CN117986269A - Camptothecin derivative, and preparation method and application thereof - Google Patents
Camptothecin derivative, and preparation method and application thereof Download PDFInfo
- Publication number
- CN117986269A CN117986269A CN202410077258.5A CN202410077258A CN117986269A CN 117986269 A CN117986269 A CN 117986269A CN 202410077258 A CN202410077258 A CN 202410077258A CN 117986269 A CN117986269 A CN 117986269A
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- substituted acyl
- reactant
- formula
- nitro
- compound shown
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- 125000002252 acyl group Chemical group 0.000 claims abstract description 130
- 239000000376 reactant Substances 0.000 claims abstract description 105
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 61
- 238000006467 substitution reaction Methods 0.000 claims abstract description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- -1 alpha-hydroxyacetyl Chemical group 0.000 claims description 57
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 238000006722 reduction reaction Methods 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 14
- 239000000611 antibody drug conjugate Substances 0.000 claims description 14
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical group O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 13
- 239000003223 protective agent Substances 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- 229910017604 nitric acid Inorganic materials 0.000 claims description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 11
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical group OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 claims description 9
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 5
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- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 3
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 36
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
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Abstract
The invention relates to the technical field of pharmaceutical chemistry, and discloses a camptothecine derivative, a preparation method and application thereof. The derivative is a compound shown in a formula (I) and/or pharmaceutically acceptable salt thereof, wherein R 1 is selected from at least one of H, -NO 2、-NH2, -OH and halogen; r 2 is selected from at least one of H, acyl and substituted acyl, and R 1 and R 2 are not H at the same time. The preparation method of the camptothecin derivative comprises the following steps: carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III); wherein the reactant is a reactant containing nitro and/or a reactant containing substituted acyl; ra is nitro and hydrogen; rb is selected from at least one of acyl, substituted acyl and hydrogen. The camptothecine derivative has higher tumor cell inhibition activity and better safety.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a camptothecin derivative, a preparation method thereof and application of the compound in preparation of antibody drug conjugates.
Background
The main function of DNA topoisomerase is to help the DNA supercoiled structure unwind and promote the transcription and replication of DNA chain. Inhibition of topoisomerase activity causes accumulation of large amounts of broken DNA within tumor cells, inducing tumor cell death. Topoisomerase is classified into topoisomerase I (Topo I) and topoisomerase II (Topo II). Camptothecin and derivatives thereof are important DNA topoisomerase I inhibitors, and camptothecin derivatives such as Li Tikang, topotecan and the like are clinically used for treating malignant tumors.
The camptothecine is obtained by separating camptotheca acuminata of Davidiaceae, has strong cytotoxicity, and has good therapeutic effect on malignant tumor such as digestive tract tumor (gastric cancer, colon cancer, rectal cancer), hepatocarcinoma, breast cancer, bladder cancer, leukemia, etc. The main disadvantages of camptothecins are their poor solubility and stability, their greater toxicity and their smaller safety window, thus limiting their clinical application.
One class of prodrugs is antibody-drug conjugates (Antibody drug conjugate, ADC), which can simultaneously increase the water solubility and therapeutic window of camptothecin derivatives through high targeting and water solubility of the antibodies and linkers to related antigens in tumor cells. If the linker is sufficiently stable, the ADC can become a slow release prodrug and also increase the therapeutic window. The camptothecin derivative Delutacon (Deruxtecan) and the ADC coupling prodrug formed by the coupling of SN38 and a plurality of antibodies are all high-quality solid tumor therapeutic drugs.
Another class of prodrugs are hypoxia-activated prodrugs (Hypoxia activated prodrugs, HAP), and mitomycin C as a prodrug relying on this activation mechanism can be used to treat gastric and pancreatic cancer. Tumor tissue is locally hypoxic due to vascular structure and metabolism that differ from normal tissue, an important mechanism by which tumors develop resistance to chemotherapy, immunotherapy, and radiation. Hypoxia upregulates various reductases, such as nitroreductases, and this tumor-specific environment can serve as an evoked mechanism for specific activation of chemotherapeutic drugs. Radiation therapy typically further up-regulates reductase and so HAP can be used as a sensitizer for radiation therapy. HAP is more convenient to use as a small molecule prodrug than ADC, and can penetrate the blood brain barrier to enter the center for treating brain tumor and brain metastasis tumor. HAP and its active metabolites can be used as a small molecule toxin to ADC molecules.
The known camptothecine derivative has lower cell proliferation inhibition activity, needs higher dosage/antibody ratio (DAR) as ADC toxin, is easy to cause the instability of the ADC, and leads to higher production cost, higher synthesis difficulty and lower safety window, so the camptothecine derivative with higher activity has great significance for the design and development of novel ADC.
Disclosure of Invention
The invention aims to solve the problems of narrow safety window and low activity of a camptothecin derivative in the prior art, and provides the camptothecin derivative, and a preparation method and application thereof. The camptothecin derivative provided by the invention has higher tumor cell inhibition activity and better safety, and has a larger safety window as ADC toxin.
In order to achieve the above object, the first aspect of the present invention provides a camptothecin derivative, which is a compound represented by formula (I):
Wherein R 1 is selected from at least one of H, -NO 2、-NH2, -OH and halogen; r 2 is selected from at least one of H, acyl and substituted acyl, and R 1 and R 2 are not H at the same time.
Preferably, the halogen is selected from at least one of F, cl and Br.
Preferably, R 1 is selected from at least one of H, -NO 2, and-NH 2, and R 2 is hydrogen or substituted acyl.
Preferably, the substituted acyl group is at least one of a hydroxy-substituted acyl group and/or an alkoxy-substituted acyl group.
Preferably, the hydroxy-substituted acyl group is an α -hydroxy-substituted acyl group; further alpha-hydroxy substituted acyl groups containing C1-C6 alkane, more preferably alpha-hydroxyacetyl; the alkoxy-substituted acyl group is a heterocyclic ring-containing alkoxy-substituted acyl group and/or a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group, more preferably a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group, and still more preferably a (1-methyl-2-nitro-1H-imidazol-5-yl) methoxyacyl group.
Preferably, the derivative is selected from:
at least one of them.
Further preferably, the derivative is selected from:
at least one of them.
In a second aspect, the present invention provides a process for preparing a camptothecin derivative, comprising the steps of:
Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a reactant containing nitro and/or a reactant containing substituted acyl; ra is nitro and hydrogen; rb is at least one selected from acyl, substituted acyl and hydrogen, preferably substituted acyl and hydrogen, ra and Rb are not H at the same time; or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV); or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
(3) Subjecting a compound represented by the formula (IV) to sandmeyer reaction; or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
(3) Carrying out a Buch-Hastey coupling reaction on a compound shown in a formula (IV);
Preferably, the compound of formula (II) is reacted with an amino protecting agent prior to the substitution reaction.
Further preferably, the amino protecting agent is selected from at least one of benzyl chloroformate, di-t-butyl dicarbonate, and 9-fluorenylmethyl chloroformate.
Preferably, the nitro-group-containing reactant is nitric acid.
Preferably, the substituted acyl group is a hydroxy substituted acyl group and/or an alkoxy substituted acyl group.
Preferably, the hydroxy-substituted acyl group is an α -hydroxy-substituted acyl group; further alpha-hydroxy substituted acyl groups containing C1-C6 alkane, more preferably alpha-hydroxyacetyl; the alkoxy-substituted acyl group is a heterocyclic ring-containing alkoxy-substituted acyl group and/or a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group, and more preferably a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group.
Further preferably, the reactant containing a substituted acyl group is selected from the group consisting of 2-glycolic acid, phenyl chloroformate and (1-methyl-2-nitro-1H-imidazol-5-yl) methyl chloroformate.
Preferably, in step (2), the reduction reaction includes a contact reaction of the compound represented by formula (III) and a reducing agent.
Further preferably, the reducing agent is tetrahydroxydiboron and/or sodium borohydride.
Preferably, when the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group, the substitution reaction includes:
Carrying out substitution reaction on a compound shown in a formula (II) and a reactant containing nitro to obtain a compound shown in a formula (V); then carrying out substitution reaction on the compound shown in the formula (V) and a reactant containing substituted acyl;
further preferably, when the reactant is a nitro group-containing reactant, the substitution reaction conditions are at least: inert gas protection, wherein the temperature is-4-0deg.C, and the time is 50-70min.
When the reactant is a substituted acyl group-containing reactant, the conditions of the substitution reaction are at least: the inert gas is used for protection, the temperature is 25-30 ℃, and the time is 120-130min.
The conditions of the reduction reaction at least satisfy: inert gas protection is carried out, the temperature is 20-25 ℃, and the time is 4-10min.
In a third aspect, the invention provides the use of the derivative according to the first aspect and the derivative prepared by the method according to the second aspect in the preparation of an anti-tumour medicament.
Preferably, the anti-tumor drug is an antibody-drug conjugate.
Further preferably, the tumor is selected from at least one of colon cancer, stomach cancer, breast cancer and lung cancer.
In a fourth aspect, the present invention provides an antibody-drug conjugate in which the derivative of the first aspect and/or the derivative prepared by the method of the second aspect is linked to and/or directly conjugated to an antibody via a linker.
Through the technical scheme, the camptothecin derivative provided by the invention has higher tumor cell inhibition activity, has huge clinical use value, and can further expand the safety window of ADC drugs as ADC toxin. The difference between the activity before and after the activation as the prodrug is large, the normal tissues are not damaged before the activation, the activity can be exerted only after the activation in tumor tissues, and the prodrug has higher tumor cell inhibition activity and better safety.
Preferably, the camptothecin derivative prodrug activated by nitroreductase has a low activity, does not harm normal tissues before activation, and has a high activity only after activation of tumor tissues. The camptothecine derivative with larger activity difference before and after activation has great clinical application value. The camptothecin derivative can improve the treatment window and the solubility at the same time and improve the drug property by introducing water-soluble groups or preparing prodrugs.
Drawings
The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate the invention and together with the description serve to explain, without limitation, the invention. In the drawings:
FIG. 1 is a hydrogen spectrum of compound 1 produced in example 1;
FIG. 2 is a hydrogen spectrum of compound 2 produced in example 2;
FIG. 3 is a hydrogen spectrum of compound 3 prepared in example 3;
FIG. 4 is a hydrogen spectrum of compound 4 produced in example 4;
FIG. 5 is a hydrogen spectrum of compound 5 produced in example 5.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
In a first aspect, the present invention provides a camptothecin derivative, which is a compound represented by formula (I):
Wherein R 1 is selected from at least one of H, -NO 2、-NH2, -OH and halogen; r 2 is selected from at least one of H, acyl and substituted acyl, and R 1 and R 2 are not H at the same time.
The inventor finds that the camptothecin derivative with the structure shown in the formula (I) has higher cancer cell inhibition activity and better safety in the research process of the camptothecin derivative, can inhibit the growth of tumor cells, and has a larger safety window as ADC toxin.
According to the present invention, "acceptable" means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
According to the present invention, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound, and that is relatively non-toxic, e.g., that does not cause an undesired biological effect or interact in a deleterious manner with any of the components of the subject to which it is administered.
According to the present invention, a "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered, and does not diminish the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.
According to the present invention, the compound represented by the formula (I) and pharmaceutically acceptable salts thereof can be formulated into various preparations which contain the compound of the present invention or pharmaceutically acceptable salts thereof in a safe and effective amount range and pharmaceutically acceptable excipients or carriers.
According to the invention, pharmaceutically acceptable salts also include the corresponding solvent-added or crystalline forms thereof, especially solvates or various crystalline forms. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water during crystallization or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (I) may be conveniently prepared or formed in accordance with the methods of the invention.
According to the present invention, the hydrate of the solvate of the compound represented by formula (I) is prepared by recrystallization from a mixed solvent of water/organic solvents, including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods of preparation provided herein, solvated forms are considered to correspond to unsolvated forms.
According to the present invention, the compounds of formula (I) may be prepared in various forms including, but not limited to, amorphous, powder and nanoparticle forms. The compound represented by the formula (I) may be in a single crystal form or in a polycrystalline form. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different influencing factors include recrystallization solvent, crystallization rate and storage temperature may cause single crystalline form dominant polymorphic compounds.
According to the invention, the compounds of formula (I) may have chiral centers and/or chiral axes and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and as single diastereomers and cis-trans isomers. Each chiral center or chiral axis will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The invention discloses a compound shown in a formula (I), which comprises all isomeric forms corresponding to the compound.
According to the invention, the compounds may contain an unnatural proportion of an atomic isotope on one or more of the atoms constituting the compound. For example, compounds such as deuterium (2 H), tritium (3 H), and C-14 (14 C) can be labeled with radioisotopes. For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In the present invention, the use of "or" and "means" and/or "unless otherwise indicated.
According to the invention, the halogen is selected from at least one of F, cl and Br; the inventors found that when R 1 is F, cl and Br, the corresponding compounds have anti-tumor activity.
According to the invention, when R 1 is selected from at least one of H, -NO 2 and-NH 2, and R 2 is hydrogen or substituted acyl, the corresponding compounds have better anti-tumor activity. The inventor unexpectedly found that the activity of the camptothecin derivative prodrug containing the nitro group is lower, but the camptothecin derivative containing the amino group after being activated by nitroreductase has higher activity, and the camptothecin derivative with larger difference between the activity before and after the activation has great clinical use value. When the substituted acyl is at least one of hydroxy substituted acyl and/or alkoxy substituted acyl, the camptothecine derivative has better activity.
According to the invention, when the hydroxy-substituted acyl is alpha-hydroxy-substituted acyl, the side chain of the derivative contains an-OH group which is convenient to connect, and the derivative has good cell activity and is suitable for being used as a small molecule toxin of ADC. Further preferably, when the α -hydroxy-substituted acyl group is an α -hydroxy-substituted acyl group containing a C1-C6 alkane, at least one of an α -hydroxy-substituted acyl group containing a C1-C6 linear alkane, an α -hydroxy-substituted acyl group containing a C1-C6 branched alkane, and an α -hydroxy-substituted acyl group containing a cycloalkyl group may be employed, and the α -hydroxy group containing a C1-C6 linear alkane, a C1-C6 branched alkane, or a cycloalkyl group may optimize the patentability and inhibitory activity of the camptothecin derivative while retaining the tumor cell inhibitory activity of the camptothecin derivative; more preferably, when the alpha-hydroxy substituted acyl is alpha-hydroxy acetyl, the camptothecine derivative has higher tumor cell inhibition activity and better safety, and has a larger safety window as ADC toxin.
According to the invention, the alkoxy substituted acyl is an alkoxy substituted acyl containing heterocycle and/or an alkoxy substituted acyl containing nitro substituted imidazole ring, and the inventor finds that when the alkoxy substituted acyl is an alkoxy substituted acyl containing heterocycle and/or an alkoxy substituted acyl containing nitro substituted imidazole ring, the alkoxy substituted acyl can be self-eliminated under the action of reductase to generate the camptothecin derivative with better tumor cell inhibition activity. Further preferably, the alkoxy substituted acyl is alkoxy substituted acyl containing nitro substituted imidazole ring, and the inventor finds that the nitro of the imidazole ring enters into tumor tissue and is reduced into amino under the catalysis of nitroreductase to form an unstable intermediate, and then the intermediate is subjected to self-elimination reaction to generate a metabolite with better activity, so that the metabolite has better prodrug property and better tumor cell inhibition activity. More preferably, the alkoxy substituted acyl is a camptothecine derivative of (1-methyl-2-nitro-1H-imidazol-5-yl) methoxyacyl, and the metabolite irinotecan with better activity is generated through self-elimination reaction, so that the camptothecine derivative has better prodrug property and better safety, and has a larger safety window as ADC toxin.
According to the invention, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.
According to the present invention, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.
According to the present invention, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1,2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5] undecyl, 1-oxa-8-azaspiro [4.5] decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl, 4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridinyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridinyl, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butanamide, glutarimide, imidazolone, hydantoin, dipentadienyl, phthalimide, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxo, thiomorpholinyl, S-thiomorpholinyl, 3-thiomorpholinyl, pyrrolyl, thiomorpholinyl, and the like.
According to the invention, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from the group consisting of-OCH 3、-OCF3、-CHF2O、-CF3CH2 O, -i-PrO-n-PrO, -i-BuO, -n-BuO or-t-BuO.
According to the invention, said derivative is selected from:
At least one of them. The inventors found that the compound having the above-described steric configuration has tumor cell inhibitory activity.
Preferably, the derivative is selected from:
At least one of the drugs has higher tumor cell inhibition activity and huge clinical use value, and can further expand the safety window of ADC drugs as ADC toxin.
According to the invention, using solid wedge-shaped keysAnd wedge dotted bond/>Representing the absolute configuration of a stereogenic center, using straight solid keys/>And straight dotted bond/>Representing the relative configuration of the three-dimensional center by wavy linesRepresenting wedge solid bond/>Or wedge dotted bond/>Or by wavy lines/>Representing straight solid line bond/>Or straight dotted bond/>Unless otherwise stated, use/>Represents a single bond or a double bond.
In a second aspect, the present invention provides a process for preparing a camptothecin derivative, comprising the steps of:
Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a reactant containing nitro and/or a reactant containing substituted acyl; ra is nitro and hydrogen; rb is at least one selected from acyl, substituted acyl and hydrogen, preferably substituted acyl and hydrogen, ra and Rb are not H at the same time; or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV); or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
(3) Subjecting a compound represented by the formula (IV) to sandmeyer reaction; or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
(3) Carrying out a Buch-Hastey coupling reaction on a compound shown in a formula (IV);
/>
The compound shown in the formula (I) can be prepared by adopting the preparation method, has higher tumor cell inhibition activity, has huge clinical use value, can further expand the safety window of ADC drugs as ADC toxin, and has simple and easy preparation process.
According to the present invention, a compound represented by the formula (II) is reacted with an amino protecting agent before the substitution reaction; the amino group is protected to avoid substitution of the amino group in the compound shown in the formula (II) in the substitution process. Preferably, the amino protecting agent is selected from at least one of benzyl chloroformate, di-tert-butyl dicarbonate and 9-fluorenylmethyl chloroformate, and the corresponding amino protecting agent may be selected according to a substituent group and reaction conditions. The amino protecting agent can also adopt other derivatives of carbobenzoxy, t-butyloxycarbonyl and fluorenylmethoxycarbonyl groups of the same type according to different reaction conditions, or other amino protecting agents with the same effect, such as carbomethoxy, allyloxycarbonyl or trityl derivatives. The inventors have found that methoxycarbonyl groups can also be introduced using methoxycarbonyl chloride, allylchloroformate introduced allyloxycarbonyl groups, or trityl ethers introduced trityl protected amino groups. The amino protecting agent can be deprotected by catalytic hydrogenolysis, acidolysis and cleavage, na/NH 3 (liquid) reduction, lewis acid and other conditions according to different protecting groups. Deprotection may be performed according to conditions for removing the amino protecting agent after completion of the substitution reaction, and then the corresponding substituent group is introduced to the amino group. The compound shown in the formula (II) and the reactant can be subjected to substitution reaction, then other groups are introduced for reaction, and if the compound has a reactive group competing with the group introduced later, the corresponding protective agent can be selected for protection and then substitution reaction is performed.
According to the invention, the nitro-containing reactant is nitric acid; the nitric acid can be used alone or in combination with other reagents, and pure nitric acid, fuming nitric acid and concentrated nitric acid can be used as the reactants of the nitro group; the nitric acid or fuming nitric acid and the concentrated sulfuric acid can be mixed according to a certain proportion to be used as a reagent of the nitro group, wherein the proportion can be 1:3-6 or the mixing proportion is well known to the person skilled in the art; nitric acid acetic anhydride solution can also be used as a reagent of nitro, and the volume ratio of nitric acid to acetic anhydride is 1:50-70.
According to the invention, when the hydroxy-substituted acyl is alpha-hydroxy-substituted acyl, the side chain of the derivative contains an-OH group which is convenient to connect, and the derivative has good cell activity and is suitable for being used as a small molecule toxin of ADC. Further preferably, when the α -hydroxy-substituted acyl group is an α -hydroxy-substituted acyl group containing a C1-C6 alkane, at least one of an α -hydroxy-substituted acyl group containing a C1-C6 linear alkane, an α -hydroxy-substituted acyl group containing a C1-C6 branched alkane, and an α -hydroxy-substituted acyl group containing a cycloalkyl group may be used, and the α -hydroxy group containing a C1-C6 linear alkane, a C1-C6 branched alkane, or a cycloalkyl group may optimize the drug formation and the inhibitory activity of the camptothecin derivative while retaining the tumor cell inhibitory activity of the camptothecin derivative. The inventor finds that when the alkoxy substituted acyl is the alkoxy substituted acyl containing the heterocycle and/or the alkoxy substituted acyl containing the nitro substituted imidazole ring in the research process, the alkoxy substituted acyl can be self-eliminated under the action of reductase to generate the camptothecine derivative with better tumor cell inhibition activity. More preferably, when the reactant containing the substituted acyl is selected from 2-glycolic acid, phenyl chloroformate and methyl chloroformate (1-methyl-2-nitro-1H-imidazol-5-yl), the synthetic route is short, the reaction condition is simple, the operation is easy, and the synthesized compound has higher tumor cell inhibition activity and better safety and has a larger safety window as ADC toxin.
According to the present invention, in step (2), the reduction reaction comprises a contact reaction of a compound represented by formula (III) with a reducing agent; the reducing agent can be tetrahydroxy diboron, sodium borohydride, lithium aluminum hydride or hydrogen as the reducing agent, or can be selected according to substituent groups. The reduction reaction system can be further added with catalysts such as 4,4' -bipyridine, raney nickel (Raney Ni), palladium carbon, platinum carbon and the like, so that the reaction process is shortened. Preferably, the reducing agent is tetrahydroxydiboron and/or sodium borohydride, which provides better reduction. When the reducing agent is tetrahydroxydiboron, 4' -dipyridine can be added as a catalyst, so that the time of the reduction reaction is shortened.
According to the present invention, when the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group, the substitution reaction includes:
Carrying out substitution reaction on a compound shown in a formula (II) and a reactant containing nitro to obtain a compound shown in a formula (V); then carrying out substitution reaction on the compound shown in the formula (V) and a reactant containing substituted acyl;
The inventor finds that the substitution step can improve the yield, reduce the generation of byproducts, and has mild reaction conditions and easy operation.
According to the invention, when the reactant is a nitro group-containing reactant, the substitution reaction conditions are at least such that: the inert gas is selected from xenon, argon or nitrogen, the temperature is-4-0 ℃, specifically-4 ℃, -3 ℃, -2 ℃, -1 ℃ and 0 ℃ or any value between the two values, the time is 50-70min, specifically 50min, 55min, 60min, 65min and 70min or any value between the two values;
When the reactant is a substituted acyl group-containing reactant, the substitution reaction conditions are at least: the inert gas is selected from xenon, argon or nitrogen, the temperature is 25-30 ℃, specifically 25 ℃, 26 ℃, 27 ℃,28 ℃, 29 ℃, 30 ℃, or any value between the two values, the time is 120-130min, specifically 120min, 121min, 122min, 123min, 124min, 125min, 126min, 127min, 128min, 129min, 130min, or any value between the two values;
The conditions of the reduction reaction at least satisfy: the inert gas is selected from xenon, argon or nitrogen, the temperature is 20-25deg.C, specifically 20 deg.C, 21 deg.C, 22 deg.C, 23 deg.C, 24 deg.C, 25 deg.C, or any value between the two values, and the time is 4-10min, specifically 4min, 5min, 6min, 7min, 8min, 9min, 10min, or any value between the two values.
The reaction solvent used in the above preparation method may be Ethyl Acetate (EA), dimethylformamide (DMF), dichloromethane (DCM) and 1, 2-Dichloroethane (DCE) or reaction solvents well known to those skilled in the art; and after the reaction is finished, carrying out post-treatment to obtain the target compound. The post-treatment process comprises quenching, extraction, washing, purification and the like, wherein the quenching reaction can select water as a quenching agent, the dosage is about 100 ml to 500ml, and the dosage can be properly enlarged and reduced according to the amount of reactants; the extraction can be carried out by adopting solvents such as methanol, acetonitrile, tetrahydrofuran, ethyl acetate, methylene dichloride and the like, the dosage of the extractant is about 300-500ml, and the dosage can be properly enlarged and reduced according to the dosage of reactants; washing with saturated saline solution, saturated sodium carbonate aqueous solution, saturated sodium bicarbonate aqueous solution, etc., and drying with anhydrous sodium sulfate or anhydrous magnesium sulfate; the crude solution is obtained after a small amount of concentration under reduced pressure before purification, and then is purified by a silica gel column or directly by a preparative liquid chromatograph (pre-HPLC). Besides main reactants and reaction solvents, catalysts, reaction auxiliaries and the like can be added into the reaction system to accelerate the reaction process and reduce the generation of byproducts. As the catalyst and the reaction auxiliary agent, palladium carbon Pd/C, 4' -bipyridine, triethylamine (TEA or Et 3 N), N, N-Diisopropylethylamine (DIEA), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU) and the like can be used. During the reaction, a small amount of the reaction product may be withdrawn by syringe for Thin Layer Chromatography (TLC) analysis or liquid phase-mass spectrometry (LC-MS) analysis, and quenching may be performed after completion of the reaction.
As a specific embodiment of the present invention, a specific method of introducing halogen substituents: the amine groups are converted to halogens by sandmeyer reactions. Specifically, under the action of CuCN, the corresponding benzonitrile is obtained, and then the corresponding halogenated derivative can be obtained by treating with CuCl or CuBr. Or heating sodium iodide to obtain iodo derivative, treating silver tetrafluoroborate to obtain diazonium fluoroborate, and heating to obtain fluoro derivative.
As a specific embodiment of the present invention, a specific method of introducing a hydroxy substituent comprises: and (3) carrying out a Buch Wald-Hartmann coupling reaction on the halogen atom substituted compound and the amino compound to obtain a substituted amino compound, and finally carrying out deprotection and hydrochloric acid acidification to obtain a hydroxyl substituted compound with Ra as a hydroxyl. Or mixing the amino-substituted compound with nitrous acid, and obtaining the hydroxyl-substituted compound with Ra being hydroxyl through the sandmeyer reaction.
In addition to the above preparation methods, the method disclosed in the present invention can be combined with known techniques disclosed in the prior art. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein may vary depending on the different reactants. The starting materials for the synthesis of camptothecin derivatives are either synthesized or commercially available. The compounds of the present invention and other related compounds having different substituents can be synthesized using well known techniques and starting materials. The general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
The compounds of formula (I) may be prepared by the methods of general schemes 1-3, for example.
General reaction scheme 1 is as follows:
Using irinotecan (compound 1A) as a starting material, protecting amino by using an amino protecting agent di-tert-butyl dicarbonate ((Boc) 2 O) to obtain a compound 1B, then carrying out substitution reaction on the compound 1B and a reactant containing nitro, and using mixed acid of nitric acid (HNO 3) and acetic anhydride (Ac 2 O) as the reactant containing nitro to obtain a compound 1C; removing Boc protecting group of compound 1C amino group by trifluoroacetic acid (TFA) after the substitution reaction with the nitro-containing reactant is completed to obtain compound 1; carrying out substitution reaction on the compound 1 and a reactant containing substituted acyl, and adopting 2-hydroxyacetic acid as the reactant containing substituted acyl to obtain a compound 2; carrying out contact reaction on the compound 2 and a reducing agent, and adopting tetrahydroxy diboron as the reducing agent to obtain a compound 3;
General reaction scheme 2 is as follows:
the compound 1C directly contacts with a reducing agent tetrahydroxydiboron to obtain a compound 1D, and the Boc protecting group of the amino group of the compound 1D is removed by trifluoroacetic acid (TFA) to obtain a compound 4;
general reaction scheme 3 is as follows:
Using irinotecan (compound 1A) as a starting material, compound 1F was obtained by reaction with phenyl chloroformate, followed by coupling with (1-methyl-2-nitro-1H-imidazol-5-yl) methanol to obtain compound 5.
The nitro group of imidazole in the compound 5 enters into tumor tissues and is reduced into amino group under the catalysis of nitroreductase to form an unstable intermediate 5A, and an active substance irinotecan (compound 1A) is generated through self-elimination reaction;
the 8-nitro in the compound 2 enters into tumor tissues and is reduced into amino under the catalysis of nitroreductase to generate an active substance compound 3;
the 8-nitro in the compound 1 enters into tumor tissues and is reduced into amino under the catalysis of nitroreductase to generate an active substance compound 4;
Although the terms range and parameters used in defining the broader aspects of the invention are approximations, the relevant values for the embodiments herein are shown as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
In a third aspect, the present invention provides the use of the derivative according to the first aspect and the derivative prepared by the method according to the second aspect for preparing an antitumor drug; the antitumor drug can adopt the camptothecine derivative as chemical drug of active ingredient, or the camptothecine derivative is used as antibody-drug conjugate of small molecule toxin; preferably, the anti-tumor drug can better exert an anti-tumor effect when being an antibody-drug conjugate, wherein the antibody can be a monoclonal antibody, a diabody or a nanobody, and can be specifically HER2, HER3, CD25, CD30, c-MET and the like, or the antibody which is used in the prior art is disclosed. The camptothecin derivatives can also be used as sensitizer for radiotherapy for adjuvant treatment.
According to the invention, the compounds of the invention can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
According to the present invention, solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
According to the invention, liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions according to the invention can also comprise adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
According to the invention, suspensions, in addition to the active compounds, may contain suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc.
In accordance with the present invention, compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
According to the present invention, the dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
According to the invention, the compounds may be administered alone or in combination with other pharmaceutically acceptable compounds or physical therapies such as radiation therapy, photodynamic therapy, ablative therapy. When a pharmaceutical composition is used, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage, typically 1 to 2000 mg, preferably 50 to 1000 mg, per day for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
According to the present invention, the terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
According to the present invention, the "active ingredient" refers to a compound represented by formula (I), and a pharmaceutically acceptable inorganic or organic salt of the compound represented by formula (I). The compounds of the invention may contain one or more asymmetric centers (chiral centers or chiral axes) and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
According to the present invention, the terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition that is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
According to the invention, the term "administration (ADMINISTERED, ADMINISTERING or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a precursor (prodrug), derivative (derivative), or analogue (analogue) of the active compound, etc.
According to the present invention, wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
According to the invention, "pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and emulsifying agent (such as) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
According to the present invention, there is provided a method of treating a disease, including but not limited to cancer or benign tumor, using a compound, antibody-drug conjugate, pharmaceutical composition, or pharmaceutical-mechanical composition of the invention, including a combination of radiation and chemotherapy.
According to the present invention, in some embodiments, there is provided a method for the treatment of cancer, the method comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition of any of the foregoing compounds, antibody-drug conjugates. In other embodiments, the cancer is hematologic and solid tumors, including, but not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or metastasis of all cancers. According to the present invention, the tumor may be a tumor of the central system, including a primary tumor and a tumor metastasized to the central system, selected from at least one of colon cancer, stomach cancer, breast cancer and lung cancer.
In a fourth aspect, the present invention provides an antibody-drug conjugate in which the derivative of the first aspect and/or the derivative prepared by the method of the second aspect is linked to and/or directly conjugated to an antibody via a linker. The antibody in the antibody-drug conjugate can be monoclonal antibody, diabody or nanobody, and specifically can be HER2, HER3, CD25, CD30, c-MET and the like, or the antibody which is used in public at present; the linker may be a cleavable linker or a non-cleavable linker, the non-cleavable linker being a maleamide-type linker and/or a thiol-caproamide-type linker; cleavable linkers are hydrazone, carbonate, polypeptide, disulfide, or other linkers that have been used currently. The structure of the camptothecin derivative provided by the invention contains different substituent groups and has different activities, and the camptothecin derivative can be directly coupled to the derivative on the antibody or fixed on the antibody through an antibody modification technology, and then coupled to the antibody.
Other terms in the present invention may be construed in a manner conventional in the art.
The invention adopts the following abbreviations: 1, 2-Dichloroethane (DCE); dichloromethane (DCM); methanol (MeOH); tetrahydrofuran (THF); dimethylformamide (DMF); triethylamine (TEA or Et 3 N); trifluoroacetic acid (TFA); di-tert-butyl dicarbonate ((Boc) 2 O); 2- (7-azobenzotriazole) -N, N' -tetramethylurea Hexafluorophosphate (HATU); n, N-Diisopropylethylamine (DIEA); palladium on carbon (Pd/C); acetic anhydride (Ac 2 O); nuclear Magnetic Resonance (NMR); liquid phase-mass spectrometer (LC-MS); thin Layer Chromatography (TLC); liquid chromatography (pre-HPLC) was prepared.
The present invention will be described in detail by examples.
In the following examples, without specific description, reagents or materials used were conventional biochemical reagent grade products, deruxtecan available from Haoyuan biomedical technologies, inc.
In the following examples 1 H-NMR (hydrogen nuclear magnetic resonance) was carried out using a Varian Mercury 400 nuclear magnetic resonance apparatus, the chemical shifts being expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
Unless otherwise specified, the room temperature described in the examples below represents 25.+ -. 5 ℃.
Example 1: synthesis of Compound 1
The specific process comprises the following steps:
(1) Synthesis of Compound 1B
1G of irinotecan (compound 1A,1.88 mmol) was dissolved in 20ml of DMF, and 570mg of triethylamine (Et 3 N,5.64 mmol) and 1g of di-tert-butyl dicarbonate ((Boc) 2 O,4.59 mmol) were added under nitrogen and mixed and reacted at room temperature under nitrogen. After 2 hours, TLC detection was complete, poured into 500ml of water, then extracted three times with 500ml of Ethyl Acetate (EA), and the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate (Na 2SO4), filtered, concentrated and purified on a silica gel column (eluent 1:5 in volume MeOH: DCM) to give compound 1B as a yellow oil (900 mg, 90% yield). LC-MS (ESI, m+h) + =536.1.
(2) Synthesis of Compound 1C
300Mg of Compound 1B (0.56 mmol) was dissolved in a mixed acid of 0.15ml nitric acid and 9ml Ac 2 O at 0deg.C under nitrogen protection, stirred for 1 hour at 0deg.C under nitrogen protection, concentrated under reduced pressure and purified by silica gel column (eluent: meOH: DCM in volume ratio 1:5) to give Compound 1C (160 mg, yield 49%) (ESI, M+H) + = 581.3 as a white solid.
(3) Synthesis of Compound 1
160Mg of Compound 1C (0.28 mmol) was dissolved in 5ml of DCM, 1ml of TFA was added at 0℃under nitrogen protection, stirred at 0℃under nitrogen protection for 1 hour, concentrated under reduced pressure and purified by preparative liquid chromatograph (Pre-HPLC) to give Compound 1 as a yellow solid (30 mg, 23% yield). LC-MS (ESI, m+h) + =481.2. The corresponding hydrogen spectrum is shown in figure 1.
1H-NMR(400MHz,DMSO-d6)
δ8.47(s,3H),7.73(d,J=10.7Hz,1H),6.76(s,1H),5.72(s,1H),5.49(s,3H),5.12(s,1H),3.09(s,2H),2.43(s,3H),2.26-1.99(m,4H),0.94(s,3H).
Example 2: synthesis of Compound 2
The specific process comprises the following steps:
68mg of Compound 1 (0.14 mmol), 32mg of 2-hydroxyacetic acid (0.42 mmol) and 80mg of HATU (0.21 mmol) were successively dissolved in 20ml of DMF at room temperature under nitrogen, 54mg of DIEA (0.42 mmol) was added thereto, and the mixture was stirred at room temperature under nitrogen for 2 hours. After concentration under reduced pressure, compound 2 (17 mg, 22% yield) was obtained as a yellow solid by purification with Pre-HPLC. LC-MS (ESI, m+h) + =539.3. The corresponding hydrogen profile is shown in figure 2.
1H-NMR(400MHz,DMSO-d6)
δ8.38(d,J=8.9Hz,1H),7.61(d,J=10.7Hz,1H),6.70(s,1H),5.58(s,1H),5.45(s,3H),5.23(s,2H),3.94(s,2H),3.24–3.09(m,2H),2.40(s,3H),2.26–1.97(m,4H),0.92(s,3H).
Example 3: synthesis of Compound 3
The specific process comprises the following steps:
14mg of Compound 2 (0.02 mmol) was dissolved in 3ml of DMF and 6.99mg of tetrahydroxydiboron (0.07 mmol) and 0.41mg of 4,4' -bipyridine were added under nitrogen protection at 25℃and mixed with stirring for 4 min, and concentrated under reduced pressure to give Compound 3 (6.7 mg, yield 45%) as a yellow solid by purification by Pre-HPLC. LC-MS (ESI, m+h) + = 509.1. The corresponding hydrogen spectrum is shown in figure 3.
1H-NMR(400MHz,DMSO-d6)δ8.35(d,J=8.9Hz,1H),7.61(d,J=11.0Hz,1H),6.98(s,1H),6.48(s,2H),5.49(s,2H),5.39(s,1H),5.31(s,1H),5.08(d,J=7.3Hz,2H),3.95(d,J=5.8Hz,2H),3.18–3.04(m,2H),2.33(s,3H),2.04(dd,J=7.4,2.1Hz,4H),0.89(s,3H).
Example 4: synthesis of Compound 4
(1) Synthesis of Compound 1D
800Mg of Compound 1C was dissolved in 10ml of DMF, followed by 372mg of tetrahydroxydiboron (4.1 mmol) and 21.5mg of 4,4' -bipyridine (0.13 mmol). After the completion of the reaction, 100ml of water was added thereto while stirring at 25℃under nitrogen gas for 5 minutes, and compound 1D (240 mg, yield 31%) as a yellow solid was collected by filtration as LC-MS (ESI, M+H) + = 551.2.
(2) Synthesis of Compound 4
240Mg of Compound 1D (0.43 mmol) was dissolved in 5ml of DCM, 1ml of TFA was added at 25℃under nitrogen protection, stirred at 25℃under nitrogen protection for 1 hour, and concentrated under reduced pressure to give Compound 4 (40 mg, 20% yield) as yellow color by preparative HPLC. LC-MS (ESI, m+h) + =451.2. The corresponding hydrogen spectrum is shown in fig. 4.
1H-NMR(400MHz,DMSO-d6)δ8.41(s,3H),7.74(d,J=11.0Hz,1H),7.07(s,2H),6.55(s,1H),5.59(s,1H),5.44(s,1H),5.38(s,2H),5.02(s,1H),3.24(s,1H),3.06(t,J=13.8Hz,1H),2.38(s,3H),2.06(s,4H),0.92(s,3H).
Example 5: synthesis of Compound 5
(1) Synthesis of Compound 1F
150Mg of irinotecan (compound 1A,0.3 mmol) was dissolved in 40ml of DMF and 3ml of THF was added at 0℃under nitrogen to give 107mg of phenyl chloroformate (0.6 mmol) solution, and 86mg of Et 3 N (0.86 mmol) was added and mixed and stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100ml of water, and isolated by filtration to give compound 1F (125 mg, 59% yield) as a yellow solid. LC-MS (ESI, m+h) + = 556.0.
(2) Synthesis of Compound 5
40Mg of Compound 1F (0.07 mmol) was dissolved in 1ml of DCE, 22mg (1-methyl-2-nitro-1H-imidazol-5-yl) methanol (0.14 mmol) was added under nitrogen protection at 25℃and after stirring for 5 minutes at 25℃the reaction temperature was raised to 85℃and stirring was continued under nitrogen protection for 16 hours and then purification was carried out by preparative HPLC to give Compound 5 (20.9 mg, yield 45%) as a white solid. LC-MS (ESI, m+h) + = 619.0. The corresponding hydrogen profile is shown in fig. 5.
1H-NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.75(s,1H),7.29(s,2H),6.51(s,1H),5.32(d,J=61.4Hz,7H),4.01(s,3H),3.28-3.20(m,1H),3.16-3.04(m,1H),2.37(s,3H),2.29-2.18(m,1H),2.18-2.06(m,1H),1.86(s,2H),0.87(s,3H).
Test case
Cell antiproliferative activity assay
Camptothecin derivative compounds 1-5 prepared in examples 1-5 of the present invention, wherein the structures of compounds 1 and 4 are similar, the structures of compound 2 and compound 3 are similar, and compound 5 can be metabolized in tumor cells to form irinotecan (compound 1A). Cell antiproliferative activity of camptothecin derivatives was determined by measuring cell proliferative activity of compounds 1-5 and Deruxtecan against gastric cancer (MKN 45), colon cancer (HCT 116), breast cancer (MCF 7) and lung cancer (a 549).
The specific test process is as follows:
Placing a culture dish filled with MKN45, HCT116 cells and a culture medium into a culture box with 5% CO 2 at 37 ℃ for culture, taking cells with good growth state, discarding the original culture medium, and re-suspending and counting by the culture medium respectively; adding the cell suspension into 96-well plates, wherein the number of cells in each well is 4000, and incubating in a 5% CO 2 cell incubator at 37 ℃ for 24 hours; the ATP content of cancer cells in each well is measured by CellTiter-Lumi after the drugs of the compounds 1-5 are diluted and cultured for 72 hours, and the ATP is a direct source of cell energy, so that the proliferation and toxicity states of the cells can be directly reflected by detecting the ATP content of the cells. The Prism software calculates an IC 50 (semi-inhibition concentration) value through the ATP content value, the software uses the inhibition rate as a y value and the drug concentration as an x value to perform four-parameter curve fitting, and the drug concentration value corresponding to the inhibition rate value between the maximum inhibition rate and the minimum inhibition rate is recorded (the software defaults to the IC 50 value). The IC 50 calculation is shown in table 1:
TABLE 1
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NA indicates that the data is being tested and/or validated.
Placing a culture dish containing MCF7, A549 cells and a culture medium into a culture box with 5% CO 2 for culture at 37 ℃, taking the cells with good growth state, discarding the original culture medium, and re-suspending and counting through the culture medium respectively; adding the cell suspension into 96-well plates, wherein the number of cells in each well is 10000, and incubating in a 5% CO 2 cell incubator at 37 ℃ for 24 hours; the reduction of MTS tetrazolium compounds by living cells in each well was measured by adding MTS substrate after dilution and incubation of the drug for 72 hours to yield a dye of colored Fuls Ma Zan that is soluble in the cell culture medium. The proliferation and toxicity states of the cells can be directly reflected by detecting the OD light absorption value at 490nm in the culture solution. Survival was found by calculating the ratio of OD values of the dosed and control non-dosed groups, multiplied by 100%. The Prism software calculates an IC 50 (semi-inhibitory concentration) value through the survival rate of each sample, the software uses the survival rate as a y value and the drug concentration as an x value to perform four-parameter curve fitting, and the drug concentration value corresponding to the survival rate value between the maximum survival rate and the minimum survival rate is recorded (the software defaults to an IC50 value). The IC 50 calculation is shown in table 2:
TABLE 2
NA indicates that the data is being tested and/or validated.
Compared with Deruxtecan, the nitro-containing compounds 1,2 and 5 prepared by the invention have weak in vitro anti-MKN 45, HCT116, MCF7 and A549 cell proliferation activity, but the anti-proliferation activity of the amino compound 3 with similar structure to that of the compound 1 is obviously superior to that of Deruxtecan in HCT116, MCF7 and A549 cells, so that the nitro compounds 1,2 and 5 can be used as prodrugs, and can be converted into active amino compounds under the catalysis of nitroreductase in hypoxic tumor cells so as to kill cancer cells. The active amino compound contains groups which are convenient to connect, such as-OH or-NH 2, in a side chain, and has strong cell activity, so that the active amino compound is suitable for being used as small molecule toxin of ADC.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. A camptothecin derivative, characterized in that the derivative is a compound represented by formula (I) and/or a pharmaceutically acceptable salt thereof:
Wherein R 1 is selected from at least one of H, -NO 2、-NH2, -OH and halogen; r 2 is selected from at least one of H, acyl and substituted acyl, and R 1 and R 2 are not H at the same time.
2. The derivative according to claim 1, wherein the halogen is selected from at least one of F, cl and Br;
Preferably, the R 1 is selected from at least one of H, -NO 2, and-NH 2, R 2 is hydrogen or substituted acyl;
Preferably, the substituted acyl group is at least one of a hydroxy-substituted acyl group and/or an alkoxy-substituted acyl group;
Preferably, the hydroxy-substituted acyl group is an α -hydroxy-substituted acyl group; further alpha-hydroxy substituted acyl groups containing C1-C6 alkane, more preferably alpha-hydroxyacetyl; the alkoxy-substituted acyl group is a heterocyclic ring-containing alkoxy-substituted acyl group and/or a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group, more preferably a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group, and still more preferably a (1-methyl-2-nitro-1H-imidazol-5-yl) methoxyacyl group.
3. Derivative according to claim 1 or 2, characterized in that it is chosen from:
At least one of (a) and (b);
Preferably, the derivative is selected from:
at least one of them.
4. A process for preparing a camptothecin derivative, comprising the steps of:
Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a reactant containing nitro and/or a reactant containing substituted acyl; ra is nitro and hydrogen; rb is at least one selected from acyl, substituted acyl and hydrogen, preferably substituted acyl and hydrogen, ra and Rb are not H at the same time; or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV); or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
(3) Subjecting a compound represented by the formula (IV) to sandmeyer reaction; or alternatively
(1) Carrying out substitution reaction on a compound shown in a formula (II) and a reactant to obtain a compound shown in a formula (III);
Wherein the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group or a reactant containing a nitro group; ra is nitro, rb is substituted acyl or hydrogen;
(2) Carrying out reduction reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
(3) Carrying out a Buch-Hastey coupling reaction on a compound shown in a formula (IV);
5. The process according to claim 4, wherein the compound of formula (II) is reacted with an amino protecting agent prior to the substitution reaction;
preferably, the amino protecting agent is selected from at least one of benzyl chloroformate, di-tert-butyl dicarbonate and 9-fluorenylmethyl chloroformate.
6. The method of claim 4, wherein the nitro-containing reactant is nitric acid;
The substituted acyl is hydroxy substituted acyl and/or alkoxy substituted acyl;
Preferably, the hydroxy-substituted acyl group is an α -hydroxy-substituted acyl group; further alpha-hydroxy substituted acyl groups containing C1-C6 alkane, more preferably alpha-hydroxyacetyl; the alkoxy-substituted acyl group is a heterocyclic ring-containing alkoxy-substituted acyl group and/or a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group, and more preferably a nitro-substituted imidazole ring-containing alkoxy-substituted acyl group;
More preferably, the reactant containing a substituted acyl group is selected from the group consisting of 2-glycolic acid, phenyl chloroformate and (1-methyl-2-nitro-1H-imidazol-5-yl) methyl chloroformate.
7. The method according to claim 4, wherein in the step (2), the reduction reaction comprises a contact reaction of a compound represented by the formula (III) with a reducing agent;
preferably, the reducing agent is tetrahydroxydiboron and/or sodium borohydride.
8. The method of any one of claims 4-7, wherein when the reactant is a mixture of a nitro-containing reactant and a substituted acyl-containing reactant, the substitution reaction comprises:
Carrying out substitution reaction on a compound shown in a formula (II) and a reactant containing nitro to obtain a compound shown in a formula (V); then carrying out substitution reaction on the compound shown in the formula (V) and a reactant containing substituted acyl;
Preferably, when the reactant is a nitro-group-containing reactant, the substitution reaction conditions are at least: inert gas protection, wherein the temperature is-4-0 ℃ and the time is 50-70min;
when the reactant is a substituted acyl group-containing reactant, the conditions of the substitution reaction are at least: inert gas protection, wherein the temperature is 25-30 ℃ and the time is 120-130min;
the conditions of the reduction reaction at least satisfy: inert gas protection is carried out, the temperature is 20-25 ℃, and the time is 4-10min.
9. Use of a derivative according to any one of claims 1-3 and a derivative prepared by a method according to any one of claims 4-8 in the preparation of an antitumor drug;
preferably, the anti-tumor drug is an antibody-drug conjugate;
preferably, the tumor is selected from at least one of colon cancer, stomach cancer, breast cancer and lung cancer.
10. An antibody-drug conjugate, wherein in the antibody-drug conjugate, the derivative according to any one of claims 1 to 3 and/or the derivative produced by the method according to any one of claims 4 to 8 is attached to the antibody and/or directly conjugated to the antibody via a linker.
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