WO2015120820A1 - 一类羧酸衍生物及其在制备前药中的用途 - Google Patents

一类羧酸衍生物及其在制备前药中的用途 Download PDF

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WO2015120820A1
WO2015120820A1 PCT/CN2015/073165 CN2015073165W WO2015120820A1 WO 2015120820 A1 WO2015120820 A1 WO 2015120820A1 CN 2015073165 W CN2015073165 W CN 2015073165W WO 2015120820 A1 WO2015120820 A1 WO 2015120820A1
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carboxylic acid
acid
derivative according
acid derivative
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French (fr)
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李勤耕
王涛
陈刚
王元忠
毛伟
吴酮
曾令国
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李勤耕
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Priority to EP15748471.8A priority Critical patent/EP3109230B1/en
Priority to US15/119,587 priority patent/US10239851B2/en
Priority to CN201580008927.2A priority patent/CN106029631B/zh
Publication of WO2015120820A1 publication Critical patent/WO2015120820A1/zh

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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F9/08—Esters of oxyacids of phosphorus
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicine, and in particular to a class of carboxylic acid derivatives and their use in the preparation of prodrugs.
  • Prodrugs also known as prodrugs, prodrugs, etc., refer to compounds that have pharmacological effects after transformation in vivo.
  • the prodrug itself has no biological activity or low activity, and is metabolized in the body to release an active substance.
  • the purpose of researching and preparing prodrugs is to increase the bioavailability of the original drug, change the solubility of the original drug, enhance targeting, or reduce the toxicity and side effects of the drug. For many drugs, especially those with low bioavailability, poor water solubility or large side effects, prodrugs have better advantages.
  • prodrugs can rapidly decompose into ligands and prodrugs when they enter the body, and the ligands are non-toxic. The original drug released can exert its effects, and the non-toxic ligand is in the body. But to achieve this goal is quite difficult.
  • sodium fospropofol marketed in the United States in 2008 is a prodrug of propofol, and its metabolism in the body is as follows:
  • fospropofol solves the problem that propofol is poorly soluble in water, it can be seen from the above formula that fospropofol metabolizes more toxic formaldehyde in the body, which is destined to cause unnecessary problems for patients. Injury; and from the published data (shown below), the amount of fospropofol used was much higher than propofol, and the incubation period and duration were much longer than propofol.
  • the "good ligand" meets the following criteria: after the ligand and the original drug constitute a prodrug, the physical and chemical properties of the original drug can be improved or the bioavailability of the original drug can be improved, and the prodrug can be rapidly decomposed into the original body after entering the body.
  • the drug, and the ligand is non-toxic or low in toxicity.
  • An object of the present invention is to provide a class of carboxylic acid derivatives for preparing a ligand for a prodrug, so that the prepared prodrug not only changes the physical and chemical properties of the original drug, but also rapidly decomposes in the body, releasing the original drug. To play a role.
  • the carboxylic acid derivative of the present invention has the following general formula (I):
  • R 1 is H or an alkyl group
  • X is H or F
  • Y is F or an alkyl group substituted by one or more fluorines
  • n 0, 1, 2, 3, 4, 5 or 6;
  • W is W 1 or W 2 ;
  • W 1 is NR 2 R 3 , NR 2 R 3 ⁇ A,
  • R 2 and R 3 are each independently H, alkyl, cycloalkyl, or an amino protecting group
  • n 0, 1, 2 or 3;
  • A is an acid
  • W 2 is COOR 4 , OPO(OR 4 ) 2 or PO(OR 4 ) 2 ;
  • R 4 is H or a protecting group for a carboxyl group or a phosphate group.
  • R 1 is H or C 1-6 alkyl.
  • R 1 is H, methyl, ethyl, n-propyl or isopropyl.
  • Y is F or a C 1-6 alkyl group substituted by one or more F.
  • Y is F, CF 3 or CHF 2 .
  • W is W 1 .
  • R 2 and R 3 are not simultaneously H.
  • R 2 and/or R 3 are each independently C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 2 and/or R 3 are each independently C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 2 and/or R 3 are each independently a C 1-6 alkoxycarbonyl group optionally substituted by phenyl, such as benzyloxycarbonyl or tert-butoxycarbonyl.
  • R 2 and/or R 3 are each independently benzyl optionally substituted by one or more halogens.
  • R 2 and/or R 3 are each independently a benzyl group optionally substituted by one or more fluoro or chloro groups, such as benzyl, 3-chlorobenzyl, 4-fluorobenzyl or 2,4- Difluorobenzyl.
  • R 2 and R 3 are each independently H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyloxy Carbonyl, tert-butoxycarbonyl, benzyl, 3-chlorobenzyl, 4-fluorobenzyl or 2,4-difluorobenzyl.
  • the acid A is an acid which can form a salt with an amine, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, acetic acid, benzenesulfonic acid or a pair. Toluenesulfonic acid.
  • an amine such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, acetic acid, benzenesulfonic acid or a pair.
  • W is W 2 .
  • R 4 is C 1-6 alkyl optionally substituted by one or more phenyl groups, for example methyl, ethyl, benzhydryl, trityl or benzyl.
  • the carbon atom bonded to X and Y at the same time may be single.
  • the compound of formula (I) can also be derivatized as a compound of formula (II) or (III) by conventional chemical means.
  • a compound of the formula (I) can be converted to the corresponding carboxylate (II) by a neutralization reaction, or by reacting with a halogenating agent such as thionyl chloride or phosphorus halide or sulfonyl chloride to give the corresponding acid halide or Sulfonic acid mixed anhydride (III).
  • R 1 , X, Y, n, W are as defined above for the carboxylic acid derivative of the formula (I);
  • M is a metal ion
  • q is the number of charges carried by M
  • G is Cl, Br or a benzenesulfonyloxy group optionally substituted by an alkyl group.
  • M in the above formula (II) is an alkali metal ion such as a sodium ion or a potassium ion, an alkaline earth metal ion such as a magnesium ion, a zinc ion or a calcium ion, or a trivalent metal ion such as an aluminum ion or Iron ions. More preferably, M is a sodium ion or a potassium ion.
  • G in the above formula (III) is Cl, Br or a benzenesulfonyloxy group optionally substituted by a C 1-6 alkyl group.
  • G is Cl, Br,
  • the carboxylic acid derivative of the invention is selected from the group consisting of
  • a further object of the present invention is to provide the use of a carboxylic acid derivative of the above formula (I), (II) or (III) for the preparation of a prodrug.
  • the prodrug is a prodrug of a propofol drug.
  • the prodrug is a prodrug of a taxane.
  • Figure 1 is a circular dichroic chromatogram of the compound of formula (VIII).
  • Figure 2 is a circular dichroic chromatogram of the compound of formula (IX).
  • Fig. 3 is a circular dichroic chromatogram of a compound of 4-N,N-dimethylamino-2(R)-2-fluorobutyric acid (I') obtained by hydrolysis of a compound of the formula (III').
  • halogen as used herein means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
  • C 1-6 alkyl refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl It is preferably a methyl group, an ethyl group or a propyl group.
  • C 3-6 cycloalkyl refers to a saturated monocyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • amino protecting group refers to a protecting group that prevents an undesired chemical reaction of an amino group, including but not limited to an alkoxycarbonyl protecting group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl. And a benzyloxycarbonyl group, and the like, and an alkyl group-protecting group, for example, an unsubstituted or substituted benzyl group on the benzene ring.
  • protecting group for a carboxy or hydroxyhydroxy group refers to a protecting group which prevents an undesired chemical reaction of a hydroxy group in a carboxyl group or a phosphoric acid, including but not limited to methyl, ethyl, propyl, diphenylmethyl, Tritylmethyl, benzyl, and the like.
  • the term "acid which can form a salt with an amine” as used herein means an inorganic or organic acid which is commonly used in the field of organic chemistry to form a salt with an amine.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydrogen Iodine, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, and the like.
  • the organic acid includes, but is not limited to, formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, acetoacetic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethyl Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid and the like.
  • benzenesulfonyloxy refers to a structure of a group attached to the remainder of the molecule through an oxygen atom that is bonded to a single bond of a sulfur atom.
  • C1-6 alkoxycarbonyl refers to alkoxy groups having a total of from 1 to 6 carbon atoms attached to the remainder of the molecule through a carbonyl linkage, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl. , tert-butoxycarbonyl, pentyloxycarbonyl and the like.
  • the compounds of the formulae (Ia), (Ib) and (Ic) are all compounds of the formula (I) which are respectively passed through an alkylating agent of a compound of the formula (IV) and an amino group. (C 1 or C 3 ) or an amino protecting agent (C 2 ) is obtained by reacting,
  • R 1 , R 2 , X, Y, n, m, A are as defined above;
  • Reagent C 1 is an amino group alkylating agent, such as formic acid / formaldehyde, dimethyl sulfate, ethyl bromide, bromopropane, chlorobutane, acetone, methyl ethyl ketone, cyclopentanone, cyclohexanone, benzaldehyde, etc.;
  • Reagent C 2 is a protective reagent for an amino group, such as benzyl chloroformate, di-tert-butoxycarbonyl carbonic anhydride, benzyl chloride, benzyl bromide, etc.;
  • Reagent C 3 is another alkylating agent of amino group, such as 1-chloro-2-bromoethane, 1-chloro-4-bromobutane, 1-chloro-5-bromopentane, etc.;
  • R 3a is alkyl or cycloalkyl, especially C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or C 3-6 cycloalkyl such as cyclopropyl Base, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 3b is an amino protecting group, in particular a C 1-6 alkoxycarbonyl group optionally substituted by phenyl (such as benzyloxycarbonyl or tert-butoxycarbonyl) or a benzyl optionally substituted by one or more halogens ( For example, benzyl, 3-chlorobenzyl, 4-fluorobenzyl or 2,4-difluorobenzyl).
  • the compounds of the formulae (Id), (Ie) and (If) all belong to the compound of the formula (I), which are respectively obtained by the following steps: respectively from the formula (Va), Compounds of Vb) and (Vc) give compounds of the formulae (VIa), (VIb) and (VIc) under the action of a protective reagent D 1 at the 1-position of a carboxyl group, and then a protective reagent D 2 at the terminal carboxyl group or a phosphate hydroxyl group.
  • R 4 , X, Y, n are as defined above;
  • the protective reagent D 1 of the 1-position carboxyl group is selected from the group consisting of methanol, silyl-substituted methanol, 9-fluorenyl methanol, 2-iodo-2-methylpropane, benzyl halide, and the like;
  • the protective group D 2 of the carboxyl group or the phosphoric acid hydroxyl group at the terminal is selected from the group consisting of methyl iodide, benzophenone, triphenyl iodomethane, benzyl halide, and the like;
  • R 4 is a protecting group for a carboxy or hydroxyhydroxy group, especially a C 1-6 alkyl group optionally substituted by one or more phenyl groups, such as methyl, ethyl, diphenylmethyl, trityl, benzyl Base
  • R 5 is a protecting group at the 1-position carboxy group, such as a methyl group, a silyl-substituted alkyl group, a 9-fluorenylmethyl group, a t-butyl group, a benzyl group or the like.
  • the compound of the formula (I) can also be derivatized into a compound of the formula (II) or (III) by a conventional chemical means.
  • a compound of the formula (I) can be converted to the corresponding carboxylate (II) by a neutralization reaction, or can be reacted with a halogenating agent (such as thionyl chloride, phosphorus halide) or sulfonyl chloride to give the corresponding acid halide or sulfonate.
  • a halogenating agent such as thionyl chloride, phosphorus halide
  • sulfonyl chloride such as thionyl chloride, phosphorus halide
  • the reaction of the compound of (VIII) to give a compound of (IX) is a SN 2 reaction in which the chiral carbon atom configuration is reversed [see, for example, (1). J. ANTIBIOTIC, 1990, 43(7), 858-872; (2). JOC, 1979, 44, 3406].
  • the circular dichroism and optical activity measurements are consistent with the literature reports.
  • the circular dichroism and optical activity measurements of the compound of formula (I') indicate that its configuration is consistent with formula (IX). From this, it is understood that when the carboxyl group ⁇ -C in the compound of the formula (IV) is a chiral carbon atom, no change in configuration occurs during the subsequent reaction to prepare the compound of the formula (I).
  • the carboxylic acid derivative of the present invention can react with a hydroxyl group in a poorly soluble drug to form an ester, thereby obtaining a water-soluble prodrug.
  • the inventors intravenously injected the physiological saline solution of the docetaxel derivative of the above formula (J) and the control compound (J-1) into the rat, respectively.
  • the inventors respectively added an equimolar amount of propofol derivative of the above formula (J') with propofol and a pair.
  • the compound (J'-1) was intravenously injected into mice, and the following results were observed:
  • the inventors also dissolved the compound of the present invention of the following formula into physiological saline, adjusted the pH of the solution to 7.4, and administered it through the tail vein of the mouse, and measured LD 0 of more than 1500 mg/kg.
  • the carboxylic acid derivative of the present invention can be chemically reacted with a hydroxyl group in a poorly soluble drug to form an ester to increase the water solubility of the poorly soluble drug, thereby producing a water-soluble prodrug for injectable use.
  • the prodrug thus prepared is easy to decompose the original drug in the body, and does not affect the physiological activity of the original drug, thereby reducing the side effects caused by the polymer cosolvent in the original drug injection, and is suitable for use.
  • the ligand of the prodrug is easy to decompose the original drug in the body, and does not affect the physiological activity of the original drug, thereby reducing the side effects caused by the polymer cosolvent in the original drug injection, and is suitable for use.
  • the ligand of the prodrug is easy to decompose the original drug in the body, and does not affect the physiological activity of the original drug, thereby reducing the side effects caused by the polymer cosolvent in the original drug injection, and is suitable for use
  • the title compound was prepared according to the method described in Example 2, using 4-amino-2,2-difluorobutanoic acid hydrochloride (1.1 g, 5.6 mmol) and benzaldehyde.
  • the title compound was prepared according to the method described in Example 6 using 4-amino-2(R,S)-fluorobutyric acid and 1-chloro-4-bromobutane as starting material.
  • the title compound was prepared according to the method described in Example 13 using 4-(dihydroxy)phosphonyl-2-(R,S)-fluorobutyric acid as the starting material.
  • the title compound was prepared according to the method described in Example 13 using 5-(dihydroxy)phosphonyl-2-(R)-fluoropentanoic acid as the starting material.
  • the inventors prepared a water-soluble prodrug by reacting a compound specified by the present invention with a taxane, as follows:
  • a water-soluble prodrug by reacting a compound specified by the present invention with a propofol drug, as follows:
  • Example 1 4-N,N-dimethylamino-2(R,S)-fluorobutyrate (using 4-amino-2(R,S)-fluorobutyrate as raw material, according to the implementation
  • the method of Example 1 was obtained by dissolving) (10 mmol) in 10 ml of thionyl chloride, slowly raising the temperature to 40 ° C, and reacting for 4 hours, removing thionyl chloride by evaporation under reduced pressure, adding anhydrous dichloromethane (DCM) 15 ml, stirring. The solvent was then removed by evaporation under reduced pressure.
  • DCM dichloromethane
  • Propofol 3-N-Cbz-N-isopropylamino-2(R,S)-fluoropropionate Propofol (2.8 mmol) was dissolved in 1.5 ml of pyridine and added dropwise in an ice bath. L0ml contains 3-N-Cbz-N-isopropylamino-2(R,S)- A solution of fluoropropionyl chloride (5 mmol) in dichloromethane was added dropwise, and the mixture was reacted at room temperature for 1 hour or more with stirring. After the reaction was completed, the HCl solution was added to a pH of about 3. The organic layer was washed with water and dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, The yield was 69%.
  • Propofol 3-N-isopropylamino-2(R,S)-fluoropropionate hydrochloride 2 g propofol 3-N-Cbz-N-isopropylamino-2 (R, S)-Fluoropropionate (4.5 mmol) was dissolved in 10 mL of acetic acid, 0.5 g of 10% palladium on carbon was added, and hydrogen was introduced at room temperature for 3 h. After the end of the reaction, 5 ml of water was added, and the mixture was filtered, and solid NaHCO 3 was added to the filtrate under ice-cooling to give no bubble. It was extracted with diethyl ether (15 ml ⁇ 3). Under ice-cooling, a saturated aqueous solution of HCl was added dropwise to a white solid, which was filtered, and then evaporated to dryness.
  • the inventors provided the following experimental examples to demonstrate the carboxylic acid derivative of the present invention as a ligand for a water-soluble prodrug and the water-soluble thereby obtained.
  • the carboxylic acid derivative can be used to prepare a water-soluble paclitaxel derivative, a water-soluble docetaxel derivative, and a water-soluble cabazitaxel derivative.
  • the numbering and characterization data for these water-soluble taxane prodrugs are shown in Table 1 below:
  • the obtained water-soluble taxane series derivatives were each formulated into an aqueous solution of 0.2 mg/ml.
  • 0.1 ml of each solution was added to 0.9 ml of fresh New Zealand white rabbit rabbit plasma (heparin anticoagulation), mixed thoroughly, and incubated in a constant temperature water bath at 37 ° C and timed.
  • 0.2 ml of each sample was taken at 5 minutes, 20 minutes, and 60 minutes after the incubation, and 0.4 ml of acetonitrile cooled to -20 ° C was added to precipitate a protein.
  • Table 4 The results are shown in Table 4 below:
  • Twelve SD rats, male, weighing 200-220 g were taken. They were randomly divided into 4 groups, and 5 mg/kg of compound 01, 02, 03 and commercially available paclitaxel were administered intravenously respectively, and the administration volume was 5 ml/kg.
  • Five minutes after the administration 0.3 ml of venous blood was taken from the posterior venous plexus of the rat, and the heparinized test tube was placed. The cells were separated by centrifugation at 11,000 rpm for 5 min, and the concentration of the compound in the plasma was determined by liquid chromatography-tandem mass spectrometry.
  • the average concentration of paclitaxel in the plasma of each group of animals was (ng/ml): 1789, 1637, 1825, 1793.
  • the plasma concentration of docetaxel in each group was (ng/ml): 1506, 1387, 1621, 769.
  • Nude mice were subcutaneously inoculated with human ovarian cancer SK-OV-3 cells. After the tumors were grown to 100-150 mm 3 , the animals were randomly divided into groups (D0), and the water-soluble paclitaxel derivatives of the present invention (structures are shown in the following figure), paclitaxel and Abraxane were administered separately, once a day for 5 days. The dosages and dosing schedules are shown in Table 5 below. The tumor volume was measured 2-3 times per week, the animal body weight was weighed, and data was recorded until the 22nd day after grouping (D22).
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width, respectively.
  • T/C (%) (TT 0 ) / (CC 0 ) ⁇ 100, where T and C are the tumor volumes at the end of the experiment; T 0 and C 0 are the tumor volumes at the beginning of the experiment.
  • Anti-tumor activity data are shown in Table 5 below:
  • the structure of the administered compound is represented by the above formula and the substituents listed in Table 5 above;
  • ⁇ is a P(D22) value of 0.000, which means that the Student's t test was used as compared with the control.
  • the water-soluble paclitaxel derivatives of the present invention have an inhibitory effect on human ovarian cancer SK-OV-3.
  • Nude mice were subcutaneously inoculated with human prostate cancer PC-3 cells. After the tumors were grown to 100-150 mm 3 , the animals were randomly divided into groups, and the water-soluble docetaxel derivatives of the present invention (structure is shown below) and docetaxel 1 (D0) were administered to each group of animals on the same day. ). The dosages and dosing schedules are shown in Table 6 below. Tumor volume was measured 2-3 times per week, animal body weight was weighed, and data was recorded until day 20 after grouping (D20).
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width, respectively.
  • T/C(%) (T-T0)/(C-C0) ⁇ 100, where T and C are the tumor volumes at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.
  • Anti-tumor activity data are shown in Table 6 below:
  • ⁇ is a P(D22) value of 0.000, which means that the Student's t test was used as compared with the control.
  • the water-soluble docetaxel derivative of the present invention has an inhibitory effect on human prostate cancer PC-3.
  • mice were subcutaneously inoculated with human prostate cancer PC-3 cells. After the tumors were grown to 100-150 mm 3 , the animals were randomly divided into groups, and the water-soluble cabazitaxel derivatives of the present invention (structure shown below) and cabazitaxel 1 (D0) were separately administered to each group of animals on the same day. . The dosages and dosing schedules are shown in Table 7 below. Tumor volume was measured 2-3 times per week, animal body weight was weighed, and data was recorded until day 20 after grouping (D20).
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width, respectively.
  • T/C (%) (TT 0 ) / (CC 0 ) ⁇ 100, where T and C are the tumor volumes at the end of the experiment; T 0 and C 0 are the tumor volumes at the beginning of the experiment.
  • the structure of the administered compound is represented by the above formula and the substituents listed in Table 7 above;
  • ⁇ is a P (D20) value of 0.000, which means that Student's t test was used as compared with the control.
  • the water-soluble cabazitaxel derivatives of the present invention have an inhibitory effect on human prostate cancer PC-3.
  • the carboxylic acid derivative of the present invention can be used to prepare a water-soluble propofol derivative.
  • the general formulas of these water-soluble propofol prodrugs are shown below, and their numbering and characterization data are shown in Table 8 below:
  • the obtained water-soluble propofol series derivative was formulated into a physiological saline solution of 1 mg/ml. 0.1 ml of each solution was added to 1 ml of rabbit plasma (to live New Zealand white rabbits, treated by conventional methods, heparin anticoagulation) or rat plasma (from living SD rats, treated according to conventional methods, heparin anticoagulation) Medium, fully mixed, placed in a constant temperature water bath at 37 ° C and timed. Samples were taken at different time points after the start and 2 ml of acetonitrile was added immediately. Shake, centrifuge for 5 minutes (15000 rpm), take the supernatant and test by HPLC. The results are as follows:
  • the anesthetic ED 50 and LD 50 values were determined by sequential method. Healthy KM mice (male), SD rats (male) and New Zealand white rabbits were taken. The rats and mice were injected uniformly through the tail vein during the experimental administration, and the injection was completed in 10 seconds. In the rabbit experiment, the drug was injected uniformly through the ear vein, and the injection was completed in 30 seconds.
  • the preliminary dose (administration volume) which can cause anesthesia (or death) of the animal was found by preliminary preliminary test before the experiment as an intermediate dose at the time of the formal experiment. A group spacing of 0.8 was used, and 2-3 dose groups were further set up and down. The disappearance or death of righting reflex is used as a judgment indicator for pharmacodynamics or toxicity.
  • TI LD 50 / ED 50 .
  • mice Male, 5 in each group. Intravenous injection, uniform injection in 10 seconds, recording the time (latency) and recovery time (duration) of the disappearance of righting reflex in mice.
  • the carboxylic acid derivative of the present invention (including the compound of the formula I, II or III and any specific compound described in the present invention) can be chemically reacted with a hydroxyl group in a poorly soluble drug to form an ester.
  • the water solubility of the poorly soluble drug is increased to prepare a water-soluble prodrug for injectable use.
  • the prodrug thus prepared is easy to decompose the original drug in the body, and does not affect the physiological activity of the original drug, thereby reducing the side effects caused by the polymer cosolvent in the original drug injection, and the mouse LD 0 is above 1500mg/kg, which is very suitable for use as a ligand for prodrugs.

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Abstract

本发明公开了一类羧酸衍生物及其在制备前药中的用途。所述羧酸衍生物具有通式（I）：其中，R1为H或烷基；X为H或F；Y为F或氟代烷基；n为0、1、2、3、4、5或6；W为W1或W2；W1为NR2R3、NR2R3·A、式（AA）、或式（BB）；R2、R3各自独立地为H、烷基、环烷基、或氨基保护基；m为0、1、2或3；A为酸；W2为COOR4、OPO(OR4)2或PO(OR4)2；R4为H，或者为羧基或磷酸羟基的保护基。

Description

一类羧酸衍生物及其在制备前药中的用途
相关申请的交叉引用
本申请要求2014年2月17日提交的中国专利申请201410053129.9和2014年4月17日提交的中国专利申请201410154956.7的优先权，所述申请的公开内容均援引加入本文。
技术领域
本发明涉及医药领域，具体涉及一类羧酸衍生物及其在制备前药中的用途。
背景技术
前药即前体药物(prodrug)，也称药物前体、前驱药物等，是指经过生物体内转化后才具有药理作用的化合物。前体药物本身没有生物活性或活性很低，经过体内代谢后释放出有活性的物质。研究和制备前药的目的在于增加原药的生物利用度、改变原药的溶解性、加强靶向性或降低药物的毒性和副作用。对于很多药物，尤其是生物利用度低、水溶性差或毒副作用大的药物而言，制成前药有着较好的优越性。
一般来说，临床要求前药进入体内后能迅速分解成配体和原药，且配体无毒。释放出的原药可发挥药效，无毒的配体于身体无碍。但要达到这一目的具有相当难度。例如2008年在美国上市的磷丙泊酚钠是丙泊酚的前药，其体内代谢如下：
Figure PCTCN2015073165-appb-000001
尽管磷丙泊酚解决了丙泊酚难溶于水的问题，但从上式中可以看出，磷丙泊酚在体内会代谢出毒性较大的甲醛，这注定会对患者造成不必要的伤害；且从公布的数据(如下所示)得知，磷丙泊酚的用药剂量大大高于丙泊酚，并且潜伏期与持续时间大大长于丙泊酚。
Figure PCTCN2015073165-appb-000002
这说明磷丙泊酚在体内难于迅速分解，并非丙泊酚的理想前药。合适的配体是能否成为理想前药的关键。因而寻找前药的良好配体是药学工作者的紧迫任务之一。其中所述“良好配体”符合以下标准：所述配体与原药构成前药后，可改善原药的理化性质或提高原药生物利用度，该前药进入体内后可迅速分解出原药，且所述配体无毒或低毒。
发明内容
本发明的一个目的在于提供一类羧酸衍生物，其用于制备前药的配体，使制得的前药不但改变了原药的理化性质，且在体内可迅速分解，释放出原药，从而发挥作用。
本发明的羧酸衍生物具有如下通式(I)：
Figure PCTCN2015073165-appb-000003
其中，
R1为H或烷基；
X为H或F；
Y为F或者被一个或多个氟取代的烷基；
n为0、1、2、3、4、5或6；
W为W1或W2；
W1为NR2R3、NR2R3·A、
Figure PCTCN2015073165-appb-000004
R2、R3各自独立地为H、烷基、环烷基，或氨基保护基；
m为0、1、2或3；
A为酸；
W2为COOR4、OPO(OR4)2或PO(OR4)2；
R4为H，或者为羧基或磷酸羟基的保护基。
根据本发明的一个实施方案，R1为H或C1-6烷基。优选地，R1为H、甲基、乙基、正丙基或异丙基。
根据本发明的一个实施方案，Y为F或者被一个或多个F取代的C1-6烷基。优选地，Y为F、CF3或CHF2。
根据本发明的一个实施方案，W为W1。
根据本发明的一个实施方案，R2、R3不同时为H。
根据本发明的一个实施方案，R2和/或R3各自独立地为C1-6烷基，例如甲基、乙基、丙基、异丙基、丁基或异丁基。
根据本发明的一个实施方案，R2和/或R3各自独立地为C3-6环烷基，例如环丙基、环丁基、环戊基或环己基。
根据本发明的一个实施方案，R2和/或R3各自独立地为任选地被苯基取代的C1-6烷氧羰基，例如苄氧羰基或叔丁氧羰基。
根据本发明的一个实施方案，R2和/或R3各自独立地为任选地被一个或多个卤素取代的苄基。优选地，R2和/或R3各自独立地为任选地被一个或多个氟或氯取代的苄基，例如苄基、3-氯苄基、4-氟苄基或2,4-二氟苄基。
根据本发明的一个实施方案，R2、R3各自独立地为H、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、苄氧羰基、叔丁氧 羰基、苄基、3-氯苄基、4-氟苄基或2,4-二氟苄基。
根据本发明的一个实施方案，所述酸A为可与胺成盐的酸，例如盐酸、氢溴酸、硫酸、磷酸、三氟乙酸、二氟乙酸、氟乙酸、乙酸、苯磺酸或对甲苯磺酸。
根据本发明的一个实施方案，W为W2。
根据本发明的一个实施方案，R4为任选地被一个或多个苯基取代的C1-6烷基，例如甲基、乙基、二苯甲基、三苯甲基或苄基。
根据本发明的一个实施方案，当X与Y不同时(即，当所述羧酸衍生物的羧基的α-C为手性原子时)，同时与X和Y连接的碳原子可为单一的R构型、单一的S构型，或R与S构型的混合物。
根据本发明的一个实施方案，通式(I)的化合物也可以通过常规化学手段衍生为通式(II)或(III)的化合物。例如可以将通式(I)的化合物通过中和反应转化成相应的羧酸盐(II)，或者通过与卤化剂(如二氯亚砜或卤化磷)或磺酰氯反应得到相应的酰卤或磺酸混酐(III)。
Figure PCTCN2015073165-appb-000005
其中，
R1、X、Y、n、W如上文中对于通式(I)的羧酸衍生物所定义；
M为金属离子；
q为M所带的电荷数；
G为Cl、Br或任选地被烷基取代的苯磺酰氧基。
根据本发明的一个实施方案，上述通式(II)中的M为碱金属离子例如钠离子或钾离子，碱土金属离子例如镁离子、锌离子或钙离子，或者三价金属离子例如铝离子或铁离子。更优选地，M为钠离子或钾离子。
根据本发明的一个实施方案，上述通式(III)中的G为Cl、Br或任选地被C1-6烷基取代的或苯磺酰氧基。优选地，G为Cl、Br、
Figure PCTCN2015073165-appb-000006
Figure PCTCN2015073165-appb-000007
根据本发明的一个实施方案，本发明的羧酸衍生物选自：
4-N,N-二甲氨基-2(R)-氟代丁酸盐酸盐；
4-N-异丙基氨基-2(R,S)-氟代丁酸盐酸盐；
4-N,N-二乙氨基-2(R,S)-三氟甲基丁酸盐酸盐；
4-N-苄基氨基-2,2-二氟代丁酸盐酸盐；
4-N-异丁基氨基-2(R,S)-二氟甲基丁酸盐酸盐；
4-N-(氮杂环丙-1-基)-2(R,S)-二氟甲基丁酸盐酸盐；
4-N-(四氢吡咯-1-基)-2(R,S)-氟代丁酸盐酸盐；
3-N-苄基氨基-2(R,S)-(1,1-二氟甲基)丙酸盐酸盐；
6-N-环己基氨基-2(R,S)-三氟甲基己酸盐酸盐；
4-苄氧基-4-氧代-2-(R,S)-氟代丁酸；
5-苄氧基-5-氧代-2-(R)-氟代戊二酸；
6-苄氧基-6-氧代-2-(S)-氟代己酸；
二苄基[1-(3-(R,S)-氟-3-羧基)丙基]磷酸三酯；
二苄基[1-(5-(S)-氟-5-羧基)戊基]磷酸三酯；
4-(二苄氧基)磷酰基-2-(R,S)-氟代丁酸；
5-(二苄氧基)磷酰基-2-(R)-氟代戊酸；
4-苄氧基-4-氧代-2-(R,S)-氟代丁酰氯；
5-苄氧基-5-氧代-2-(R)-氟代戊酸钠；
二苄基[1-(3-(R,S)-氟-4-氧代-4-氯)丁基]磷酸三酯；
二苄基[1-(4-(S)-氟-5-羧酸钾)戊基]磷酸三酯；
4-(二苄氧基)磷酰基-2-(R,S)-氟代丁酰氯；
4-N,N-二甲氨基-2(R,S)-氟代丁酸钠；
4-N,N-二乙氨基-2(R,S)-氟代丁酸钙；
3-N-苄基氨基-2(R,S)-苄氧基丙酸铝；
4-N,N-二甲氨基-2(R,S)-氟代丁酰氯盐酸盐；
4-N-苄基氨基-2,2-二氟代丁酰氯盐酸盐；
4-N,N-二甲氨基-2(R,S)-氟代丁酸；和
4-N,N-二甲氨基-2(S)-氟代丁酸盐酸盐。
本发明的又一目的在于提供上述通式(I)、(II)或(III)的羧酸衍生物在制备前药中的用途。
根据本发明的一个实施方案，所述前药为丙泊酚类药物的前药。
根据本发明的一个实施方案，所述前药为紫杉烷类药物的前药。
附图说明
图1为式(VIII)的化合物的圆二色谱图。
图2为式(IX)的化合物的圆二色谱图。
图3为式(III’)的化合物水解得到的4-N,N-二甲基氨基-2(R)-2-氟代丁酸(I’)的化合物的圆二色谱图。
具体实施方式
定义
本文所用的术语“卤素”是指氟、氯、溴或碘，优选为氟、氯或溴。
本文所用的术语“C1-6烷基”是指具有1-6个碳原子的饱和的直链或支链烃基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等，优选甲基、乙基、丙基、异丙基、丁基或异丁基，优选甲基、乙基或丙基。
本文所用的术语“C3-6环烷基”是指具有3-6个碳原子的饱和的单环烃基，例如环丙基、环丁基、环戊基或环己基。
本文所用的术语“氨基保护基”是指防止氨基发生不期望的化学反应的保护基，包括但不限于烷氧羰基类保护基例如甲氧羰基、乙氧羰基、丙氧羰基、叔丁氧羰基、苄氧羰基等，以及烷基类保护基例如在苯环上未取代或取代的苄基等。
本文所用的术语“羧基或磷酸羟基的保护基”是指防止羧基或磷酸中的羟基发生不期望的化学反应的保护基，包括但不限于甲基、乙基、丙基、二苯甲基、三苯甲基、苄基等。
本文所用的术语“可与胺成盐的酸”是指有机化学领域常用的可与胺反应形成盐的无机酸或有机酸。所述无机酸包括但不限于盐酸、氢溴酸、氢 碘酸、硫酸、焦硫酸、磷酸、硝酸等。所述有机酸包括但不限于甲酸、乙酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、樟脑磺酸等。
本文所用的术语“苯磺酰氧基”是指结构为
Figure PCTCN2015073165-appb-000008
的基团，其通过与硫原子单键连接的氧原子与分子的其余部分相连。
本文所用的术语“C1-6烷氧羰基”是指总共具有1-6个碳原子的通过羰基键与分子的其余部分相连的烷氧基，例如甲氧羰基、乙氧羰基、丙氧羰基、叔丁氧羰基、戊氧羰基等。
反应路线
当W为W1时，本发明的通式(I)的羧酸衍生物可采用如下所示的反应路线1来制备：
反应路线1
Figure PCTCN2015073165-appb-000009
在上述反应路线1中，通式(Ia)、(Ib)和(Ic)的化合物均属于通式(I)的化合物，其分别是通过由通式(IV)的化合物与氨基的烷化剂(C1或C3)或氨基的保护试剂(C2)反应而得到，
其中，
R1、R2、X、Y、n、m、A如上文中所定义；
试剂C1为一种氨基的烷化剂，如甲酸/甲醛、硫酸二甲酯、溴乙烷、溴丙烷、氯丁烷、丙酮、丁酮、环戊酮、环己酮、苯甲醛等；
试剂C2为氨基的保护试剂，如氯甲酸苄酯、二叔丁氧羰基碳酸酐、氯化苄、溴化苄等；
试剂C3为另一种氨基的烷化剂，如1-氯-2-溴乙烷、1-氯-4-溴丁烷、1-氯-5-溴戊烷等；
R3a为烷基或环烷基，特别是C1-6烷基如甲基、乙基、丙基、异丙基、丁基或异丁基，或C3-6环烷基如环丙基、环丁基、环戊基或环己基。
R3b为氨基保护基，特别是任选地被苯基取代的C1-6烷氧羰基(如苄氧羰基或叔丁氧羰基)或任选地被一个或多个卤素取代的苄基(如苄基、3-氯苄基、4-氟苄基或2,4-二氟苄基)。
当W为W2时，本发明的通式(I)的羧酸衍生物可采用如下所示的反应路线2来制备：
反应路线2
Figure PCTCN2015073165-appb-000010
在上述反应路线2中，通式(Id)、(Ie)和(If)的化合物均属于通式(I)的化合物，其分别是通过以下步骤得到的：分别由通式(Va)、(Vb)和(Vc)的化合物在1-位羧基的保护试剂D1的作用下得到式(VIa)、(VIb)和(VIc)的化合物，然后在末位羧基或磷酸羟基的保护试剂D2的作用下得到通式(VIIa)、(VIIb)和(VIIc)的化合物，最后脱去1-位羧基保护基R5，得到通式(Id)、(Ie)和(If)的化合物，
其中，
R4、X、Y、n如上文中所定义；
所述1-位羧基的保护试剂D1选自甲醇、甲硅烷基取代的甲醇、9-芴甲醇、2-碘代-2-甲基丙烷、卤化苄等；
所述末端的羧基或磷酸羟基的保护试剂D2选自碘甲烷、二苯甲腙、三苯基碘甲烷、卤化苄等；
R4为羧基或磷酸羟基的保护基，特别是任选地被一个或多个苯基取代的C1-6烷基，如甲基、乙基、二苯甲基、三苯甲基、苄基等；
R5为1-位羧基的保护基，如甲基、甲硅烷基取代的烷基、9-芴甲基、叔丁基、苄基等。
以上反应路线中的通式(IV)和(V)(包括通式(Va)、(Vb)和(Vc))的化合物可按照相应文献所报道的方法而获得。所述文献参见例如[1]Chencomm,1999：1739-1740；[2]J.Med.Chem,2011,44：2849-2856；[3]JCS Perkin I 1980：2029-2032；[4]Journal of Fluorine Chemistry(23),1983：241-259；[5]Journal of Fluorine Chemistry,2004,vol.125(4):509–515；[6]Phosphorus,Sulfur and Silicon and the Related Elements,1995,105(1-4):205–212；[7]Tetrahedron Letters,2007,48(4):711–714；[8]Helvetica Chimica Acta,1958,1163,1167；[9]Justus Liebigs Annalen der Chemie,1962,655:70-80。
另外，如上文中所述，通式(I)的化合物也可以通过常规化学手段衍生为通式(II)或(III)的化合物。例如通式(I)的化合物可通过中和反应转化成相应的羧酸盐(II)，或者通过与卤化剂(如二氯亚砜、卤化磷)或磺酰氯反应得到相应的酰卤或磺酸混酐(III)。
为了了解当原料(IV)中的羧基α-C为手性碳原子时，化合物在后续反应过程中是否发生构型改变，发明人设计了反应路线3的方法。
反应路线3
Figure PCTCN2015073165-appb-000011
以S构型的式(VIII)的化合物为原料([a]2 D 4＝+14.91°(c＝0.209g/100ml，MeOH)，酯化后，用氟代试剂DAST将羟基氟代得到式(IX)的化合物(
Figure PCTCN2015073165-appb-000012
Figure PCTCN2015073165-appb-000013
(c＝0.453g/100ml，MeOH))。以上反应路线3中，由(VIII’)的化合物氟代得到(IX)的化合物的反应为SN2反应，其中手性碳原子构型发生翻转[参见例如(1).J.ANTIBIOTIC,1990,43(7),858-872；(2).J.O.C,1979,44,3406]。其圆二色谱图和光学活性测定与文献报道一致。式(IX)的化合物经水解得到式(IV’)的化合物，再采用上文中所述的本发明的方法反应可制备得到式(I’)的化合物(
Figure PCTCN2015073165-appb-000014
(c＝0.315g/100ml，H2O))和式(III’)的化合物，式(III’)的化合物经水解可得式(I’)的化合物。式(I’)的化合物的圆二色谱图和光学活性测定表明，其构型与式(IX)一致。由此可知，当通式(IV)的化合物中的羧基α-C为手性碳原子时，在后续制备通式(I)的化合物的反应过程中不会发生构型改变。
在制备前药中的应用
本发明的羧酸衍生物可与难溶性药物中的羟基反应以形成酯，从而得到水溶性前药。
例如，本发明的羧酸衍生物可与多西他赛形成以下水溶性前药(其中Y＝F)：
Figure PCTCN2015073165-appb-000015
发明人还同时制备了上述化合物(J)的对照化合物(J-1)，其与化合物(J)的区别仅在于其中Y＝H。
发明人分别将上述通式(J)的多西他赛衍生物和对照化合物(J-1)的生理盐水溶液静脉注射到大鼠体内。
对于其中Y＝H的对照化合物(J-1)，在注射后5-10分钟取血检测，在血浆中检测到对照化合物(J-1)的比例高于多西他赛。
而对于其中Y＝F的多西他赛衍生物(J)，在注射后立即取血检测，在血浆中检测到多西他赛衍生物(J)几乎全部分解为多西他赛。
又如，本发明的羧酸衍生物可与丙泊酚形成以下水溶性前药(其中Y＝F)：
Figure PCTCN2015073165-appb-000016
发明人还同时制备了上述化合物(J’)的对照化合物(J’-1)，其与化合物(J’)的区别仅在于其中Y＝H。
发明人分别将与丙泊酚等摩尔量的上述通式(J’)的丙泊酚衍生物和对 照化合物(J’-1)静脉注射到小鼠体内，之后观察到以下结果：
其中Y＝H的对照化合物(J’-1)的催眠潜伏期和持续期大大长于丙泊酚，且小鼠苏醒后呈短暂偏瘫。
而其中Y＝F的丙泊酚衍生物(J’)的催眠潜伏期和持续期几乎与丙泊酚相当，且未见任何神经毒性反应。
发明人还将下式的本发明的化合物溶于生理盐水，调节溶液pH至7.4，将其经小鼠尾静脉给药，测得的LD0大于1500mg/kg。
Figure PCTCN2015073165-appb-000017
从以上可以看出，本发明的羧酸衍生物可以通过化学方法与难溶性药物中的羟基反应形成酯，以增加难溶性药物的水溶性，从而制得可注射用的水溶性前药。令人惊讶地，由此制得的前药易于在体内分解出原药，且不影响原药的生理活性，从而可减少原药注射液中的高分子助溶剂带来的副作用，适合用做前药的配体。
实施例
为了使本发明的目的和技术方案更加清楚，下面对本发明的优选实施例进行详细的描述。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
实施例1
4-N,N-二甲氨基-2(R)-氟代丁酸盐酸盐的制备
于圆底烧瓶中加入4-氨基-2(R)-氟代丁酸盐酸盐(1.1g，7.0mmol)，用饱和Na2CO3水溶液调节pH值至8，再加入88％的甲酸(6ml)和35％的甲醛水溶液(5ml)，缓慢升温到80℃，反应15小时，冷却至室温，加入6N盐酸2ml，然后减压浓缩，得到浅黄色固体。加入10ml甲醇加以溶解，将其置于冰浴中搅拌30min，过滤，将滤液浓缩，将残余物用6N的盐酸(100ml)回流4小时，通过旋转蒸发除去液体，所得固体经乙腈处理，得到白色 固体1.1g，收率85％。
m.p.：136-138℃；
1H-NMR(400MHz,D2O)：δ4.72(ddd,1H),2.90(dtd,2H),2.43(s,6H),1.93(m,2H)；
13C-NMR(600MHz,D2O)：δ173.13,86.90,53.49,42.83,26.91；
ESI-MS m/z[M+H]+150.13。
实施例2
4-N-异丙基氨基-2(R,S)-氟代丁酸盐酸盐的制备
于50ml圆底烧瓶中加入4-氨基-2(R,S)-氟代丁酸盐酸盐(1.1g，7.0mmol)，用饱和Na2CO3水溶液调节pH值至8，加入丙酮(15ml)和5％Pd-C(100mg)，用氮气置换空气后再用氢气置换氮气，在室温下反应6小时，过滤除去Pd-C，用6N盐酸调节溶液pH至酸性，减压浓缩，得到浅黄色固体。加入10ml甲醇加以溶解，将其置于冰浴中搅拌30min，过滤，将滤液浓缩，将残余物用6N的盐酸(100ml)回流4小时，通过旋转蒸发除去溶剂，所得固体经乙腈处理，得到白色固体1.05g，收率75％。
ESI-MS m/z[M+H]+164.12。
实施例3
4-N,N-二乙氨基-2(R,S)-三氟甲基丁酸盐酸盐的制备
于50ml圆底烧瓶中加入4-氨基-2-三氟甲基丁酸盐酸盐(2.07g，10mmol)，用1N NaHCO3水溶液调节pH值至8，加入乙腈50ml，滴加溴乙烷(2.18g，20mmol)与乙腈的混合溶液(10ml)，用碳酸氢钠溶液维持反应液pH 7-8，在反应结束后，加盐酸调节pH至5以下，减压浓缩，得到浅黄色固体。加入10ml甲醇，搅拌30min，过滤，将滤液浓缩，将残余物用6N盐酸(100ml)回流4小时，通过旋转蒸发除去溶剂，得到白色固体，收率13％。
ESI-MS m/z[M+H]+228.16。
实施例4
4-N-苄基氨基-2,2-二氟代丁酸盐酸盐的制备
以4-氨基-2,2-二氟代丁酸盐酸盐(1.1g，5.6mmol)和苯甲醛为原料，按照实施例2中所述的方法制备标题化合物，收率73％。
ESI-MS m/z[M+H]+230.06。
实施例5
4-N-异丁基氨基-2(R,S)-二氟甲基丁酸盐酸盐的制备
以4-氨基-2(R,S)-二氟甲基丁酸盐酸盐(1.90g，10mmol)和丁酮(15ml)为原料，按照实施例2中所述的方法制备标题化合物，得到白色固体1.1g，收率45％。
m.p.：141-142℃；
ESI-MS m/z[M+H]+210.1。
实施例6
4-N-(氮杂环丙-1-基)-2(R,S)-二氟甲基丁酸盐酸盐的制备
于50ml圆底烧瓶中加入4-氨基-2(R,S)-二氟甲基丁酸盐酸盐(1.90g，10mmol)，用NaHCO3水溶液调节pH至7-8，加入乙腈15ml及1-氯-2-溴乙烷(10mmol)，在常温下反应0.5h，加热回流反应2h，通过减压蒸发除去溶剂，在残余物中加入10ml甲醇，将其置于冰浴中搅拌30min，过滤，将滤液浓缩，将残余物用6N的盐酸(100ml)回流4小时，通过旋转蒸发除去溶剂，得到白色固体0.7g。
ESI-MS m/z[M+H]+180.14。
实施例7
4-N-(四氢吡咯-1-基)-2(R,S)-氟代丁酸盐酸盐的制备
以4-氨基-2(R,S)-氟代丁酸和1-氯-4-溴丁烷为原料，按照实施例6中所述的方法制备标题化合物。
ESI-MS m/z[M+H]+176.1。
实施例8
3-N-苄基氨基-2(R,S)-(1,1-二氟甲基)丙酸盐酸盐的制备
以3-氨基-2(R,S)-(1,1-二氟甲基)丙酸盐酸盐和苯甲醛为原料，按照实施例2中所述的方法制备标题化合物。
ESI-MS m/z[M+H]+230.19。
实施例9
6-N-环己基氨基-2(R,S)-三氟甲基己酸盐酸盐的制备
以6-氨基-2(R,S)-三氟甲基己酸盐酸盐和环己酮为原料，按照实施例2中所述的方法制备标题化合物。
ESI-MS m/z[M+H]+282.08。
实施例10
4-苄氧基-4-氧代-2-(R,S)-氟代丁酸的制备
室温下，将2-(R,S)-氟代丁二酸(10mmol)溶于溶于甲醇(30ml)中，搅拌2h，通过减压蒸发除去溶剂，得到2-(R,S)-氟代丁二酸-1-甲酯。
ESI-MS m/z[M-H]-149.01。
室温下，将2-(R,S)-氟代丁二酸-1-甲酯(5mmol)溶于干燥的二氯甲烷(20ml)中，加入二氯亚砜(0.3ml)，缓慢加热至回流，反应3小时，通过减压蒸发除去剩余的二氯亚砜和溶剂，得到氟代丁酰氯。
冰浴条件下，将氟代丁酰氯(4mmol)的二氯甲烷溶液(5ml)滴加到苄醇(4mmol)与吡啶(5mmol)的二氯甲烷溶液(10ml)中，在冰浴下反应1h，用pH 3的盐酸水溶液洗涤有机层，将有机层用无水硫酸钠干燥，通过减压蒸发除去溶剂，得到4-苄氧基-4-氧代-2-(R,S)-氟代丁酸甲酯。
ESI-MS m/z[M﹢H]﹢241.18。
冰浴条件下，将4-苄氧基-4-氧代-2-(R,S)-氟代丁酸甲酯(7mmol)溶于甲醇(10ml)中，加入1N的NaOH溶液(1ml)，在冰浴下反应1h，通过减压蒸发除去甲醇，加入水(10ml)，用1N的盐酸中和反应至pH为1以下，将水层用乙醚萃取，合并乙醚层，用无水硫酸钠干燥，过滤，通过减压蒸发除去溶剂，得到4-苄氧基-4-氧代-2(R,S)-氟代丁酸，收率40％。
ESI-MS m/z[M-H]-225.18。
实施例11
5-苄氧基-5-氧代-2-(R)-氟代戊酸的制备
以2-(R)-氟代戊二酸为原料，按照实施例10中所述的方法制备标题化合物。
ESI-MS m/z[M-H]-239.19。
实施例12
6-苄氧基-6-氧代-2-(S)-氟代己酸的制备
以2-(S)-氟代己二酸为原料，按照实施例10中所述的方法制备标题化合物。
ESI-MS m/z[M-H]-253.17
实施例13
二苄基[1-(3-(R,S)-氟-3-羧基)丙基]磷酸三酯的制备
室温下，将[1-(3-(R,S)-氟-3-羧基)丙基]磷酸单酯(10mmol)溶于甲醇(10ml)中，搅拌1h，通过减压蒸发除去甲醇，得到[1-(3-(R,S)-氟-4-氧代-4-甲氧基)丁基]磷酸单酯。
ESI-MS m/z[M-H]-215.07。
室温下，将[1-(3-(R,S)-氟-4-氧代-4-甲氧基)丁基]磷酸单酯(7mmol)溶于干燥的乙腈(20ml)中，加入无水碳酸钾(17mmol)和溴化苄(17mmol)，缓慢加热至回流，经TCL监测反应完全，冷却，过滤，通过旋转蒸发除去溶剂，将残余物用柱色谱法纯化(EA:PE＝1:3)，得到二苄基[1-(3-(R,S)-氟-4-氧代-4-甲氧基)丁基]磷酸三酯。
ESI-MS m/z[M﹢H]﹢397.08。
冰浴下，将二苄基[1-(3-(R,S)-氟-4-氧代-4-甲氧基)丁基]磷酸三酯(10mmol)溶于四氢呋喃(10ml)中，缓慢加入1N的NaOH溶液(1ml)，在冰浴下搅拌1h，有白色固体析出，过滤，将滤饼溶于10ml水中，用浓盐酸调节pH至1以下，将水层用乙醚萃取，合并乙醚层，用无水硫酸钠干燥，通过旋转蒸发除去乙醚，得到产物，收率63.5％。
ESI-MS m/z[M-H]-381.29。
实施例14
二苄基[1-(5-(S)-氟-5-羧基)戊基]磷酸三酯的制备
以[1-(5-(S)-氟-5-羧基)戊基]磷酸单酯为原料，按照实施例13中所述的方法制备标题化合物。
ESI-MS m/z[M-H]-409.29
实施例15
4-(二苄氧基)磷酰基-2-(R,S)-氟代丁酸的制备
以4-(二羟基)磷酰基-2-(R,S)-氟代丁酸为原料，按照实施例13中所述的方法制备标题化合物。
ESI-MS m/z[M-H]-365.28
实施例16
5-(二苄氧基)磷酰基-2-(R)-氟代戊酸的制备
以5-(二羟基)磷酰基-2-(R)-氟代戊酸为原料，按照实施例13中所述的方法制备标题化合物。
ESI-MS m/z[M-H]-379.31。
参照上述实施例，发明人还制得了以下化合物：
4-苄氧基-4-氧代-2-(R,S)-氟代丁酰氯(ESI-MS m/z[M-H]245.01)；
5-苄氧基-5-氧代-2-(R)-氟代戊酸钠(ESI-MS m/z[M-H]240.05)；
二苄基[1-(3-(R,S)-氟-4-氧代-4-氯)丁基]磷酸三酯(ESI-MS m/z[M-H]401.02)；
二苄基[1-(4-(S)-氟-5-羧酸钾)戊基]磷酸三酯(ESI-MS m/z[M-H]396.01)；
4-(二苄氧基)磷酰基-2-(R,S)-氟代丁酰氯(ESI-MS m/z[M-H]385.04)；
4-N,N-二甲氨基-2(R,S)-氟代丁酸钠(ESI-MS m/z[M-H]149.03)；
4-N,N-二乙氨基-2(R,S)-氟代丁酸钙(ESI-MS m/z[M-H]177.08)；
3-N-苄基氨基-2(R,S)-苄氧基丙酸铝(ESI-MS m/z[M-H]197.04)；
4-N,N-二甲氨基-2(R,S)-氟代丁酰氯盐酸盐(ESI-MS m/z[M-H]168.01)；
4-N-苄基氨基-2,2-二氟代丁酰氯盐酸盐(ESI-MS m/z[M-H]248.03)；
4-N,N-二甲氨基-2(R,S)-氟代丁酸(ESI-MS m/z[M-H]150.08)；和
4-N,N-二甲氨基-2(S)-氟代丁酸盐酸盐(ESI-MS m/z[M-H]150.11)。
发明人通过用本发明指定的化合物与紫杉烷类药物进行反应以制备水溶性前药，具体如下：
实施例17
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐(化合物编号01)
1)4-N,N-二甲氨基-2(R)-氟代丁酰氯盐酸盐的制备：将4-(N,N-二甲基)氨基-2-(R)-氟代丁酸盐酸盐(10mmol)，置于10ml二氯亚砜中，缓慢升温至40℃，反应4小时，减压挥去二氯亚砜，加入无水二氯甲烷(DCM)，搅拌后减压挥去溶剂；残余物中加入无水二氯甲烷60ml备用。
2)在-50℃下，在150ml二氯甲烷(DCM)中加入紫杉醇1.6g、4-N,N-二甲基吡啶1.4g，搅拌使之溶解，缓缓滴加1)制备的4-N,N-二甲氨基-2(R)- 氟代丁酰氯盐酸盐的二氯甲烷溶液，通过HPLC检测反应，反应完全后用饱和氯化钠水溶液(盐酸调节pH为约3.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM得到标题化合物，收率50％。
ESI-MS m/z[M+H]+：985.4。
1H-NMR(400MHz,DMSO)：δ7.86(m,2H),7.79(m,2H),7.68(t,1H),7.59(m,3H),7.48(t,2H,),7.38(m,2H),7.25(m,3H),6.18(s,1H),6.15(s,1H),5.79(s,1H),4.98(t,2H),4.85(d,J＝6.24Hz,1H),4.26(d,1H,),3.72(d,J＝7.62Hz,1H),3.64(t,1H),2.89(t,2H),2.54(s,1H),2.26(t,2H),2.18(m,13H),2.01(s,3H),1.95(m,2H),1.86(m,1H),1.75(m,1H),1.68(m,1H),1.52(s,6H),1.41(s,3H)。
13C-NMR(600MHz,DMSO)：δ203.64,171.32,170.65,169.63,168.96,165.98,165.86,140.36,140.21,137.12,134.65,134.12,133.98,133.89,133.21,130.65,129.94,128.98,128.54,128.43,128.12,85.12,81.45,80.65,78.23,76.58,76.46,76.45,74.98,72.56,70.23,59.64,54.87,53.03,48.65,43.45,42.26,42.15,41.96,38.96,34.45,28.20,23.97,21.65,21.01,11.23。
实施例18
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]紫杉醇盐酸盐(化合物编号03)
在-50℃下，在150ml二氯甲烷(DCM)中加入紫杉醇2g、4-N,N-二甲基吡啶1.9g，搅拌使之溶解，缓缓滴加4-N,N-二甲氨基-2(R,S)-氟代丁酰氯盐酸盐的二氯甲烷溶液(以4N,N-二甲氨基-2(R,S)-氟代丁酸盐酸盐为原料，按照实施例17方法获得)，HPLC检测反应至完全。用饱和氯化钠水溶液(盐酸调节pH约3.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，得到固体,收率43％。
实施例19
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代丁酰基]多西他赛盐酸盐(化合物编号04)
在-15℃下，在150ml二氯甲烷(DCM)中加入多西他赛2.1g、4-N,N-二甲基吡啶1.8g，搅拌使之溶解，缓缓滴加4-N,N-二甲氨基-2(R)-氟代丁酰氯盐酸盐的二氯甲烷溶液(按实施例17方法获得)，HPLC检测反应至完 全；饱和氯化钠水溶液(盐酸调节pH约3.0)洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去DCM，得固体，收率51％。
ESI-MS m/z[M+H]+：939.54。
1H-NMR(400MHz,DMSO)：δ7.93(dd,2H),7.64(dt,1H),7.40(m,2H),7.19(d,J＝6.42Hz,2H),5.82(s,3H),5.38(m,1H),5.33(m,1H),5.23(d,J＝7.64Hz,2H),5.13(m,1H),5.00(d,J＝5.23Hz,1H,),4.89(m,1H),4.44(s,1H,),4.00(s,3H),3.63(d,J＝7.17Hz,2H),2.59(dd,1H),2.45(s,1H),2.43(m,3H,),2.14(m,6H),2.06(m,5H),1.88(s,3H),1.61(m,1H),1.33(s,1H),1.14(m,7H),0.97(s,15H),0.82(t,3H)。
13C-NMR(600MHz,DMSO)：δ209.458,169.376,168.425,167.682,167.513,166.869,165.229,155.167,137.026,136.896,135.884,133.171,131.278,129.960,129.539,128.542,128.044,127.201,86.406,85.187,83.701,80.367,79.033,78.811,78.596,76.788,75.416,74.703,73.715,71.883,70.710,67.308,57.007,54.708,51.949,45.925,42.867,42.515,42.086,39.909,39.771,39.625,39.488,39.350,39.212,39.074,38.077,36.391,34.675,29.777,28.980,28.337,28.061,26.566,26.436,26.298,23.209,22.405,20.627,13.806,13.614,10.717,9.667。
参照实施例18或者实施例19制得以下化合物：
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代丁酰基]紫杉醇盐酸盐(化合物编号02)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代丁酰基]多西他赛盐酸盐(化合物编号05)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]多西他赛盐酸盐(化合物编号06)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代丁酰基]卡巴他赛盐酸盐((化合物编号07)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代丁酰基]卡巴他赛盐酸盐(化合物编号08)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]卡巴他赛盐酸盐(化合物编号09)；
2′-O-[4-氨基-2-(R)-二氟甲基丁酰基]卡巴他赛硫酸氢钠盐(化合物编号10)；
2′-O-[4-(N,N-二乙基)氨基-2-甲基-2(R)-2-三氟甲基丁酰基]卡巴他赛甲磺酸盐(化合物编号11)；
2′-O-[4-(N-甲基-N-乙基)氨基-2(R)-2-二氟乙基戊酰基]多西他赛盐酸盐(化合物编号12)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代戊酰基]多西他赛甲磺酸盐(化合物编号13)；
2′-O-[4-N-(氮杂环丙烷-1-基)-2,2-二氟代庚酰基]多西他赛甲磺酸盐(化合物编号14)；
2′-O-[4-(N-甲基-N-环戊基)氨基-2(R,S)-2-三氟甲基-2-氟代辛酰基]紫杉醇甲磺酸盐(化合物编号15)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代丁酰基]紫杉醇甲磺酸盐(化合物编号C1)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代丁酰基]紫杉醇甲磺酸盐(化合物编号C2)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]紫杉醇甲磺酸盐(化合物编号C3)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代丁酰基]多西他赛甲磺酸盐(化合物编号C4)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代丁酰基]多西他赛甲磺酸盐(化合物编号C5)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]多西他赛甲磺酸盐(化合物编号C6)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代丁酰基]卡巴他赛甲磺酸盐(化合物编号C7)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代丁酰基]卡巴他赛甲磺酸盐(化合物编号C8)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]卡巴他赛甲磺酸盐(化合物编号C9)；
2′-O-[4-(N-甲基-N-乙基)氨基-2(R)-氟代丁酰基]紫杉醇甲磺酸盐(化合物编号16)；
2′-O-[4-(N,N-二乙基)氨基-2(S)-氟代丁酰基]紫杉醇富马酸盐(化合物编号17)；
2′-O-[4-(N-甲基-N-异丙基)氨基-2(R,S)-氟代丁酰基]紫杉醇盐酸盐(化合物编号18)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-2-三氟甲基丁酰基]紫杉醇对甲苯磺酸盐(化合物编号19)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-2-二氟甲基丁酰基]紫杉醇盐酸盐(化合物编号20)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代戊酰基]紫杉醇马来酸盐(化合物编号21)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-2-二氟甲基己酰基]紫杉醇硫酸盐(化合物编号22)；
2′-O-[4-(N-甲基-N-乙基)氨基-2(R)-氟代丁酰基]多西他赛甲磺酸盐(化合物编号23)；
2′-O-[4-(N,N-二乙基)氨基-2(S)-氟代丁酰基]多西他赛马来酸盐(化合物编号24)；
2′-O-[4-(N-甲基-N-异丙基)氨基-2(R)-氟代丁酰基]多西他赛盐酸盐(化合物编号25)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-2-三氟甲基丁酰基]多西他赛甲磺酸盐(化合物编号26)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-2-二氟甲基丁酰基]多西他赛盐酸盐(化合物编号27)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代戊酰基]多西他赛甲磺酸盐(化合物编号28)；
2′-O-[4-(N,N-二甲基)氨基-2(S)-氟代己酰基]多西他赛硫酸盐(化合物编号29)；
2′-O-[4-(N-甲基-N-乙基)氨基-2(R)-氟代丁酰基]卡巴他赛马来酸盐(化合物编号30)；
2′-O-[4-(N,N-二乙基)氨基-2(R)-氟代丁酰基]卡巴他赛甲磺酸盐(化合物编号31)；
2′-O-[4-(N-甲基-N-异丙基)氨基-2(R)-氟代丁酰基]卡巴他赛盐酸盐(化合物编号32)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-2-三氟甲基丁酰基]卡巴他赛甲磺酸盐(化合物编号33)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-2-二氟甲基丁酰基]卡巴他赛对甲苯磺酸盐(化合物编号34)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代戊酰基]卡巴他赛盐酸盐(化合物编号35)；
2′-O-[4-(N,N-二甲基)氨基-2(R)-氟代己酰基]卡巴他赛硫酸盐(化合物编号36)；
2′-O-[4-(N,N-二乙基)氨基-2(R,S)-氟代丁酰基]卡博他赛盐酸盐(化合物编号37)；
2′-O-[4-氨基-2(R,S)-三氟甲基丁酰基]多西他赛甲磺酸盐(化合物编号38)；
2′-O-[4-(N,N-二甲基)氨基-2-(R,S)-二氟甲基丁酰基]紫杉醇枸橼酸盐(化合物编号39)；
2′-O-[4-(N,N-二甲基)氨基-2(R,S)-氟代丁酰基]多西他赛盐酸盐(化合物编号40)；
2′-O-[4-(N,N-二乙基)氨基-2(R)-氟代丁酰基]紫杉醇盐酸盐(化合物编号41)；
2′-O-[4-(N-苄基)氨基-2(S)-氟代丁酰基]多西他赛盐酸盐(化合物编号42)；
2′-O-[4-(N-异丙基)氨基-2(R,S)-三氟甲基丁酰基]紫杉醇盐酸盐(化合物编号43)；
2′-O-[4-环丙氨基-2-(R,S)-三氟甲基丁酰基]卡博他赛甲磺酸盐(化合物编号44)；
2′-O-[4-(N-甲基)氨基-2-(R)-三氟甲基丁酰基]紫杉醇盐酸盐(化合物编号45)；
2′-O-[4-(N,N-二甲基)氨基-2-(S)-三氟甲基丁酰基]卡博他赛盐酸盐(化合物编号46)；
2′-O-[4-(N,N-二甲基)氨基-2-(R)-二氟甲基丁酰基]多西他赛盐酸盐(化合物编号47)；
2′-O-[3-(N,N-二甲基)氨基-2-(R,S)-氟代丙酰基]紫杉醇盐酸盐(化合物编号48)；
2′-O-[3-(N,N-二乙基)氨基-2-(R,S)-三氟甲基丙酰基]多西他赛盐酸盐(化合物编号49)；
2′-O-[3-(N-异丙基)氨基-2-(R,S)-二氟甲基丙酰基]卡博他赛盐酸盐(化合物编号50)；
2′-O-[δ-(N,N-二甲基)氨基-2-(R)-氟代戊酰基]紫杉醇盐酸盐(化合物编号51)；
2′-O-[δ-(N,N-二甲基)氨基-2-(S)-三氟甲基戊酰基]多西他赛盐酸盐(化合物编号52)；
2′-O-[4-(N-苄基)氨基-2-甲基-2-(R,S)-氟代丁酰基]紫杉醇盐酸盐(化合物编号53)；
2′-O-[3-环戊氨基-2-乙基-2-(R,S)-三氟甲基丙酰基]多西他赛盐酸盐(化合物编号54)；
2′-O-[δ-(N-苄基)氨基-2-苄基-2-(R)-二氟甲基戊酰基]卡博他赛盐酸盐(化合物编号55)；和
2′-O-[4-(4-哌啶-1-基)-2-(S)-三氟甲基丁酰基]卡博他赛盐酸盐(化合物编号56)。
发明人在对上述紫杉烷类衍生物的实验过程中发现，本发明制备的紫杉烷类衍生物的水溶性良好，能够在血浆中很快分解并释放出原药，从而发挥抗肿瘤活性，适合作为紫杉烷类药物的前药。
并且，发明人还通过用本发明指定的化合物与丙泊酚类药物进行反应以制备水溶性前药，具体如下：
实施例20
丙泊酚4-(N,N-二甲基)氨基-2-(R,S)-氟代丁酸酯盐酸盐(化合物编号E1)
将4-N,N-二甲氨基-2(R,S)-氟代丁酸盐酸盐(以4-氨基-2(R,S)-氟代丁酸盐酸盐为原料，按照实施例1方法获得))(10mmol)溶于10ml二氯亚砜中，缓慢升温至40℃，反应4小时，通过减压蒸发除去二氯亚砜，加入无水二氯甲烷(DCM)15ml，搅拌后通过减压蒸发除去溶剂。在残余物中加入无水二氯甲烷60ml，于-78℃下滴加丙泊酚(4.5mmol)。其后，缓缓加入含4-N,N-二甲基吡啶(8.2mmol)的二氯甲烷溶液20ml。通过HPLC检测反应进程。待反应完全后，用pH约1.0的盐酸水溶液洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去大部分DCM，缓缓滴入乙醚至大量固体析出，冷冻析晶，过滤并干燥后得到白色固体，收率83％。
实施例21
丙泊酚4-(N,N-二甲基)氨基-2-(R)-氟代丁酸酯盐酸盐(化合物编号E2)
在-30℃下，以4-N,N-二甲氨基-2(R)-氟代丁酰氯盐酸盐()(10mmol)、丙泊酚(10mmol)和DMAP(15mmol)为原料，按照实施例20中所述的方法制备标题化合物，收率87％，纯度99.4％。
1H-NMR(CDCl3)：δ1.22(9H,d,Me),2.10(3H,m,Me),2.88(6H,m,NMe),3.32(2H,m,CH2),5.43(1H,m,F-CH),7.21(3H,m,Ph)；
ESI-MS m/z[M+H]+310.1。
实施例22
丙泊酚3-(N,N-二乙基)氨基-2-(R,S)-氟代丙酸酯盐酸盐(化合物编号E18)
在-50℃下，以3-(N,N-二乙基)氨基-2-(R,S)-氟代丙酰氯盐酸盐(7mmol)、丙泊酚(4.4mmol)和DMAP(10mmol)为原料，按实施例20的操作，制得丙泊酚3-(N,N-二乙基)氨基-2-(R,S)-氟代丙酸酯盐酸盐，收率81％。ESI-MS m/z[M+H]+324.17
实施例23
丙泊酚3-N-异丙基氨基-2(R,S)-氟代丙酸酯盐酸盐(化合物编号E19)
丙泊酚3-N-Cbz-N-异丙基氨基-2(R,S)-氟代丙酸酯：将丙泊酚(2.8mmol)溶于1.5ml吡啶中，冰浴冷却下滴加l0ml含3-N-Cbz-N-异丙基氨基-2(R,S)- 氟代丙酰氯(5mmol)的二氯甲烷溶液，滴毕，在搅拌下室温反应l小时以上。在反应结束后，加入HCl溶液至pH＝3左右。用水洗至中性，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂，通过柱色谱法(硅胶：200-300目)纯化，通过减压蒸发除去溶剂，得到油状物0.86g，收率69％。
丙泊酚3-N-异丙基氨基-2(R,S)-氟代丙酸酯盐酸盐：将2g丙泊酚3-N-Cbz-N-异丙基氨基-2(R,S)-氟代丙酸酯(4.5mmol)溶于l0ml乙酸中，加入0.5g l0％钯炭，室温下通入氢气3h。在反应结束后，加水5ml，过滤，冰浴下向滤液中加入固体NaHCO3至无气泡产生。用乙醚萃取(15ml×3)，用无水硫酸钠干燥乙醚层，过滤，浓缩乙醚至6ml。冰浴搅拌下，滴加饱和的HCl的乙醚溶液直至白色固体析出，过滤，室温下减压干燥，得到白色固体0.81g，收率52％。
ESI-MS m/z[M+H]+310.3。
参照实施例20-23制得以下化合物：
丙泊酚4-(N,N-二甲基)氨基-2-(R)-2-三氟甲基丁酸酯盐酸盐(化合物编号E3)；
丙泊酚4-(N-甲基-N-乙基)氨基-2-(R,S)-2-氟代丁酸酯盐酸盐(化合物编号E4)；
丙泊酚5-(N-甲基-N-苄基)氨基-2-(S)-2-氟代戊酸酯盐酸盐(化合物编号E5)；
丙泊酚3-(N-异丙基)氨基-2-(R,S)-2-单氟甲基丙酸酯甲磺酸盐(化合物编号E6)；
丙泊酚4-N-(氮杂环丙烷-1-基)-2-(S)-2-氟代丁酸酯盐酸盐(化合物编号E7)；
丙泊酚4-(四氢吡咯-1-基)-2-(R)-2-氟代丁酸酯盐酸盐(化合物编号E8)；
丙泊酚4-羧基-2-(R,S)-氟代戊酸酯钠盐(化合物编号F1)；
丙泊酚4-羧基-2-(S)-氟代戊酸酯钾盐(化合物编号F2)；
丙泊酚4-羧基-2-(R)-2-三氟甲基戊酸酯锂盐(化合物编号F3)；
二[丙泊酚7-羧基-2-(R,S)-氟代辛酸酯]钙盐(化合物编号F4)；
二[丙泊酚5-羧基-2-(S)-氟代己酸酯]锌盐(化合物编号F5)；
三[丙泊酚8-羧基-2-(R,S)-单氟甲基壬酸酯]铝盐(化合物编号F6)；
丙泊酚3-羧基-2-(R)-氟代丁酸酯钠盐(化合物编号F7)；
丙泊酚2-羧基-2-(S)-氟代丙酸酯钠盐(化合物编号F8)；
{1-[4-(2,6-二异丙基苯氧基)-4-氧代-3-(R,S)-3-氟代-1-丁基]}磷酸单酯二钾盐(化合物编号G1)；
{1-[4-(2,6-二异丙基苯氧基)-4-氧代-3-(S)-3-氟代-1-丁基]}磷酸单酯二钠盐(化合物编号G2)；
{1-[4-(2,6-二异丙基苯氧基)-4-氧代-3-(R)-3-三氟甲基-1-丁基]}磷酸单酯二锂盐(化合物编号G3)；
丙泊酚4-磷酰基-2-(R,S)-氟代丁酸酯钙盐(化合物编号G4)；
丙泊酚5-磷酰基-2-(S)-氟代戊酸酯锌盐(化合物编号G5)；
三[丙泊酚3-磷酰基-2-(R,S)-2-单氟甲基丙酸酯]二铝盐(化合物编号G6)；
丙泊酚4-(N-甲基-N-异丙基)氨基-2(R,S)-氟代丁酸酯甲磺酸盐(化合物编号E9)；
丙泊酚4-(N-甲基-N-苄基)氨基-2(R,S)-三氟甲基丁酸酯盐酸盐(化合物编号E10)；
丙泊酚4-(N-环丙基-N-甲基)氨基-2(R)-二氟甲基丁酸酯盐酸盐(化合物编号E11)；
丙泊酚3-(四氢吡咯-1-基)-2(S)-三氟甲基丙酸酯盐酸盐(化合物编号E12)；
丙泊酚5-N-环戊基氨基-2,2-二氟戊酸酯盐酸盐(化合物编号E13)；
丙泊酚δ-(N,N-二甲基)氨基-2(R)-氟代戊酸酯盐酸盐(化合物编号E14)；
丙泊酚3-N-甲基-N-环己基氨基-2-(R,S)-氟代丙酸酯盐酸盐(化合物编号E15)；
丙泊酚4-(N,N-二甲基)氨基-2-(R)-三氟甲基丁酸酯盐酸盐(化合物编号E16)；
丙泊酚4-N-甲基-N-苄基氨基-2-(R)-氟代丁酸酯盐酸盐(化合物编号E17)；
丙泊酚-2-(R)-氟代丙酸单酯钠盐(化合物编号F9)；
丙泊酚4-羧基-2-(R)-氟代丁酸酯钠盐(化合物编号F10)；
丙泊酚4-羧基-2-(S)-三氟甲基丁酸酯铵盐(化合物编号F11)；
丙泊酚5-羧基-2-(R,S)-二氟甲基戊酸酯钾盐(化合物编号F12)；
{1-[3-(2,6-二异丙基苯氧基)-3-氧代-2-(R)-氟-1-丙基]}磷酸单酯二钾盐(化合物编号G7)；
{1-[4-(2,6-二异丙基苯氧基)-4-氧代-2-(R)-三氟甲基-1-丁基]}磷酸单酯二锂盐(化合物编号G8)；
{1-[6-(2,6-二异丙基苯氧基)-6-氧代-5-(S)-二氟甲基-1-己基]}磷酸二精氨酸盐(化合物编号G9)；
丙泊酚4-磷酰基-2-(R)-氟代丁酸酯二钠盐(化合物编号G10)；
丙泊酚3-磷酰基-2-(R,S)-氟代丙酸酯锌盐(化合物编号G11)。
发明人在对上述丙泊酚衍生物的实验过程中发现，本发明制备的丙泊酚类衍生物的水溶性良好，能够在血浆中很快分解并释放出原药，从而发挥活性，适合作为丙泊酚类药物的前药。
为了进一步说明本发明的羧酸衍生物在水溶性前药中的用途，发明人提供以下实验例来证明作为水溶性前药的配体的本发明的羧酸衍生物以及由此制得的水溶性前药的令人惊讶且出乎预料的有益效果。
实验例1
本发明的羧酸衍生物用于水溶性紫杉烷类前药的应用示例：
当本发明所述的羧酸为氨基酸时，所述羧酸衍生物可用于制备得到水溶性紫杉醇衍生物、水溶性多西他赛衍生物、水溶性卡巴他赛衍生物。这些水溶性紫杉烷类前药的编号与表征数据如下表1所示：
表1.由本发明的羧酸衍生物制备的水溶性紫杉烷类前药的编号及表征数据
Figure PCTCN2015073165-appb-000018
Figure PCTCN2015073165-appb-000019
Figure PCTCN2015073165-appb-000020
实验例1.1.在生理盐水中的溶解度：
Figure PCTCN2015073165-appb-000021
表2.水溶性紫杉烷类衍生物生理盐水溶解度表
Figure PCTCN2015073165-appb-000022
实验例1.2.体外鼠血浆分解：
将所得的水溶性紫杉烷类系列衍生物分别配制成0.2mg/ml的水溶液。各取0.1ml溶液，分别加入到0.9ml新鲜的SD大鼠血浆中(肝素抗凝)，充分混匀，置于37℃恒温水浴中孵育并计时。在孵育后2分钟、5分钟、10分钟各样本分别取0.2ml溶液，加入冷却到-20℃的乙腈0.4ml以沉淀蛋白质。振摇，离心10分钟(10000转/分)，取上清液，经HPLC检测。结果见下表3：
表3.水溶性紫杉烷类衍生物的体外鼠血浆分解实验表
Figure PCTCN2015073165-appb-000023
实验例1.3.体外兔血浆分解：
将所得的水溶性紫杉烷类系列衍生物分别配制成0.2mg/ml的水溶液。 各取0.1ml溶液，分别加入到0.9ml新鲜的新西兰大白兔兔血浆中(肝素抗凝)，充分混匀，置于37℃恒温水浴中孵育并计时。在孵育后5分钟、20分钟、60分钟各样本分别取0.2ml溶液，加入冷却到-20℃的乙腈0.4ml以沉淀蛋白质。振摇，离心10分钟(10000转/分)，取上清液，经HPLC检测。结果见下表4：
表4.水溶性紫杉烷类衍生物的体外兔血浆分解实验表
Figure PCTCN2015073165-appb-000024
实验例1.4.水溶性紫杉醇衍生物的大鼠体内初步代谢实验：
研究方法：
取SD大鼠12只，雄性，体重200-220g。随机分为4组，分别静脉注射给药5mg/kg的化合物01、02、03和市售紫杉醇，给药体积为5ml/kg。化合物01、02、03用pH＝5的5％葡萄糖注射液配制，紫杉醇为市售注射药。于给药后5min，经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管 中，在11000rpm下离心5min，分离血浆，经液相色谱-串联质谱法测定血浆中化合物的浓度。
结果：
静脉注射化合物01、02、03后，血浆中未检测到化合物01、02、03，而只能检测到紫杉醇。
每组动物血浆中紫杉醇平均浓度依次为(ng/ml)：1789、1637、1825、1793。
实验例1.5.水溶性多西他赛衍生物的大鼠体内代谢实验：
研究方法：
取SD大鼠12只，雄性，体重200-220g。随机分为4组，分别静脉注射给药5mg/kg的化合物04、05、06和市售多西他赛，给药体积为5ml/kg。化合物04、05、06用pH＝5的5％葡萄糖注射液配制，多西他赛为市售注射药。于给药后5min，经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管中，在11000rpm下离心5min，分离血浆，经液相色谱-串联质谱法测定血浆中化合物的浓度。
结果：
静脉注射化合物04、05、06后，血浆中未检测到化合物04、05、06，而只能检测到多西他赛。
每组动物血浆中多西他赛浓度依次为(ng/ml)：1506、1387、1621、769。
实验例1.6.水溶性紫杉烷类衍生物的抗肿瘤活性实验：
1.6.1.水溶性紫杉醇衍生物的抗人卵巢癌SK-OV-3裸鼠皮下移植瘤活性实验——评价并比较本发明的水溶性紫杉醇衍生物、紫杉醇和
Figure PCTCN2015073165-appb-000025
的抗人卵巢癌SK-OV-3裸鼠皮下移植瘤活性。
给药方案与实验步骤：
裸小鼠皮下接种人卵巢癌SK-OV-3细胞。待肿瘤生长至100-150mm3后，将动物随机分组(D0)，分别给药本发明的水溶性紫杉醇衍生物(结构见下图)、紫杉醇和Abraxane，每天给药一次，共5天。给药剂量和给药方案见下表5。每周测量肿瘤体积2-3次，称量动物体重，记录数据，直至分组 后的第22天(D22)。
肿瘤体积(V)的计算公式为：V＝1/2×a×b2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100，其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抗肿瘤活性数据见下表5：
Figure PCTCN2015073165-appb-000026
Figure PCTCN2015073165-appb-000027
所给药化合物的结构以上式与上表5中所列的取代基表示；
D0：第一次给药时间；
△为P(D22)值为0.000，指与对照相比，采用Student’s t检验。
实验开始时小鼠数目：对照组n＝10，给药组n＝6。
结论：本发明的水溶性紫杉醇衍生物对人卵巢癌SK-OV-3均有抑制作用。
1.6.2.水溶性多西他赛衍生物的抗人前列腺癌PC-3裸鼠皮下移植瘤活性实验——评价并比较水溶性多西他赛衍生物、多西他赛抗人前列腺癌PC-3裸鼠皮下移植瘤活性。
给药方案与实验步骤：
裸小鼠皮下接种人前列腺癌PC-3细胞。待肿瘤生长至100-150mm3后，将动物随机分组，于当天向各组动物分别给药本发明的水溶性多西他赛衍生物(结构见下图)和多西他赛1次(D0)。给药剂量和给药方案见下表6。每周测量肿瘤体积2-3次，称量动物体重，记录数据，直至分组后第20天(D20)。
肿瘤体积(V)计算公式为：V＝1/2×a×b2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100，其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抗肿瘤活性数据见下表6：
Figure PCTCN2015073165-appb-000028
Figure PCTCN2015073165-appb-000029
所给药化合物的结构以上式与上表6中所列的取代基表示；
D0：第一次给药时间；
△为P(D22)值为0.000，指与对照相比，采用Student’s t检验。
实验开始时小鼠数目：对照组n＝10，给药组n＝6。
结论：本发明的水溶性多西他赛衍生物对人前列腺癌PC-3均有抑制作用。
1.6.3.水溶性卡巴他赛衍生物的抗人前列腺癌PC-3裸鼠皮下移植瘤活性实验——评价并比较水溶性卡巴他赛衍生物和卡巴他赛的抗人前列腺癌PC-3裸鼠皮下移植瘤活性。
给药方案与实验步骤：
裸小鼠皮下接种人前列腺癌PC-3细胞。待肿瘤生长至100-150mm3后，将动物随机分组，于当天向各组动物分别给药本发明的水溶性卡巴他赛衍生物(结构如下图所示)和卡巴他赛1次(D0)。给药剂量和给药方案见下表7。每周测量肿瘤体积2-3次，称量动物体重，记录数据，直至分组后第20天(D20)。
肿瘤体积(V)计算公式为：V＝1/2×a×b2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100，其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抗肿瘤活性结果如下表7：
Figure PCTCN2015073165-appb-000030
Figure PCTCN2015073165-appb-000031
所给药化合物的结构以上式与上表7中所列的取代基表示；
D0：第一次给药时间；
△为P(D20)值为0.000，指与对照相比，采用Student’s t检验。
实验开始时小鼠数目：对照组n＝10，给药组n＝6。
结论：本发明的水溶性卡巴他赛衍生物对人前列腺癌PC-3均有抑制作用。
实验例2
本发明的羧酸衍生物用于水溶性丙泊酚前药的应用示例：
本发明的羧酸衍生物可用于制备得到水溶性丙泊酚衍生物。这些水溶性丙泊酚类前药的通式如下所示，其编号与表征数据如下表8所示：
Figure PCTCN2015073165-appb-000032
表8.由本发明的羧酸衍生物制备的水溶性丙泊酚类前药的编号及表征数据
Figure PCTCN2015073165-appb-000033
Figure PCTCN2015073165-appb-000034
实验例2.1.水溶性丙泊酚的体外血浆分解实验：
将所得的水溶性丙泊酚类系列衍生物配制成1mg/ml的生理盐水溶液。各取0.1ml溶液，分别加入到1ml兔血浆(来至活体新西兰大白兔，按常规的方法处理，肝素抗凝)或大鼠血浆(来自活体SD大鼠，按常规方法处理，肝素抗凝)中，充分混匀，置于37℃恒温水浴中并计时。在开始后不同时间点取样，并立即加入2ml乙腈。振摇，离心5分钟(15000转/分)，取上清液，经HPLC检测。结果如下：
表9.式E表示的氨基酸类丙泊酚衍生物的体外血浆分解率
Figure PCTCN2015073165-appb-000035
Figure PCTCN2015073165-appb-000036
Figure PCTCN2015073165-appb-000037
表10.式F表示的二酸类单酯类丙泊酚衍生物的体外血浆分解率
Figure PCTCN2015073165-appb-000038
Figure PCTCN2015073165-appb-000039
Figure PCTCN2015073165-appb-000040
表11.式G表示的有机磷酸酯类丙泊酚衍生物的体外血浆分解率
Figure PCTCN2015073165-appb-000041
Figure PCTCN2015073165-appb-000042
实验例2.2.水溶性丙泊酚类衍生物的药效学实验(取化合物(E2)、(F1)、(F7)、(G2)进行实验)：
2.2.1.实验药品与给药：
称取适量化合物(E2、F1、F7、G2)，加入一定量的生理盐水，形成3mg/ml或6mg/ml的药液，超声使之溶解。用于家兔试验的供试品则根据预试验结果配制成相应浓度。取丙泊酚脂肪乳注射液(市售，10mg/ml)，用生理盐 水稀释成3mg/ml作为对照品。对大鼠、小鼠固定给药浓度，给药体积则根据实际情况而变化。家兔给药体积为1mL/kg体重。
2.2.2.化合物的ED50及LD50测试：
采用序贯法测定麻醉ED50及LD50值。取健康合格的KM小鼠(雄性)、SD大鼠(雄性)和新西兰白兔。大鼠、小鼠实验给药时经尾静脉匀速注射，10秒钟注射完。家兔实验时经耳缘静脉匀速注射药物，30秒钟注射完。实验前经初步预试验找出能够导致动物麻醉(或死亡)的大致剂量(给药体积)，作为正式实验时的中间剂量。采用0.8的组间距，向上向下分别再设2-3个剂量组。以翻正反射消失或死亡作为药效或毒性的判断指标。正式实验时首先从中间剂量开始给药。若动物被麻醉，则降低一个剂量给药；若动物未被麻醉，则增大一个剂量给药，直到出现3-4个反复。采用序贯法aot425软件进行LD50及ED50的计算。TI的计算公式为：TI＝LD50/ED50。
2.2.3.化合物的催眠潜伏期及持续期测定
取昆明种小鼠，雄性，每组5只。静脉注射，10秒钟匀速注射完，记录小鼠翻正反射消失的时间(潜伏期)及恢复时间(持续期)。
2.2.4.实验结果
2.2.4.1.化合物的鼠LD50/ED50及TI指数测试结果。试验结果见下表12：
表12.化合物的鼠LD50/ED50及TI指数测试结果(n＝10-20)
Figure PCTCN2015073165-appb-000043
Figure PCTCN2015073165-appb-000044
*数值为第一次实验数据。其他数据为验证实验数据。
2.2.4.2.化合物的兔LD50/ED50及TI指数测试结果。试验结果见下表13：
表13.化合物的兔LD50/ED50及TI指数测试结果
药品名 LD50(mg/kg) ED50(mg/kg) TI指数
E2 28(23.0-34.2) 8(5.7-10.5) 3.5
F1 34.4(32.1-36.5) 12.2(10.6-14.6) 2.8
F7 36.7(33.8-39.4) 13.9(11.1-16.8) 2.6
G2 38.7(35.1-41.3) 14.7(12.6-19.1) 2.6
2.2.4.3.化合物的小鼠催眠潜伏期及持续期测定结果。试验结果见下表14：
表14.化合物的小鼠催眠潜伏期及持续期测定结果(小鼠，mg/kg，分组法n＝10)
药品名 剂量(mg/kg) 潜伏期(S) 持续期(S)
E2(3mg/ml) 36(2*ED50) 14.6±0.9 383.6±242.1
E2(6mg/ml) 30(2*ED50) 14.2±1.9 543±231
F1(3mg/ml) 42(2*ED50) 18.6±0.7 349.7±229.4
F1(6mg/ml) 36(2*ED50) 15.2±1.4 523±248
F7(3mg/ml) 43(2*ED50) 20.2±0.6 335.5±218.1
F7(6mg/ml) 41(2*ED50) 16.2±2.2 517±231
G2(3mg/ml) 47(2*ED50) 16.3±0.8 383.6±242.1
G2(6mg/ml) 51(2*ED50) 15.7±2.3 571±173
Propofol(3mg/ml) 25(2*ED50) 8.4±1.1 324.8±98.9
结论：本发明的水溶性丙泊酚衍生物麻醉作用起效迅速，持续时间短。
本发明具有如下有益效果：
以上实验结果进一步证明了，本发明的羧酸衍生物(包括通式I、II或III的化合物及本发明记载的任意具体化合物)可以通过化学方法与难溶性药物中的羟基反应形成酯，以增加难溶性药物的水溶性，从而制得可注射用的水溶性前药。令人惊讶地，由此制得的前药易于在体内分解出原药，且不影响原药的生理活性，从而可减少原药注射液中的高分子助溶剂带来的副作用，其小鼠LD0在1500mg/kg以上，非常适合用做前药的配体。

Claims (28)

  1. 具有如下通式(I)的羧酸衍生物：
    Figure PCTCN2015073165-appb-100001
    其中，
    R1为H或烷基；
    X为H或F；
    Y为F或者被一个或多个F取代的烷基；
    n为0、1、2、3、4、5或6；
    W为W1或W2；
    W1为NR2R3、NR2R3·A、
    Figure PCTCN2015073165-appb-100002
    R2、R3各自独立地为H、烷基、环烷基，或氨基保护基；
    m为0、1、2或3；
    A为酸；
    W2为COOR4、OPO(OR4)2或PO(OR4)2；
    R4为H，或者为羧基或磷酸羟基的保护基。
  2. 具有如下通式(II)或(III)的羧酸衍生物：
    Figure PCTCN2015073165-appb-100003
    其中，
    R1为H或烷基；
    X为H或F；
    Y为F或者被一个或多个F取代的烷基；
    n为0、1、2、3、4、5或6；
    W为W1或W2；
    W1为NR2R3、NR2R3·A、
    Figure PCTCN2015073165-appb-100004
    R2、R3各自独立地为H、烷基、环烷基，或氨基保护基；
    m为0、1、2或3；
    A为酸；
    W2为COOR4、OPO(OR4)2或PO(OR4)2；
    R4为H，或者为羧基或磷酸羟基的保护基；
    M为金属离子；
    q为M所带的电荷数；
    G为Cl、Br或任选地被烷基取代的苯磺酰氧基。
  3. 如权利要求2所述的羧酸衍生物，其特征在于：所述金属离子为碱金属离子、碱土金属离子或三价金属离子。
  4. 如权利要求3所述的羧酸衍生物，其特征在于：所述碱金属离子为钾离子或钠离子。
  5. 如权利要求3所述的羧酸衍生物，其特征在于：所述碱土金属离子为镁离子、锌离子或钙离子。
  6. 如权利要求3所述的羧酸衍生物，其特征在于：所述三价金属离子为铝离子或铁离子。
  7. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：R2、R3不同时为H。
  8. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：所述烷基为C1-6烷基。
  9. 如权利要求8所述的羧酸衍生物，其特征在于：所述C1-6烷基为甲基、乙基、丙基、异丙基、丁基或异丁基。
  10. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：R1为H、甲基、乙基、正丙基或异丙基。
  11. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：Y为F、CF3或CHF2。
  12. 如权利要求2-6中任一项所述的羧酸衍生物，其特征在于：G为Cl、Br、
    Figure PCTCN2015073165-appb-100005
  13. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：所述环烷基为C3-6环烷基。
  14. 如权利要求13所述的羧酸衍生物，其特征在于：所述C3-6环烷基为环丙基、环丁基、环戊基或环己基。
  15. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：所述氨基保护基为任选地被苯基取代的C1-6烷氧羰基或任选地被一个或多个卤素取代的苄基。
  16. 如权利要求15所述的羧酸衍生物，其特征在于：所述氨基保护基为苄氧羰基或叔丁氧羰基。
  17. 如权利要求15所述的羧酸衍生物，其特征在于：所述卤素为氟、氯或溴。
  18. 如权利要求17所述的羧酸衍生物，其特征在于：所述氨基保护基为苄基、3-氯苄基、4-氟苄基或2,4-二氟苄基。
  19. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：R2、R3各自独立地为H、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、苄氧羰基、叔丁氧羰基、苄基、3-氯苄基、4-氟苄基或2,4-二氟苄基。
  20. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：所述羧基或磷酸羟基的保护基为任选地被一个或多个苯基取代的C1-6烷基。
  21. 如权利要求20所述的羧酸衍生物，其特征在于：所述羧基或磷酸羟基的保护基为甲基、乙基、二苯甲基、三苯甲基或苄基。
  22. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：所述酸A为可与胺成盐的酸。
  23. 如权利要求22所述的羧酸衍生物，其特征在于：所述酸A为盐酸、氢溴酸、硫酸、磷酸、三氟乙酸、二氟乙酸、氟乙酸、乙酸、苯磺酸或对甲苯磺酸。
  24. 如权利要求1-6中任一项所述的羧酸衍生物，其特征在于：当所述羧酸衍生物的羧基的α-C为手性原子时，其为单一的R构型、单一的S构型，或R与S构型的混合物。
  25. 如权利要求1或2所述的羧酸衍生物，其选自：
    4-N,N-二甲氨基-2(R)-氟代丁酸盐酸盐；
    4-N-异丙基氨基-2(R,S)-氟代丁酸盐酸盐；
    4-N,N-二乙氨基-2(R,S)-三氟甲基丁酸盐酸盐；
    4-N-苄基氨基-2,2-二氟代丁酸盐酸盐；
    4-N-异丁基氨基-2(R,S)-二氟甲基丁酸盐酸盐；
    4-N-(氮杂环丙-1-基)-2(R,S)-二氟甲基丁酸盐酸盐；
    4-N-(四氢吡咯-1-基)-2(R,S)-氟代丁酸盐酸盐；
    3-N-苄基氨基-2(R,S)-(1,1-二氟甲基)丙酸盐酸盐；
    6-N-环己基氨基-2(R,S)-三氟甲基己酸盐酸盐；
    4-苄氧基-4-氧代-2-(R,S)-氟代丁酸；
    5-苄氧基-5-氧代-2-(R)-氟代戊二酸；
    6-苄氧基-6-氧代-2-(S)-氟代己酸；
    二苄基[1-(3-(R,S)-氟-3-羧基)丙基]磷酸三酯；
    二苄基[1-(5-(S)-氟-5-羧基)戊基]磷酸三酯；
    4-(二苄氧基)磷酰基-2-(R,S)-氟代丁酸；
    5-(二苄氧基)磷酰基-2-(R)-氟代戊酸；
    4-苄氧基-4-氧代-2-(R,S)-氟代丁酰氯；
    5-苄氧基-5-氧代-2-(R)-氟代戊酸钠；
    二苄基[1-(3-(R,S)-氟-4-氧代-4-氯)丁基]磷酸三酯；
    二苄基[1-(4-(S)-氟-5-羧酸钾)戊基]磷酸三酯；
    4-(二苄氧基)磷酰基-2-(R,S)-氟代丁酰氯；
    4-N,N-二甲氨基-2(R,S)-氟代丁酸钠；
    4-N,N-二乙氨基-2(R,S)-氟代丁酸钙；
    3-N-苄基氨基-2(R,S)-苄氧基丙酸铝；
    4-N,N-二甲氨基-2(R,S)-氟代丁酰氯盐酸盐；
    4-N-苄基氨基-2,2-二氟代丁酰氯盐酸盐；
    4-N,N-二甲氨基-2(R,S)-氟代丁酸；和
    4-N,N-二甲氨基-2(S)-氟代丁酸盐酸盐。
  26. 如权利要求1-25中任一项所述的羧酸衍生物在制备前药中的用 途。
  27. 如权利要求26所述的用途，其中所述前药为丙泊酚类药物的前药。
  28. 如权利要求26所述的用途，其中所述前药为紫杉烷类药物的前药。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432141A (zh) * 2016-07-19 2017-02-22 浙江大学 卡巴他赛药物前体的制备方法和应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2701123T3 (es) * 2014-02-17 2019-02-20 Jiangsu Nhwaluokang Pharmaceutical Res And Development Co Ltd Derivados de taxano solubles en agua y sus usos
EP3109229B1 (en) * 2014-02-17 2019-06-05 Jiangsu Nhwaluokang Pharmceutical Research and Development Co. Ltd. Water-soluble propofol derivatives and uses thereof
US11628178B2 (en) 2019-03-26 2023-04-18 Epalex Corporation Fospropofol methods and compositions
US11547714B2 (en) 2020-02-05 2023-01-10 Epalex Corporation Fospropofol salts, methods and compositions
US11439653B1 (en) 2021-03-30 2022-09-13 Epalex Corporation Fospropofol formulations
US11478490B1 (en) 2021-03-30 2022-10-25 Epalex Corporation Fospropofol formulations
CN116023284B (zh) * 2021-10-26 2023-09-22 中山万汉制药有限公司 丙泊酚衍生物与药学上可接受的酸的加成盐及其组合物与用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1907954A (zh) * 2006-08-16 2007-02-07 重庆医科大学医药研究所 麻醉药2,6－二异丙基苯酚的水溶性衍生物及其制备方法
CN101094840A (zh) * 2004-12-29 2007-12-26 韩美药品株式会社 抑制癌细胞生长的喹唑啉衍生物和制备其的方法
CN101898978A (zh) * 2009-05-31 2010-12-01 徐锋 依氟鸟氨酸前药和偶合物及其使用方法
CN102015621A (zh) * 2008-04-28 2011-04-13 中央硝子株式会社 α-氟-β-氨基酸类的制造方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435425A (en) * 1982-04-09 1984-03-06 Merrell Toraude Et Compagnie Fluorinated diaminobutane derivatives
JPH0778034B2 (ja) * 1986-09-24 1995-08-23 ダイセル化学工業株式会社 含フツ素有機化合物
WO2004106349A1 (en) * 2003-05-27 2004-12-09 E.I. Dupont De Nemours And Company Fuel cell membrane containing zirconium phosphate
CN1895676B (zh) * 2005-07-14 2010-11-10 上海艾力斯医药科技有限公司 聚乙二醇为载体的紫杉醇或多烯紫杉醇的前药
CN1907945B (zh) 2006-08-18 2011-04-27 上海化学试剂研究所 甲基丙烯酸三氟乙酯的制备方法
ES2701123T3 (es) 2014-02-17 2019-02-20 Jiangsu Nhwaluokang Pharmaceutical Res And Development Co Ltd Derivados de taxano solubles en agua y sus usos
EP3109229B1 (en) 2014-02-17 2019-06-05 Jiangsu Nhwaluokang Pharmceutical Research and Development Co. Ltd. Water-soluble propofol derivatives and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101094840A (zh) * 2004-12-29 2007-12-26 韩美药品株式会社 抑制癌细胞生长的喹唑啉衍生物和制备其的方法
CN1907954A (zh) * 2006-08-16 2007-02-07 重庆医科大学医药研究所 麻醉药2,6－二异丙基苯酚的水溶性衍生物及其制备方法
CN102015621A (zh) * 2008-04-28 2011-04-13 中央硝子株式会社 α-氟-β-氨基酸类的制造方法
CN101898978A (zh) * 2009-05-31 2010-12-01 徐锋 依氟鸟氨酸前药和偶合物及其使用方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DESMOULIN ET AL.: "Metabolism of Capecitabine, An Oral Fluorouracil Prodrug: 19F NMR Studies in Animal Models and Human Urine", DRUG METABOLISM AND DISPOSITION, vol. 30, no. 11, 5 August 2002 (2002-08-05), pages 1221 - 1229, XP055357568 *
HOOK, D.F. ET AL.: "Probing the Proteolytic Stability of beta-peptides Containing a-fluoro- and alpha-hydroxy-beta-amino Acids", vol. 5, 31 December 2004 (2004-12-31), pages 691 - 706, XP008143749 *
JURCIK, V. ET AL.: "Single Enantiomer Synthesis of alpha-(trifluoromethyl)-beta-lactam", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 7, no. 86, 6 June 2011 (2011-06-06), pages 759 - 766, XP055357577 *
See also references of EP3109230A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432141A (zh) * 2016-07-19 2017-02-22 浙江大学 卡巴他赛药物前体的制备方法和应用

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