CN112300099A

CN112300099A - Ketal derivatives of drugs, preparation method thereof, pharmaceutical compositions and uses

Info

Publication number: CN112300099A
Application number: CN202010175551.7A
Authority: CN
Inventors: 郭术涛; 于娜; 徐杨; 刘涛; 钟海平; 穆菁青; 史林启
Original assignee: Nankai University
Current assignee: Nankai University
Priority date: 2019-08-02
Filing date: 2020-03-13
Publication date: 2021-02-02

Abstract

The invention relates to a ketal derivative of a medicament, a preparation method, a pharmaceutical composition and application thereof. Wherein the ketal derivative comprises a compound represented by the following formula (I), a racemate, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

the ketal derivatives of the invention can significantly improve the physical, chemical and/or pharmaceutical properties of the original starting drug.

Description

Ketal derivatives of drugs, preparation method thereof, pharmaceutical compositions and uses

The application requires that the patent application number is 201910713864.0, which is submitted to the intellectual property office of China in 2019, 8, 2, and the invention name is ' ketal derivative of medicine and preparation method, pharmaceutical composition and application thereof ' priority of prior application '. The entire disclosure of this application is incorporated by reference into this application.

Technical Field

The invention belongs to the technical field of prodrug compounds, and particularly relates to a ketal derivative of a medicament, a preparation method, a pharmaceutical composition and application thereof.

Background

Prodrugs are an important class of derivatives of pharmaceutical compounds. Prodrug derivatives have been reported to include carrier prodrugs and biological prodrugs. Wherein, carrier prodrug means that the active compound is combined with the carrier with the transportation function through covalent bond, and the carrier is removed through simple hydrolysis in vivo to exert pharmacological action by the active compound. Carrier prodrugs tend to be less active or inactive than the parent compound. The structure of the carrier is mostly lipophilic, and is required to be harmless to organisms and to release the active compound in a timely manner. The oral penicillin drugs in the market often adopt a carrier prodrug mode to improve the bioavailability; biological prodrugs differ from carrier prodrugs in that the active substance does not bind to the carrier temporarily, but rather acts by changing its molecular structure. Biological prodrugs are generally inactive per se, but active as in vivo metabolites. Some non-steroidal anti-inflammatory drugs (e.g., sulindac) have been designed based on this concept.

As prodrug derivatives are widely used in improved drug development, their position in new drug development is also becoming more important. Statistically, in year 2008-2017, a total of 30 U.S. FDA-approved new drugs belong to prodrug compounds, which are about 10% of the total amount of FDA-approved drugs. Among the us FDA-approved new drugs in 2017, the prodrug compound ratio was about 17% (nat. rev. drug discov.2018,17(8): 559-.

Among the drug compounds, the drugs containing hydroxyl groups (including phenolic, carboxylic and alcoholic hydroxyl groups) account for about 51% of small molecule drugs (https:// pubs. ac. org. ccidex. cn/doi/pdf/10.1021/cc9800071), which includes most molecules of several major classes of drugs such as taxanes, glucocorticoids, prostaglandin analogs, antibiotics, antivirals and terpenes. Ester formation is the most common modification in prodrug design. Of the prodrugs that are marketed, approximately 49% are active by enzymatic hydrolysis. For example, the hydroxyl group of poorly water soluble drugs is often designed as phosphate to improve their water solubility, more suitable for oral or injectable administration. Carbonate and carbamate prodrugs of hydroxyl groups may be more stable to enzymes.

Chinese patent applications CN107353399A and CN103285400A disclose acid-sensitive polymeric prodrugs in which an acetal bond is used to link a drug molecule to a polymer to modify the release of the drug molecule when circulating in vivo. However, the molecular fragments produced when their prodrugs are released may have certain properties that are not beneficial to humans, or their release characteristics in physiological or acidic environments in vivo remain to be further improved (Louse, Benoit, Mies J. Van Steenbergen, Lutz Nuhn, Martijn DP Risseuw, IZet Karaic, John wine, Large Van Calenbergh, Wim E. Hennink, and Bruno G.De Geest. "Micellar tablet-associated RAFT polymer conjugates with acid-sensitive detector." ACS. Macro Letters 6, 3(2017): 272; Zhai, Yingelei, XZhou, Lina Jia, Changze Mazeo, Yang, Hu hong, Hu Zhen, Weldu, Zhen Shu-7, polymeric PEG 9, polymeric primer, and primer.

To this end, there is a need for further development of new prodrugs that may facilitate the metabolism of the prodrug, improve the release characteristics, and/or reduce the physiological toxicity or other side effects of the molecules that they release.

Disclosure of Invention

In order to improve the technical problems, the present invention provides a compound represented by the following formula (I), a racemate, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein D is selected from the group consisting of a drug compound having at least one hydroxyl group, from which a hydrogen atom on one hydroxyl group has been removed;

R₁selected from unsubstituted or optionally substituted by one, two or more R_aSubstituted of the following groups: c_1-40Alkyl radical, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl;

R₂selected from or unsubstituted or optionally substituted by one, two or more R_bSubstituted radicals-O-R₄；

R₃Selected from unsubstituted or optionally substituted by one, two or more R_cSubstituted C_1-40An alkyl group;

R₄selected from substituents other than hydrogen;

each R_aIndependently selected from halogen (such as F, Cl, Br, I), OH, SH, CN, N₃Or unsubstituted or optionally substituted by one or more R_bSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl radical, C_3-20Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C_6-20Aryl radical, C_6-20Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, NR_dR_e、-CONR_dR_e、-C(O)YR_f、-Y(O)CR_f、-YP(O)(OM₁)(OM₂)、-YS(O)₂OM₃；

Each R_bIndependently selected from F, Cl, Br, I, OH, SH, CN, N₃Or unsubstituted or optionally substituted by one or more R_cSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl radical, C_3-20Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C_6-20Aryl radical, C_6-20Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, NR_dR_e、-CONR_dR_e、-C(O)YR_f、-Y(O)CR_f、-YP(O)(OM₁)(OM₂)、-YS(O)₂OM₃；

Each R_cIndependently selected from F, Cl, Br, I, OH, SH, CN, N₃Or unsubstituted or optionally substituted by one or more R_aSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C₆-₂₀Aryl, 5-20 membered heteroaryl, NR_dR_e、-CONR_dR_e、-C(O)YR_f、-Y(O)CR_f、-YP(O)(OM₁)(OM₂)、-YS(O)₂OM₃；

Each R_dAnd R_eIndependently of one another, selected from H, or unsubstituted or optionally substituted by one or more R_mSubstituted of the following groups: c_1-40Alkyl radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl, -CONR_fR_g、-C(O)YR_f、-Y(O)CR_f、-YP(O)(OM₁)(OM₂)、-YS(O)₂OM₃；

Each R_fAnd R_gIndependently of one another, selected from H, or unsubstituted or optionally substituted by one or more R_mSubstituted of the following groups: c_1-40Alkyl radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl, COOH, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl;

each R_mIndependently selected from H, F, Cl, Br, I, OH, SH, CN, N₃Or unsubstituted or optionally substituted by one or more R_aSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl, NR_dR_e、-CONR_dR_e、-C(O)YR_f、Y(O)CR_f、-YP(O)(OM₁)(OM₂)、-YS(O)₂OM₃；

Each Y is independently selected from the group consisting of a bond, -O-, -S-, or unsubstituted or optionally substituted with one or more R_asubstituted-NH-, C_1-40Alkyl radical, C_1-40Alkoxy radical, C_3-20Cycloalkyl, 3-20 membered heterocyclyl, C_6-20Aryl, 5-20 membered heteroaryl, - (CH)₂CH₂O)_mWherein m is an integer of 0 or more, for example, an integer of 0 to 10;

M₁、M₂、M₃independently of one another, selected from H, or unsubstituted or optionally substituted by one or more R_aSubstituted C_1-40An alkyl group.

According to an embodiment of the present invention, wherein D is selected from the group consisting of a pharmaceutical compound having at least one hydroxyl group, wherein the hydrogen atom of one of the hydroxyl groups of the pharmaceutical compound is removed, wherein the pharmaceutical compound having at least one hydroxyl group may be selected from the group consisting of, but not limited to, the following pharmaceutical compounds:

taxanes (e.g., paclitaxel, docetaxel, cabazitaxel);

glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone, triamcinolone acetonide acetate, mometasone, testosterone, estradiol, ethinyl estradiol, lineestrol);

prostaglandin analogs (e.g., tafluprost, latanoprost, travoprost, bimatoprost, unoprostone isopropyl ester);

paliperidone;

artemisinin analogs (e.g., dihydroartemisinin);

nucleoside analogs (gemcitabine, trifluridine, idoxuridine, floxuridine, capecitabine, zalcitabine, cytarabine);

antiviral drugs (ganciclovir, acyclovir, emtricitabine, zidovudine, lamivudine, tenofovir, entecavir);

antibiotics (doxorubicin);

naltrexone;

rotigotine;

rapamycin, tacrolimus;

treprostinil;

amshufaxin;

etoposide; halofuginone;

combretastatin;

SN-38；

rapamycin;

fulvestrant;

abiraterone;

statins (simvastatin and lovastatin);

analgesic drugs (buprenorphine, oxymorphone, nalbuphine, levorphanol, hydromorphone, butorphanol);

IDO inhibitor NLG 919; and

terpenoid drugs;

when the pharmaceutical compound containing at least one hydroxyl group comprises two or more hydroxyl groups, at least one other hydroxyl group in the group D may be further removed from a hydrogen atom and reacted with-CR₁R₂R₃A group shown is bonded, wherein R₁、R₂、R₃Which may be the same or different at each occurrence, independently of one another, have the definitions described above.

According to an embodiment of the invention, the pharmaceutical compound is selected from the group comprising, but not limited to, the following compounds containing at least one hydroxyl group: paclitaxel, docetaxel, cabazitaxel, dexamethasone, tafluprost, paliperidone, dihydroartemisinin, gemcitabine, zidovudine, testosterone, etoposide, NLG919, halofuginone, combretastatin, SN-38, rapamycin, fulvestrant, abiraterone, or simvastatin.

According to an embodiment of the invention, R₁Can be selected from unsubstituted or optionally substituted by one, two or more R_aSubstituted of the following groups: c_1-6Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-10Aryl, 5-6 membered heteroaryl;

according to an embodiment of the invention, R₃Selected from unsubstituted or optionally substituted by one, two or more R_cSubstituted C_1-6An alkyl group;

according to an embodiment of the invention, R₄Is selected from C_1-40Alkyl radical, C_2-40Alkenyl radical, C_3-20Cycloalkyl radical, C_3-20Cycloalkenyl group, 3-20 membered heterocyclic group, C_6-20Aryl, 5-20 membered heteroaryl, -C_1-40alkyl-OC (O) -PEG, -C_1-40alkyl-OC (O) -PEG-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) -PDLLA-PEG, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) -PDLLA-PEG-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) - (O-C)_1-40alkyl-CO)_p-(O-C_1-40Alkyl radical)_q-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) - (O-C)_1-40alkyl-CO)_p-(O-C_1-40Alkyl radical)_q-H、-C_1-40alkyl-OCO₂-(C_1-40alkyl-O)_r-C_1-40Alkyl, -C_1-40alkyl-OCO₂-(C_1-40alkyl-O)_r-H、-C_3-20cycloalkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-O-C_1-40Alkyl, -C_3-20cycloalkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-OH、-C_1-40alkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-O-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-OH、-C_3-20cycloalkyl-O- (C)_1-40alkyl-O)_r-C_1-40Alkyl, -C_3-20cycloalkyl-O- (C)_1-40alkyl-O)_r-H、-(C_1-40alkyl-O)_r-C_1-40Alkyl, - (C)_1-40alkyl-O)_r-H、-C_3-20cycloalkyl-C_1-40Alkyl, -hydroxy or C_1-40An alkyl hydroxy-substituted 3-20 membered heterocyclic group; wherein the subscripts of the repeating units, such as p, q, r, are the same or different from each other and are independently selected from a number of from 1 to 500, such as a number of from 1 to 200, for example an integer of from 1 to 200;

according to an embodiment of the invention, R₄Is selected from C_1-20Alkyl radical, C_2-20Alkenyl radical, C_3-20Cycloalkyl radical, C_3-20Cycloalkenyl, 3-20 membered heterocyclyl, -C_1-20alkyl-OC (O) -PEG, -C_1-20alkyl-OC (O) -PEG-C_1-20Alkyl, -C_1-20alkyl-OC (O) -C_1-20alkyl-C (O) -PDLLA-PEG, -C_1-20alkyl-OC (O) -C_1-20alkyl-C (O) -PDLLA-PEG-C_1-20Alkyl, -C_1-20alkyl-OC (O) -C_1-20alkyl-C (O) - (O-C)_1-20alkyl-CO)_p-(O-C_1-20Alkyl radical)_q-C_1-20Alkyl, -C_1-20alkyl-OC (O) -C_1-20alkyl-C (O) - (O-C)_1-20alkyl-CO)_p-(O-C_1-20Alkyl radical)_q-H、-C_1-20alkyl-OCO₂-(C_1-20alkyl-O)_r-C_1-20Alkyl, -C_1-20alkyl-OCO₂-(C_1-20alkyl-O)_r-H、-C_3-20cycloalkyl-OC (O) -C_1-20Alkyl- [ O-C_1-20alkyl-C (O)]_p-(O-C₁2₀Alkyl radical)_q-O-C_1-20Alkyl, -C_3-20cycloalkyl-OC (O) -C_1-20Alkyl- [ O-C_1-20alkyl-C (O)]_p-(O-C_1-20Alkyl radical)_q-OH、-C_1-20alkyl-OC (O) -C_1-20Alkyl- [ O-C_1-20alkyl-C (O)]_p-(O-C_1-20Alkyl radical)_q-O-C_1-20Alkyl, -C_1-20alkyl-OC (O) -C_1-20Alkyl- [ O-C_1-20alkyl-C (O)]_p-(O-C_1-20Alkyl radical)_q-OH、-C_3-20cycloalkyl-O- (C)_1-20alkyl-O)_r-C_1-20Alkyl, -C_3-20cycloalkyl-O- (C)_1-20alkyl-O)_r-H、-(C_1-20alkyl-O)_r-C_1-40Alkyl, - (C)_1-20alkyl-O)_r-H、-C_3-20cycloalkyl-C_1-20Alkyl, -hydroxy or C_1-20An alkyl hydroxy-substituted 3-20 membered heterocyclic group; (ii) a Wherein p, q, r are the same or different and are independently selected from the group consisting of a number from 1 to 500, such as a number from 1 to 200, for example an integer from 1 to 200;

or, -O-R₄Selected from ethylene glycol, ethylene glycol monoalkyl ethers (e.g. polyethylene glycol mono C)_1-40Alkyl ethers), polyethylene glycol (PEG) or polyethylene glycol monoalkyl ethers (e.g. polyethylene glycol mono C)_1-40Alkyl ether) to remove a hydrogen atom from a hydroxyl group at the end of polyethylene glycol;

according to an embodiment of the invention, the PDLLA may optionally be bonded to other groups by removing a hydrogen atom from one of the hydroxyl groups.

According to embodiments of the invention, the PEG may be bonded to other groups, optionally by removal of a hydrogen atom from one or both of the hydroxyl groups.

The R is_a、R_b、R_cIdentical or different, independently of one another, from the group consisting of F, Cl, Br, I, OH, SH, CN, N₃、＝O、C₁-₂₀Alkyl radical, C_2-20Alkenyl radical, C_3-20A cycloalkyl group.

According to an embodiment of the invention, the molecular weight of the PEG and the PDLLA are the same or different and are independently selected from 100 to 5000, e.g. 150 to 3000, such as 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000.

According to an embodiment of the invention, said R₁Is selected from-CH₃、-Ph、-CH₂Br、-CH₂I、-CH₂N₃、-C₆H₁₃Or

According to an embodiment of the invention, said R₂Is selected from a substituent obtained by removing a hydrogen atom on one hydroxyl group of polyethylene glycol, or a substituent obtained by removing a hydrogen atom on one hydroxyl group of polyethylene glycol monoalkyl ether, or is selected from the following groups:

wherein

Is a connection site.

The invention also provides a preparation method of the compound shown in the formula (I), racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which comprises the following steps of reacting the compound shown in the formula D-H with the compound shown in the formula (I-1) to obtain the compound shown in the formula (I):

wherein, D, R₁、R₂、R₃Independently of one another have the definitions stated above;

R_hh selected from CH and D-H capable of being linked thereto combines to form R₃Or R is_hIs selected from R₃Removal of the group CH₂The resulting radical.

For example, R_hCan be selected from H, R_cOr optionally substituted by one, two or more R_cSubstituted C_1-39An alkyl group; as an example, when R₃When selected from methyl, R_hIs H. Preferably, R_hIs inert in the reaction.

According to an embodiment of the invention, the reaction may be carried out in an inert atmosphere, for example in a nitrogen atmosphere.

According to an embodiment of the invention, the reaction may be carried out in the presence of a catalyst, for example in the presence of a protic acid such as at least one of p-toluenesulfonic acid, pyridine p-toluenesulfonic acid, 1, 2-dichloroacetic acid.

According to the embodiment of the present invention, when the drug D-H contains a plurality of hydroxyl groups, the OH group at the reaction site may be protected by a conventional method and then reacted with the compound represented by formula (I-1); and after the reaction is finished, removing the protecting group by adopting a conventional method to obtain the compound shown in the formula (I).

According to an embodiment of the invention, the reaction further comprises the preparation of a compound of formula (I-1), comprising at least one of the following processes:

the method comprises the following steps: in nonpolar solvent, ketal compounds are prepared from triflate siloxanyl compounds (TMSOTf, etc.) and organic base (such as Et)₃N, DIPEA, etc.) to yield:

or

The second method comprises the following steps: when R is_hWhen it is H, in a non-polar solvent, compound R₁C(O)OR₄Reaction with Tebbe reagent gives:

or

The third method comprises the following steps: the ketal compound is heated to eliminate one molecule of alcohol under the catalysis of acid (p-toluenesulfonic acid and the like) to obtain:

wherein R is₁、R₄、R_hAre independent of each otherThe ground has the definition as described above.

According to an embodiment of the present invention, the non-polar solvent may be selected from, for example, one, two or more of halogenated hydrocarbons, ethers, aromatic hydrocarbon solvents, such as Dichloromethane (DCM), Tetrahydrofuran (THF), toluene.

The present invention also provides a compound represented by the formula (I-1):

wherein R is₁、R₂、R_hIndependently of one another have the definitions stated above;

the invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound shown in the formula (I), and racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

According to an embodiment of the present invention, the pharmaceutical composition may optionally further comprise pharmaceutically acceptable excipients, such as carriers, excipients. By way of example, the adjuvants may be selected from one or more of the following: disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.

According to an embodiment of the present invention, the pharmaceutical composition may be a pharmaceutical formulation, which may be selected from dosage forms including, but not limited to, injection solutions, nanoparticles, micelle formulations, and the like.

The invention also provides application of the compound shown in the formula (I), racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof in preparing medicaments.

According to an embodiment of the present invention, the drug has the same use as the above-described drug compound containing at least one hydroxyl group, for example, it may be a taxane, a glucocorticoid, a prostaglandin analog, paliperidone, an artemisinin analog, a nucleoside analog, an antibiotic, an antiviral drug, naltrexone, rotigotine, rapamycin, tacrolimus, treprostinil, amsufamine, etoposide, halofugine, combretastatin, SN-38, rapamycin, fulvestrant, abiraterone, a statin, an analgesic, an IDO inhibitor NLG919, or a terpenoid.

The invention also provides a compound shown in the formula (I), a racemate, a stereoisomer, a tautomer or pharmaceutically acceptable salts thereof, or the use of said pharmaceutical composition in the prevention or treatment of a disease or condition which can be treated by a pharmaceutical compound containing at least one hydroxyl group as described above, such as those that may be alleviated or alleviated by administration of a taxane, glucocorticoid, prostaglandin analog, paliperidone, artemisinin analog, nucleoside analog, antibiotic, antiviral drug, naltrexone, rotigotine, rapamycin, tacrolimus, treprostinil, amsufamine, etoposide, halofuginone, combretastatin, SN-38, rapamycin, fulvestrant, abiraterone, statin, analgesic, IDO inhibitor NLG919 or terpenoid.

The invention also provides a compound shown in the formula (I), a racemate, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in improving the physical property, the chemical property or the pharmaceutical property of the pharmaceutical compound containing at least one hydroxyl.

The invention also provides a compound shown in the formula (I), a racemate, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in improving the metabolism or release characteristics of the pharmaceutical compound containing at least one hydroxyl.

The invention also provides a compound shown in the formula (I), a racemate, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in improving the solubility of the pharmaceutical compound containing at least one hydroxyl in water or an organic solvent.

The invention also provides a compound shown in the formula (I), a racemate, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in improving the drug effect or side effect of the pharmaceutical compound containing at least one hydroxyl.

Advantageous effects

1) The prodrug of the invention can obviously improve the physical and chemical properties of the original initial drug, such as solving the problem of poor solubility of the original initial drug such as taxane drugs in water. The hydrophilic ketal improves the solubility of the medicinal compound in water, improves the anti-tumor effect of the medicament in vivo, and even can reduce the toxic and side effects caused by certain auxiliary materials (such as auxiliary materials in taxane injections) of the original initial medicinal preparation; in addition, the fat-soluble ketal prodrug makes the variety of abundant pharmaceutical preparations possible, and the pharmacological action (such as in vivo antitumor effect) of the ketal prodrug is obviously superior to that of the commercial preparation.

2) The prodrug of the invention can improve the solubility of the original initial drug in an organic solvent, for example, facilitates the preparation of a glucocorticosteroid nano preparation and improves the in-vivo treatment effect.

3) The fat-soluble prodrugs of the present invention can reduce the solubility of the original starting drug in aqueous solution, thereby being useful for achieving a long-lasting sustained release against chronic disease-treating drugs (such as glucocorticoids, prostaglandin analogs, paliperidone, dihydroartemisinin, nucleoside analogs, antiviral drugs, etc., as exemplified herein).

Definition and description of terms

Unless otherwise indicated, the definitions of radicals and terms described in the specification and claims of the present application, including definitions thereof as examples, preferred definitions, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

Where a range of numerical values is recited in the specification and claims herein, and where the range of numerical values is defined as an "integer," it is understood that the two endpoints of the range are recited and each integer within the range is recited. For example, "an integer of 0 to 10" should be understood to describe each integer of 0,1, 2,3,4, 5,6, 7, 8, 9, and 10. An integer of "0 to 200" is to be understood as each integer describing 0,1, 2,3,4, 5,6, 7, 8, 9,10, 11, … …,100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, … …, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200.

When a range of values is defined as "a number," it is understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited.

The term "halogen" refers to F, Cl, Br and I. In other words, F, Cl, Br, and I may be described as "halogen" in the present specification.

The term "C_1-40Alkyl is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C_1-20Alkyl, further preferably C_1-10An alkyl group. "C_1-10Alkyl "is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group. In particular, the radicals have 1,2, 3,4, 5,6 carbon atoms ("C)_1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)_1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.

The term "C_2-40Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having from 2 to 40 carbon atoms, preferably" C_2-20Alkenyl ", alsoPreferably "C_2-10Alkenyl ". "C_2-10Alkenyl "is understood to preferably mean a straight-chain or branched, monovalent hydrocarbon radical which contains one or more double bonds and has 2,3,4, 5,6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C_2-3Alkenyl "), it being understood that in the case where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl group and 1-isopropylvinyl group.

The term "C_2-40Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C₂-C₂₀Alkynyl ", also preferred is" C₂-C₁₀Alkynyl ". The term "C₂-C₁₀Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3,4, 5,6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C₂-C₃-alkynyl "). Said alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynylBut-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylpropan-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, di-n-3-alkynyl, di-n-2-alkynyl, di-n-3-methylbut, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C_3-20Cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C_3-10Cycloalkyl groups ". The term "C_3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is_3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.

The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a5, 5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a5, 6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.

The term "C_6-20Aryl "is understood to preferably mean a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6 to 20 carbon atoms, preferably" C_6-14Aryl ". The term "C_6-14Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6, 7, 8, 9,10, 11, 12, 13 or 14 carbon atoms (" C_6-14Aryl group "), in particular a ring having 6 carbon atoms (" C₆Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C₉Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C₁₀Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C₁₃Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)₁₄Aryl), such as anthracenyl.

The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9,10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.

The above for the term "alkyl", e.g. "C_1-40The definition of alkyl "applies equally to compounds containing" C_1-40Other terms for alkyl radicals, e.g. the term "C_1-40Alkoxy "and the like.

The term "inert atmosphere" according to the present invention shall be understood as an atmosphere inert to the reaction, including, but not limited to, one, two or more atmospheres selected from helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe), nitrogen.

Drawings

FIG. 1 shows Oleyl-K-7-PTX/DSPE-PEG₂₀₀₀Characterization of nanoparticles: transmission electron microscopy (left panel) and dynamic light scattering (right panel).

FIG. 2 shows mPEG₂₀₀₀The treatment effect of the-K-7-PTX injection and the self-made commercial Genex xol paclitaxel micelle preparation on the tumor of an A2780 tumor-bearing mouse (left panel) and the weight change graph of a nude mouse (right panel). The time points indicated by the arrows are injection time points.

FIG. 3 shows Oleyl-K-7-PTX/DSPE-PEG₂₀₀₀The effect of nanoparticles and self-made commercial taxol on the tumor inhibition of MDA-MB-231 tumor-bearing mice is shown in the figure. Dosage: 20mg/kg paclitaxel; the time points indicated by the arrows are injection time points.

FIG. 4 is a graph showing the inhibitory effect of mPEG-PDLLA-K-2' -PTX micelles and the commercially available Genex paclitaxel micelle preparation on MDA-MB-231 tumor-bearing mice tumors. Dosage: 10mg/kg paclitaxel; the time points indicated by the arrows are injection time points.

FIG. 5 shows mPEG₁₀₀₀The effect of-K-Cab injection and the home-made commercial cabazitaxel preparation on the inhibition of MDA-MB-231 tumor-bearing mice tumors is shown. mPEG₁₀₀₀-K-Cab dose: 10mg/kg cabazitaxel; dose of the self-made commercial cabazitaxel formulation: 3mg/kg cabazitaxel; the time points indicated by the arrows are injection time points.

FIG. 6 shows SA-K-DEX/DSPE-PEG₂₀₀₀Characterization of nanoparticles: transmission electron microscopy (left panel) and dynamic light scattering (right panel).

FIG. 7 shows the tail vein injection of SA-K-DEX/DSPE-PEG₂₀₀₀The effect of the nanoparticles on treating arthritis of rats is shown in the figure. Dosage: 1.0mg/kg dexamethasone; the time points indicated by the arrows are injection time points.

Fig. 8 is a MicroCT image of the joint after the rat arthritis treatment experiment was completed.

FIG. 9 is the distribution of dexamethasone in the rat joints 4 hours after tail vein injection. Dosage: corresponding to 1.0mg/kg dexamethasone.

FIG. 10 is an optical microscope photograph of SA-K-DEX nanocrystals.

FIG. 11 is a graph showing the therapeutic effect of SA-K-DEX nanocrystals injected into the joints of rats on arthritis. Dosage: equivalent to 2.5mg/kg dexamethasone; the time points indicated by the arrows are injection time points.

FIG. 12 is a test of dexamethasone concentration in blood after intra-articular injection of SA-K-DEX nanocrystals in rats. Dosage: corresponding to 2.5mg/kg dexamethasone.

FIG. 13 shows SA-K-TAF/DSPE-PEG₂₀₀₀Characterization of nanoparticles: transmission electron microscopy (left panel) and dynamic light scattering (right panel).

FIG. 14 is a graph showing changes in intra-ocular pressure of New Zealand rabbits. Dosage: equivalent to 10 mug/body of tafluprost; the time points indicated by the arrows are injection time points.

FIG. 15 shows intramuscular injection of Oleyl-K-PAL/DSPE-PEG to rats₂₀₀₀The concentration of paliperidone in blood after nanoparticles was tested. Dosage: equivalent to paliperidone 20 mg/kg; the time points indicated by the arrows are injection time points.

FIG. 16 shows the intramuscular injection of SA-K-DHA/DSPE-PEG to rats₂₀₀₀And (4) testing the concentration of dihydroartemisinin in blood after nanoparticles are generated. Dosage: equivalent to 20mg/kg of dihydroartemisinin; the time points indicated by the arrows are injection time points.

FIG. 17 shows the results of the SA-K-5' -GEM cytotoxicity assay.

FIG. 18 shows rat intramuscular injection of SA-K-5' -AZT/DSPE-PEG₂₀₀₀Concentration of zidovudine in blood after nanoparticles was tested. Dosage: equivalent to 20mg/kg of zidovudine; the time points indicated by the arrows are injection time points.

FIG. 19 shows rat blood injection of mPEG₂₀₀₀Measurement of the concentration of testosterone in the blood after K-TES. Dosage: equivalent to testosterone 1 mg/kg; the time points indicated by the arrows are injection time points.

FIG. 20 shows the therapeutic effect of β -glucose-K-etoposide injection and Toposar, a commercially available etoposide preparation, on A549 tumor-bearing mice. The time points indicated by the arrows are injection time points. The dose is 15mg/kg etoposide.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Liquid chromatograph: agilent 1260Infinity II, Agilent technologies, Inc.; nuclear magnetism: switzerland brueck, AV 400; a multifunctional microplate reader: bio Tek, Synergy 4.

The control groups referred to in the following examples in comparison with the activity of the commercial preparations mean, unless otherwise specified, the groups to which no drug was administered.

The experimental animal source is as follows: nude mice: beijing Wittiulihua laboratory animal technology Co., Ltd, balb/c-Nude, 6-8 weeks, female, 20 g; adult SD rats: beijing Wittiulihua laboratory animal technology Co., Ltd, 9-11 weeks, female, 200-; 2.5-3kg of New Zealand rabbits. Experimental rats were housed in an SPF-scale experimental environment, while rabbits were housed in a common clean environment.

EXAMPLE 1 Synthesis of hexanol isopropenyl ether

Reference is made to The literature methods (Killian, D.B., G.F.Hennion, and J.A.Nieuwland. "The Preparation of The Some α -unreacted Ethers from 2, 2-dimethyl-akutanes 1." Journal of The American Chemical Society 57.3(1935): 544-545.).

120g of 2, 2-methoxyoctane and 0.05g of p-toluenesulfonic acid were placed in a 250mL round-bottom flask and heated to reflux. After refluxing reaction for 4h, reduced pressure distillation is carried out to obtain the product hexanol isopropenyl ether.¹H NMR (400MHz, benzene-d)₆)：δ3.90(dd,J＝7.9,1.3Hz,2H),3.52(t,J＝6.5Hz,2H),1.81(s,3H),1.55(dt,J＝14.7,6.6Hz,2H),1.32–1.10(m,6H),0.84(t,J＝7.0Hz,3H)。

EXAMPLE 2 Synthesis of (1-methoxyvinyl) benzene

Reference is made to the literature (Pine S H, Zahler R, Evans D A, et al titanium-functionalized ethylene-transfer reactions direct conversion of esters inter vinyl ethers [ J ] Journal of the American Chemical Society,1980,102(9): 3270) 3272).

1mmol of methyl phenylacetate was dissolved in 2ml of a mixed solvent of toluene and tetrahydrofuran (3:1), the system was cooled to-40 ℃ and then a toluene solution (0.55M) of 1.1mmol of Tebbe reagent was slowly added dropwise thereto, the reaction was continued at this temperature for 30min, then warmed to room temperature and continued for 1.5h,after the reaction is completed, the system is cooled to-10 ℃, 1ml of 15% sodium hydroxide aqueous solution is added to the system for quenching, then the system is warmed to room temperature, ether extraction is carried out, anhydrous sodium sulfate is dried, filtration and concentration are carried out, and a colorless liquid product is obtained after silica gel column chromatography separation and purification.¹H NMR (400MHz, benzene-d)₆)：δ7.73–7.67(m,2H),7.17–7.05(m,3H),4.65(d,J＝2.7Hz,1H),4.05(d,J＝2.7Hz,1H),3.31(s,3H)。

Example 3 Synthesis of Cholesterol isopropenyl Ether

Reference is made to the literature (Dujardin, G., Rossgnol, S., & Brown, E. (1995). effective Current polymerization-free preparation of vinyl and isopentene ethers of basic secondary alcohols and. alpha. -hydroxyers. tetrahedron leaves, 36(10), 1653-. The specific method comprises the following steps:

adding 10mmol of cholesterol, 25mL of dichloromethane and 60mmol of 2-methoxypropene into a reaction bottle, adding 0.05mmol of p-toluenesulfonic acid (p-TSA) as a catalyst under the protection of nitrogen, adding 0.5mL of triethylamine after the reaction is completely monitored by a dot plate to terminate the reaction, removing the solvent, and carrying out silica gel column chromatography to obtain the ketal protected cholesterol.

Adding 1mmol of ketal-protected cholesterol, 5mL of tetrahydrofuran and 1.3mmol of DIPEA into a reaction bottle, cooling to-20 ℃, slowly dropwise adding 1mmol of trimethylsilyl trifluoromethanesulfonate into the reaction bottle, returning to room temperature, and stirring for reaction overnight. After the reaction was completed, 3mL of 1M aqueous sodium hydroxide solution was added thereto, liquid separation was performed, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain a colorless liquid product.¹H NMR (400MHz, benzene-d)₆):δ5.33–5.39(m,1H,CH,＝CH),3.93–4.05(m,3H,CH,＝CH₂),2.68(m,1H,CH),2.40–2.50(m,1H,CH),2.00–2.09(m,2H,CH₂),1.93(m,1H,CH),1.86(s,3H,CH₃),1.50–1.73(m,6H,3CH₂),1.36–1.46(m,6H,3CH₂),0.98–1.31(m,14H,CH₃,4CH₂,3CH),0.92–0.95(m,9H,3CH₃),0.67(s,3H,CH₃).¹³C NMR(100MHz,C₆D₆):δ157.87,140.38,121.87,81.61,75.67,56.72,56.24,50.21,42.28,39.87,39.60,38.46,37.16,36.78,36.35,35.87,32.01,31.87,28.28,28.06,27.95,24.26,24.02,22.67,22.42,21.50,21.06,19.14,18.71,11.73.HRMS(ESI):m/z calcd for C₃₀H₅₀O[M+Na]⁺:449.3754；found 449.3759。

EXAMPLE 4 Synthesis of beta-2, 3,4, 6-tetrabenzyl-D-glucopyranose isopropenyl ether

Beta-1-chloro-2, 3,4, 6-tetrabenzyl-D-glucopyranose (24.3mmol), bisacetylmethylmercury and chloroform are added into a 500mL two-neck flask and reacted under reflux. The expected product is obtained in the form of a yellow solid, 8.9g, yield 70.5%.¹H NMR(CDCl₃):δ7.38–7.25(m,17H),7.18(dd,J＝6.9,2.6Hz,3H),4.96(d,J＝10.9Hz,2H),4.90–4.73(m,5H),4.65–4.50(m,4H),4.27(d,J＝1.9Hz,1H),4.13(s,1H),3.81–3.51(m,4H),1.92(s,3H).

Example 5: hexanol-2 '-paclitaxel acetonide conjugate (HE-K-2' -PTX)

Paclitaxel (0.1mmol, 1eq), dichloromethane 1.5mL, hexanol isopropenyl ether (0.6mmol) were added to The reaction flask under nitrogen (Killian, D.B., G.F. Hennion, and J.A. Nieuwland. "The Preparation of The sodium α -unreacted Ethers from 2, 2-dimethyl yalkanes1." The Journal of The American Chemical Society 57.3(1935):544 and 545.), followed by The addition of The catalyst dichloroacetic acid (0.05 eq). After TLC monitoring raw material paclitaxel reaction is complete, adding 200. mu.L triethylamine to stop reaction, concentrating, and separating by silica gel column chromatography to obtain white solid product HE-K-2' -PTX with yield of 80.3%.¹H NMR (400MHz, acetonitrile-d)₃):δ8.1–8.1(m,2H),7.8–7.8(m,2H),7.7–7.7(m,1H),7.6–7.5(m,4H),7.5(dd,J＝7.9,1.7Hz,4H),7.4(t,J＝7.7Hz,2H),7.3–7.2(m,1H),6.3(s,1H),6.1–6.0(m,1H),5.6(d,J＝7.2Hz,1H),5.5(dd,J＝8.3,6.1Hz,1H),4.9(dd,J＝9.7,2.2Hz,1H),4.6(d,J＝6.2Hz,1H),4.3(dd,J＝11.0,6.6Hz,1H),4.1(s,2H),3.7(d,J＝7.1Hz,1H),3.4–3.3(m,1H),3.0(dt,J＝8.9,6.7Hz,1H),2.8(s,1H),2.5–2.4(m,1H),2.4(s,3H),2.1(s,3H),2.1–2.0(m,1H),1.9(d,J＝1.5Hz,3H),1.8–1.7(m,1H),1.7–1.7(m,1H),1.6(s,3H),1.3(s,4H),1.3(s,3H),1.3–1.2(m,10H),1.1(s,3H),1.1(s,3H),0.9(t,J＝7.1Hz,3H).

Example 6: synthesis of Oleyl-7-taxol acetonide conjugate (Oleyl-K-7-PTX)

Wherein Oleyl represents Oleyl.

PTX-2' -TBS (0.1mmol, 1eq), dichloromethane (1.5 mL), Oleyl isopropenyl ether (0.6mmol) (Oleyl isopropenyl ether reference line S H, Zahler R, Evans D A, et al titanium-functionalized ethylene-transfer reactions, direct conversion of esters in vinyl ethers [ J ] Journal of the American Chemical Society,1980,102(9): 3272) was added under nitrogen protection, followed by dichloroacetic acid (0.05eq), and 200. mu.L of triethylamine was added thereto after TLC monitoring the completion of the reaction of the starting material PTX-2' -TBS, to terminate the reaction, and the resulting white solid product Oleyl-K-7-PTX-2' -TBS was directly charged to the next step.

Under the protection of nitrogen, crude Oleyl-K-7-PTX-2' -TBS (0.1mmol) in the previous step and 0.5mL of tetrahydrofuran are added into a tetrafluoroethylene reaction bottle, TBAF (0.15mmol) is added into the tetrafluoroethylene reaction bottle, the mixture is stirred at room temperature overnight, 5mL of saturated sodium bicarbonate aqueous solution is added into the tetrafluoroethylene reaction bottle after the raw materials are completely reacted, liquid separation is carried out, aqueous phase is extracted by DCM (3X 5mL), organic phase is combined, water washing is carried out, saturated salt water washing is carried out, anhydrous sodium sulfate is dried, filtering is carried out, concentration is carried out, silica gel column chromatography separation is carried out, and white solid product Oleyl-K-7-PTX is obtained, wherein.¹H NMR (400MHz, chloroform-d): δ 8.15-8.07 (m,2H), 7.79-7.72 (m,2H), 7.65-7.57 (m,1H), 7.54-7.45 (m,5H), 7.43-7.30 (m,5H), 7.19-7.12 (m,1H),6.40(s,1H), 6.21-6.12 (m,1H),5.78(dd, J ═ 8.9,2.7Hz,1H),5.66(d, J ═ 6.9Hz,1H), 5.41-5.28 (m,2H),4.90(dd, J ═ 9.9,2.1Hz,1H),4.77(d, J ═ 2.7Hz,1H),4.39(dd, J ═ 6, J ═ 6.9, 2.1H), 4.7H, 3.3H, 3.7H, 3.3H, 3.7H, 3H, 4H) 1.74(s,3H),1.50(s,3H),1.40(m,2H), 1.35-1.14 (m,33H),0.87(t, J ═ 6.8Hz,3H).

Example 7: polyethylene glycol monomethyl ether₂₀₀₀-7-Taxol acetonide conjugate (mPEG)₂₀₀₀Synthesis of (E) -K-7-PTX)

To a reaction flask were added PTX-2' -TBS (0.1mmol, 1eq), dichloromethane 1.5mL, polyethylene glycol monomethyl ether (molecular weight 2000g/mol) isopropenyl ether (0.6mmol) (polyethylene glycol monomethyl ether isopropenyl ether references Pine S H, Zahler R, Evans D A, et al titanium-functionalized ethylene-transfer reactions, direct conversion of esters inter vinyl ethers [ J]The method described in Journal of the American Chemical Society,1980,102(9):3270-3272), followed by addition of dichloroacetic acid (0.05eq) as a catalyst, termination of the reaction by TLC monitoring the completion of the reaction of the starting PTX-2' -TBS with 200. mu.L of triethylamine, concentration and mPEG as a white solid product₂₀₀₀the-K-7-PTX-2' -TBS was directly subjected to the next step.

Adding the crude mPEG of the previous step into a tetrafluoro reaction bottle under the protection of nitrogen₂₀₀₀-K-7-PTX-2' -TBS (0.1mmol), tetrahydrofuran 5mL, adding TBAF (0.15mmol), stirring at room temperature overnight, after the raw materials completely react, adding 5mL saturated sodium bicarbonate aqueous solution, separating, extracting aqueous phase with DCM (3X 5mL), combining organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating, and separating by silica gel column chromatography to obtain white solid product mPEG₂₀₀₀-K-7-PTX, two-step yield 53%.¹H NMR (400MHz, B)Nitrile-d₃)：δ8.15–8.07(m,2H),7.94–7.89(m,2H),7.71–7.63(m,1H),7.57(t,J＝7.6Hz,2H),7.54–7.47(m,3H),7.47–7.37(m,4H),7.31–7.24(m,1H),6.35(s,1H),6.14–6.01(m,1H),5.61(dd,J＝8.5,4.8Hz,1H),5.56(d,J＝7.1Hz,1H),4.91(dd,J＝9.9,2.1Hz,1H),4.74(d,J＝4.9Hz,1H),4.41(dd,J＝10.8,6.4Hz,1H),4.18–4.07(m,2H),3.81–3.69(m,3H),3.55(s,220H),3.37(dd,J＝5.8,3.7Hz,1H),3.29(s,3H),2.59–2.47(m,1H),2.37(s,3H),2.26(dt,J＝15.4,7.9Hz,2H),2.12(s,3H),2.02(dd,J＝13.5,7.7Hz,2H),1.88(d,J＝1.4Hz,3H),1.66(s,3H),1.45(s,3H),1.16(s,3H),1.12(s,6H).

Example 8: synthesis of methanol-2 '-paclitaxel acetophenone conjugate (Ph-K-2' -PTX)

Paclitaxel (0.1mmol, 1eq), dichloromethane 1.5mL, 1-methoxyvinylbenzene (0.6mmol) (1-methoxyvinylbenzene reference: Tebbe, f.n., Parshall, g.w.,&reddy, G.D. (1978), Olefine homology with titanium methyl compounds, journal of the American chemical society,100(11), 3611-3613). To this was then added the catalyst dichloroacetic acid (0.005 mmol). After TLC monitoring raw material paclitaxel reaction is complete, adding 200. mu.l triethylamine to stop reaction, concentrating, and separating by silica gel column chromatography to obtain white solid product Ph-K-2' -PTX with yield of 70%.¹H NMR (400MHz, acetonitrile-d)₃):δ8.14–8.05(m,2H),7.88–7.80(m,2H),7.69–7.62(m,1H),7.55(td,J＝7.1,4.4Hz,4H),7.47(t,J＝7.6Hz,2H),7.38(d,J＝5.1Hz,4H),7.24(ddd,J＝20.8,8.0,5.6Hz,4H),7.12(d,J＝7.2Hz,2H),6.33(s,1H),6.03(t,J＝9.1Hz,1H),5.61–5.51(m,2H),4.92(dd,J＝9.7,2.2Hz,1H),4.32(dd,J＝11.0,6.6Hz,1H),4.22(d,J＝4.4Hz,1H),4.12(s,2H),3.71(d,J＝7.1Hz,1H),3.07(s,3H),2.80(s,2H),2.44–2.35(m,1H),2.23–2.16(m,1H),2.14(s,3H),2.00(s,3H),1.82(dd,J＝15.5,9.0Hz,1H),1.71(m,1H),1.58(d,J＝1.7Hz,6H),1.13(s,3H),1.08(s,3H).

Example 9: synthesis of hexanol-2 '-docetaxel acetonide (HE-K-2' -DOC) conjugate

Docetaxel (0.1mmol, 1eq), dichloromethane (1.5 mL), hexanol isopropenyl ether (0.6mmol) were added to a reaction flask under nitrogen (hexanol isopropenyl ether reference Killian, D.B., G.F.Hennion, and J.A. Nieuwland. "The Preparation of The sodium α -unreacted Ethers from 2, 2-dimethyl yalkanes1." Journal of The American Chemical Society 57.3(1935): 544-) 545) followed by The addition of The catalyst dichloroacetic acid (0.05 eq). After TLC monitoring material docetaxel reaction is completed, adding 200. mu.L triethylamine to terminate the reaction, concentrating, and separating by silica gel column chromatography to obtain white solid product HE-K-2' -DOC with yield of 64%.¹H NMR (400MHz, acetonitrile-d)₃):δ8.16–8.10(m,2H),7.73–7.67(m,1H),7.61(t,J＝7.5Hz,2H),7.39(d,J＝6.5Hz,4H),7.27(td,J＝6.4,3.0Hz,1H),6.06(t,J＝9.1Hz,2H),5.56(d,J＝7.0Hz,1H),5.08(s,1H),5.01(dd,J＝9.8,2.0Hz,1H),4.81(s,1H),4.45(d,J＝5.0Hz,1H),4.22–4.10(m,2H),3.87(dd,J＝10.6,6.5Hz,1H),3.78(d,J＝6.9Hz,1H),3.37(s,3H),3.26(s,3H),2.87–2.66(m,3H),2.43(s,3H),2.15(d,J＝26.6Hz,1H),1.68–1.58(m,4H),1.38(s,9H),1.34–1.15(m,15H),1.13(s,3H),1.10(s,3H),0.91(t,J＝7.1Hz,3H).

Example 10: polyethylene glycol monomethyl ether₁₀₀₀-Cabazitaxel acetonide conjugate (mPEG)₁₀₀₀Synthesis of-K-Cab)

Cabazitaxel (0.1mmol, 1eq), dichloromethane (1.5 mL), TES mono-protected hexanediol isopropenyl ether (0.6mmol) (TES mono-protected hexanediol isopropenyl ether reference Tebbe, f.n., Parshall, g.w., & Reddy, g.d. (1978) made by the method of Olefin polymerization with titanium methyl ether compounds. journal of the American chemical society,100(11), 3611-3613) were added to a reaction flask under nitrogen, followed by the catalyst dichloroacetic acid (0.05 eq). After TLC monitoring the reaction of the raw material cabazitaxel is completed, 200 mu L of triethylamine is added to the mixture to terminate the reaction, the mixture is concentrated, and the obtained white solid is directly put into the next step.

Adding the crude product (0.1mmol) of the previous step and 5mL of tetrahydrofuran into a 15mL tetrafluoroethylene reaction bottle under the protection of nitrogen, adding TBAF (0.15mmol), stirring overnight at room temperature, adding 5mL of saturated sodium bicarbonate aqueous solution after the raw materials react completely, separating, extracting the aqueous phase with DCM (3X 5mL), combining the organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating, and separating by silica gel column chromatography to obtain a white solid product C₆diol-K-2' -Cab, two-step yield 63%.

Adding the product C in the last step into a reaction bottle under the protection of nitrogen₆diol-K-2' -Cab (0.1mmol), dichloromethane (5.0 mL), triethylamine (0.6mmol), polyethylene glycol monomethyl ether (molecular weight 1000g/mol) p-nitrophenyl carbonate (0.11mmol) are added, TLC monitors that the raw materials react completely, then the raw materials are directly concentrated, and the product mPEG is obtained after silica gel column chromatography₁₀₀₀-K-Cab, yield 75%.¹H NMR (400MHz, acetonitrile-d)₃)：δ8.16–8.10(m,2H),7.75–7.68(m,1H),7.62(dd,J＝8.3,6.8Hz,2H),7.45–7.35(m,4H),7.30–7.24(m,1H),6.10–5.98(m,2H),5.55(d,J＝7.0Hz,1H),5.15–5.06(m,1H),5.02(dd,J＝9.8,2.0Hz,1H),4.81(s,1H),4.45(d,J＝4.9Hz,1H),4.26–4.06(m,7H),3.87(dd,J＝10.7,6.5Hz,1H),3.81–3.72(m,2H),3.70–3.44(m,105H),3.37(s,3H),3.32(s,3H),3.27(s,3H),3.21(s,1H),2.94(q,J＝7.3Hz,2H),2.81–2.65(m,3H),2.44(s,3H),2.19(d,J＝11.2Hz,1H),1.95(s,5H),1.63(d,J＝5.1Hz,6H),1.39(s,9H),1.36–1.16(m,17H),1.13(s,3H),1.09(s,3H).

Example 11: synthesis of polyethylene glycol monomethyl ether-polylactic acid-2 '-paclitaxel acetonide conjugate (mPEG-PDLLA-K-2' -PTX)

Paclitaxel (1mmol, 1eq) and TES monoprotected hexanediol isopropenyl ether (6mmol) were charged into a 100mL Schlenk flask, the nitrogen gas was replaced, methylene chloride (25mL) was added and the mixture was dissolved with stirring, and dichloroacetic acid (0.05eq) was added. Triethylamine is added into a system after the raw materials completely react, then the mixture is subjected to desolventizing and column chromatography to obtain a compound PTX-K-C6-OTES, a white solid is obtained, and the yield is as follows: 36 percent.

PTX-K-C6-OTES (0.36mmol) was added to a 10mL Schlenk tube, THF (2mL) was added and dissolved with stirring, followed by TBAF tetrahydrofuran solution (0.40 mmol). After the reaction is finished, adding a saturated sodium bicarbonate diluting system, dissolving ethyl acetate, extracting with water and saturated sodium chloride, drying with anhydrous sodium sulfate, removing the solvent from the filtrate, and performing column chromatography to obtain white solid PTX-K-C6-OH with the yield of 71%.

To a 25mL Schlenk tube was added mPEG with a carboxylic acid end group₂₀₀₀-PDLLA₁₇₅₀(0.12mmol), DMAP (0.012mmol), EDC (0.16mmol) and dichloromethane (4mL) were dissolved with stirring and pyridine (0.6mL) was added. After activating the system for 20min, the PTX-K-C6-OH (0.144mmol) prepared in the previous step is added into the system, and the reaction is carried out at 25 ℃. After the reaction is finished, adding dichloromethane to dilute the system, washing twice with a small amount of water and a saturated NaCl solution in sequence, then drying with anhydrous sodium sulfate, desolventizing, and carrying out column chromatography to obtain a compound mPEG-PDLLA-K-2' -PTX, wherein the white solid is obtained in yield: 75 percent.¹H NMR (400MHz, chloroform-d): δ 8.12(d, J ═ 7.6Hz,2H),7.76(d, J ═ 7.8Hz,2H),7.61(s,1H),7.56 to 7.39(m,11H),7.19(d, J ═ 8.1Hz,1H),6.28(s,1H),6.24(t, J ═ 8.1,1H),5.67(d, J ═ 7.1Hz,1H),5.59(dd, J ═ 8.1,3.7Hz,1H),5.18 to 5.09(m,24H),4.97(d, J ═ 9.7Hz,1H),4.67(d, J ═ 3.6Hz,1H),4.36 to 4.16(m,9H),4.05(t, J ═ 6, 3.7H, 1H),4.36 to 4.16(m,9H),4.05(t, J ═ 6, 3.7, 3.68H), 3.67 (m,1H), 3.23.6H, 1H), 3.23, 1H, 3.23.6H, 1H, 3.6H, 1H, 3.6H, 1.

The taxane ketal derivatives of tables 1-3 were prepared from the above drugs by the methods of reference examples 5-11.

Example 12: hydrolysis rate test of taxane ketal prodrug conjugates

mu.L of the prodrug to be tested (prodrug prepared in the above example) in acetonitrile (7.5mM) was added to 3mL of hydrolysis buffer (pH 5.0, 50mM, containing 40% V acetonitrile) at 37.0 ℃. Rapidly taking 100 mu L of hydrolysis sample at 1min,3min,5min,15min,0.5h,1h,2h,4h,8h,12h,24h and 48h, adding 100 mu L of hydrolysis termination buffer solution (pH 8.0, 200mM containing 40% V acetonitrile) to terminate hydrolysis, uniformly mixing, measuring the contents of hydrolysis raw materials and hydrolysis products by liquid chromatography, fitting a hydrolysis curve, calculating the hydrolysis half-life period, and testing for 4 times in parallel. The test results are shown in tables 1-3.

As can be seen from tables 1 to 3, the taxane ketal prodrug conjugate has a very obvious acid sensitivity property, and the half-life period is as short as 3mins at the shortest and 29838mins at the longest under the condition of pH 5.0, so that the purpose of controlling the acid sensitivity degree of the taxane drugs can be achieved through molecular design.

The hydrolysis activity of different reaction sites of the paclitaxel is different, and the reaction activity of the 7 site of the paclitaxel is obviously better than that of the 2' site. Meanwhile, the hydrolytic activity and the structure of the same reaction site are closely related, and the following rules are found: when the substituent on the ketal is a cyclic structure, the hydrolytic activity of the ketal is superior to that of a chain structure; the carbon atom connected with the ketal is a secondary carbon atom, and the reactivity is better than that of a primary carbon; the hydrolytic activity of the electron withdrawing group is reduced.

Example 13: cytotoxicity testing of taxane conjugate prodrugs

Cell culture conditions: DMEM high-sugar medium, 10% FBS, 1% P/S, 37 ℃, 5% CO₂。

MDA-MB-231 cells were seeded into 96-well plates at 3000/well density the day before the experiment. On the day of the experiment, the prodrug prepared in the above example was dissolved in DMSO, the drug was diluted to various concentrations with the medium, and added to a 96-well plate (n ═ 4). After the cells were incubated with the pro-drugs prepared in the above examples for an additional 3 days in the incubator, the medium was changed to 100. mu.L of fresh medium + 10. mu.L of CCK-8 solution. After further incubation for 2h, OD 450nm was measured and IC calculated according to CCK-8 instructions₅₀. The test results are shown in tables 1-3.

It can be seen from tables 1-3 that the pro-drugs prepared by the present invention have a killing effect on cancer cells close to that of paclitaxel. Meanwhile, the cytotoxicity data are identical with the results of in vitro hydrolysis experiments, which shows that the prodrug constructed by utilizing the acid-sensitive ketal bond has high utilization value.

Example 14: preparation of hydrophilic taxane ketal conjugate prodrug injection

For water soluble ketal prodrugs mPEG₂₀₀₀-K-7-PTX and mPEG₁₀₀₀-K-Cab, the water-soluble prodrugs were dissolved directly in 10mM PB buffer (pH 7.4), respectively. After the dissolution, the mixture was filtered through a 0.45 μm sterile filter to obtain an injection, and the concentration of the drug was measured by HPLC.

Example 15: preparation of lipophilic taxane ketal couple prodrug nanoparticles

Taking Oleyl-K-7-PTX as an example: accurately weighing 7mg of Oleyl-K-7-PTX and 3mg of DSPE-mPEG₂₀₀₀Dissolving the two in 350 mu L of absolute ethyl alcohol, slowly dripping the ethanol solution into a PBS (pH 8.0) buffer solution (6.7mM) under stirring, stabilizing for 5min, removing the ethanol by using a rotary evaporator to obtain prodrug nanoparticles, filtering by using a 0.45 mu m sterile filter membrane, measuring the concentration of the prodrug in the nanoparticles by using HPLC, and performing DLS and TEM tests on the prepared prodrug nanoparticles. The detection result is shown in FIG. 1, and it can be seen from FIG. 1 that DLS data and TEM data are consistent, and Oleyl-K-7-PTX/DSPE-PEG prepared by the invention₂₀₀₀The particle size of the nanoparticles is about 100nm, which is beneficial to the enrichment of the nano-drugs on tumor parts through EPR effect.

Example 16: preparation of amphiphilic taxane ketal conjugate prodrug micelle

Using mPEG-PDLLA-K-2' -PTX as an example, 5mg of amphiphilic taxane ketal prodrug was dissolved in 500. mu.L of acetone and added dropwise slowly with stirring to a 25mL round-bottomed flask containing 5.0mL of pH 7.4PB buffer (10 mM). Prodrug micelles were prepared by rotary evaporation at room temperature for 15min to remove acetone, ultracentrifugation (10K MWCO) to concentrate mPEG-PDLLA-K-2' -PTX micelles to 0.5 mL. HPLC was used to calculate the drug concentration in the micelles.

Example 17: in vivo antitumor evaluation of taxane conjugate prodrug preparation

Female balb/c-nu nude mice with age of 4-6 weeks and weight of 16-20g are purchased from Beijing Witonglihua laboratory animal technology Limited and bred in SPF-level laboratory animal houses.

The right armpit of the nude mouse is implanted with 5 multiplied by 10 under the skin⁶A2780 or MDA-MB-231 cells. The tumor volume is about 100mm³At the same time, tumor-bearing mice were randomly grouped (7-10 mice per group). The preparation for the treatment control group was prepared in the laboratory according to the formulation of the commercially available paclitaxel. After intravenous injection, the tumor growth size and the weight of each group of nude mice are recorded, and a tumor growth curve chart and a weight change rate chart are drawn. Tumor volume calculation formula: v_tumor＝(length×width²)/2。

When the tumor volume of A2780 is up to 2000mm³MDA-MB-231 tumor volume up to 1000mm³At that time, the nude mice were sacrificed.

mPEG₂₀₀₀The test results of the-K-7-PTX injection are shown in FIG. 2, and mPEG can be obtained from FIG. 2₂₀₀₀the-K-7-PTX injection has good safety and drug effect, the administration dosage can be improved to more than 3 times of the highest tolerance dosage of the commercial drug, the injection has good anti-tumor activity, the side effect (such as weight reduction degree) is obviously reduced, and the effect of the injection is better than that of the commercial drug paclitaxel micelle.

Oleyl-K-7-PTX/DSPE-PEG₂₀₀₀The results of the testing of the nanoparticles and the home-made commercially available taxol are shown in fig. 3. As can be seen from FIG. 3, the nano-preparation prepared by the invention has good anti-tumor activity under the dosage of 20mg/kg paclitaxel, and the effect is better than that of the commercial drug (20mg/kg paclitaxel). In addition, compared with taxol in use, the preparation of the invention only needs to be diluted by PBS and does not need to be dissolved by castor oil and ethanol, so that the preparation is safer and easier to administer.

The results of the testing of mPEG-PDLLA-K-2' -PTX micelles and the home-made commercial paclitaxel micelle Genexol formulation (dose 10mg/kg based on paclitaxel) are shown in FIG. 4. As can be seen from FIG. 4, the mPEG-PDLLA-K-2' -PTX micelle prepared by the invention has obviously better anti-tumor activity than that of the conventional medicine under the condition of the same dosage (10mg/kg of paclitaxel).

mPEG₁₀₀₀The results of the tests on the injection of-K-Cab and the injection of cabazitaxel on the market are shown in FIG. 5, and it can be seen from FIG. 5 that mPEG prepared by the present invention is measured at the maximum tolerance of mice₁₀₀₀The in vivo anti-tumor activity of the-K-Cab injection (10mg/kg cabazitaxel) is obviously better than that of the commercial cabazitaxel injection (3mg/kg cabazitaxel). At the same time, mPEG can be realized₁₀₀₀The high-dose administration of the-K-Cab injection is obviously better than that of the Cabazitaxel injection on the market in safety.

Example 18: synthesis of stearyl alcohol-dexamethasone acetonide conjugate (SA-K-DEX)

Dexamethasone (1mmol) and stearyl isopropenyl ether (6mmol, 1eq) (stearyl isopropenyl ether reference: Pine S H, Zahler R, Evans D A, et al titanium-modified methyl-transfer reactions, direct conversion of esters inter vinyl ethers [ J]Journal of the American Chemical Society,1980,102(9):3270-3272) was placed in a Schlenk bottle, and the gas in the replacement system was nitrogen. 5mL of tetrahydrofuran was added to dissolve the resulting solution, and then dichloroacetic acid (0.2eq) was added to react at 25 ℃. The reaction was followed by TLC, and after completion of the reaction, 100. mu.L of triethylamine was added to quench the reaction. The solvent was spin dried and purified on silica gel column to give white powder with a yield of 92%.¹H NMR (400MHz, chloroform-d): δ 7.18(d, J ═ 10.1Hz,1H),6.33(d, J ═ 10.1Hz,1H),6.11(s,1H),4.45(d, J ═ 17.8Hz,1H),4.38(d, J ═ 10.0Hz,1H),4.20(d, J ═ 17.8Hz,1H),3.39(t, J ═ 7.0Hz,2H), 3.11-3.01 (m,1H),2.90(s,1H),2.61(m,1H),2.37(m,3H), 2.26-2.16 (m,1H), 1.87-1.68 (m,2H),1.54(s,3H), 1.51-1.47 (m,3H),1.43(s,1H), 1.86 (s,1H),6.93 (s,6H), 6.07 (s,1H), 1H, 6.07 (s, 3H).

The glucocorticoid ketal derivatives of table 4 were prepared starting from the above drugs by the method of reference example 18.

Example 19: hydrolysis rate test of dexamethasone ketal couple prodrug

The dexamethasone ketal conjugate prodrug is dissolved in 600 μ L acetonitrile and mixed with 12.5mL of pH 5.0 digest (containing 0.1% Tween 80) to a final dexamethasone ketal conjugate prodrug concentration of about 50 μ M. Shaking table incubation at 37.0 deg.C for hydrolysis of prodrug (100rpm), caching 100 μ L of sample in 3min,6min,9min,15min,25min,30min,45min,1h,1.5h,2h,3h,6h, adding 100 μ L of phosphate buffer (200mM) pH 8.0, mixing, and placing in a refrigerator at 4 deg.C. Finally, the hydrolysis half-life and solubility were determined by HPLC, and the results of the measurements are shown in Table 4.

As can be seen from table 4, by replacing different R side chains, the dexamethasone acetonide prodrug exhibited different physicochemical properties, such as exhibiting different solubility and hydrolysis half-lives. Increasing the carbon chain length of the aliphatic side chain can significantly increase the solubility of the prodrug in methylene chloride. The different types of side chains also have an effect on the hydrolysis rate of the prodrug, generally speaking, secondary aliphatic alcohol side chains hydrolyze faster than primary aliphatic alcohol side chains, and PEG side chains hydrolyze faster than primary aliphatic alcohol side chains. Therefore, the hydrolysis speed and the solubility of the dexamethasone acetonide prodrug prepared by the invention in an organic solvent are obviously improved, so that the preparation of a nano preparation is more convenient, and the in-vivo treatment effect is improved.

Example 20: SA-K-DEX/DSPE-PEG₂₀₀₀Preparation of nanoparticles

6mg of SA-K-DEX and 4mg of DSPE-PEG₂₀₀₀Dissolving in 1mL of absolute ethanol, and performing ultrasonic treatment until the solution is clear. This ethanol solution was slowly dropped into 10mL of a pH 8.0PBS buffer (6.7mM) while stirring. Stirring at room temperature until ethanol is completely volatilized, and filtering with 0.45 μm filter membrane to obtain SA-K-DEX/DSPE-PEG₂₀₀₀And (3) carrying out ultracentrifugation on the nanoparticle solution until the concentration of SA-K-DEX in the solution is 1 mg/mL. The solution can be stored in a refrigerator at 4 deg.C, and diluted to a specific concentration with PBS (6.7mM) pH 8.0 according to the requirement of intravenous injection. The transmission electron microscopy image (left image) and the dynamic light scattering image (right image) of the nanoparticles are shown in FIG. 6.

As shown in FIG. 6, SA-K-DEX/DSPE-PEG₂₀₀₀The nanoparticles are typically spherical, the particle size distribution of the nanoparticles is narrow, and the average particle size is about 58 nm.

Example 21: in-vivo efficacy evaluation of SA-K-DEX/DSPE-PEG nanoparticles

Establishment of a CIA rat model: 180-200g male SD rats were bred for one week and acclimatized. Mixing 2mg/mL cattle type II collagen and incomplete adjuvant in equal volume, emulsifying completely, and preparing into emulsion with collagen final concentration of 1 mg/mL. For the initial immunization, 200. mu.L of the emulsion was injected into the tail group of rats, and 100. mu.L of the emulsion was injected into the tail group after 7 days. The foot of the rat started to red and swollen 10 days after the primary immunization. The experiment set up model group (dexamethasone phosphate injection), normal control group, medication group (SA-K-DEX/DSPE-PEG nanoparticles), each group of 7 rats.

Nanoparticle dosing regimen: the administration was carried out on

days

15, 20 and 25 after the primary immunization, the rats were sacrificed by injecting nanoparticle solution (1mg/kg) into the tail vein and ending the experiment on day 28, and the effect of the treatment was observed by MicroCT.

The therapeutic effect is shown in fig. 7 and 8. In the rat CIA model used in the experiment, the hindpaw of the rat started to become red and swollen at the 10 th day after the initial immunization, and the swelling peak is reached at the 15 th day. SA-K-DEX/DSPE-PEG was seen after three tail vein injections of the drug₂₀₀₀The nanoparticle group and the dexamethasone sodium phosphate injection group have treatment effects compared with the control group. The average plantar thickness of the SA-K-DEX/DSPE nanoparticle group at 28 days is 5.3cm, which is not different from that of normal rats, while the average plantar thickness of the dexamethasone sodium phosphate injection group is 6.2cm, which has swelling phenomenon and more obvious inflammation rebound tendency. It can be seen that the nano preparation of the invention improves the treatment effect on arthritis, and the main reason is that the nano particles can effectively enrich at the arthritis focus part through the isolation (ELVIS) function of permeable blood vessels and inflammatory cells mediated, and simultaneously release free dexamethasone through acidolysis. After the rats are sacrificed at 28 days, the results of the micct scanning of the ankle joints of the rats are shown in fig. 8, the bone surface near the inflamed joints is seriously damaged, the joint bone surface of the SA-K-DEX/DSPE nanoparticle group is smooth, and the bone density approaches to normal, which shows that the SA-K-DEX/DSPE nanoparticles prepared by the invention have better prevention and treatment effects on the arthritis bone damage.

Example 22: SA-K-DEX/DSPE-PEG nanoparticle joint distribution

The rats were sacrificed 4 hours after single injection of SA-K-DEX/DSPE-PEG nanoparticles and dexamethasone phosphate injection into the CIA rats, and the inflammatory joints were removed. Samples were processed according to the standard procedures for LC-MS testing, and the concentration of dexamethasone drug in the joint was determined by LC-MS. To determine the overall concentration of dexamethasone in the joint, the sample needs to be subjected to acidolysis to release dexamethasone.

The results of LC-MS data in the drug in vivo distribution experiment are shown in FIG. 9. As can be seen from FIG. 9, the overall content and the free content of dexamethasone are higher than those of dexamethasone sodium phosphate injection group at the inflamed ankle joint, and significant differences exist, which proves that the nanoparticles have an enrichment effect at the inflamed joint part and are the key point for improving the drug effect of SA-K-DEX.

Example 23: preparation of SA-K-DEX nanocrystals

A2 mL centrifuge tube was charged with 500mg of zirconia steel beads and 300. mu.L of SA-K-DEX absolute ethanol solution (containing 3mg of SA-K-DEX), followed by 600. mu.L of aqueous pH 9.0 NaOH. The centrifuge tube is opened and put into a refrigerator at 4 ℃ to volatilize ethanol for about 48 hours.

Adding 100 μ L of 2% Tween 80 aqueous solution into the rest solution, and stirring with vortex instrument (2700 rpm) for 0.5-6 h to obtain size-adjustable SA-K-DEX nanocrystal. The morphology and size of the nanocrystals can be roughly observed by optical microscopy.

The results of light microscope examination of the nanocrystals are shown in fig. 10. As can be seen from FIG. 10, under the optical microscope, the SA-K-DEX nanocrystals showed needle-like crystals with a length of 10-15 μm.

After stirring was complete, the well dispersed liquid was transferred to a centrifuge tube. After centrifugation, the supernatant was discarded. An appropriate amount of aqueous solution containing 0.1% tween 80 was added. Repeating the steps for 3 times, and freeze-drying the nanocrystalline for later use. Before use, resuspend with pH 7.4PBS and disperse well using vortex.

Example 24: in vivo efficacy evaluation of dexamethasone formulations

The model was made as in example 21, nanocrystal dosing schedule: rats were injected with SA-K-DEX nanocrystals (dose 2.5mg/kg SA-K-DEX) at the ankle cavity on day 21 after the initial immunization, and the experiment was sacrificed at the end of day 50.

The test results are shown in fig. 11. As can be seen in FIG. 11, the therapeutic effect was stable for at least 28 days after administration after the intra-articular injection of SA-K-DEX nanocrystals.

Example 25: determination of dexamethasone concentration in dexamethasone nanocrystalline blood

After 14, 21 and 28 days of injection of SA-K-DEX nanocrystals (dose in SA-K-DEX: 2.5mg/kg) in inflamed joints of rats, blood was taken. The samples were processed according to the standard procedures for LC-MS testing of blood samples, and the concentration of dexamethasone drug in the blood was determined by LC-MS. To determine the overall concentration of dexamethasone in the blood, the sample needs to be subjected to acidolysis to release dexamethasone.

The dexamethasone concentration in the rat plasma was measured periodically and the results of the LC-MS data are shown in fig. 12. As can be seen from FIG. 12, total dexamethasone with a concentration of more than 20ng/mL can be detected at

days

14, 21 and 28, which indicates that SA-K-DEX nanocrystal can be slowly hydrolyzed and released in rat articular cavity, significantly prolongs the retention time of dexamethasone in rat body, and improves the treatment effect.

Example 26: synthesis of stearyl alcohol-tafluprost acetonide conjugate (SA-K-TAF)

TBS-TAF (0.1mmol, 1eq) and stearyl isopropenyl ether (0.6mmol) were placed in a Schlenk flask, and the atmosphere inside the replacement system was nitrogen. 2mL of tetrahydrofuran was added to dissolve the resulting solution, and dichloroacetic acid (0.2eq) was added to react at 25 ℃. The reaction was followed by TLC, and after completion of the reaction, 100. mu.L of triethylamine was added to quench the reaction. The solvent was spin-dried and purified on silica gel column to give a colorless oil.

This oil was dissolved in tetrahydrofuran, tetrabutylammonium fluoride (0.08mmol) was added, and the reaction was stirred at 25 ℃. After the reaction is completed, the solvent is dried by spinning, and then the mixture is purified by a silica gel column to obtain colorless oily substance SA-K-TAF, wherein the yield is 60%.¹H NMR (400MHz, chloroform-d): δ 7.35-7.27 (m,2H), 7.03-6.96 (m,1H),6.91(d, J ═ 9.7Hz,2H),6.09(m,1H), 5.88-5.70 (m,1H), 5.45-5.28 (m,2H),5.08–4.94(m,1H),4.32–4.13(m,3H),3.89(s,1H),3.42(m,2H),2.46–2.38(m,1H),2.32–2.13(m,4H),2.12–1.99(m,3H),1.95–1.82(m,1H),1.67(d,J＝7.6Hz,2H),1.56–1.46(m,2H),1.35(d,J＝6.6Hz,6H),1.25(s,32H),1.22(d,J＝6.3Hz,6H),0.88(t,J＝6.8Hz,3H).

example 27: synthesis of Cholesterol-Tafluprost acetonide conjugate (Chol-K-TAF)

TBS-TAF (0.1mmol) and cholesterol isopropenyl ether (0.6mmol, 1eq) (cholesterol isopropenyl ether reference: Dujardin, G., Rosssignol, S.,&brown, E. (1995), effective current-free preparation of vinyl and isopropyl ethers of basic secondary alcohols and alpha-hydroxyers. tetrahedron letters,36(10), 1653) 1656) was placed in a Schlenk flask and the gas in the displacement system was nitrogen. 2mL of tetrahydrofuran was added to dissolve the resulting solution, and dichloroacetic acid (1.0eq) was added to react at 25 ℃. The reaction was followed by TLC, and after completion of the reaction, 100. mu.L of triethylamine was added to quench the reaction. The solvent was spin-dried and purified on silica gel column to give a colorless oil. This oil was dissolved in tetrahydrofuran, tetrabutylammonium fluoride (0.08mmol) was added, and the reaction was stirred at 25 ℃. After the reaction is completed, the solvent is dried by spinning, and then the product is purified by a silica gel column to obtain a colorless oily substance Chol-K-TAF, wherein the yield is 65 percent.¹H NMR (400MHz, chloroform-d): δ 7.29(m,2H),6.99(t, J ═ 7.4Hz,1H),6.91(d, J ═ 8.8Hz,2H),6.09(m,1H),5.75(m,1H), 5.42-5.26 (m,3H),4.99(m,1H), 4.29-4.13 (m,3H),3.87(q, J ═ 5.2Hz,1H),3.51(m,1H), 2.45-2.39 (m,1H), 2.33-2.14 (m,6H), 2.08-1.92 (m,6H),1.81(d, J ═ 4.0Hz,4H), 1.76-1.69 (m,2H), 1.65-1.60 (m,2H),1.60 (m, 1.8H), 1.38(m, 1H), 1.9-1H, 1.8 (m,1H), 1.9-1.6H), 1.6H, 1.8 (m,1H), 1.6H, 1.

(d,J＝6.3Hz,6H),1.19–1.04(m,8H),0.99(s,3H),0.91(d,J＝6.5Hz,3H),0.86(m,6H),0.66(s,3H).

Ketal derivatives of prostaglandin analogs are prepared according to the methods of examples 26-27 starting with the above drugs.

Example 28: preparation of tafluprostone ketal prodrug nanoparticles

7mg of SA-K-TAF and 3mg of DSPE-PEG₂₀₀₀Dissolved in 1mL acetone and sonicated until the solution is clear. This acetone solution was slowly dropped into 10mL of pH 8.0PBS buffer (6.7mM) while stirring. Stirring at room temperature until acetone is completely volatilized, and filtering with 0.45 μm filter membrane to obtain SA-K-TAF/DSPE-PEG₂₀₀₀And (3) carrying out ultracentrifugation on the nanoparticle solution until the concentration of the prodrug in the solution is 1 mg/mL. The solution can be stored in a refrigerator at 4 ℃ and can be diluted to a specific concentration by using a PBS (6.7mM) buffer solution with the pH of 8.0 according to the requirement of intravenous injection amount when in use. As can be seen from FIG. 13, SA-K-TAF/DSPE-PEG was prepared₂₀₀₀The nano-particles are uniform and have the size of about 50 nanometers.

With reference to the above method, Chol-K-TAF nanoparticles were also prepared.

Example 29: effect of sub-conjunctival injection of Tafluprostone ketal prodrug nanoparticles on Normal Rabbit intraocular pressure

The experimental animals were New Zealand rabbits (body weight 3.5-4.5 kg) with normal intraocular pressure, and each group had 2 animals. Anaesthetizing New Zealand rabbit, dripping proparacaine hydrochloride eye drops into left eye, and mixing 100 μ L SA-K-TAF/DSPE-PEG with 27 # needle sterile injector₂₀₀₀The nanoparticle solution (equivalent to 10. mu.g of tafluprost after hydrolysis) was injected under the conjunctiva. Intraocular pressure was measured continuously with a small animal tonometer for one week at fixed times. Wherein animals as control group were not administered.

The test results are shown in fig. 14. As shown in FIG. 14, SA-K-TAF/DSPE-PEG₂₀₀₀The intraocular pressure of the rabbit can be effectively reduced within seven days after the nanoparticle subconjunctival injection, and the long-acting effect is expected to be realized.

Example 30: synthesis of Oleyl alcohol-paliperidone acetonide conjugate (Oleyl-K-PAL)

Adding paliperidone (0.1mmol, 1eq), dichloromethane (1.5 mL) and dichloroacetic acid (0.1mol) into a reaction flask under the protection of nitrogen, stirring at room temperature for 30min, adding Oleyl isopropenyl ether (0.6mmol), adding 400 uL triethylamine to the paliperidone after TLC monitoring the reaction of the raw material, stopping the reaction, concentrating, and separating by silica gel column chromatography to obtain a white solid product, namely Oleyl-K-7-PAL, with the yield of 83%.¹H NMR (400MHz, chloroform-d): δ 7.66(dd, J ═ 8.7,5.1Hz,1H),7.18(dd, J ═ 8.5,2.1Hz,1H),6.99(td, J ═ 8.9,2.2Hz,1H),5.33 to 5.24(m,2H),4.72(t, J ═ 4.1Hz,1H),4.04(dt, J ═ 13.4,6.4Hz,1H),3.91(dt, J ═ 14.3,6.3Hz,1H),3.46(dt, J ═ 8.7,6.9Hz,1H),3.33(dt, J ═ 8.9,7.1Hz,1H),3.17 to 3.09(m,2H),3.08 to 2.97, 2.7, 1H, 3.7.7.7.1H, 1H, 3.17 to 3.09(m,2H), 3.7.7.7 (m-2H), 6.7, 6.7.7.7, 6.7.7H, 6.6.6H, 1H, 6H, 6.7H, 6.7.7H, 3H) in that respect

Example 31: Oleyl-K-PAL/DSPE-PEG₂₀₀₀Preparation of nanoparticles

Accurately weighing 7mg of Oleyl-K-PAL and 3mg of DSPE-mPEG₂₀₀₀Dissolving the two solutions in 350 μ L of anhydrous ethanol, slowly dropping the ethanol solution into PBS buffer (6.7mM) with pH 8.0 under stirring, stabilizing for 5min, removing ethanol with rotary evaporator, filtering with sterile filter membrane, and measuring drug concentration with HPLC.

Example 32: intramuscular injection of Oleyl-K-PAL/DSPE-PEG₂₀₀₀Determination of paliperidone concentration in blood after nanoparticles

Injection of Oleyl-K-PAL/DSPE-PEG in the hind leg muscle of rats₂₀₀₀Nanoparticles (dose: 20mg/kg) were bled at the indicated time points. The samples were processed according to the standard procedures for LC-MS testing of blood samples, and the concentration of paliperidone in the blood was determined by LC-MS.

The test results are shown in fig. 15. As shown in FIG. 15, Oleyl-K-PAL/DSPE-PEG₂₀₀₀The concentration of paliperidone in blood can be measured within 28 days after intramuscular injection of the nanoparticles, and the long-acting effect is expected to be realized.

Example 33: synthesis of stearyl alcohol-dihydroartemisinin acetonide conjugate (SA-K-DHA)

Dihydroartemisinin (0.3mmol, 1eq) and stearyl alcohol isopropenyl ether (1.8mmol) were placed in a Schlenk flask with nitrogen as the gas in the displacement system. After dissolving in 4mL of tetrahydrofuran, pyridine p-toluene sulfonic acid (PPTS) (0.05eq) was added and reacted at 25 ℃. The reaction was followed by TLC, and after completion of the reaction, 100. mu.L of triethylamine was added to quench the reaction. After the solvent is dried by spinning, the solvent is purified by a silica gel column to obtain white powder SA-K-DHA with the yield of 60 percent.¹H NMR (400MHz, chloroform-d): δ 5.45(s,1H),5.23(d, J ═ 3.5Hz,1H),3.42(t, J ═ 7.0Hz,2H), 2.72-2.62 (m,1H),2.37(m,1H), 2.07-1.97 (m,1H), 1.90-1.77 (m,2H),1.76(d, J ═ 4.1Hz,1H),1.63(dd, J ═ 13.2,3.4Hz,1H), 1.57-1.45 (m,7H),1.41(s,3H),1.36(m,4H),1.26(s,32H),0.96(d, J ═ 6.3, 3H),0.88(dd, 7.1, 6.6, 6H).

Example 34: SA-K-DHA/DSPE-PEG₂₀₀₀Preparation of nanoparticles

Accurately weighing 7mg of SA-K-DHA and 3mg of DSPE-mPEG₂₀₀₀Dissolving the two solutions in 350 μ L of anhydrous ethanol, slowly dropping the ethanol solution into PBS buffer (6.7mM) with pH 8.0 under stirring, stabilizing for 5min, removing ethanol with rotary evaporator, filtering with sterile filter membrane, and measuring drug concentration with HPLC.

Example 35: intramuscular injection of SA-K-DHA/DSPE-PEG₂₀₀₀Determination of dihydroartemisinin concentration in blood after nanoparticles

Injection of SA-K-DHA/DSPE-PEG into the hind leg muscle of rats₂₀₀₀Nanoparticles (dose: 20mg/kg) were bled at the indicated time points. The samples were processed according to the standard procedures for LC-MS testing of blood samples, and the concentration of dihydroartemisinin in blood was determined by LC-MS.

The test results are shown in fig. 16. As shown in FIG. 16, SA-K-DHA/DSPE-PEG₂₀₀₀The concentration of dihydroartemisinin in blood can be measured within 28 days after the nanoparticle is injected into muscles, and long-acting effect is expected to be realized.

Example 36: synthesis of stearyl alcohol-5 '-gemcitabine acetonide conjugate (SA-K-5' -GEM)

0.44mmol of Fmoc-protected amino-gemcitabine (0.44mmol) was added to the reaction flask under nitrogen (Fmoc-protected amino-gemcitabine reference: Peter G.M.Wuts. (2014.) Greene's Protective Groups in Organic Synthesis, John Wiley&Sons, Inc. (prepared by the method of Fifth Edition), stearyl isopropenyl ether (1.32mmol), 4mL of tetrahydrofuran, and finally dichloroacetic acid (0.1eq) as a catalyst were added and reacted at 30 ℃. After TLC monitoring of the reaction, 10mL of dichloromethane and 0.2mL of DBU (1, 8-diazabicycloundecen-7-ene) were added. After the Fmoc deprotection in the TLC monitoring reaction was completed, 100mL of ethyl acetate was added for dilution, the mixture was washed with saturated sodium bicarbonate solution and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain a white waxy solid SA-K-5' -GEM with a yield of 77%.¹H NMR (400MHz, chloroform-d): δ 7.81(d, J ═ 7.5Hz,1H),6.30(t, J ═ 7.1Hz,1H),5.85(d, J ═ 7.5Hz,1H),4.06(d, J ═ 8.4Hz,1H),3.82(d, J ═ 11.0Hz,1H),3.68(d, J ═ 11.5,3.3Hz,1H),3.37(t, J ═ 6.8Hz,2H), 1.57-1.44 (m,2H),1.37(s,6H), 1.32-1.21 (m,30H),0.87(t, J ═ 6.6Hz,3H).

Example 37: synthesis of stearyl alcohol-5 '-zidovudine acetonide conjugate (SA-K-5' -AZT)

0.75mmol (1eq) of zidovudine, stearyl alcohol isopropenyl ether (2.25mmol) and 5mL of tetrahydrofuran were added to a reaction flask under nitrogen protection, and finally dichloroacetic acid (0.1eq) was added to react at 30 ℃. After TLC monitoring reaction, 0.5mL triethylamine is added to stop reaction, and white waxy solid SA-K-5' -AZT is obtained after concentration and silica gel column chromatography separation, and the yield is 78%.¹H NMR (400MHz, chloroform-d): δ 7.52(d, J ═ 1.3Hz,1H),6.23(t, J ═ 6.2Hz,1H), 4.27-4.19 (m,1H), 4.04-3.98 (m,1H),3.73(dd, J ═ 11.0,2.8Hz,1H),3.62(dd, J ═ 11.1,2.8Hz,1H), 3.45-3.32 (m,2H), 2.46-2.38 (m,1H), 2.34-2.25 (m,1H),1.91(d,J＝1.2Hz,3H),1.62–1.48(m,2H),1.40(d,J＝3.9Hz,6H),1.33–1.20(m,30H),0.86(t,3H)。

the acetonide prodrug was prepared according to the methods of examples 36-37 starting from the following drug molecules trifluridine, idoxuridine, floxuridine, capecitabine, lamivudine, emtricitabine, zalcitabine, cytarabine, ganciclovir, acyclovir, and doxorubicin, etc.

Example 38: cytotoxicity assays for gemcitabine conjugate prodrugs

A2780 or a549 cells were seeded into 96-well plates at 3000/well density the day before the experiment. On the day of the experiment, SA-K-5' -GEM was dissolved in DMSO, the drug was diluted to different concentrations with medium and added to 96-well plates (n ═ 4). After the cells were incubated with the pro-drugs prepared in the above examples for an additional 3 days in the incubator, the medium was changed to 100. mu.L of fresh medium + 10. mu.L of CCK-8 solution. After further incubation for 2h, OD 450nm was measured and IC calculated according to CCK-8 instructions₅₀。

The test results are shown in fig. 17. As can be seen from FIG. 17, stearyl alcohol-5 '-gemcitabine acetonide conjugate (SA-K-5' -GEM) has stronger antitumor activity than gemcitabine.

Example 39: SA-K-5' -AZT/DSPE-PEG₂₀₀₀Preparation of nanoparticles

Accurately weighing 7mg of SA-K-5' -AZT and 3mg of DSPE-mPEG₂₀₀₀Dissolving the two solutions in 350 μ L of anhydrous ethanol, slowly dropping the ethanol solution into PBS buffer (6.7mM) with pH 8.0 under stirring, stabilizing for 5min, removing ethanol with rotary evaporator, filtering with sterile filter membrane, and measuring drug concentration with HPLC.

Example 40: intramuscular injection of SA-K-5' -AZT/DSPE-PEG₂₀₀₀Determination of zidovudine concentration in blood after nanoparticles

Injection of SA-K-5' in the hind leg muscle of ratsAZT/DSPE-PEG₂₀₀₀Nanoparticles (dose: 20mg/kg) were bled at the indicated time points. The samples were processed according to the standard procedures for LC-MS testing of blood samples, and the concentration of zidovudine in blood was determined by LC-MS. The test results are shown in fig. 18. As can be seen in FIG. 18, SA-K-DHA/DSPE-PEG₂₀₀₀The concentration of zidovudine in blood can be measured within 28 days after intramuscular injection of the nanoparticles, and the long-acting effect is expected to be realized.

Example 41: polyethylene glycol monomethyl ether-testosterone acetonide conjugate (mPEG)₂₀₀₀-K-TES) Synthesis

0.75mmol of polyethylene glycol monomethyl ether (molecular weight is 2000g/mol) isopropyl ether and 0.04mmol of p-toluenesulfonic acid are dissolved in 20mL of tetrahydrofuran, 0.1mmol of testosterone is added into the system, and the reaction is carried out at room temperature. After the reaction was complete, quench with 400. mu.L of TEA. The system was spun dry and purified to give 102mg of a white solid in 46% yield.¹H NMR (400MHz, chloroform-d)₃)：δ5.72(s,1H),3.82(t,J＝4.8Hz,1H),3.64(s,193H),3.49–3.44(m,1H),3.38(s,3H),2.47–2.23(m,4H),2.06–1.90(m,2H),1.84(d,J＝15.8Hz,2H),1.73–1.35(m,7H),1.32(s,6H),1.19(s,3H),1.14–0.86(m,5H),0.79(s,3H)。

Ketal prodrugs of the testosterone, estradiol, ethinyl estradiol and lineestrol sex hormones listed above were prepared according to the method of example 41.

Example 42: intravenous injection mPEG of rat tail₂₀₀₀Determination of the concentration of testosterone in the blood after-K-TES

mPEG injection in tail vein of rat₂₀₀₀K-TES (dose: 1mg/kg) and blood was taken at the indicated time points. The samples were processed according to the standard procedures for LC-MS testing of blood samples, and the concentration of testosterone in the blood was determined by LC-MS.

The test results are shown in fig. 19. ByFIG. 19 shows that mPEG₂₀₀₀After intravenous injection, the-K-TES can be effectively converted into testosterone in blood, is a good water-soluble testosterone prodrug and can quickly take effect after injection.

Example 43: synthesis of beta-Glucose-K-etoposide acetonide conjugate (beta-Glucose-K-ETP)

To a 10mL Schlenk flask were added etoposide (0.1mmol), β -2,3,4, 6-tetrabenzyl-D-glucopyranose isopropenyl ether (0.6mmol), and dichloromethane (3 mL). After stirring well, a solution of dichloroacetic acid in dichloromethane (0.02mmol) was added to the system. The reaction was stirred at 30 ℃ for 5 hours. After the reaction was completed, triethylamine was added to quench the reaction. The system was desolventized and chromatographed on silica gel column to give the intermediate, white solid, 41 mg. After adding the intermediate (41mg,0.4mmol) to a 15mL hydrogenation tube and adding extra dry ethanol (1mL) and stirring well, 5% palladium hydroxide on carbon (100mg) was added to the system, with water previously removed with extra dry ethanol. Screwing down the hydrogenation reaction kettle, and filling 4 atmospheres to react for 96 hours. After the kettle is removed, the system is filtered to remove palladium carbon, the filtrate is desolventized, and a compound beta-Glucose-K-ETP is obtained by silica gel column chromatography, white solid is 26mg, yield: 90 percent.¹H NMR(CDCl₃):δ6.86(s,1H),6.51(s,1H),6.23(s,2H),5.96(s,2H),4.94(d,J＝3.2Hz,1H),4.71–4.65(m,2H),4.58(d,J＝5.3Hz,1H),4.53(d,J＝7.6Hz,1H),4.46–4.39(m,1H),4.24–4.14(m,2H),3.84–3.77(m,3H),3.74(s,6H),3.55–3.44(m,5H),3.41–3.33(m,4H),3.23–3.13(m,2H),2.90–2.80(m,1H),1.50(d,J＝2.8Hz,6H),1.33(d,J＝4.9Hz,3H).

Example 44: in vivo antitumor evaluation of beta-glucose-K-etoposide prodrug

The right armpit of the nude mouse is implanted with 5 multiplied by 10 under the skin⁶And a549 cells. The tumor volume is about 100mm³In time, tumor-bearing mice were randomly grouped into groups. The formulation for the treatment control group was self-made in the laboratory according to the formulation of the commercially available formulation Toposar. After injection (dose: 15mg/kg etoposide), the tumor growth size and the weight of each group of nude mice are recorded, and a tumor growth curve chart and a weight change rate chart are drawn. Tumor volume calculation formula: v_tumor＝(length×width²)/2。

The test result of the beta-Glucose-K-ETP treatment is shown in figure 20, and as can be seen from figure 20, the beta-Glucose-K-ETP injection has good safety and drug effect, good anti-tumor activity and better effect than the commercial etoposide injection.

Example 45: synthesis of stearyl alcohol-NLG 919 acetonide conjugate (SA-K-NLG919)

1.0mmol of NLG919, stearyl isopropenyl ether (6.0mmol) and 20mL of dichloromethane were added to a reaction flask under nitrogen protection to dissolve, and dichloroacetic acid (0.7eq) was added to the mixture to react at 30 ℃ for 2 hours. After TLC monitoring reaction, 0.2mL triethylamine is added to stop reaction, and after concentration, silica gel column chromatography separation is carried out to obtain mucoid SA-K-NLG919 with the yield of 20%.¹H NMR (400MHz, chloroform-d): δ 7.74(s,1H), 7.56-7.49 (m,1H),7.41(dd, J ═ 7.6,1.0Hz,1H),7.34(dd, J ═ 8.7,6.3Hz,1H),7.22(td, J ═ 7.5,1.2Hz,1H),7.17(d, J ═ 2.8Hz,1H),5.23(t, J ═ 5.9Hz,1H),3.92(td, J ═ 6.4,3.2Hz,1H), 3.49-3.31 (m,2H), 2.26-2.08 (m,3H), 1.88-1.51 (m,6H), 1.49-1.13 (m,42H), 0.90-0.84 (m,3H).

Example 46: synthesis of stearyl alcohol-Halofuginone acetonide conjugate (SA-K-Halofuginone)

Fmoc-protected amino-halofuginone (0.08mmol) (ref: Peter G.M.Wuts. (2014.) Greene's Protective Groups in Organic Synthesis, John Wiley&Sons, Inc (Fifth Edition)), stearyl alcohol isopropenyl ether(0.48mmol), 4mL of tetrahydrofuran was dissolved, and pyridinium p-toluenesulfonate (0.05eq) was added to react at 30 ℃ for 10 min. After completion of the TLC monitoring reaction, 10mL of dichloromethane and 0.08mL of DBU (1, 8-diazabicycloundecen-7-ene) were added, and after 5min at room temperature, 100mL of ethyl acetate was added for dilution, and the mixture was washed with saturated sodium bicarbonate solution and brine, and the organic phase was dried over anhydrous sodium sulfate. After concentration, white solid SA-K-Halofuginone is obtained by column chromatography separation, and the yield is 70 percent.¹H NMR (400MHz, chloroform-d): δ 8.32(s,1H),8.04(s,1H),7.85(s,1H),4.80(q,2H), 3.53-3.33 (m,3H),3.09(dd, J ═ 16.1,4.0Hz,1H), 3.00-2.87 (m,2H),2.22(d, J ═ 12.1Hz,1H), 1.77-1.66 (m,1H), 1.59-1.45 (m,3H),1.36(d, J ═ 9.6Hz,6H), 1.33-1.20 (m,32H),0.88(t,3H).

Example 47: synthesis of stearyl alcohol-combretastatin acetonide conjugate (SA-K-CA4)

A15 ml Schlenk tube was taken, and 0.1mmol of the starting material combretastatin, 2.0ml of methylene chloride, and 0.6mmol of stearyl isopropenyl ether were added thereto, and 0.005mmol of 1, 2-dichloroacetic acid was added thereto with stirring. Reacting at room temperature, detecting by a dot plate, adding 300 mu l of triethylamine to terminate the reaction after the reaction is complete, directly carrying out spin drying, and carrying out silica gel column chromatography separation to obtain a white waxy product SA-K-CA4 with the yield of 73%.¹H NMR (400MHz, chloroform-d): δ 7.16(s,1H),6.93(d, J ═ 8.4Hz,1H),6.74(d, J ═ 8.4Hz,1H),6.47(d, J ═ 7.4Hz,3H),6.39(d, J ═ 12.1Hz,1H),3.80(s,3H),3.78(s,3H),3.66(s,6H),3.54(t, J ═ 6.8Hz,2H),1.40(s,8H),1.25(d, J ═ 7.0Hz,37H),0.86(t, J ═ 6.7Hz,3H).

Example 48: synthesis of stearyl alcohol-7-ethyl-10-hydroxycamptothecin acetonide conjugate (SA-K-SN-38)

Taking a 15ml Schlenk tube, adding raw materials of 0.1mmol of 7-ethyl-10-hydroxycamptothecin, 2.0ml of dichloromethane and stearyl alcohol0.6mmol of isopropenyl ether, to which 0.005mmol of 1, 2-dichloroacetic acid was added with stirring. Reacting at room temperature, detecting by a dot plate, adding 300 mu l of triethylamine to the reaction solution after the reaction is completed, stopping the reaction, directly carrying out spin-drying, and carrying out silica gel column chromatography separation to obtain white solid SA-K-SN-38 with the yield of 76%.¹H NMR (400MHz, chloroform-d): δ 8.14(d, J ═ 9.2Hz,1H),7.86(d, J ═ 2.4Hz,1H),7.68(s,1H),7.57(dd, J ═ 9.2,2.4Hz,1H),5.73(d, J ═ 16.2Hz,1H), 5.36-5.26 (m,1H),5.24(s,2H),3.66(dt, J ═ 19.9,6.8Hz,4H),3.13(q, J ═ 7.7Hz,2H), 1.98-1.82 (m,2H), 1.71-1.49 (m,10H), 1.45-1.15 (m,58H),0.87(t, J ═ 6.6Hz,3H).

Example 49: synthesis of stearyl alcohol-rapamycin acetonide conjugate (SA-K-Rap)

A15 ml Schlenk tube was taken, and 0.1mmol of rapamycin, 2.0ml of methylene chloride and 0.6mmol of stearyl isopropenyl ether as a raw material were added thereto, and 0.005mmol of 1, 2-dichloroacetic acid was added thereto with stirring. Reacting at room temperature, detecting by a dot plate, adding 300 mu l of triethylamine to terminate the reaction after the reaction is completed, directly carrying out spin-drying, and carrying out silica gel column chromatography separation to obtain white solid SA-K-Rap (mixture) with the yield of 46%.¹H NMR (400MHz, chloroform-d): δ 6.36(qd, J ═ 14.9,10.1Hz,2H), 6.26-6.06 (m,2H),5.94(dd, J ═ 30.5,10.6Hz,1H), 5.62-5.38 (m,2H),5.29(d, J ═ 5.8Hz,1H), 5.21-5.08 (m,1H), 4.35-4.14 (m,2H), 3.93-3.79 (m,2H), 3.75-3.65 (m,2H), 3.54-3.45 (m,4H),3.42(s,3H),3.39(d, J ═ 3.9Hz,2H),3.34(s,3H),3.15(s,3H), 2.97-2.82 (m,2H),2.73(dd, 3.73, J ═ 3.9Hz,2H), 6.7, 6.15 (m,6H), 1.9H, 6.18H), 7, 6.15 (m,1H), 6.9H, 1H, 6H, 1H, 7 (1H), 3.9H, 6H, 7 (1H), 3.15 (1H), 3.9H, 6H, 1H, 6H), 3.9H, 1H, 6H, 1H, 6H, 1H), j ═ 12.5,6.8Hz,11H).

Example 50: synthesis of stearyl alcohol-fulvestrant acetonide conjugate (SA-K-FUL)

A15 ml Schlenk tube was taken, and 0.1mmol of fulvestrant protected with TBS, 2.0ml of methylene chloride and 0.6mmol of stearyl isopropenyl ether were added thereto, and 0.005mmol of 1, 2-dichloroacetic acid was added thereto with stirring. Reacting at room temperature, detecting by using a dot plate, adding 300 mu l of triethylamine after the reaction is completed, stopping, directly spin-drying, then adding 3ml of tetrahydrofuran, adding 1.0mmol of tetra-n-butylammonium fluoride, after the reaction is completed, adding 10ml of water, extracting by using ethyl acetate, collecting an organic phase, washing by using saturated salt water, using anhydrous sodium sulfate, filtering, concentrating, and separating by using silica gel column chromatography to obtain white solid SA-K-FUL with the yield of two steps of 61%.¹H NMR (400MHz, chloroform-d): δ 7.15(d, J ═ 8.6Hz,1H),6.91(dd, J ═ 8.5,2.6Hz,1H),6.79(d, J ═ 2.5Hz,1H),3.74(t, J ═ 8.5Hz,1H),3.62(t, J ═ 6.9Hz,2H),2.87(dd, J ═ 16.8,5.4Hz,1H), 2.78-2.61 (m,5H), 2.37-2.23 (m,4H), 2.21-2.11 (m,3H),1.91(dt, J ═ 12.5,3.1Hz,1H),1.76(m,4H),1.61(m,5H),1.48(d, J ═ 2.9, 9H),1.26(s,47, 0.47H), t, 6.7H, 3H, 7H).

Example 51: synthesis of stearyl alcohol-abiraterone acetonide conjugate (SA-K-ABI)

Taking a 15ml Schlenk tube, adding 0.1mmol of abiraterone, 2.0ml of dichloromethane and 0.6mmol of n-tetradecyloxy isopropenyl ether which are raw materials into the Schlenk tube, adding 0.015mmol of 1, 2-dichloroacetic acid into the Schlenk tube under stirring, reacting at room temperature, adding 300 mu l of triethylamine into the Schlenk tube after the point plate detection reaction is completed, stopping direct spin-drying, and performing silica gel column chromatography separation to obtain a colorless oily product SA-K-ABI with the yield of 83%.¹H NMR (400MHz, chloroform-d): δ 8.60(s,1H),8.43(d, J ═ 4.8Hz,1H),7.62(dt, J ═ 8.0,2.0Hz,1H),7.19(dd, J ═ 7.9,4.8Hz,1H),5.97(t, J ═ 2.7Hz,1H),5.33(t, J ═ 5.0Hz,1H), 3.65-3.55 (m,1H),3.43(t, J ═ 7.1Hz,2H), 2.36-2.15 (m,3H),2.04(ddd, J ═ 16.1,8.4,4.1Hz,3H), 1.88-1.40 (m,13H), 1.39-1.15 (m,28H), 1.14-0.97 (m,12H), t, 6.85H (t, 6H).

Example 52: synthesis of polyethylene glycol monomethyl ether-simvastatin acetonide conjugate (mPEG1000-K-SIM)

Simvastatin (0.1mmol) and mPEG1000 isopropenyloxy ether (0.6mmol) were placed in a Schlenk flask, dissolved by adding 2mL of tetrahydrofuran, followed by dichloroacetic acid (0.2eq) and reacted at 25 ℃. The reaction was followed by TLC, and after completion of the reaction, 100. mu.L of triethylamine was added to quench the reaction. After the solvent was spin-dried, the column was purified to obtain a white solid with a yield of 68%.¹H NMR (400MHz, chloroform-d): δ 5.99(d, J ═ 9.7Hz,1H),5.78(m,1H),5.51(s,1H),5.37(d, J ═ 3.1Hz,1H), 4.67-4.56 (m,1H), δ 5.82-5.75 (m,1H), 3.85-3.79 (m,1H), 3.69-3.63 (m,90H),3.55(d, J ═ 2.0Hz,4H),3.38(s,3H),2.60(d, J ═ 25.7Hz,1H), 2.53-2.32 (m,3H), 2.29-2.19 (m,1H), 2.05-1.84 (m,6H), 1.73-1.65 (m,2H), 1.59-1.50 (m,3H),1.35 (m,6H), 1.15-6H), 1.9-6H (m, 1H).

Referring to the procedure of example 52, a acetonide prodrug thereof was prepared using lovastatin as a starting material.

TABLE 1 hydrolysis half-life and half inhibitory concentration of 2' -Taxol acetonide prodrug on MDA-MB-231 cells

TABLE 2 hydrolysis half-life and semi-inhibitory concentration of 2' -Taxol ketal prodrug on MDA-MB-231 cells

TABLE 3.7 hydrolysis half-life of paclitaxel acetonide prodrug and half inhibitory concentration on MDA-MB-231 cells

R-OH	t_1/2(pH 5.0，min)	IC₅₀(nM)
			Methanol	31	18
Cyclohexanol	3	13
			Oleyl alcohol	11	800
2-hexadecanol	4	356
			Polyethylene glycol monomethyl ether (molecular weight 164)	53	32
Polyethylene glycol monomethyl ether (molecular weight 2000)	297	32

TABLE 4 dexamethasone acetonide prodrug hydrolysis half-life and solubility in dichloromethane

R-OH	t_1/2(pH 5.0，h)	Solubility (mM)
			Stearyl alcohol	1.1	178
Oleyl alcohol	1.2	229
			2-octanol	0.7	53
2-hexadecanol	0.6	148
			2-nonadecanol	0.6	185
Menthol	0.3	85
			Polyethylene glycol monomethyl ether (molecular weight 1000)	0.3	112

The inventors found that, similarly to the test results of the above-mentioned compounds, the solubility of the prodrug prepared via the above-mentioned examples can be significantly favorably improved relative to each starting drug, and the pharmacological activity thereof is also significantly superior to that of the commercially available starting drug, thereby making an unexpected significant improvement in improvement of the therapeutic effect and the kind of formulation.

Illustrative embodiments of the invention are described herein. It should be understood, however, that the scope of the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound represented by the following formula (I), a racemate, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

R₄selected from substituents other than hydrogen;

Each R_bIndependently selected from F, Cl, Br, I, OH, SH, CN, N₃Or unsubstituted or optionally substituted by one or more R_cSubstituted of the following groups: c_1-40Alkyl radical, C_1-40Alkoxy radical, C_2-40Alkenyl radical, C_2-40Alkynyl, C_3-20Cycloalkyl radical, C_3-20Cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C_6-20Aryl radical, C_6-20Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxyGroup NR_dR_e、-CONR_dR_e、-C(O)YR_f、-Y(O)CR_f、-YP(O)(OM₁)(OM₂)、-YS(O)₂OM₃；

M₁、M₂、M₃independently of one another, selected from H, or unsubstituted or optionally substituted by one or more R_aSubstituted C_1-40An alkyl group;

2. The compound, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1, wherein D is selected from the group consisting of pharmaceutical compounds containing at least one hydroxyl group, from which a hydrogen atom on one of the hydroxyl groups is removed, and which may be selected from the group consisting of, but not limited to:

taxanes (e.g., paclitaxel, docetaxel, cabazitaxel);

glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone, testosterone, estradiol, ethinyl estradiol, lynestrenone);

paliperidone;

artemisinin analogs (e.g., dihydroartemisinin);

antibiotics (doxorubicin);

naltrexone;

rotigotine;

rapamycin, tacrolimus;

treprostinil;

amshufaxin;

etoposide; halofuginone;

combretastatin;

SN-38；

rapamycin;

fulvestrant;

abiraterone;

statins (simvastatin and lovastatin);

analgesic drugs (buprenorphine, oxymorphone, nalbuphine, levorphanol, hydromorphone, butorphanol); IDO inhibitor NLG 919; and

terpenoids are used as medicaments.

3. A compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein:

R₁can be selected from unsubstituted or optionally substituted by one, two or more R_aSubstituted of the following groups: c_1-6Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-10Aryl, 5-6 membered heteroaryl;

preferably, R₃Selected from unsubstituted or optionally substituted by one, two or more R_cSubstituted C_1-6An alkyl group;

preferably, R₄Is selected from C_1-40Alkyl radical, C_2-40Alkenyl radical, C_3-20Cycloalkyl radical, C_3-20Cycloalkenyl group, 3-20-membered heterocyclic group, C_6-20Aryl, 5-20 membered heteroaryl, -C_1-40alkyl-OC (O) -PEG, -C_1-40alkyl-OC (O) -PEG-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) -PDLLA-PEG, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) -PDLLA-PEG-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) - (O-C)_1-40alkyl-CO)_p-(O-C_1-40Alkyl radical)_q-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40alkyl-C (O) - (O-C)_1-40alkyl-CO)_p-(O-C_1-40Alkyl radical)_q-H、-C_1-40alkyl-OCO₂-(C_1-40alkyl-O)_r-C_1-40Alkyl, -C_1-40alkyl-OCO₂-(C_1-40alkyl-O)_r-H、-C_3-20cycloalkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-O-C_1-40Alkyl, -C_3-20cycloalkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-OH、-C_1-40alkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-O-C_1-40Alkyl, -C_1-40alkyl-OC (O) -C_1-40Alkyl- [ O-C_1-40alkyl-C (O)]_p-(O-C_1-40Alkyl radical)_q-OH、-C_3-20cycloalkyl-O- (C)_1-40alkyl-O)_r-C_1-40Alkyl, -C_3-20cycloalkyl-O- (C)_1-40alkyl-O)_r-H、-(C_1-40alkyl-O)_r-C_1-40Alkyl, - (C)_1-40alkyl-O)_r-H、-C_3-20cycloalkyl-C_1-40Alkyl, -hydroxy or C_1-40An alkyl hydroxy-substituted 3-20 membered heterocyclic group; wherein the subscripts of the repeating units, such as p, q, r, are the same or different from each other and are independently selected from a number of from 1 to 500, such as a number of from 1 to 200, for example an integer of from 1 to 200;

or, -O-R₄Selected from ethylene glycol and ethylene glycolGlycol monoalkyl ethers (e.g. polyethylene glycol mono C)_1-40Alkyl ethers), polyethylene glycol (PEG) or polyethylene glycol monoalkyl ethers (e.g. polyethylene glycol mono C)_1-40Alkyl ether) to remove a hydrogen atom from a hydroxyl group at the end of polyethylene glycol;

the R is_a、R_b、R_cIdentical or different, independently of one another, from the group consisting of F, Cl, Br, I, OH, SH, CN, N₃、＝O、C₁-₂₀Alkyl radical, C_2-20Alkenyl radical, C_3-20A cycloalkyl group;

preferably, the molecular weight of the PEG and the molecular weight of the PDLLA are the same or different, and are independently selected from 100-5000.

4. A compound according to any one of claims 1 to 3, racemates, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

the R is₁Is selected from-CH₃、-Ph、-CH₂Br、-CH₂I、-CH₂N₃、-C₆H₁₃Or

Preferably, said R is₂Is selected from a substituent obtained by removing a hydrogen atom on one hydroxyl group of polyethylene glycol, or a substituent obtained by removing a hydrogen atom on one hydroxyl group of polyethylene glycol monoalkyl ether, or is selected from the following groups:

wherein

Is connected withA ligation site.

5. The compound, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is selected from the group consisting of:

6. a process for the preparation of a compound according to any one of claims 1 to 5, racemates, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, comprising reacting a compound of formula D-H with a compound of formula (I-1) to give a compound of formula (I):

wherein, D, R₁、R₂、R₃Independently of each other, have the definitions in any one of claims 1 to 5;

7. A compound represented by the following formula (I-1):

wherein R is₁、R₂、R_hIndependently of one another, have the definitions in claim 6.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-5, racemates, stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

9. The use of a compound according to any one of claims 1 to 5, racemates, stereoisomers, tautomers or pharmaceutically acceptable salts thereof in the prevention or treatment of disease or condition, said disease being a disease or condition which can be treated by said pharmaceutical compound containing at least one hydroxyl group, such as those that can reduce or alleviate signs or symptoms of a disease or condition upon administration of a taxane, glucocorticoid, prostaglandin analog, paliperidone, artemisinin analog, nucleoside analog, antibiotic, antiviral drug, naltrexone, rotigotine, rapamycin, tacrolimus, treprostinil, amsufamine, etoposide, halofugine, combretastatin, SN-38, rapamycin, fulvestrant, abiraterone, statin, analgesic, IDO inhibitor NLG919, or terpenoid.

10. The compound shown in the formula (I), racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the application of the pharmaceutical composition in improving the physical property, the chemical property or the pharmaceutical property of the pharmaceutical compound containing at least one hydroxyl.