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CN-122029214-A - Phospholipid drug conjugate and preparation method and application thereof

CN122029214ACN 122029214 ACN122029214 ACN 122029214ACN-122029214-A

Abstract

The invention discloses a phospholipid drug conjugate, a preparation method and application thereof, wherein the phospholipid drug conjugate is shown in a formula (I) or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. The phospholipid drug conjugate has good water solubility, can form a nano structure by self-assembly, and has excellent tumor inhibiting effect.

Inventors

  • ZHANG FUYAO
  • CAI SHENGYUN
  • CHEN XIANJIE

Assignees

  • 上海弼领生物技术有限公司

Dates

Publication Date
20260512
Application Date
20240927
Priority Date
20230927

Claims (18)

  1. A phospholipid drug conjugate shown as a formula (I), Or a stereoisomer of said phospholipid drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Wherein: X 0 is O or S; x 1 is O, S or NR 1a ; X 2 is O, S or NR 2a ; L 1 、L 2 is absent or a linking unit; M 0 is OR 0a 、SR 0b 、NR 0c R 0d OR T 0 -(L-D) n ; K 1 is P 1 or Y 1 is a branching center, P 1 is a drug generation regulating part unit, and M 1 is T 1 -(L-D) n ; Y 2 is a branching center; M 2 is absent or T 2 -(L-D) n ; At least one of M 0 、M 1 and M 2 contains an L-D fragment; Q 2a is T 2a -R 1 or absent, Q 2b is T 2b -R 2 or absent, and at least one of Q 2a and Q 2b is present; t 0 、T 1 、T 2 are each independently selected from the absence or extension; T 2a 、T 2b is absent or a linking unit; l 3 -L s ,L 3 is an environmentally-responsive linking unit selected from the group consisting of an enzyme-responsive linker, a pH-responsive linker, a light-responsive linker and a redox-responsive linker, L s being present or absent, when present, a self-releasing linking moiety; D is a bioactive molecule fragment, and when the conjugate contains a plurality of D, the D can be the same or different; R 1a and R 2a are each independently selected from hydrogen, C 1 ～C 10 alkyl, C 1 ～C 10 alkoxy, C 3 ～C 10 alkenyl, C 3 ～C 10 alkynyl, C 3 ～C 8 cycloalkyl, C 2 ～C 8 heterocycloalkyl, C 6 ～C 10 aryl, C 5 ～C 10 heteroaryl, or an amino protecting group; Each R 0a is independently selected from hydrogen, C 1 ～C 10 alkyl, C 1 ～C 10 alkoxy, C 3 ～C 10 alkenyl, C 3 ～C 10 alkynyl, C 3 ～C 8 cycloalkyl, C 2 ～C 8 heterocycloalkyl, C 6 ～C 10 aryl, C 5 ～C 10 heteroaryl, or hydroxy protecting group; R 0b is selected from hydrogen, C 1 ～C 10 alkyl, C 1 ～C 10 alkoxy, C 3 ～C 10 alkenyl, C 3 ～C 10 alkynyl, C 3 ～C 8 cycloalkyl, C 2 ～C 8 heterocycloalkyl, C 6 ～C 10 aryl, C 5 ～C 10 heteroaryl, or a sulfhydryl protecting group; r 0c and R 0d are each independently selected from hydrogen, C 1 ～C 10 alkyl, C 1 ～C 10 alkoxy, C 3 ～C 10 alkenyl, C 3 ～C 10 alkynyl, C 3 ～C 8 cycloalkyl, C 2 ～C 8 heterocycloalkyl, C 6 ～C 10 aryl, C 5 ～C 10 heteroaryl, or an amino protecting group; R 1 and R 2 are each independently selected from saturated or unsaturated C 1 ～C 50 alkyl, cholesterol, retinoid and tocopherols, said C 1 ～C 50 alkyl, cholesterol, retinoid and tocopherols optionally being substituted with one or more substituents selected from hydroxy, halogen, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl and 3-12 membered heterocycloalkyl, said C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl and 3-12 membered heterocycloalkyl optionally being substituted with one or more substituents selected from hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl N is an integer of 1 to 10, and when n is more than 1, L-D can be the same or different; Hydrogen attached to carbon in the compound of formula (I), wherein one or more hydrogen may be substituted with deuterium; Hydrogen linked to carbon in the compound of formula (I), wherein one or more hydrogen may be substituted with an optional substituent; phospholipid isomers include phosphine-chiral center compounds selected from the group consisting of: Or a chiral mixture thereof.
  2. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claim 1, wherein the phospholipid parent nucleus in formula (I) One or more of the following conditions are satisfied: (1) (2) (3) Wherein at least one of the atoms to which X 2 、X 1 、M 0 is attached to P is not an oxygen atom.
  3. The phospholipid drug conjugate according to claims 1-2, or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, wherein the phospholipid drug conjugate has a nanosize, preferably the nanosize is in the range of 1-500 nm, more preferably the average particle size is in the range of 5-100 nm.
  4. A phospholipid drug conjugate or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof according to claims 1-3, wherein one or more of the following conditions are met: (1) L 1 、L 2 is absent or present, and when present, L 1 、L 2 is each independently an alkane, a heterocycloalkyl, an aromatic hydrocarbon, a heterocycloalkyl, a substituted or unsubstituted amino acid, or a polypeptide made up of them, or a combination of them, wherein the functional linking moiety at the junction of each end of L 1 、L 2 is selected from: Wherein R La 、R Lb 、R Lc 、R Ld is each independently selected from hydroxy, C1-C5 alkyl, or C1-C5 alkoxy; R Le is hydrogen, hydroxy, C1-C5 alkyl or C1-C5 alkoxy; L 1a 、L 1b are each independently selected from O, NR Lf , S, S-S, Or directly attached (absent), R Lf is hydrogen or C1-C5 alkyl; (2) T 0 、T 1 、T 2 is each independently absent or present and when present, T 0 、T 1 、T 2 is each independently an alkane, a heterocycloalkyl, an aromatic hydrocarbon, a heterocycloalkyl, a substituted or unsubstituted amino acid, or a polypeptide made up of them, or a combination of them, wherein the functional groups at the junction of each end of T 0 、T 1 、T 2 are selected from: Wherein R La 、R Lb 、R Lc 、R Ld is each independently selected from hydroxy, C1-C5 alkyl, or C1-C5 alkoxy; R Le is hydrogen, hydroxy, C1-C5 alkyl or C1-C5 alkoxy; L 1a 、L 1b are each independently selected from O, NR Lf , S, S-S, Or directly attached (absent), R Lf is hydrogen or C1-C5 alkyl; (3) T 2a 、T 2b is absent or present, and when present, T 2a 、T 2b is each independently an alkane, a heterocycloalkyl, an aromatic hydrocarbon, a heterocycloalkyl, a substituted or unsubstituted amino acid, or a polypeptide made up of them, or a combination of them, wherein the functional groups at the junction of each end of T 2a 、T 2b are selected from: Wherein L 1a 、L 1b is each independently selected from O, NR Lf , S, S-S, Or directly attached (absent), R Lf is hydrogen or C1-C5 alkyl; (4) L 3 is selected from the group consisting of an enzyme-responsive linker, a pH-responsive linker, a light-responsive linker and a redox-responsive linker, preferably from the group consisting of an enzyme-responsive linker, a pH-responsive linker and a redox-responsive linker, more preferably an enzyme-responsive linker; (5) Y 1 、Y 2 is at least trifunctional branching center selected from trifunctional amino acids, polypeptides or the following structures: Wherein R y0 is selected from hydrogen, deuterium, halogen, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing primary, secondary, tertiary amine, hydroxyl, mercapto, carboxyl, ester, amide, boric acid, borate, phosphoric acid, sulfonic acid, sulfoxide, aldehyde, ketone functional groups; r y1 is selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, and C2-C8 heterocycloalkyl; R y2 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, C5-C10 heteroaryl, or a group containing primary, secondary, tertiary amine, hydroxyl, mercapto, carboxyl, ester, amide, boric acid, borate, phosphoric acid, sulfonic acid, sulfoxide, aldehyde, ketone functional groups; The A ring is C 6 ～C 20 aryl or C 5 ～C 20 heteroaryl, wherein hetero atoms in the C 5 ～C 20 heteroaryl are O, S or N, the number of the hetero atoms is one or more, and when the hetero atoms are a plurality of hetero atoms, the hetero atoms are the same or different; The E ring is C2-C8 heterocycloalkyl, wherein hetero atoms in the heterocycloalkyl are O, S or N, the number of the hetero atoms is one or more, and when the hetero atoms are a plurality of hetero atoms, the hetero atoms are the same or different; (6) P 1 is a drug-substituted regulatory moiety unit selected from polyethylene glycol, sugar, oligosaccharide and polysaccharides (such as hyaluronic acid, chondroitin sulfate, chitosan, heparin, tea polysaccharide, dextran, polysialic acid, chitosan, dextran, sodium alginate, cellulose, polysucrose, cyclodextrin), polymyosine, polyphosphoester, polyglycerol, polyvinylpyrrolidone, polyoxazoline, polyamino acid, polyacrylic acid residue, polymethacrylic acid residue, quaternary ammonium salt derivative, carboxyl group-containing derivative, sulfonic group-containing derivative, phosphoric group-containing derivative, zwitterionic derivative or zwitterionic polymer.
  5. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-4, wherein one or more of the following conditions are met: (1) When said L 3 is an enzyme-responsive linker, it is cleavable by one or more enzymes selected from the group consisting of secreted phospholipase A2, acid phosphatase, serum alkaline phosphatase, cytochrome P450, sulfatase, prostate-specific antigen, phospholipase A1, phospholipase A2, phospholipase B, phospholipase C, phospholipase D, neutrophil elastase, cysteine proteinase-3, cathepsin, matrix metalloproteinase, beta-glucuronidase, beta-galactosidase, nitroreductase, reduced coenzyme II, aminopeptidase N, carboxylesterase, diaphorase, histone deacetylase, asparaginase, urokinase-type plasminogen activator receptor, collagenase, preferably by one or more enzymes selected from the group consisting of cysteine proteinase-3, cathepsin, matrix metalloproteinase, elastase and beta-glucosidase; (2) When the L 3 is a pH responsive linker, it comprises one or more of hydrazone, imine, oxime, carboxylate, thioester, sulfate, sulfonate, orthoester, carbonate, carbamate, substituted carbamate, ketal, acetal, silyl ether, phosphate, borate, phosphoramide, or cis-aconitate groups; (3) When the L 3 is a light-responsive linker, it comprises one or more of o-nitrobenzene, coumarin, benzoin, BODIPY or cyanine groups; (4) When L 3 is a redox-responsive linker, it comprises one or more of thioketal, phenylboronate, phenylboronic acid, oxalate, vinyl ether, thio ether, amino acrylate, dithio, diseleno, 2, 4-dinitrobenzenesulfonate, 2-azidomethyl benzoate, 4-azidobenzyl, unsaturated acid ester, or azo phenyl group.
  6. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-5, wherein one or more of the following conditions are met: (1) When L 3 is an enzyme-responsive linker selected from the group consisting of short peptides consisting of 2-10 amino acid residues Val, D-Val, cit, phe, lys, leu, gly, ala, asn, asp, arg, pro, tyr, ile, his, ser, gln, glu, met, preferably 2-10 short peptides consisting of Val, cit, phe, lys, ala, leu, gly, asn, asp amino acids, preferably L 3 is selected from the following structures: (2) When present, L s is selected from the following structures: Preferably, L s is selected from the following structures: (3) When L 3 is a pH-responsive linker, it is selected from the following structures: Wherein pm=0 to 4, R p3 、R q1 is selected from H, substituted or unsubstituted C1-C10 alkyl; Preferably, L 3 is selected from the following structures: (4) When L 3 is a light responsive linker, it is selected from the following structures: (5) When L 3 is a redox-responsive linker, it comprises the following structure:
  7. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-4, wherein P1 is selected from the group consisting of: (1) The polyethylene glycol derivative residue is selected from the following structures: Wherein pa1 is selected from an integer of 5-250, pr1 is selected from an integer of 0-8, R p1 is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C3-C10 cycloalkyl, C3-C10 alkenyl, C3-C10 alkynyl or hydroxy protecting group; Preferably, pa1 is selected from an integer of 5 to 150, pr1 is selected from an integer of 0 to 8, and R p1 is hydrogen, C1-C10 alkyl or hydroxy protecting group; More preferably, pa1 is selected from an integer of 10 to 60, pr1 is selected from an integer of 1 to 2, and R p1 is a C1-C10 alkyl group; (2) The polymorphous acid derivative residue is selected from the following structures: Wherein pb1 is selected from an integer of 5 to 250, R p2 is selected from hydrogen, C1 to C10 alkyl, C1 to C10 alkoxy, C3 to C10 alkenyl, C3 to C10 alkynyl, C3 to C8 cycloalkyl, C2 to C8 heterocycloalkyl, C6 to C10 aryl, C5 to C10 heteroaryl OR an amino protecting group, R p3 is selected from OR p3a OR NR p3b R p3c , wherein R p3a is selected from hydrogen, C1 to C10 alkyl, C3 to C10 alkenyl, C3 to C10 alkynyl, C3 to C8 cycloalkyl, C2 to C8 heterocycloalkyl, C6 to C10 aryl OR C5 to C10 heteroaryl, R p3b 、R p3c is each independently selected from hydrogen, C1 to C10 alkyl, C1 to C10 alkoxy, C3 to C10 alkenyl, C3 to C10 alkynyl, C3 to C8 cycloalkyl, C2 to C8 heterocycloalkyl, C6 to C10 aryl, C5 to C10 heteroaryl OR a cyclic amino protecting group, R p3b is formed by a common connection with R42 and R57; preferably, pb1 is selected from integers of 5 to 150; (3) The quaternary ammonium salt derivative residue is selected from the following structures: Wherein pc1 is selected from integers of 0-10, and A - is selected from R p3 、R p4 、R p5 is each independently selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl or C2-C8 heterocycloalkyl; (4) Zwitterionic derivatives or zwitterionic polymers: Wherein, the Pd1 is an integer from 5 to 250; R p6 is selected from: pc1 and pe1 are selected from integers of 0-10, and A - is selected from R p3 、R p4 、R p5 is independently selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl or C2-C8 heterocycloalkyl, L p is an absent or linking unit selected from alkanes, heterocycloalkanes, aromatic hydrocarbons, heterocycloalkanes or a combination thereof; (5) Polysaccharide polymer: Wherein pf1, pf2, pg1, pg2, ph1, ph2, pi1, pi2 and m are selected from integers between 1 and 250, preferably between 1 and 50, for example between 1 and 5, between 4 and 24, or between 5 and 25.
  8. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-4, wherein the biologically active molecular fragment D is selected from the group consisting of: small molecule drugs, peptides, proteins, nucleic acids, carbohydrates, in particular anesthetics, ophthalmic drugs, central nervous system drugs, pain therapeutics, anti-arthritic drugs, anticonvulsants, antihistamines, antiulcer drugs, behavior correcting drugs, respiratory drugs, antispasmodics, muscle relaxants, anti-inflammatory drugs, appetite suppressants, growth promoters, hemostatic drugs, immunostimulants, immunomodulators, muscle relaxants, obesity therapeutics, osteoporosis drugs, tranquilizers, neuroleptic drugs, migraine-treating agents, muscle contractants, antiinfectives, antirheumatics, antimalarials, antiemetics, bronchodilators, antithrombotics, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxidants, antiasthmatics, diuretics, lipid modulators, antiandrogens, antiparasitics, anticoagulants, antitumor drugs, hypoglycemic drugs, nutritional agents, growth supplements, anti-enteritis agents, vaccines, antibodies, radionuclides, diagnostic agents and contrast agents; preferably selected from small molecule drugs or peptide drugs, more preferably from antineoplastic drugs, such as cytotoxic drugs, small molecule targeting drugs, hormones, biological response modifiers (e.g. immunomodulators), tumor helper drugs and nuclides.
  9. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-8, wherein the phospholipid drug conjugate has a structure according to formula (II): Wherein ,X 0 、X 1 、L 1 、P 1 、X 2 、L 2 、Y 2 、Q 2a 、Q 2b 、Y 2 、D is as described in claims 1-7; Wherein T 0 is present or absent and, when present, is selected from the group consisting of Wherein R 01 is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L 3 -L s ,L 3 is an environmental response type connecting unit, L s is present or absent and is a self-releasing connecting part when present, L 3 is directly connected with the P end when T 0 is absent, and the functional group at the connecting part is a nitrogen atom.
  10. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claim 9, wherein the phospholipid drug conjugate is a pharmaceutically acceptable salt or solvate thereof: X 0 、X 1 、X 2 is O; L 1 、L 2 is selected from the group consisting of absent or present, and when present, from: is a joint of the P end and the connecting part, Is P 1 or Y 2 terminal connection, l1a is selected from integers between 0 and 10, preferably from integers between 1 and 5; Y 2 is selected from the group consisting of, Preferably, Y 2 is selected from More preferably, Y 2 is selected from Is the joint of the L 2 ends; P 1 is selected from polyethylene glycol derivative residues with the number of repeating units pa1 and the end group R p1 , wherein pa1 is selected from integers between 10 and 60, preferably 15 to 50, such as 21,22,44 or 45, R p1 is C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl; Or P 1 is selected from the residues of polymorphous acid derivatives with the number of repeating units of pb1 and end groups of R p2 : Wherein pb1 is selected from an integer of 10 to 60, preferably an integer of 15 to 50, R p2 is selected from hydrogen, C1 to C10 alkyl, C1 to C10 alkoxy, C3 to C10 alkenyl, C3 to C10 alkynyl, C3 to C8 cycloalkyl, C2 to C8 heterocycloalkyl, C6 to C10 aryl, C5 to C10 heteroaryl or an amino protecting group; q 2a is T 2a -R 1 ,Q 2b and T 2b -R 2 ,T 2a 、T 2b are as defined in claim 1, R 1 、R 2 is selected from: wherein r1a and r1b are integers from 1 to 30.
  11. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-3 or8, wherein the biologically active molecular fragment D is selected from the group consisting of: (1) Cytotoxic drugs: a topoisomerase inhibitor camptothecin represented by formula (III): Wherein R x1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C1-C4 deuterated alkyl, C2-C4 alkynyl or C2-C4 alkenyl; R x2 、R x3 、R x4 and R x5 are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a mercapto group, a sulfone group, a sulfoxide group, a substituted or unsubstituted amino group, a nitro group, an alkynyl group, an alkenyl group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group, an alkylthio group, a heterocycloalkyl group, a deuterated alkyl group, an aryl group, or a heteroaryl group; Or R x1 and R x2 、R x2 and R x3 、R x3 and R x4 、R x4 and R x5 each form together with the carbon atom to which they are commonly attached a 5-7 membered cycloalkyl or heterocycloalkyl; X is selected from O or S; z is selected from OH or F; n1 is selected from 0 or 1; preferably selected from the following structures: Tubulin inhibitors, preferably selected from: Nucleic acid transcripts, preferably selected from: Acting on the DNA structural class of drugs, preferably selected from: Wherein R t1 is selected from hydrogen, alkyl, alkoxy, heteroalkyl, aryl, or heteroaryl; (2) Small molecule targeted drugs: EGFR inhibitors, such as gefitinib, erlotinib, icotinib, afatinib, or octtinib; HER2 inhibitors such as lapatinib, pyrroltinib, nerariib, or tocatinib; ALK inhibitors, for example: crizotinib, aprtinib, soritinib, lazotinib, or bragg tinib; MEK inhibitors such as trametinib, cabotinib or bimetanib; MET inhibitors such as cerutinib, voritinib, or carbamazepine; BRAF inhibitors such as sorafenib, dabrafenib, vemurafenib, vitamin Mo Feini or Kang Naifei; CDK4/6 inhibitors, e.g. palbociclib, rebabociclib, abbe cilib or PARP inhibitors such as olaparib, nilaparib, ruaparib or taprazoparb; BTK inhibitors, for example: acartinib, ibutenib, zebutinib zebutitin a nylon material; protease inhibitors, for example: bortezomib Carfilzomib or Isa zomib; mTOR inhibitors, such as temsirolimus Mo Sihuo everolimus; JAK inhibitors such as, for example, pontine, tofacitinib, wu Pati, baryttinib, dyotidine, piracettinib, faigue tinib, abystinib, panatinib, or deuterocoxetine; PI3K inhibitors such as eritiris, panitusiban, du Weili siban or Wu Pali si; VEGFR inhibitors, for example: sorafenib, axitinib, apatinib sunitinib, regorafenib, vandetanib sunitinib, regorafenib, and vandetanib (vandetanib); PDGFR, c-Kit inhibitors such as imatinib, nilotinib, or avatinib; BCL inhibitors such as valnemulin; HDAC inhibitors such as vorinostat, romidepsin, belinostat, panobinostat, or sidamamine; FLT3 inhibitors, such as midostaurin, gelitinib, or quezatinib; RET inhibitors such as, for example, celetinib or platirinib; KRAS inhibitors, such as sotoraciclovir or adaglazeb; IDH inhibitors such as exendin, ilotinib tablet or olanzapine; BCR-ABL inhibitors such as imatinib, dasatinib, nilotinib, pluratinib or ox Lei Bati; (3) Hormonal molecules, such as fulvestrant, abiraterone, prednisone, dexamethasone, bicalutamide, enzalutamide, tamoxifen, toremifene, letrozole, exemestane, goserelin, or leuprorelin; (4) Immunotherapeutic molecules, such as small molecule PD-L1 small molecule inhibitors, TLR agonists, interferon gene Stimulators (STING) agonists or indoleamine-2, 3-dioxygenase (IDO) inhibitors; (5) Other small molecules and polypeptides, such as lenalidomide, thalidomide, pomalidomide, ib Bei Du amine, octreotide, lanreotide, or pasireotide (Pasireotide).
  12. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-11, wherein L-D is selected from any one of the following conditions: (1) When the drug molecule D has the structure in which the site of attachment to L is The representation is: l is selected from the following structures, and is used for connecting part with medicine D The representation is: (2) When the drug molecule D has the structure in which the site of attachment to L is The representation is: l is selected from the following structures, and is used for connecting part with medicine D The representation is:
  13. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 9-12, wherein the phospholipid drug conjugate has a structure according to formula (IV): Wherein, the (1) Selected from the following structures: Wherein x and q are integers from 10 to 60, and pf1, pf2, ph1, ph2 and pi are integers from 1 to 100; (2) selected from the following structures: wherein y, z, y1, y2, z1, z2, z3 are integers selected from 1-20; (3) selected from the following structures:
  14. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claim 1, which satisfies one or more of the following conditions: (1) X 0 is O; (2) X 1 is O; (3) X 2 is O; (4) M 0 is-T 0 -(L-D) n , preferably-L-D, n preferably being 1; (5) T 0 is absent or present, when present T 0 is preferably selected from the group consisting of-NHCH 2 -and Wherein the C-terminal is preferably attached to L; (6) M 2 is absent; (7) L 1 is Preferably is Is connected with the X 1 and is connected with the X 1 , In connection with P 1 , l1a is selected from integers from 0 to 10, preferably from integers from 0 to 5, for example 1 or 2; (8) L 2 is Is connected with the X 1 and is connected with the X 1 , Is linked to P 1 , l1a is selected from integers from 0 to 10, preferably from integers from 0 to 5, for example 0 or 2; (9) K 1 is P 1 ,P 1 , which is a drug-substituted regulating part unit, selected from polyethylene glycol derivative residues, polymaleic acid derivative residues, quaternary ammonium salt derivative residues, zwitterionic derivatives or zwitterionic polymers, and polysaccharide polymers, preferably selected from polyethylene glycol derivative residues, polymaleic acid derivative residues, quaternary ammonium salt derivative residues and polysaccharide polymers, more preferably polyethylene glycol derivative residues, wherein the polyethylene glycol derivative residues are preferably Pa1 is selected from an integer of 5 to 250, preferably from an integer of 5 to 150 (e.g., 22,45 or 113), more preferably from an integer of 10 to 60 (e.g., 45), pr1 is selected from an integer of 0 to 8, preferably from an integer of 0 to 2, e.g., 0, R p1 is hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, C3-C10 cycloalkyl, C3-C10 alkenyl, C3-C10 alkynyl or hydroxy protecting group, preferably hydrogen, C1-C10 alkyl or hydroxy protecting group, more preferably C1-C10 alkyl, said polymaleic derivative residue is preferably Pb 1is selected from an integer of 5 to 250, preferably from an integer of 5 to 150, more preferably from an integer of 10 to 50, for example 28; R p2 is selected from hydrogen, C1 to C10 alkyl, C1 to C10 alkoxy, C3 to C10 alkenyl, C3 to C10 alkynyl, C3 to C8 cycloalkyl, C2 to C8 heterocycloalkyl, C6 to C10 aryl, C5 to C10 heteroaryl and an amine protecting group, preferably an amine protecting group, for example-C (O) CH 3 ; the quaternary ammonium salt derivative residue is preferably R p3 、R p4 、R p5 is each independently selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl or C2-C8 heterocycloalkyl, preferably C1-C10 alkyl, for example methyl, and the polysaccharide polymer is preferably selected from: Wherein pf1, pf2 and m are each independently selected from an integer between 1 and 250, preferably an integer between 1 and 50, for example an integer between 1 and 5, an integer between 4 and 24, or an integer between 5 and 25; (10) Y 2 is a branching center selected from Preferably selected from More preferably Is the joint of the L 2 ends; (11) T 2a 、T 2b is absent or present, and when present, T 2a 、T 2b are each independently selected from-C (O) -; (12) In R 1 and R 2 , the C 1 ～C 50 alkyl groups are each independently C 8 ～C 50 alkyl groups, more preferably C 10 ～C 30 alkyl groups, even more preferably C 10 ～C 20 alkyl groups, preferably R 1 and R 2 are each independently selected from Preferably selected from Wherein r1a and r1b are selected from integers of 1-30, said Optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl and 3-12 membered heterocycloalkyl, said C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl and 3-12 membered heterocycloalkyl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl; Or R 1 and R 2 are each independently preferably selected from More preferably selected from Wherein r1a and r1b are selected from integers of 1-30, a modified amino acid sequence Optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl and 3-12 membered heterocycloalkyl, said C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl and 3-12 membered heterocycloalkyl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl; (13) The bioactive molecule fragment D is preferably selected from the group consisting of cytotoxic drugs, small molecule targeting drugs, hormonal molecules, and other small molecules and polypeptides; The cytotoxic drugs are preferably selected from topoisomerase inhibitor camptothecins shown in the formula (III), tubulin inhibitors and drugs acting on DNA structures, more preferably selected from topoisomerase inhibitor camptothecins shown in the formula (III) and tubulin inhibitors, and the topoisomerase inhibitor camptothecins shown in the formula (III) are preferably selected from: The tubulin inhibitors are preferably The drugs acting on DNA structures are preferably selected from Wherein Rt1 is selected from the group consisting of hydrogen, alkyl, alkoxy, heteroalkyl, aryl, and heteroaryl; the small molecule targeting drug is preferably selected from ALK inhibitor, CDK4/6 inhibitor and PARP inhibitor, the ALK inhibitor is preferably crizotinib, and the CDK4/6 inhibitor is preferably selected from palbociclib and Parp inhibitor The PARP inhibitor is preferably nilaparib; the hormonal molecule is preferably fulvestrant; The other small molecule and polypeptide is preferably octreotide.
  15. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claim 1, which satisfies one or more of the following conditions: (1) R 1 and R 2 are each independently selected from Preferably selected from Or R 1 and R 2 are each independently preferably selected from More preferably (2) Q 2a and Q 2b are each independently selected from Preferably selected from Or Q 2a and Q 2b are each independently preferably selected from More preferably selected from (3) D is selected from the following structures: (4) L is selected from the following structures (for the connection part with D Representation): When L is When T 0 is-NHCH 2 -, wherein the C-terminal is attached to L, when L is In this case, T 0 is preferably Wherein the C-terminus is linked to L, and T 0 is preferably absent when L is other fragments.
  16. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claim 1, which satisfies one or more of the following conditions: (1) selected from the following structures: (2) selected from the following structures: (3) selected from the following structures:
  17. The phospholipid drug conjugate or stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-16, wherein the phospholipid drug conjugate is selected from the group consisting of the following structures:
  18. The use of a phospholipid drug conjugate or a stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof according to claims 1-17, or a pharmaceutical composition for the prevention, alleviation and/or treatment of abnormal cell proliferation, infections (e.g. viral infections such as HIV, HBV, etc.), inflammatory diseases (e.g. rheumatoid arthritis, etc.), autoimmune diseases (e.g. psoriasis, lupus erythematosus, diabetes, etc.), cardiovascular diseases (e.g. stroke, myocardial infarction, atherosclerosis, etc.), ocular diseases or neurodegenerative diseases (e.g. alzheimer's disease, parkinson's disease, etc.), wherein the abnormal cell proliferation disease may be cancer; the cancer preferably includes breast cancer, ovarian cancer, brain cancer, prostate cancer, melanin cancer, nasopharyngeal cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer (e.g., colon cancer, rectal cancer, etc.), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, undifferentiated carcinoma, etc.), kidney cancer, skin cancer, neuroblastoma, sarcoma, liposarcoma, osteochondral tumor, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor (e.g., cervical cancer, endometrial cancer, etc.), head and neck tumor (e.g., laryngeal cancer, pharyngeal cancer, tongue cancer, etc.), multiple myeloma, malignant lymphoma (e.g., reticulocyte sarcoma, hedge lymphosarcoma, hodgkin's lymphoma, mantle cell lymphoma, etc.), polycythemia vera, leukemia (e.g., acute granulocytic leukemia, chronic granulocytic leukemia, etc.), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, etc.), thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorionic epithelial cancer, or pediatric tumor (e.g., neuroblastoma, embryonic testicular cancer, retinoblastoma, etc.).

Description

Phospholipid drug conjugate and preparation method and application thereof The present application claims priority from China patent application 2023112617069 with application date 2023/9/27. The present application incorporates the entirety of the above-mentioned chinese patent application. Technical Field The invention belongs to the field of drug delivery, and in particular relates to a phospholipid drug conjugate, a preparation method and application thereof. Background Cancer morbidity and mortality have increased year by year, and have become a major public health problem threatening the health of humans. In recent years, despite the tremendous effort and great progress made in cancer, the therapeutic outcome remains limited. Among the three methods of cancer treatment (surgery, chemotherapy, radiation therapy), chemotherapy plays a central role in the treatment of a variety of tumors. However, contemporary chemotherapy drugs are administered primarily intravenously, and there are several limitations, including uncontrolled distribution of the drug in the tissue to produce cytotoxicity to normal cells, poor drug permeability, poor retention of passive diffusion, frequent administration may induce drug resistance, thus exhibiting too narrow a therapeutic window, poor drug safety, all due to poor delivery of the drug in the body. In order to solve these obstacles, various coping strategies have been formulated. The method comprises (1) physically packaging drug molecules by using nano carrier, improving drug properties, improving solubility of insoluble drug, enhancing enrichment of drug in focus tissue, improving bioavailability of drug, and reducing toxicity. However, nano-drugs packaged with physical interactions have poor in vivo stability, lack of active targeting, and affect delivery and release efficiency in vivo. (2) Polymer drug conjugate the polymer drug conjugate can be used for drug delivery by means of coupling similar prodrug through compound bond, can greatly improve solubility of drug, slowly release active drug component, has long-circulating pharmacokinetics characteristic, but its inherent defects still exist, including complicated synthetic procedure, difficult control of drug loading, large molecular weight, poor film permeability, no active targeting, and potential systemic toxicity, and these defects further limit its clinical development. Compared with the traditional polymer prodrug, nano-carrier and the like, the small molecular lipid (such as phospholipid, fatty acid, cholesterol, glyceride and the like) has rich sources, has the advantages of no toxicity, good biocompatibility, biodegradability and the like, and is an ideal choice for designing drug conjugates and nano-carriers. The invention provides a novel phospholipid conjugate, which can be self-assembled into nano particles by connecting a response type connector with a drug, improves the stability of nano drugs in vivo, and can release drug molecules through response of focus environment, thereby achieving good therapeutic effect. Disclosure of Invention The invention aims to overcome the defect of insufficient drug conjugates in the prior art. Therefore, the invention provides a phospholipid drug conjugate, and a preparation method and application thereof. The phospholipid drug conjugate has one or more of the following advantages of (1) excellent anti-tumor effect, (2) effective release of bioactive molecules/drugs, (3) nano size and (4) good water solubility. The invention solves the technical problems by the following technical scheme: The invention provides a drug conjugate which is shown in a formula (I), has nanometer size and contains a responsive linker phospholipid, Or a stereoisomer of said phospholipid drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, Wherein: X 0 is O or S; x 1 is O, S or NR 1a; X 2 is O, S or NR 2a; L 1、L2 is absent or a linking unit; M 0 is OR 0a、SR0b、NR0cR0d OR T 0-(L-D)n; K 1 is P 1 or Y 1 is a branching center, P 1 is a drug generation regulating part unit, and M 1 is T 1-(L-D)n; Y 2 is a branching center; M 2 is absent or T 2-(L-D)n; At least one of M 0、M1 and M 2 contains an L-D fragment; Q 2a is T 2a-R1 or absent, Q 2b is T 2b-R2 or absent, and at least one of Q 2a and Q 2b is present; t 0、T1、T2 are each independently selected from the absence or extension; T 2a、T2b is absent or a linking unit; L 3-Ls,L3 is an environmentally responsive linking unit, L s is present or absent, when present, a self-releasing linking moiety; D is a bioactive molecule fragment, and when the conjugate contains a plurality of D, the D can be the same or different; R 1a and R 2a are each independently selected from hydrogen, C 1～C10 alkyl, C 1～C10 alkoxy, C 3～C10 alkenyl, C 3～C10 alkynyl, C 3～C8 cycloalkyl, C 2～C8 heterocycloalkyl, C 6～C10 aryl, C 5～C10 heteroaryl, or an amino protecting group; Each R 0a is independently selecte