stably growing and reached 1.5 g endpoint with MDS = 37.4 days (2nd) group). This 9% increase in survival compared to the first control group was not statistically different (p = 〇 82; unpaired t-test). One of the animals in Group 2 died on Day 32, possibly due to drug-related side effects. The fifth mouse in Group 2 did not experience net tumor growth in the 91-day study; the cancer on day 6 was the same size as Day 91 (196 mg). At the dose of 18 mg / kg, according to the daily limit of 94 - paper size, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is set --------- Line-Γ. 1282793 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 B7 V. INSTRUCTIONS (92) Schedule, paclitaxel administered in the peritoneal cavity (Group 3) is highly toxic. All five mice died of drug-related side effects, including substantial (often greater than 20%) weight loss. Antitumor compounds 0503 and 0838 produced a total response rate of at least 50%. Antitumor compound 0838 (Group 8) was active, yielding 2 complete responses and 60 0/. Total response rate. Antitumor compound 0503 (Group 5) resulted in a complete response to the mix, partial response, stable disease response, and extended MDS値 compared to the first control group. The anti-tumor compounds 0499, 0670 and 0706 achieved a total response rate between 20% and 50%. Compound 0706 (Group 7) produced 2 complete responses with a stable disease condition, and the MDS of the remaining 2 mice was 67.4 days (the strong trend orientation was significantly different from the MDS = 34.3 days of the 1st control group, at p = 〇.〇7下·, unpaired t-test). Antitumor compound 0706 is also well tolerated. The other four compounds produced a complete response, partial response, stable disease status, and MDS値, which were fully extended compared to the 34.3 days MDS of Group 1. Two compounds, 0854 and 1011, caused at least two toxic lethalities (4 〇〇 /. mortality or higher) from the five animals treated with each compound at the doses administered. Antitumor compound 0854 was 100% lethal to the rats at the doses administered. All of these compounds produced weight loss of more than 2% in many treated mice prior to their death. . The remaining compounds were well tolerated in this test, each causing no or only one toxic death, and in the second week of the trial, 8-12% of the most average weight loss was produced. These moderate side effects are well within the NCI guidelines for the acceptable toxicity of chemotherapeutic drugs in mice. 95- This paper scale applies the Chinese National Standard (CNS) A4 specification (21〇X 297 Love) I.--L. ------1 · 1111111 ^--------1 (Please read the notes on the back and fill out this page) 1282793 Α7 Β7 Ministry of Economic Affairs Intellectual Property Office staff consumption Co-operative printing 5, invention description (93) sex 0: an example 15 anti-tumor compound resistance to A2780 human printed cancer xenografts in vivo evaluation of anti-tumor compounds in the manner described in Example 10 solution 1, in ethanol, Made with 5% Crem〇Ph〇r and 90% isotonic saline. Paclitaxel (Breakfast) (Bristol Meyers Squibb) and Taxotere (docetaxel; Rhone-Poulenc Rorer) were obtained from commercially available medicines. The volume of the drug is 0.3 ml per 20 g. Female NCr-hairless mice were implanted subcutaneously into the lumbar fossa using a cubic millimeter of A278 〇 melanoma fragments and selected as a treatment group for each of the five mice. The only group of the yew sage treatment group consisting of six mice group. The average size of the A278〇 group ranged from 237 to 243 mg. The medication started on the first day. The anti-tumor compound is administered intravenously at a maximum allowable dose (MTD) for each agent, on a daily schedule (single dose of the compound). Intravenous paclitaxel was administered at two separate doses (between one hour) on a daily schedule of 12 mg/kg (total dose = 24 mg/kg). Paclitaxel was also administered intraperitoneally at a dose of 15 g/kg on a daily schedule of 5 times. The yew buds were administered intravenously at a dose of 7 mg/kg per day. The vehicle was administered intravenously to the control mice of Group 1 under a daily schedule. This research was terminated on the 6th day. The treatment groups are detailed in Table 7. ________ -96- Machinery 5^ Applicable (CNS) A4 Specifications (21G χ 297 public) .I — ί--------- — — I—^---------Ί 41^ · c Please read the notes on the back and fill out this page. 1282793 Five 'Inventions' (94 A7 B7 16 oligo alcohol ^0503 0536 0663 0687 0706 0947 095Γ 0983 0999Tool ΐ〇ΐΤ _ 紫 / kg route schedule --- ---- Once a day in the vein - 24 an intravenously once a day ----------- In the luminal cavity ^ 5 times a day -------- — 72.6 A daily pulse within 1 Times-----.--Intravenous once a day ------- Intravenous once a day ---------- 1 time in the meal every day #1 times per day _ 159.4 &quot ;&quot;&quot;Intravenous once a day----- 丨 intravenously once a day intravenously once a day intravenously once a day 49 intravenously once a day - 49 intravenously once a day intravenously once a day - — Intravenous once a day --- ' 依 仟 外 丄 丄 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十The average number of days of survival is that the tumor reaches a size of 2.0 grams. &lt; days and euthanasia. If the tumor size is reduced to less than the size of the first day of the curse, a full response is obtained. When the treatment is limited (please read the back note and fill out this page) -- -------Book---------Line' Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printed tumors to a small size, when the study did not reach the size of 2.0 grams, it will happen '' Stabilize the disease. -97- The paper size applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 1282793 A7

V. Description of the invention (95)

Group MDS(8) Toxic death survivors Complete response Partial response to stable disease average score 11.7 Soil 2.5 (5) 0 0 〇__ 0 0 1.2 ± 0.2 __2 21.9 + 5.5 (5) 0 1 0 _0 1.8 ± 0.4 _3 26.5 (1 ) 4 0 〇---- 0 0 0.6 ± 0.6 _4 32.4 + 4.7 (5) 0 0 0 0 0 2.8 ± 0.2 _5 42.6 + 3.3 (5) 0 0 〇0 0 3 Earth 0 _6 36.7 + 7.0 (3) 0 2 0 ———— 1 1 4.4 Soil 1 —7 28.6 + 4.1 (5) 0 0 〇0 0 2.4 Soil 0.4 —8 37_0 Soil 4.1 (5) 0 0 ---- 0 0 0 3 Earth 0 9 43· 1 Soil 8.0(2) 1 2 0 1 1 3.8 Soil 1.5 10 32.7 Soil 5.4 (2) 1 2 〇2 0 4.8 ± 1.8 _11 43.2 ± 2.5 (4) 0 1 0 ----- 0 1 3.6 Earth 0.6 J2 I.5 0 0 0 0 0 0:13 29.1 ± 9.2(3) 0 2 1 0 1 4_4 ± 1.5 14 39.5 ± 10.2 (3) 0 2 0 2 0 4.6 Earth 1.2 15 34.4(1) 0 4 1 3 0 8 Soil 1.3 16 27·4 ± 3.5 (6) 0 0 0 0 0 2.5 Earth 0.3 (Please read the note on the back and fill out this page) --- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on the receiving media In the first group of the agent, the ovarian tumors in all five mice gradually grew and reached the 2 〇 値 値 値, where MD S値 is 11.7 days. Thus, this ovarian cancer xenograft is a rapidly growing tumor that kills its host in a relatively short period of time. Paclitaxel (Group 2) was administered on a daily schedule and was moderately effective in this trial. The 21.9 days MDS 计算 calculated for the second group of mice showed a survival rate of 87 〇/ compared with the first group of control animals. Increased, it is not significant (under p - 0.13; unpaired t-test). One of the animals in the second group was a green condition of the stable disease on the 61st day. Paclitaxel administered intraperitoneally at a dose of 15 mg/kg, 5 times a day - 98 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Order----- ----Line 1282793 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed A7 B7 V. Description of invention (96) Table (Group 3) 'is highly toxic; Western mice die from drug-related side effects. In this experiment, yew tibia (7 mg/kg; intravenous; i times per day) was more active than paclitaxel. The MDS of the five old Tibetans in group 16 = 27·4 days' compared with the first control group, the calculated survival extension rate was 134%, which was statistically significant at ρ = 〇 〇〇7 (unpaired t-test). Six anti-tumor compounds (0663, 0908, 0947, 0999, 1003, and 1〇11) produced at least one complete response or partial response (total response rate of at least 20%) in mice bearing A2780 ovarian cancer. Compoundion (Group 15) was derived from five animals, resulting in three partial responses and one full response, with a total response rate of 8〇%. The anti-tumor compound 1011 treatment was also well tolerated, resulting in non-toxic death and the maximum mean weight loss on day 5 was lu%. Two other compounds, 0947 and 10〇3, each produced 2 parts in five treated old gases; These compounds also caused several stable disease conditions, and a significant survival extension was generally achieved compared to the third control group. For example, compound 0663 (MDS = 36.7 days) and 〇9〇8 (MDS = 43.1 days), when compared with the first group, the individual survival rate increased by 214% and 268% (1) 値 individual discussion 6 0.003; unpaired t_test). Compound 0951 produced a stable disease with high mds値, but no tumor shrinkage. The anti-tumor compound 0951 produced a stable disease condition and was compared with the third control group (ρ&lt;ο·οοιι; unpaired t·test), and the survival was extended to 269% (mds = 432 days). Four of the compounds (0503, 0536, 0687 and 0706) achieved significant _値' but did not result in any complete response, partial response or stable disease. -99- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). #_! (Please read the notes on the back and fill out this page) · - Line. 1282793 A7 B7 _ V. Invention description (97) (Please read the note on the back and fill in this page) Compare with the first control group Treatment with such compounds can cause approximately 1% _3 〇〇〇. Prolonged survival. Compared with the first control group (p < 〇 0001; unpaired t-test), the antitumor compound 0536 produced a 264% increase = 42 6 days). Only compound 0803 demonstrated excessive toxicity. All five rats (Group 12) treated with Compound 〇 983 at their 72. 6 mg/kg dose were toxic and lethal at the doses administered. In this study, only two other toxic deaths occurred in each of the 9th (0908) and 10 (0947) groups. The group treated with anti-tumor compounds (except group 12), near the η day, was the most severe group group with a weight reduction of 3〇/. Within the range of 19%, and the animal's body weight subsequently returned. Therefore, the side effects recorded for all antitumor compounds (except 〇 983) were within the acceptable range of NCI and showed that the animals in the Α2780 experiment received the appropriate MTD dose. Example 16 Antitumor Compounds Resistant to Α375 Human Melanoma In Vivo Assessment of Xenografts Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Antitumor compounds were in the manner described in Example 10, Solution 1, at 5% ethanol, 5°7. Cremophor and 90°/. Made of isotonic saline in a vehicle. Paclitaxel (Pecillinol; Bristol Meyers Squibb) and Taxus (Rh〇ne-Poulenc Rorer) were obtained from commercially available medicines. The volume of the drug was 0.3 ml per 20 g mouse. Female NCi:-hairless mice were implanted into the lumbar fossa by subcutaneously using 1 cubic millimeter of A375 melanoma fragments, and selected as a treatment group for each of the six mice, except for the group of seven mice in the treatment group of the yews. group. A375 tumor group Ping-100- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 -------B7 _ V. Invention description (98) The average size range is 206 -212 mg. The medicine is started on the first day. The anti-tumor compound is administered intravenously at a maximum allowable dose (MTD) for each agent, on a daily schedule (single dose of the compound). Intravenous paclitaxel was administered at a dose of 12 mg/kg (total dose = 24 mg/kg) at two separate doses (between one hour) on a daily schedule. Paclitaxel was also administered intraperitoneally at a daily dose of 18 mg/kg on a daily schedule of 5 times. The yew buds are administered intravenously at a dose of 70 mg/kg once a day. The vehicle was administered intravenously to the first group of control mice on a daily schedule. This study was terminated on day 60. The treatment groups are detailed in Table 9. Table 9 Groups of Pharmacy mg/kg Pathway Schedule 1 Vehicle-- Intravenous once a day 2 Paclitaxel 24 Intravenous once a day 3 Paclitaxel 18 Peritoneal cavity 5 times a day 4 0499 77 Intravenous daily 1 Time 5 0503 72.6 Intravenous once a day 6 0670 123.1 Intravenous once a day 7 0706 '107.6 Intravenous once a day 8 0838 72.6 Intravenous once a day 9 0854 63.3 Intravenous once a day 10 1011 107.6 Intravenous once a day 11 紫衣帖里 701 Intravenous once a day, the results are extracted in Table 10, and include the average number of days of survival (MDS) 'the number of toxic deaths, the number of survivors, the number of complete or partial responses' and have stability The number of diseases. The average number of days of survival was the number of days after the tumor reached a size of 2.0 g and the animals were euthanized. If the tumor size is reduced to less than -101 ·______ --- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) _"! 1_丨",! #·! (Please read the notes on the back and then fill out this page) Order · Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282793 A7 B7 V. Invention Description (&quot;) (Please read the notes on the back first) Fill in this page again. The size of the study on the first day, - then get a full response. When the treatment limits tumor growth to a small size, it does not reach 2.0 grams when the study is terminated, and a "stable disease" occurs. Table 10 Group MDS (8) Toxic death survivors redundant response partial response to stable disease average score 1 14.4 soil 0.9 (6) 0 0 0 0 0 1 ± 0 2 18.1 soil 0.6 (4) 2 0 0 0 0 〇 · 8 ± 0.3 3 ... 6 0 0 0 0 0 Soil 0 4 30·5 Soil 3.5 (3) 2 1 0 0 1 2.3 ± 0.9 5 28.1 ± 5.8(3) 2 1 1 0 0 2·8 ± 1.5 6 15·3 ± 1.5 (6) 0 0 0 0 0 1.2 Soil 0.2 7 28.3 Soil 1.6(5) 1 0 0 0 0 1.8 ± 0.4 8 33·5 ± 3.4(5) 0 1 1 0 0 3.8 Earth 1.2 9 ... 6 0 0 0 0 0 土0 10 47.5 土5.4 (3) 3 0 0 0 0 1·5 ± 0.7 11 21.5 ± 0.5 (7) 0 0 0 0 0 2 Gentry A375 melanoma implant is treated with vehicle The six mice grew rapidly and progressively (Group 1). These tumors reached a cutoff of 2.0 g and had an MDS値 of 14.4 days. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed on a daily basis (24 ‘mg/kg; Group 2), intravenously administered paclitaxel to animals with a moderate therapeutic benefit from chemotherapeutic drugs. Compared to the first control group, the 18.1 day MDS tether showed a 26% survival prolongation. This increase in survival was statistically significant (ρ == 0.016; unpaired t&gt; test). Paclitaxel (18 mg/kg; intraperitoneal) administered on a daily schedule of 5 times was highly toxic to mice. Six animals of the whole Shao, who took the drug at 18 mg/kg, died of toxicity. In the dose of 70 mg / kg, the intravenous administration of the yew syrup (per -102- ___ this paper scale applies the Chinese National Standard (CNS) A4 specification (210 297 297 mm) 1282793 A7 Ministry of Economic Affairs Intellectual Property Bureau The employee consumption cooperative printed five, the invention description (100) once a day; the eleventh group), the rapture λ / ΓΤΛ € n generated MDS = 21.5 days. Compared with the i-th control group, P&lt;〇== (not as experimental), this 49% survived two anti-tumor compounds (〇499, (10)3 and 〇838) on the first day (when the study was terminated, each produced to y-self) Complete response, partial response or stable disease, and prolonged survival in other treated mice, as indicated by the swelling of the drug. Antitumor compounds (4) 3 (Group 5) cause H/ The end of the response to the king's response and the survival of the first control group was extended to 95% (significant at ρ = 0·012; unpaired t• test). A complete response was based on the antitumor compound 〇 838 (p. Group 8) was achieved by administration, while the remaining five old Tibetans experienced a 133% survival prolongation, exceeding the third control group (p = _2; unpaired test). Antitumor compound 0499 caused a stable disease condition, and significant MDS 値When compared with the first control group, anti-tumor compound 0706 improved survival rate at p &lt; 005 (unpaired test). An anti-tumor compound, 〇67〇, was inactive in this study. Tumor compounds (0854 and 1011) are receiving each of these compounds Each of the six mice caused at least three toxic deaths. In general, for animals treated with these compounds, the average group weight loss was recorded in 2〇_3〇%. For other groups of antitumor compounds administered The distribution of side effects was generally within the NCI guidelines; in the early stages of the trial, the average weight loss range of the group was between 5-19%, and then the animal's body weight recovered. In the A375 experiment, the effective agent was seen. The acceptable level of weight loss is TF. This temple is treated with such anti-tumor compounds, and has a reasonable MTD 〇 (please read the back note before filling this page) -# 订-线- -103 '纸The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (101) Example 17 Anti-tumor compound resistance pan〇l human pancreatic cancer xenogeneic In vivo evaluation of the graft The antitumor compound was prepared as described in Example 1 〇 Solution 1 in a vehicle of 5% ethanol, 5% Ciremophor*, and 90% isotonic saline. Krista; Bristol Meyer Squibb) was obtained as a commercial medicine. The volume of the drug was 0.3 ml per 20 g of mice. Female Ncr-hairless mice were implanted subcutaneously with 1 cubic millimeter of Pan (&gt;1 pancreatic cancer fragments). Into the lumbar fossa, and selected to treat each of the six mice. Panc-Ι tumor group average size ranged from 215 to 223 mg. The medication started on the first day. Anti-tumor compounds are estimated for each drug. At the maximum allowable dose (MTD), intravenous administration is given on a daily schedule (single dose of the compound). Intravenous paclitaxel was administered at two separate doses (between one hour) on a daily schedule of 13 mg/kg (total dose = 36 mg/kg). The vehicle was administered intravenously to control mice in the first group on a daily schedule. This study was terminated on day 60. The treatment groups are detailed in Table 11. Table 11 Group mg/kg route schedule _ 1 vehicle - intravenously 1 _ 2 paclitaxel 36 intravenously daily 1, 9 _, 3 0499 77 1 day intravenously _. 4 0503 72.6 1 day intravenously 5 0670 123.1 Intravenous daily 'color one - 6 0706 107.6 intravenous 1 apricot per day _ 7 0838 72.6 intravenous 1 8 0854 76.9 per day intravenously 1 -104- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public) (Please read the notes on the back and fill out this page)

1282793 Ministry of Economic Affairs Intellectual Property Office employees 3⁄4. Fee Cooperatives printed A7 B7 V. Invention Description (102) The results are summarized in Table 12, 1 including the average number of days of survival (MDS), the number of toxic 叱nr, the number of survivors , the number of responses in whole or in part, and the number of stable diseases. The average number of days of survival was the number of days after the tumor reached a height of 15 grams and the animals were euthanized. If the tumor size is reduced to less than the first day of the study (size, a complete response is obtained. When the treatment limits the growth of the tumor to a small size and does not reach 15 grams at the end of the study, π-stable disease π occurs. Table 12 Group MDS(8) Maternal death survivors Complete response Partial response to stable disease average ~ Score 1 18.5 ± 1.8(6) 0 1 0 0 0 0 1·2 ± 0 2 41.9 Soil 5.1(3) 3 0 0 0 0 1.6 ± 0?^ 3 56.1 ± 1.0(2) 0 4 2 1 1 7.4 Gentry 4 52.5 Earth 2.1 (3) 0 3 0 0 3 3.6 Earth 0^* 5 51.2 ± 5.9(2) 1 3 1 0 2 4.2 Soil 1 6 59,5 (1) 0 5 0 3 2 6.6 ± 1 7 54.2 ± 0.9 (2) 1 3 0 2 3 3.6 Soil 7 8 6 0 0 Ί Amd 0 0 Earth 0,

The Pane-Ι tumor line grew progressively in all six mice (Group!) treated with vehicle; this control group ‘calculated _3==18.5 days. Intravenous administration of 36 grams/kg paclitaxel (1 time per day; group 2), compared with the first control group, caused a 126% survival extension in three mice (MDS = 41.9 days) (at ρ = 〇· 〇〇09 is very significant; unpaired ^ test). Three other animals receiving paclitaxel died of toxicity. Three anti-tumor compounds (0499, 0670 and 〇7〇6) produced a total response rate of 20%, 50. /. Within the scope. Compound 0499 (Group 3) achieved 2 complete responses and 1 partial response (with a stable disease condition) from six animals. in? ___- 105- __ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)--- &quot; C Please read the back of the &gt;1 meanings and then fill out this page)

-· · H |Bind---------Line· 1282793 A7 _______B7 _ V. Description of invention (1〇3) (Please read the notes on the back and fill out this page) 1 The other compounds (0503 and 0838) did not cause any complete response or partial response, but each produced three stable disease conditions. In this experiment (0499, 0503, 0670, 0706 and 0838), the MDS(R) calculated for the compound (〇854 New Year's Eve) was in the range of 47-56 days, substantially compared to the control group of the first group. The calculated MDS j was longer for 18.5 days (all numbers were significant at p $ 〇〇5; unpaired t-test). Antitumor compound 0854 (Group 8) is highly toxic to older gases at a dose of 76.9 mg/kg. All six animals receiving 0854 died of drug-related side effects. A toxic death line was recorded in each of Group 5 (〇67〇) and Group 7 (0838); both animals experienced severe weight loss before dying from toxicity. In other respects, the mean group weight loss was in the range of 2% -12%, which means that in this experiment, reasonable MTD has been selected for all anti-tumor compounds, except for compound 0854. Example 18 In vivo evaluation of antitumor compounds 0854 and 1011 against Panc-1 human pancreatic cancer Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed antitumor compounds in the manner described in Example 10, Solution 1, in ethanol, 5% Cremophor and Made in 90% isotonic saline medium. Paclitaxel (Pecillinol; Bristol Meyers Squibb) was obtained as a commercial medicine. The volume of the drug was 0.3 ml per 20 g mouse. Female NCr-hairless mice were implanted into the lumbar fossa with 1 cubic millimeter of Pan (&gt;1 pancreatic cancer fragments) and selected into treatment groups of six mice. The Panc-1 tumor group average size range was 192-213 mg. The medication started on the first day. The anti-tumor compound is estimated to be the maximum allowable for each agent -106- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A7 ___ B7______ V. Inventive Note (104) At dose (MTD), intravenous administration is given on a daily schedule (single dose of compound). Intravenous paclitaxel is administered on a daily schedule of two Separate dose (between one hour), 12 mg/kg per dose (total dose = 24 mg/kg). Paclitaxel was also administered intraperitoneally at a dose of 15 mg/kg on a 5-day schedule. The vehicle was administered intravenously to the control mice of Group 1 on a daily schedule. The trials were terminated on Day 63. The treatment groups are detailed in Table 13. Table 13 Groups of mg/kg of the drug Route schedule 1 vehicle... intravenous Once a day 2 Paclitaxel 24 Intravenous once a day 3 Paclitaxel 15 Peritoneal cavity 5 times a day 4 0854 46.6 Intravenous once a day 5 1011 107.6 Intravenous once a day (please read the back note first and then fill out this page) - -- The results printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs are summarized in Table 14 and include the average number of days of survival (mdS), the number of maternal deaths, the number of survivors, the number of full or partial responses. And the number of stable diseases. The average number of days of survival is the number of days after the tumor reaches 15 grams in size and the animal is euthanized. If the tumor size is reduced to less than its size on the first day of the study, a complete response is obtained. Limiting the growth of the tumor to a small size 'when the sample is not reached at the end of the study, it will occur." The stable disease π. Order---------Line. ___ -107- This paper scale applies to the Chinese national standard ( CNS) A4 size (210 X 297 mm) 1282793 A7 B7 V. Description of invention (1〇5) : Table 14 Group MDS(8) Toxic death survivors Full response Partial response to stable disease average score 1 23.0 ± 3.1 0 1 0 0 1 2 士0·8 2 34.7 土3.4 1 1 0^ 0 1 2·2 Earth 0·8 3 4 1 0 1 0 1.2 + 1.2 4 — 6 0 Bu 0 0 0 Bu 0 + 0 5 3 3 0 3 0 4 + 1.8 A Panc-Ι赘 tumor of a double-dose mouse (Group 1), reaching a 1.5 gram cut-off, with a calculated MDS of 23.0 days. One of the cancer control groups did not grow, which was presumed to be due to sampling of adverse tumors. Buddy 1—'_! Dream (please read the note on the back and then fill out this page) At a dose of 24 mg/kg (once a day), intravenously administered paclitaxel (Group 2) to produce a stable The disease condition and MDS were 34.7 days in four other mice (significantly different from the first control group at p = 0.038; unpaired t-test). One mouse died of toxicity due to this paclitaxel dose. At a dose of 15 mg/kg (5 times a day), paclitaxel administered intraperitoneally caused four toxic deaths in the sixth group of animals. The anti-tumor compound 1011 produced a total response rate of 100%. Anti-tumor compound 1011 produced three partial responses, but also caused three toxic lethalities at the doses administered. Antitumor compound 0854 was toxic; all animals receiving this drug died of drug-related side effects. Example 19 In Vivo Evaluation of Antitumor Compounds Against VM46 Human Colon Cancer The antitumor compound was in the manner described in Example 10, Solution 1, at 5 Å. Ethanol, 5°/. Cremophor and 90. '/. Made of isotonic saline in a vehicle. Paclitaxel (Peak-108-__ This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1282793 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventions (106) Risotto · 'Bristo Meyers Squibb): with the yew sage (thanks to him; Rhone-

PoulencRorer) is obtained from commercially available medicine. The volume of the drug is 3 ml per 2 g of mice. Female NCr-hairless mice were implanted subcutaneously into the lumbar fossa using a 1 mm mm VM46 colon cancer fragment and selected for treatment in each of the six mice. The average size of the VM46 tumor group ranged from 181.188 mg. The medication started on the first day. The anti-tumor compound is administered intravenously at a maximum allowable dose (MTD) for each agent as estimated on a daily schedule (single dose of the compound). Intravenous paclitaxel was administered in two separate doses per day (between one hour) at a dose of 12 mg/kg (total dose = 24 mg/kg). Paclitaxel was also administered intraperitoneally at a dose of 15 mg/kg on a 5-day schedule. The yew buds are administered intravenously at a dose of 70 g/kg on a daily schedule. The vehicle was administered intravenously to control mice in the Dijon group on a daily schedule. The trial was terminated on day 64. The treatment groups are detailed in Table 15. Table 15

109- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------------------- Order------- --Line» (Please read the notes on the back and fill out this page) 1282793 A7 B7 V. INSTRUCTIONS (1〇7 The results are summarized in Table 16, including the average number of days of survival (MDS), toxic death The number, the number of survivors, the number of complete or partial responses, and the number of stable illnesses. The average number of days of survival is the number of days after the tumor reaches 15 grams and the animal is euthanized. If the tumor size is reduced to less than When the size of the study was studied on the first day, a complete response was obtained. When the treatment restricted the growth of the tumor to a small size and did not reach the size of h5 g at the end of the study, π-stable disease occurred. Table 16 VM46 study (colon cancer) Response Summary---------------- (Please read the note on the back and fill out this page) Group MDS(8) Toxic Death Survivors Complete Response Partial Response to Stability Disease Average Score 1 31.0 ± 4.4(6) 0 0 0 0 0 1.2 Soil 0.2 2 43·3 ± 3·7 (4) 0 2 0 1 1 3.8 ± 1.4 3 36.1 ± 12.2 (2 3 1 0 1 0 1·8 ± 1.3 4 41.9 Soil 4.2(5) 0 1 0 0 1 2 Soil 0.3 5 56.1 (1) 0 5 0 4 1 7.3 Soil 1.2 6 40.1 Soil 5·8(5) 0 1 0 1 0 2·8 ± L2 7 48·6 Soil 0.9 (3) 0 3 1 2 0 6.2 Soil L4 8 49.9 ± 13.3 (2) 0 4 0 1 3 4.8 ± 1 9 52.9 Soil 6.6 (2) 1' 3 0 2 1 4.7 Soil 1.6 10 56.0 Soil 6.8 (2) 3 1 0 0 1 1.7 ± 0.8 11 45.3 Soil 3.6(6) 0 0 0 0 0 2 ± 〇·. -丨线- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Colon cancer lines printed in all six mice (Group 1) receiving vehicle were progressively grown and reached a 1.5 gram end point with a calculated MDS 3 of 31.0 days at 24 mg/kg (intravenous; Paclitaxel (Group 2) administered once a day, resulting in a partial response, a stable disease condition, and the MDS of the remaining four mice in this cohort = 43.3 days (not significantly different from the control group, Under ρ = 〇·〇86; unpaired t-test). Paclitaxel-110- administered intraperitoneally

1282793 A7 B7 V. INSTRUCTIONS (108) (Please read the note on the back and fill out this page). At 15 mg/kg (5 times a day), it is overly toxic and causes in six treated animals. Three deaths. MDS値 was generated in the yew stalk for 45.3 days (compared to the first control group, significant at p S 0.05; unpaired t-test). The two antitumor compounds 0503 and 0706 each produced a response rate of 66.7% and 56%, indicating that the two compounds were effective in the subjects tested. Anti-tumor compound 0503 produced four partial responses and two stable disease conditions, while anti-tumor compound 0706 caused a complete response and two partial responses. The response rates for the three other compounds (0670, 0838 and 0854) ranged from 16.7% to 40〇/〇. Survival in the range of 11 to 20 days longer than compound 0854 obtained for the MDS 31.0 days calculated for the control group was obtained. Compound 0083 with a 0% response rate when compared to the first control group produced a statistically significant (p$0.05) MDS値. Five of the seven anti-tumor compounds (0499, 0503, 0670, .0706 and 0838) printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs were well tolerated in the VM46 study and did not cause toxic death. The highest average group weight loss at 8 days was in the range of 3% -14%. Acceptable toxicity was also reported for Compound 0854 (no more than one death per group and the highest average weight loss was below 12%). One anti-tumor compound 0893 produced toxicity, resulting in the death of three animals in Group 10. Example 20 In Vivo Evaluation of Anti-Tumor Compounds 0503 Against SKMES Human Lung Cancer Xenografts In one study, anti-tumor compound 0503 was formulated for intravenous administration, covering a broad range of doses to detect this compound against SKMES human-111 - ____ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1282793 Α7 Β7 V. Description of invention (109) Effect of lung cancer xenografts. The anti-tumor compound was in the form of Example 9 Emulsion 3 at 10% ethanol and 90%. /〇 Made in Liposyn III. Female Nu/Nu mice (6-8 weeks old; 1 mm mm SKMES lung cancer pieces, implanted in the lumbar fossa) were selected as the five treatment groups for each of the six mice. The SKMES size range and the group average SKMES size range are 126-405 mg and 235-240 mg, respectively. The treatment group included: vehicle only (Group 1), and antitumor compound 0503 (individual doses were 104 mg/kg, 72.8 mg/kg, 41.6 mg/kg, and 10.4 mg/kg·, group 2-5) . The therapeutic drug was administered as a single intravenous bolus on day 1 and the study was terminated on day 60. The results are summarized in Table 17, and include the average number of days of survival (MDS), the number of toxic deaths, the number of survivors, the number of complete or partial responses, and the number of stable disease. The average number of days of survival was the number of days after the SKMES tumor reached a size of 2.0 g and the animals were euthanized. If you do not know that you have a tumor at the end of the study, you will get a full response. A partial response is obtained if the tumor size is reduced to less than the size of the day of study. When the treatment limits the growth of the tumor to a small size, a stable disease occurs when the size of the tumor is not reached at the end of the study. Table 17 Group MDS (η) Toxic death survivors Complete response Partial response to stable disease Total response % 1 17.4 Soil 1.3(6) 0 0 0— 0 0 0 2 46.6 Soil 3.2 (3) 0 3 3 1 0 0 50.0 3 37.4 Soil 5.2 (4) 0 2 1 1 0 333 _ 4 33·8 Soil 3.4(5) 0 1 0 0 1 --------- 0_ 5 26.0 ± 2.5 (6) 0 Γ 0 0 0 0 -------— 0 ——.—·————1 -112- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Γ Read the back of the note beforehand Fill in this page) --------Book ------ Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282793 A7 B7 V. Invention Description (11Q) Two mice in the second group , was recorded as complete tumor regression. For the third group, a full response and a partial response were recorded. The MDS値 (individually 46.6 days and 37.4 days) of the other old m* in groups 2 and 3 were highly significant, outperforming the treatment group with only vehicle (group 1), based on the difference in MDS値 (ρ =0·0001 and ρ=0·0019; unpaired t_test). Survival of other mice was prolonged, 167 for group 2. /. And for the third group is U4%. Example 21 Oral Administration of Antitumor Compound 0687 to Resist SKMES Human Lung Cancer Xenograft In Vivo Evaluation In one study, antitumor compound 0687 was administered as a single bolus by oral route to probe this compound against SKMES human The efficacy of lung cancer xenografts 'covers a broad range of doses. Antitumor compounds were prepared in the manner described in Shell 6 in a vehicle of 5% ethanol, 5% Cremophor and 90% isotonic saline. Female Nu/Nu mice (6-8 weeks old; 1 mm mm SKMES lung cancer fragment implanted into the lumbar fossa) were selected for treatment in each of the six mice. SKMES large, small range and group average SKMES size range, 126,448 mg and 238-241 mg, respectively. Treatment groups included: untreated (group i), vehicle only (group 2) 'antitumor compound 0687 (228 mg/kg; group 4) and antitumor compound 0503 (73 mg/kg; group 5) . The therapeutic drug was administered as a single oral bolus, administered on day 1, and the study was terminated on day 60. The results are summarized in Table 18 and include the average number of days of survival (MOS), the number of toxic deaths, the number of survivors, the number of complete or partial responses, and the number of stable disease. The average number of days of survival is SKMES赘113- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) _ (please read the notes on the back and fill out this page) --- Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1282793

V. Description of the invention (the number of days after the tumor reaches 2.0 g in size, and the animal is euthanized. If the tumor is not touched when the research is ~ bundle, then a complete response is obtained. If the tumor size is less than the i-th in the study In the case of the size of the day, a partial response is obtained. Each treatment limits the growth of the tumor to a small size, and when the study is terminated, it does not reach ^, that is, a stable disease occurs.

Antitumor compound 0687 is administered in a single oral dose and is highly active. The overall response rate is 100. /. . The overall response rate is defined as the percentage of evaluable animals (excluding death due to procedure or toxicity) that have been fully or partially responded to at the end of the study in a group. The anti-tumor compound 〇5〇3 also caused three complete responses. Both compounds were significantly more effective than paclitaxel, and paclitaxel did not show a statistically significant response. Example 22 Oral Administration of Antitumor Compounds to Resist MX-1 In vivo Evaluation of Human Breast Cancer Xenografts In one study, anti-tumor compounds were administered orally to investigate whether such formulations are effective against MX-1 human breasts. Cancer xenografts. Antitumor compound 0499 was formulated as Example 1 Solution 1. Anti-tumor compound 0550 桉 _-114-____ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) - Order---- ----Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1282793 A7 ------Β7____ V. Invention Description (112) Example 6 Solution 2 Preparation. Antitumor compound 0611 was formulated as Example 3 Solution 3. Antitumor compound 0748 was formulated as Example 4 Solution 4. Other anti-tumor compounds are formulated in a similar manner. The compound was prepared in a medium of 9 〇〇 / 0 saline, 5 〇 / 〇 Cremophor and 5% ethanol. Female nu/nu mice (1M2 weeks old; 1 cubic millimeter MX-1 human breast cancer shards were implanted subcutaneously into the lumbar fossa) were selected as a control group (n=10) with four treatments (n== 6) Group (group mean tumor size 47-49 mg). The therapeutic drug was administered to the treatment group on day 1 as a single oral bolus, as summarized in Table 19. This study was terminated on the 63rd day. The results are summarized in Table 19 and include the average number of days of survival (mds), the number of toxic deaths, the number of survivors, the number of complete or partial responses' and the number of stable disease. The average number of days of survival is the number of days after the tumor reaches a size of 1.5 grams and the animals are euthanized. If the tumor is not touched at the end of the study, a full response is obtained. A partial response was obtained if the tumor size was reduced to less than its size on study day 1. When treatment limits tumor growth to a small size, a stable disease occurs when the study does not reach a size of 1.5 grams at the end of the study. (Please read the notes on the back and fill out this page) f ----Book---------Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Table 19 Group Antitumor Compound Dose (mg / kg) Average number of days of survival (8) Maximum weight loss (days) Complete response to toxic death Partial response to stable disease 1 Vehicle n/a 21.5 ± 0.7 (8) n/a 0 0 0 2 2499 80 56.6 ± 2.1 (3) -11.4% (7) _0 2 〇3 0550 73 n/a ± (0) -16.1% (5) ---- 6 -~~^ Λ 4 0611 113 58.5 Soil 0(1) -15.0% (5) La 4 〇U Λ 5 0748 200 32.4 ± 1.4 (5) -4.6% (5) _0 0 0 U 1 a has nothing to do with toxicity _-115- National Standard (CNS) A4 Specification (210 X 297 mm 1282793 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 B7 V. INSTRUCTIONS (113) The anti-tumor e-compound evaluated by Da Shaofen, in the Mx-1 human breast cancer xenograft model, at a good tolerable dose, is In this study, antitumor compound 0550 was potent and produced six complete tumor regressions in six treated animals. Compound 〇61丨 is almost active. Four complete tumor regressions were generated in five treated mice (one death was non-therapeutic). Compound 0499 caused complete tumor regression in two of the six treated mice, and other mice in this group reached Before the end of the study, there was a highly significant increase in survival relative to the control group. The response from compound 0748 was characterized by a significant prolongation of survival compared to vehicle control mice. In addition to survival and tumor regression responses, the evaluation of treatment was The role of the blood corpus group. The main role of these anti-tumor compounds in the blood spheroid population is a significant decrease in the number of neutrophils. Moreover, for each anti-tumor compound, the single-cell depletion system is very fascinating. There is a strong association between leukopenia. This anti-tumor compound does not affect the general white blood cell population, lymphocytes and platelets. There is a correlation between anti-tumor activity and reduction of neutrophil count. In general, toxicity (when When measured by neutrophil depletion, it is associated with weight loss, system and efficacy. The most effective anti-tumor Compound 0550 produced complete mitigation in all six treated mice, with most weight loss (16.1%, day 5) and highest neutropenia (95 9%, day 4). Importantly, The toxicity found by extremely potent anti-tumor compounds is easily treated and reversible; neutrophil counts and body weight are recovered within a few days, ie from their low point. Table 20 summarizes the weight loss on day 4, neutrophils and single cell measurements, where tumor weight reduction is applied to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) on the -116- paper scale. ) --------------------- Order --------- Line ' (Read the back of the note before you fill out this page) 1282793 A7 B7 V. Description of the invention (114) Calculated in 18 days · Group anti-tumor compound dose (mg / kg) Weight (mg) ° '. Decreased neutrophil (K/L) % Decreased single cell (K/L) % decreased 1 vehicle n/a 868.5 0.9115 0.096 2 0499 80 0 100.0% 0,077 91.6% 0.073 24.0% 3 0550 73 0 100.0% 0.037 95.9 % 0.019 80.2% 4 0611 113 0 100.0% 0.057 93.7% 0.042 56.3% 5 0748 200 268.7 69.1% 0.269 70.5% 0.117 Summary of the results of the lotus-free system In the animal studies described in the above examples, the anti-tumor compound 0503 , 0706, 0838 and 1011, the tumors in these studies, consistently demonstrated superior efficacy scores. The 75 percentile score for all anti-tumor compounds against specific tumor patterns was calculated. These four anti-tumor compounds were scored at or above the 75th percentile score. Antitumor compounds 0947 and 1003 were also well graded in their tested mode. (Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs -117- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

Claims (1)

A8 B8 128219 Fine Patent 9319 Patent Application Chinese Patent Application Substitution (95-month) g8 Patent Application Fan Xingyi - 8 Health Correction A Taxane Compound with the following formula Supplemental 丨%1 "turn R2 to benzamidineoxy; ~ is light base; Ri 〇 is Ri 〇a C00,; X3 is a 5- or 6-membered heterocyclic group including at least one nitrogen, oxygen or sulfur atom. X5 is -COXi 〇, wherein X is phenyl, furyl, pyridyl, phenyl-c3-c5 or c3-c5 or χ5 is -co〇x1(), wherein 乂10 is (: 3-(:6 alkyl; R1 0 a is C2_C6 alkyl or C2_c6; and Ac is ethyl acetyl. 2. According to the patent application scope, the yew compound of the first item, wherein &amp; Is 2-p-folyl, 3-furyl, 2-thienyl, 3-pyridenyl, 2-pyridyl, 3-pyridyl or 4-acridinyl. 3. According to the scope of claim 2 Taxanes, wherein χ5 is -COXi 〇' and 乂丨〇 is phenyl, 2-indolyl, 3-indolyl, 2-ρ-sepeno, 3-thienyl, 2-pyridyl, 3- Pyridyl, 4-pyridyl, c3-C5 alkyl or C3-C5 alkenyl, or X5 is -COOX1(), and χ10 is c3-c6 alkyl. 72864-951005.DOC - 1 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1282793 έβ8 C8 D8 VI. Patent application scope 4. According to the yew compound of claim 2, wherein X5 is -COXi 〇, and Xi 〇 is phenyl, or X5 is -COOXi 〇, and Xi 〇 is a third-butyl group. a yew of the item 1, wherein X3 is a furyl group or a far phenyl group. 6. The yew compound according to item 5 of the patent application, wherein X5 is -COXi 〇, and Xi 〇 is phenyl, 2-furyl, 3-furanyl, 2-nonyl, 3-p-secenyl, 2-p-predated, 3-p-predated, 4-p-decyl, C3-C5 alkyl or C3_C5 fluorenyl, Or X5 is -COOXi 〇, and 乂丨ο is q-C8 alkyl. 7. The yew compound according to item 5 of the patent application, wherein X5 is -COXi 〇, and X! 〇 is phenyl, or X5 is -COOXi 〇, and 乂丨〇 is a third butyl group. 8. According to the yew compound of claim 1, the center Qa is ethyl or propyl. 9. According to the patent item range 8 Cedar, wherein X3 is 2-furyl, 3-mercapto, 2-homyl, 3-p-septenyl, 2-p-ratio, 3-p-dipyl or 4-p-bityl 10. According to the yew compound of claim 9 of the scope of patent application, X5 -COXi 〇, and Xi 〇 is phenyl, 2-furyl, 3-furanyl, 2-pyrimenyl, 3- far phenyl, 2-p aryl, 3-p decyl, 4-ton A decyl group, a C3-C5 alkyl group or a C3_C5 cation group, or X5 is -COOXi oxime, and hydrazine is a CVC8 alkyl group. 11. The yew compound according to item 9 of the patent application, wherein x5 is -COXi 〇, and Xi 〇 is phenyl, or X5 is -COOXi 〇, and Xi 〇 is 72864-951005.DOC - 2 - paper The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 8 8 8 8 AB c D 1282793 6. Apply for the patent Fanyuan Tri-Butyl. 12. The yew compound according to item 8 of the scope of the patent application, wherein X3 is a furyl group or a p-secenyl group. 13. The yew compound according to item 12 of the patent application, wherein X5 is -COXi 〇, and Xi 〇 is phenyl, 2-furyl, 3-furyl, 2-pyromyl, 3-nonyl , 2-p is a decyl group, a 3-p-precipitate group, a 4-hydrazino group, a C3-C5 alkyl group or a C3-C5 fluorenyl group, or X5 is -COOX! oxime, and hydrazine is a q-C8 alkyl group. 14. The yew compound according to claim 12, wherein X5 is -COXi 〇, and Xi 〇 is phenyl, or X5 is -COOXi 〇, and X! 0 is a third-butyl group. 15. The yew compound according to item 8 of the patent application, wherein x3 is a pyridyl group. 16. The yew compound according to item 15 of the patent application, wherein X5 is -COXi 〇, and Xi 〇 is phenyl, 2-furyl, 3-furyl, 2-pyromyl, 3-p-septene a group, a 2-p-precipitate group, a 3-p-precipitate group, a 4-p-pretide group, a C3-C5 alkyl group or a C3-C5-mercapto group, or X5 is -COOXi 〇, and 乂丨〇 is q-C8 alkyl. _ 17. The yew compound according to item 15 of the patent application, wherein Χ5 is -COXi 〇, and X! 〇 is phenyl, or Χ5 is -COOX! 〇, and 乂丨0 is the third-butyl group. 18. The yew compound according to item 1 of the patent application, wherein X3 is a furyl group or a porphinyl group, the cardioside a is an ethyl group, and X5 is -COXi 〇, and &amp; 〇 is a phenyl group, or X5 is - COOXi 〇, and X1() is a third-butyl group. 19. The yew compound according to the scope of patent application No. 1, wherein X3 is substituted 72864-951005.DOC - 3 - This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1282793 έ88 C8 'Applicable patent garden or unsubstituted furanyl, Rl 0 a is ethyl, and X5 is _C0X1 Ο, and parent 1 〇 is phenyl, or Χ 5 is -COOX! 〇, and Χ 10 is third-butyl base. 20. The yew compound according to item 1 of the scope of the patent application, wherein Χ3 is a substituted or unsubstituted stalking base 'Rl 〇a is ethyl' and Χ5 is &quot;&quot;COX! 〇' and Xi 〇 Phenyl, or X5 is -COOXi 〇, and x10 is a third butyl group. 21. The yew compound according to item 1 of the patent application, wherein X3 is 2-furyl or 2-pyromyl, 〇 a is ethyl, X5 is -COOXi 〇, and 乂丨〇 is second-butyl base. 22. The yew compound according to claim 1 wherein χ3 is 2-furyl, R10a is ethyl, X5 is -C〇〇X10, and Χίο is a third butyl group. 23. The yew compound according to claim 1, wherein χ3 is 2-dethiophene' Ri 〇 a is ethyl' is -COOXi 〇 ' and Χι 〇 is di-butyl. 24. The yew compound according to item 1 of the scope of the patent application, wherein X3 is a p-bite base '-COOXi 〇 ' and Χι 〇 is a di-butyl group. 25. The yew compound according to claim 1, wherein χ5 is -COOX10 and X10 is a third-butyl group, and R1〇a is an ethyl group, a propyl group, an isopropyl group or a trans-propyl group. And X3 is a 2-p ratio decidyl group, a 3-ρ ratio decyl group or a 4-p ratio decidyl group. 26. The yew compound according to item 1 of the scope of the patent application, wherein χ5 is -COOX1() and Χ1〇 is the third butyl' R1〇a is ethyl, propyl, isopropyl or trans-propyl The group, and X 3 is 2 · furanyl or 3-furyl. 27. The yew compound according to item 1 of the scope of the patent application, wherein χ5 is -COOX1〇&amp;X1〇 is a third-butyl group, and R1〇a is an ethyl group, a propyl group, an isopropyl group or a trans-propenyl group. And X 3 is 2-pyromyl or 3-pyrimenyl. 72864-951005.DOC . 4 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1282793 έ88 C8 D8____ VI. Application for patent garden 28. According to the patent application, the yew compound according to item 1 of the patent scope, X 5 is _COOX10 and X1G is a third butyl group, R1Ga is a cyclopropyl group or an isobutylene group, and X 3 is a 2-pyridyl group or a 4-pyridyl group. 29. The yew compound according to item 1 of the patent application, wherein X5-COOX1()&amp;X1() is a third-butyl group, Ri〇a is a 2-sulfenyl group or a 2-furyl group, and X3 is 2_pyridyl, 3-pyridyl or 4-pyridyl. 30. The yew compound according to item 1 of the patent application, wherein X5 is -COOX10 and X10 is a third-butyl group, Ri〇a is a 2-thienyl group or a 2-furyl group, and X 3 is a 2-furyl group. , 3-furyl, 2-pyrimenyl or 3- far phenyl. 31. The yew compound according to claim 1 wherein X5 is -COX10 and X10 is phenyl, R10a is ethyl, and X3 is 2-pyridyl, 3 - ρ is more than decyl, 4 - ρ is more A group, a 2-carbyl group, a 3-n-butyl group, a 2- far phenyl group or a 3-n-thyl group. 32. The yew compound according to item 1 of the scope of the patent application, wherein X 5 is -C Ο Ο X 1 〇 and X 1 〇 is ethyl 'R 1 〇a is ethyl, propyl or propyl, And X 3 is a 2- far phenyl group or a 2- fluorenyl group. 33. The yew compound according to item 1 of the scope of the patent application, wherein X5 is -COXio and Χίο is 2 - bromo or 2-P phenantyl ' Rl 〇 a is ethyl, cyclopropyl or propyl, and X3 is 2-pyromenyl. 34. The yew compound according to item 1 of the scope of the patent application, wherein 乂5 is -COOX1G and X1() is a third-butyl group, R1()a is a cyclopropyl group, and X3 is a 2-anthranyl group, 3 - thiol, 2 - ρ thiophene or 3 _ ρ thiophene. 35. The yew compound according to item 1 of the scope of the patent application, wherein X5 is -COOX1() and Χ1() is isobutyl, R10a is cyclopropyl or propyl, 72864-951005.DOC - 5 - paper scale Applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 A8 B8 C8 D8 and X3 are 2-anthranyl or 3-anthranyl. 36. The yew compound according to claim i, wherein χ5 is -coox10 and x10 is isobutyl, Ri〇a4 cyclopropyl, propyl or ethyl, and X3 is 2-p-septenyl. 37. The yew compound according to the scope of the patent application, wherein &amp; is -COX1G and X1G is trans-propenyl, isobutenyl or butenyl, R i 0 a is propyl, cyclopropyl or ethyl And X3 is 2 _thienyl. 38. The yew compound according to item 1 of the patent application, wherein &amp; is -COX1() and X1() is butyl or trans-propyl, Κι&quot; is propyl, cyclopropyl or ethyl And X3 is 2-anthranyl. 39. The yew compound according to claim 1, wherein L is -COX1() & X1() is 3-pyridyl, R1〇a is propyl, cyclopropyl or ethyl, and X3 is 2 -Thienyl. 40. The yew compound according to item 1 of the patent application, wherein &amp; _COX1() and Χ10 are trans-propenyl, Ri "is n-propyl, cyclopropyl or ethyl, and X3 is 3 - 唉 基 。. 41. The yew compound according to the scope of claim 1 wherein -COX1?KX1() is phenyl, R10.a is cyclopropyl, and 3 is 2-pyridyl or 4 - Said decyl. 42. According to the patent application range 1, the yew compound, wherein χ5 is -COX1 () and Χ1 () is phenyl, R10a is cyclopropyl, and is 2-bityl, 3 - A ruthenium group, a 2 - π-thenyl group or a 3 1 thiophene group. 43. The yew compound according to the scope of claim 1 wherein &amp; is -COX10 and Χ1() is n-propyl, R1〇a It is a cyclopropyl, ethyl or propyl ' and X 3 is a 2-n-butyl group. -6 - 72864-951005.DOC This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1282793 έ88 C8 D8 VI. Patent Application Area 44. The yew compound according to item 1 of the patent application scope, wherein χ5 is -COX10 and Χ10 is n-propyl' RlOa is cyclopropyl or propyl, and X3 is 2-ρ plug吩基. 45. According to the scope of patent application The yew compound, wherein χ5 is - COOX10 and X10 are isobutyl 'Ri〇a is propyl, and χ3 is 2·furanyl. 46. The yew compound according to claim 1 of the patent scope, wherein χ5 is -(^〇〇10 and 乂10 are isobutyl' RlOa is n-propyl, cyclopropyl or ethyl, and X3 is 3-sulfenyl. 47. Yew according to item 1 of the patent application a compound wherein χ5 is -C Ο X 1 〇 and Xiq is propyl 'Rl〇a is ethyl, cyclopropyl or propyl, and X 3 is 2-thienyl or 2-furyl. 48. The yew compound of the first aspect of the patent, wherein χ5 is -COOX1() and X10 is a third-butyl' R10a is an isobutyl fluorenyl group, and X 3 is a 2-mercapto group, a 3-mercapto group, a 2 ·吩 or 3 - p thiophene. 49. The yew compound according to item 1 of the scope of the patent application, wherein χ5 is -COXi〇 and Χ10 is 2-bito or 2-p-septyl, Ethyl, propyl or propyl, and X3 are 2-furyl. 50. The yew compound according to item 1 of the patent application, wherein &amp; is -COX10 and (a) is bucket-1? R10a is ethyl, and &amp; is 2_ disc phenyl. Taxus patent scope thereof, Paragraph 1, wherein &amp; is - COX10 and X10 is trans - Xi propyl group, R1〇a cyclopropyl, and X 3 is 3 - ρ plug thienyl. 52. The yew compound according to item 1 of the scope of patent application, wherein &amp; 72864-951005.DOC - 7 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 8 8 8 8 A BCD 1282793 々 The patent application is -COX1〇&amp;X1〇 is a phenyl group, R10a is a propyl group, and X3 is a 2-furyl group or a 2-p-thenyl group. 53. The yew compound according to claim 1, wherein X5 is -COOXio and Χίο is a second-pentyl group, Ri〇a is an ethyl group, and X3 is a 2-anthracene group. 72864-951005.DOC - 8 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)