A diketopiperazine compound and its application

Abstract

The present invention discloses a diketopiperazine compound and its application. The present invention provides a diketopiperazine compound as shown in formula I or a pharmaceutically acceptable salt thereof, which can be used as a self-assembled drug-loaded microsphere to achieve effective drug delivery.

Description

Technical Field

[0001] The invention relates to a diketopiperazine compound and application thereof. Background Art

[0002] Drug delivery systems have always been an important direction in drug preparation research. Traditional methods are affected by the pH environment of the digestive tract and various enzymes, which causes some bioactive substances such as calcitonin, insulin, and mucopolysaccharides to be affected in the gastrointestinal tract and quickly destroyed or inactivated. At the same time, due to the physical and chemical properties of the drugs themselves, some sensitive drugs are prone to degradation, and poorly soluble drugs have low bioavailability. Developing an efficient delivery system can enhance drug efficacy and reduce toxic side effects.

[0003] Diketopiperazine derivatives are a new type of material that can precipitate and self-assemble into microspheres in acidic solutions. The microspheres have a large surface area, high drug loading capacity, and a simple manufacturing process. They are suitable for the preparation of various types of drugs, such as cationic drugs with API molecular weights of 500-140000Da, anionic drugs, hydrophilic / lipid drugs, peptides, proteins, and small molecule drugs.

[0004] Due to its small diameter, the dry powder of microspheres prepared by this technology can be used for pulmonary inhalation administration, and its in vivo absorption rate can reach the absorption rate of simulated arterial injection; or it can be used directly for injection. Both routes can avoid the first-pass effect of the liver and peripheral circulation degradation.

[0005] Preparation of microspheres using fumaryl diketopiperazine (FDKP, CAS: 176738-91-3) as carrier Technology is a novel drug delivery technology. Mannkind used this technology to produce a rapid-acting insulin called Afrezza, which was approved by the FDA in 2014 and is currently the only insulin inhalation preparation on the market.

[0006]

[0007] The key carrier material FDKP patent of the technology (WO2013 / 162764, CN104797563) mentioned the synthesis method of the material. The synthesis method of its mother core was proposed by Katchalski in 1946, which was to dehydrate and cyclize the dimer of amino acid ester derivatives such as dipeptide esters. The synthesis method of diketopiperazine organic compounds proposed by Kopple in 1968 was to thermally dehydrate amino acid derivatives in high boiling organic solvents. Yu Qing reported the synthesis method of 3,6-bis (4-bis-trans-butylene diaminobutyl) -2,5-diketopiperazine and its salt substitutes in CN201010206311.5.

[0008] Since diketopiperazine derivatives can self-assemble into drug-loaded microspheres by adjusting the pH value of the preparation system, they have certain advantages as carriers. Therefore, replacing FDKP with new diketopiperazine derivatives and developing a series of successful and effective substances and their salt substitutes have practical significance for achieving effective drug delivery. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the single defect of diketopiperazine derivatives in the prior art, and to provide a diketopiperazine compound with novel structure and its application. The diketopiperazine compound provided by the present invention can be used as self-assembled drug-loaded microspheres to achieve effective drug delivery.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a diketopiperazine compound or a pharmaceutically acceptable salt thereof as shown in Formula I,

[0012]

[0013] wherein n1 and n2 are independently 0, 1, 2, 3 or 4;

[0014] R a and R a 'Independently selected from halogen, cyano and -LR 1 ;

[0015] -L- is selected from the group consisting of a linking bond, -O-, -S-, -C(=O)-, -C(=O)-O- (including -OC(=O)-), -N(R 2 )- and -S(=O) 2 -;

[0016] R 2 Selected from H, C 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 The alkyl group;

[0017] R 1 is selected from H, or, optionally substituted by a substituent: C 1 -C 8 Alkyl, C 2 -C 8 Heteroalkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl and 5-10 membered heteroaryl; the C 2 -C 8In the heteroalkyl group of 2 One or more of the heteroatoms or heteroatom groups are 1-3, and the group is connected to -L- through a carbon atom; the heteroatoms in the 3-7 membered heterocycloalkyl are selected from N, O, S, S(=O) and S(=O) 2 One or more of, the number of heteroatoms is 1-3; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of N, O and S, the number of heteroatoms is 1-4; when there are multiple substituents, they are the same or different;

[0018] The substituents are independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, C substituted by one or more halogen 1 -C 6 Alkyl-O- or =O (when -CH 2 - when replaced);

[0019] The carbon atom with "*" indicates that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.

[0020] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0021] R a and R a 'Halogen independently selected from halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0022] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0023] When R 2 C 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl group 1 -C 6 Alkyl and C substituted by one or more halogen 1 -C 6 The C in the alkyl 1 -C 6 The alkyl groups are independently C1 -C 4 Alkyl, the C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.

[0024] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0025] When R 2 is C substituted by one or more halogens 1 -C 6 When the alkyl group is substituted with halogen, the number of halogens may be 1-3; the halogen is fluorine, chlorine, bromine or iodine, such as fluorine or chlorine; for example, one or more halogen-substituted C 1 -C 6 The alkyl group is trifluoromethyl.

[0026] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0027] When R 1 is C optionally substituted by a substituent 1 -C 8 When the alkyl group 1 -C 8 The alkyl groups are independently C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl), preferably C 1 -C 4 Alkyl, the C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.

[0028] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0029] When R 1 is C optionally substituted by a substituent 6 -C 10 When the C 6 -C 10 Aryl is phenyl or naphthyl; for example phenyl.

[0030] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0031] When R 1 is C optionally substituted by a substituent 3 -C 12 When cycloalkyl, the C 3 -C 12 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; for example cyclopentyl.

[0032] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0033] When R 1 When it is a 3-7 membered heterocycloalkyl group optionally substituted by a substituent, the 3-7 membered heterocycloalkyl group is morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl, 1,4-dioxanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridine, diazepanyl or pyrazolidinyl; for example

[0034] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0035] When R 1 When it is a 5-10 membered heteroaryl group which is optionally substituted by a substituent, the 5-10 membered heteroaryl group is furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl or triazinyl; for example

[0036] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0037] When R 1 When the substituents in are independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0038] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0039] When R 1 The substituents are independently C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl-O- 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, and C substituted by one or more halogen 1 -C 6 The C in the alkyl-O- 1 -C 6 The alkyl groups are independently C 1 -C 4 Alkyl, the C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.

[0040] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0041] When R 1 The substituents are independently C substituted by one or more halogens. 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl-O- is substituted with alkyl-O-, the number of the halogens may be 1-3; the halogens are fluorine, chlorine, bromine or iodine, such as fluorine or chlorine; for example, one or more halogen-substituted C 1 -C 6 The alkyl group is trifluoromethyl.

[0042] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0043] n1 and n2 are independently 0 or 1.

[0044] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0045] -L- is selected from a linking bond, -O-, -S- or -N(R 2 )-; for example, a linking bond, -O- or -N(R 2 )-.

[0046] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0047] R 2 H or C 1 -C 6 Alkyl; for example, C 1 -C 6 of alkyl.

[0048] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0049] R 1 is selected from H, or, optionally substituted by a substituent: C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0050] For example, H, C substituted by one or more halogens 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl and 5-10 membered heteroaryl.

[0051] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0052] R 1 The substituent described in is halogen.

[0053] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0054] -LR 1 Selected from hydroxyl, C 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C 1 -C 8 Alkyl-N(C 1 -C 6 alkyl)-, C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl and 5-10 membered heteroaryl.

[0055] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0056] R a and R a 'Independently selected from halogen and -LR 1 .

[0057] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0058] R a and R a 'Same or different, e.g. same.

[0059] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0060]

[0061] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0062]

[0063] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0064] In the diketopiperazine compound as shown in Formula I, The configuration is mainly (Right now ), (Right now ), (Right now )or (Right now ) shown in the configuration,

[0065] For example (Right now ), (Right now )or (Right now );

[0066] Another example (Right now );

[0067] For example, for each chiral center, greater than 80% ee; for another example, for each chiral center, the configuration is about 85%-90% excess over the other configuration, more preferably about 95%-99% excess, more preferably about 99% excess, or no other configuration can be detected.

[0068] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0069] R a and R a ' is independently H, fluorine, hydroxyl, methyl, methoxy, trifluoromethyl, Cyclopentyl, phenyl or Preferably H, fluorine, methyl, methoxy, trifluoromethyl, phenyl or More preferred are H, fluorine, methoxy and trifluoromethyl.

[0070] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0071] for

[0072] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0073] for

[0074] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0075] for For example,

[0076] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0077] Same or different, e.g. same.

[0078] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0079] for

[0080] n1 and n2 are independently 0 or 1;

[0081] R a and R a 'Independently selected from halogen and -LR 1 ;

[0082] -L- is selected from a linking bond, -O-, -S- or -N(R 2 )-; for example, a linking bond, -O- or -N(R 2 )-;

[0083] R 2 H or C 1 -C 6 Alkyl; for example, C 1 -C 6 The alkyl group;

[0084] R 1 Selected from H, or, optionally substituted by a substituent: C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl and 5-10 membered heteroaryl; for example, H, C substituted by one or more halogens 1 -C 8Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0085] same.

[0086] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0087] for

[0088] n1 and n2 are independently 0 or 1;

[0089] R a and R a 'Independently selected from halogen and -LR 1 ;

[0090] -LR 1 Selected from hydroxyl, C 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C 1 -C 8 Alkyl-N(C 1 -C 6 alkyl)-, C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl;

[0091] same.

[0092] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0093] for

[0094] n1 and n2 are independently 0 or 1;

[0095] R a and R a 'Independently selected from halogen and -LR1 ;

[0096] -LR 1 Selected from H, OH, C 1 -C 8 Alkyl, C substituted by one or more halogen 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 5-10 membered heteroaryl;

[0097] same.

[0098] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0099] for

[0100] n1 and n2 are independently 0 or 1;

[0101] R a and R a 'Independently selected from halogen and -LR 1 ;

[0102] -LR 1 Selected from C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 1 -C 8 Alkyl-O-, C substituted by one or more halogen 1 -C 8 The alkyl group;

[0103] same.

[0104] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0105] for

[0106] n1 and n2 are independently 0 or 1;

[0107] R a and R a'Independently selected from halogen and -LR 1 ;

[0108] -LR 1 Selected from H, OH, C 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C substituted by one or more halogen 1 -C 8 Alkyl, -N(R 2 )-C 1 -C 8 Alkyl, C 3 -C 12 Cycloalkyl, C 2 -C 8 heteroalkyl, 5-10 membered heteroaryl; R 2 Select from H or C 1 -C 6 The alkyl group;

[0109] same.

[0110] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0111] for

[0112] n1 and n2 are independently 0 or 1;

[0113] R a and R a 'Independently selected from halogen and -LR 1 ;

[0114] -LR 1 Selected from H, C 1 -C 8 Alkyl, C 2 -C 8 heteroalkyl, 5-10 membered heteroaryl, C 1 -C 8 Alkyl-O-, -N(R 2 )-C 1 -C 8 Alkyl; R 2 Selected from H, C 1 -C 6 The alkyl group;

[0115] same.

[0116] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0117] for

[0118] n1 and n2 are independently 0 or 1;

[0119] R a and R a 'Independently selected from halogen and -LR 1 ;

[0120] -LR 1 Selected from H, C 1 -C 8 Alkyl-O-, 5-10 membered heteroaryl;

[0121] same.

[0122] In certain preferred embodiments of the present invention, certain groups in the diketopiperazine compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application),

[0123] The pharmaceutically acceptable salt may be a monovalent alkali metal salt and / or a divalent alkali metal salt; for example, the monovalent alkali metal is Na + , K + and Li + One or more of; the divalent alkali metal is Mg 2+ and / or Ca 2+ .

[0124] In one embodiment of the present invention, the diketopiperazine compound as shown in Formula I is selected from any of the following structures:

[0125]

[0126]

[0127] In the present invention, the diketopiperazine compound or its pharmaceutically acceptable salt as shown in Formula I has one or more chiral carbon atoms, so it can be separated to obtain optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or separation by chiral preparative columns.

[0128] In the present invention, the diketopiperazine compound or its pharmaceutically acceptable salt as shown in Formula I may exist in a crystalline or amorphous form. The term "crystalline form" means that the ions or molecules therein are arranged in a strict periodic manner in three-dimensional space in a certain manner, and have a regularity of periodic repetition at a certain distance; due to the different periodic arrangements, there may be multiple crystalline forms, that is, polymorphism. The term "amorphous form" means that the ions or molecules therein are in a disorderly distribution state, that is, there is no periodic arrangement between the ions and molecules.

[0129] In the present invention, the diketopiperazine compound or its pharmaceutically acceptable salt as shown in Formula I, if stereoisomers exist, can exist in the form of a single stereoisomer or a mixture thereof (e.g., a racemate). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral separation by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

[0130] In the present invention, if the diketopiperazine compound as shown in Formula I or its pharmaceutically acceptable salt exists in tautomers, it may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a relatively stable tautomer as the main tautomer.

[0131] The present invention also includes isotopically labeled diketopiperazine compounds of the present invention as shown in Formula I or pharmaceutically acceptable salts thereof, wherein one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur and chlorine (e.g. 2 H, 3 H, 13 C, 14 C, 15 N, 18 Oh, 17 Oh, 18 F, 35 S and 36 Cl). Isotopically labeled compounds of the invention can be used in assays for tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such assays include 3 H and 14C. Further, in some cases, substitution with heavier isotopes such as deuterium (2H or D) can afford increased metabolic stability which affords therapeutic advantages such as increased in vivo half-life or reduced dosage requirements.

[0132] Isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0133] In the present invention, the diketopiperazine compound or its pharmaceutically acceptable salt as shown in formula I can be synthesized by methods similar to those known in the chemical field, and the steps and conditions thereof can refer to the steps and conditions of similar reactions in the art, especially according to the description herein. The starting materials are usually from commercial sources, such as Aldrich, or can be easily prepared using methods known to those skilled in the art (obtained through SciFinder, Reaxys online database).

[0134] In the present invention, the diketopiperazine compound as shown in Formula I or a pharmaceutically acceptable salt thereof can also be prepared by peripherally modifying the prepared diketopiperazine compound as shown in Formula I or a pharmaceutically acceptable salt thereof using conventional methods in the art to obtain other diketopiperazine compounds as shown in Formula I or a pharmaceutically acceptable salt thereof.

[0135] The necessary raw materials or reagents for preparing the diketopiperazine compounds or pharmaceutically acceptable salts thereof as shown in Formula I can be commercially available or prepared by synthetic methods known in the art. The method described in the following experimental section can prepare the compounds of the present invention in the form of free bases or salts thereof by addition of acids. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the effects of the parent compound. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent for an organic base and treating according to conventional methods to prepare pharmaceutically acceptable salts.

[0136] Examples of salt formation include: For base addition salts, it is possible to prepare alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., aluminum, magnesium, calcium, zinc or bismuth) salts by treating a compound of the invention having an appropriate acidic proton with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., ethanolate or methanolate) or a suitable basic organic amine (e.g., diethanolamine, choline or meglumine) in an aqueous medium.

[0137] Alternatively, for acid addition salts, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.

[0138] The "compounds of the present invention" or "compounds shown in the present invention" include any diketopiperazine compound shown in Formula I or a pharmaceutically acceptable salt thereof. The compounds of the present invention may also exist in the form of hydrates or solvates.

[0139] The present invention also provides a pharmaceutical composition, which comprises the diketopiperazine compound as shown in Formula I or a pharmaceutically acceptable salt thereof, one or more active pharmaceutical ingredients; and may also comprise one or more other pharmaceutical excipients.

[0140] The pharmaceutical composition can be a microsphere drug delivery system. The diketopiperazine compound or a pharmaceutically acceptable salt thereof as shown in formula I is a self-assembled microsphere.

[0141] The weight percentage of the drug in the pharmaceutical composition is 10% to 90%, for example 20% to 80%.

[0142] The active pharmaceutical ingredient (drug) can be a cationic drug, anionic drug, hydrophilic / lipid drug, polypeptide, protein, or small molecule drug with an API molecular weight of 500-140,000 Da; for example, selected from insulin, dolutegravir, sildenafil, etc.

[0143] For example, the active pharmaceutical ingredient (drug) is a poorly soluble drug.

[0144] The preparation method of the pharmaceutical composition as described above can be conventional in the art.

[0145] The present invention also provides a method for preparing the pharmaceutical composition as described above, comprising the following steps:

[0146] After adding the solution containing the active pharmaceutical ingredient (drug) to the alkaline solution containing the diketopiperazine compound or its pharmaceutically acceptable salt as shown in Formula I, adjusting the pH to precipitate solids, the pharmaceutical composition can be obtained. The mass ratio of the active pharmaceutical ingredient (drug) to the diketopiperazine compound or its pharmaceutically acceptable salt as shown in Formula I can be 7:10; the alkaline solution can be obtained by adding 1% ammonia water (v / v); the pH can be 5.0; the adjusted pH can be obtained by adding 10% glacial acetic acid aqueous solution (v / v); the obtained pharmaceutical composition is preferably filtered, washed and then dried.

[0147] The present invention also provides a use of the diketopiperazine compound or a pharmaceutically acceptable salt thereof as shown in Formula I as described above as a preparation excipient; for example, it forms drug-loaded microspheres. Specifically, the diketopiperazine compound or a pharmaceutically acceptable salt thereof as shown in Formula I can be made into drug carrier particles with suitable properties (such as particle size, shape, structural strength, solubility, and low toxicity, etc.), and the drug microparticles formed by loading the effective drug ingredients onto such drug carrier particles can be stable at low pH values, decompose at physiological pH values, and are suitable for oral administration, injection, or inhalation and other administration methods to achieve effective drug delivery. ).

[0148] The present invention also provides a method for preparing the diketopiperazine compound as shown in formula I as described above, which comprises the following steps: in a solvent, in the presence of a base, subjecting the compound as shown in formula II to a saponification reaction as shown below to obtain the diketopiperazine compound as shown in formula I;

[0149]

[0150] Among them, *, n1, n2, R a and R a ' are defined as above; R' and R" are independently C 1 -C 8 Alkyl groups (e.g. C 1 -C 6 Alkyl, such as C 1 -C 4 Alkyl, the C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; also for example methyl).

[0151] In the method for preparing the diketopiperazine compound as shown in Formula I, the conditions and operation of the saponification reaction shown can be conventional conditions and operations in this type of reaction in the art; in the present invention, the following are preferred:

[0152] Wherein, the solvent may be an alcohol solvent (such as ethanol and / or ethanol). The amount of the solvent used is not affected by the reaction, for example, the mass volume ratio of the compound shown in Formula II to the solvent is 0.1 g / L-5 g / L (such as 0.5 g / L-1 g / L).

[0153] The base may be an alkali metal hydroxide (eg, sodium hydroxide and / or potassium hydroxide).

[0154] The molar ratio of the base to the compound of formula II may be 1:1-10:1 (e.g. 1:7-8:1).

[0155] The temperature of the saponification reaction shown may be from room temperature to 80°C (eg, 60-70°C).

[0156] The progress of the saponification reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally taken as the disappearance or no-reaction of the compound shown in Formula II.

[0157] The preparation method may further include post-treatment and crystallization; the post-treatment may include the following steps: after the saponification reaction is completed, acid is added for neutralization (such as glacial acetic acid), solids are precipitated, and the diketopiperazine compound shown in Formula I is obtained.

[0158] The crystallization may include the following steps: filtering the mixture of the diketopiperazine compound shown in Formula I and trifluoroacetic acid obtained after the above-mentioned post-treatment, mixing the filtrate with glacial acetic acid, cooling to precipitate solid, filtering, washing, and obtaining the crystal of the diketopiperazine compound shown in Formula I. The mixture of the diketopiperazine compound shown in Formula I and trifluoroacetic acid may be obtained by mixing the diketopiperazine compound shown in Formula I with trifluoroacetic acid at 50°C-100°C (e.g., 80°C-90°C). The solvent used for the washing may be an alcohol solvent (e.g., ethanol and / or ethanol).

[0159] The preparation method may further include the following steps: in a solvent, in the presence of a base and a condensing agent, subjecting the compound represented by formula III to a condensation reaction as shown below to obtain the compound represented by formula II;

[0160]

[0161] Among them, *, n1, n2, R a , R a ', R' and R' are as defined above;

[0162] and same.

[0163] The conditions and operations of the condensation reaction shown may be conventional conditions and operations in this type of reaction in the art; in the present invention, the following are preferred:

[0164] Wherein, the solvent can be one or more of amide solvents (e.g., N,N-dimethylformamide DMF and / or N,N-dimethylacetamide DMA), sulfoxide solvents (e.g., dimethyl sulfoxide DMSO), halogenated hydrocarbon solvents (e.g., dichloromethane DCM) and cyclic ether solvents (e.g., tetrahydrofuran THF); for example, amide solvents (e.g., N,N-dimethylformamide DMF and / or N,N-dimethylacetamide DMA), sulfoxide solvents (e.g., dimethyl sulfoxide DMSO), halogenated hydrocarbon solvents (e.g., dichloromethane DCM) and cyclic ether solvents (e.g., tetrahydrofuran THF). The amount of the solvent used is such that it does not affect the reaction.

[0165] In the condensation reaction, the base may be an organic base (eg, triethylamine). The molar ratio of the base to the compound of formula III is 1.5:1-3:1 (eg, 2:1-2.5:1).

[0166] In the condensation reaction, the condensing agent may be one or more of HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), EDTA (ethylenediaminetetraacetic acid) and HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), preferably HATU and / or EDTA. The molar ratio of the condensing agent to the compound shown in Formula III is 1.0:1-2:1 (e.g., 1:1-1.5:1).

[0167] In the condensation reaction, the molar ratio of the compound represented by Formula IV to the compound represented by Formula III is 1.5:1-1:1.5 (eg, 1:1-1.1:1).

[0168] The condensation reaction temperature may be from room temperature to 80° C. (eg, 10-30° C.).

[0169] The progress of the condensation reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally taken as the disappearance or no-reaction of the compound shown in Formula III.

[0170] The preparation method may further include post-treatment and crystallization; the post-treatment and crystallization may include the following steps: after the condensation reaction is completed, the filter cake obtained by filtration is crystallized in glacial acetic acid and water to precipitate a solid to obtain the compound shown in Formula II.

[0171] The present invention also provides a compound as shown in formula II,

[0172]

[0173] Among them, *, n1, n2, R a , R a R', R' and R' are as defined above.

[0174] In a certain embodiment of the present invention, the compound as shown in Formula II is any of the following structures:

[0175]

[0176]

[0177] The present invention also provides a method for preparing the compound shown in Formula II, which comprises the following steps: in a solvent, in the presence of a base and a condensing agent, subjecting the compound shown in Formula III to a condensation reaction as shown below to obtain the compound shown in Formula II;

[0178]

[0179] Among them, *, n1, n2, R a , R a ', R' and R' are defined as in any of the above schemes;

[0180] The conditions and operations of the preparation method can be as described in any of the above schemes.

[0181] In the present invention, the following definitions are used:

[0182] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0183] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.

[0184] Certain chemical groups defined herein are preceded by simplified notations to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5, or 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

[0185] As used herein, numerical ranges defined in substituents such as 0 to 4, 1-4, 1 to 3, etc. indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

[0186] According to the common practice in the art, the structural formula used herein is Used to delineate the bond at the point of attachment of a radical moiety or substituent to the core or backbone structure.

[0187] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0188] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0189] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.

[0190] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0191] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1 ~C 6Alkyl" or "C 1 ~C 6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 Alkyl; "C 1-4 "Alkyl" refers specifically to independently disclosed methyl, ethyl, C 3 Alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 Alkyl (ie, butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

[0192] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0193] The term "alkoxy" refers to the group -OR X , where R X is alkyl as defined above.

[0194] As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon chain, such as a straight or branched saturated hydrocarbon chain containing 1 to 20 carbon atoms. x -C y "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, "C 1 -C 8 "Alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 8 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0195] As used herein, the term "heteroalkyl" refers to an alkyl group in which one or more CH 2 or CH is independently selected by O, S, S(O), SO 2 , N or NH substituted groups, and connected through carbon atoms. For example, C 2 -C 8 The heteroalkyl group refers to a group containing 2 to 8 saturated carbon atoms and one or more independently selected from O, S, S(O), SO 2 , N and NH groups, and are connected through carbon atoms.

[0196] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic ring containing no heteroatoms, such as phenyl or naphthyl.

[0197] As used herein, the term "cycloaliphatic" refers to a monocyclic or bridged carbocyclic ring system (e.g., "cycloalkyl," "cycloalkenyl"). A monocyclic cycloalkyl is a carbocyclic ring system containing 3 to 10 carbon atoms, zero heteroatoms, saturated or unsaturated (non-aromatic rings). Examples of saturated monocyclic ring systems ("cycloalkyl") include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Saturated monocyclic "cycloalkyl" may contain one or two alkylene bridges, each comprising one, two, or three carbon atoms, each bridge connecting two non-adjacent carbon atoms of the ring system. Representative examples of such bridged cycloalkyl ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.0 3,7]nonane (octahydro-2,5-methylenepentalene or noradamantane), and tricyclo[3.3.1.1 3,7]decane (adamantane). Some unsaturated monocyclic rings may contain olefinic bonds and have four to ten carbon atoms and zero heteroatoms ("cycloalkenyl"). "Cycloalkenyl" of a four-membered ring system has one double bond, "cycloalkenyl" of a five- or six-membered ring system has one or two double bonds, "cycloalkenyl" of a seven- or eight-membered ring system has one, two or three double bonds, and "cycloalkenyl" of a nine- or ten-membered ring system has one, two, three or four double bonds. Representative examples of unsaturated monocyclic "cycloalkenyl" include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unsaturated monocyclic "cycloalkenyl" may contain one or two alkylene bridges, each of which includes one, two or three carbon atoms, each bridge connecting two non-adjacent carbon atoms of the ring system. Representative examples of "cycloalkenyl" of an unsaturated bridged ring containing an olefinic bond include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthyl and 1,6-dihydro-pentalene. Monocyclic and bridged ring "cycloaliphatic" (eg, "cycloalkyl," "cycloalkenyl") groups can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems.

[0198] As used herein, the term "heterocycloaliphatic" or "heterocycle" refers to a saturated or unsaturated (non-aromatic ring) (e.g., "heterocycloalkyl", "heterocycloalkenyl"), monocyclic or bridged three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom, the heteroatoms being independently selected from O, N, and S. The nitrogen and sulfur heteroatoms in the heterocycle may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Representative examples of saturated "heterocycloalkyl" include, but are not limited to, morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl, 1,4-dioxanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridinyl, diazepanyl, dithiolanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothiophenyl, thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, and trithianyl. Representative examples of unsaturated "heterocycloalkenyl" containing olefinic bonds include, but are not limited to, 1,4,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, dihydropyranyl, imidazolinyl, isothiazolinyl, oxadiazolinyl, isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl, thiadiazolinyl, thiazolinyl and thiopyranyl. Unsaturated heterocyclic rings also include the following groups: The monocyclic and bridged heterocyclic rings can be attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring.

[0199] As used herein, the term "heteroaryl", "heteroaromatic ring" or "aromatic heterocycloalkyl" refers to a five-membered or six-membered aromatic ring having at least one carbon atom and one or more independently selected nitrogen, oxygen or sulfur atoms. The heteroaromatic rings of the present invention are connected through any adjacent atoms in the ring, provided that normal atomic valence is maintained. Representative examples of heteroaryl include, but are not limited to, furanyl (including, but not limited to, furan-2-yl), imidazolyl (including, but not limited to, 1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridyl (e.g., pyridin-4-yl, pyridin-2-yl and pyridin-3-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl (including, but not limited to, thien-2-yl and thien-3-yl), triazolyl and triazinyl. The structural units represented by the following are:

[0200]

[0201] As used herein, the term "optionally substituted" means that the modified group contains no substituents, or contains substituents, such as 1, 2 or 3 substituents. When the "optionally substituted" group contains substituents, such as 1, 2 or 3 substituents, the "substituents" can be independently selected from hydroxy, carboxyl, halogen, alkyl, alkoxy, aryl, aromatic heterocyclic group, acyl, sulfonyl, mercapto, alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, ester or trifluoromethyl, wherein the group (such as alkyl, etc.) can be further optionally substituted by, such as 1, 2 or 3 independently selected substituents. Sometimes, when the "optionally substituted" group contains substituents, such as 1, 2 or 3 substituents, the "substituents" can be preferably independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, etc.), halogen, especially fluorine, or trifluoromethyl. For example, "optionally substituted alkyl" includes unsubstituted alkyl and alkyl substituted with 1, 2 or 3 groups independently selected from hydroxy, carboxyl, halogen (e.g., F), alkyl (e.g., C 1～6 alkyl), heteroalkyl (e.g. C 1～6 Heteroalkyl), alkoxy (e.g. C 1～6 The alkyl group may be substituted with a cycloalkyl group, a dicycloalkyl group, a cyano group, a ester group or a trifluoromethyl group.

[0202] The term "solvate" refers to a substance formed by the combination of a compound of the present invention and a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may exist in an ordered or non-ordered arrangement. The solvent includes, but is not limited to, water, methanol, ethanol, etc.

[0203] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[0204] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids. When a compound of the present invention contains relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, which include but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, phosphorous acid, sulfuric acid, hydrogen sulfate, etc. The pharmaceutically acceptable acids include organic acids, which include but are not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citrate, oleic acid, tannic acid, pantothenic acid, acid hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (such as glutamic acid, arginine), etc. When a compound of the present invention contains relatively basic functional groups, it can be converted into acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0205] In the term "solvate of a pharmaceutically acceptable salt", "pharmaceutically acceptable salt" and "solvate" are as described above, and refer to substances formed by the compounds of the present invention 1. prepared with relatively non-toxic, pharmaceutically acceptable acids or bases, and 2. combined with stoichiometric or non-stoichiometric solvents.

[0206] As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.

[0207] When it is not specified which atom of a listed substituent is attached to a compound included in the chemical structure formula but not specifically mentioned, such a substituent can be bonded through any of its atoms. Combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0208] When a group is listed without explicitly indicating that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1 ~C 4 When there is no “substituted or unsubstituted” before “alkyl”, it only refers to “C 1 ~C 4 "Alkyl" itself or "unsubstituted C 1 ~C 4 alkyl".

[0209] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0210] In some specific structures, when an alkyl group is explicitly indicated as a linking group, the alkyl group represents a linking alkylene group, for example, the group "halo-C 1 -C 6 C in "alkyl" 1 -C 6 Alkyl is understood to be C 1 -C 6 Alkylene.

[0211] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0212] It should be understood that the singular forms used in the present invention, such as "a", include plural references unless otherwise specified. In addition, the term "comprising" is an open limitation and not a closed one, that is, including the contents specified in the present invention, but not excluding other aspects.

[0213] Unless otherwise specified, the present invention adopts conventional methods of mass spectrometry and elemental analysis, and each step and condition can refer to conventional operating steps and conditions in the art.

[0214] Unless otherwise indicated, the present invention adopts standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance testing.

[0215] In addition, it should be noted that, unless otherwise explicitly stated, the description method "... independently are" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can independently be the same or different specific groups. In more detail, the description method "... independently are" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

[0216] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0217] The reagents and raw materials used in the present invention are commercially available.

[0218] The positive and progressive effect of the present invention is that the diketopiperazine compounds provided by the present invention can be used as self-assembled drug-loaded microspheres to achieve effective drug delivery. DETAILED DESCRIPTION

[0219] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0220] Example 1

[0221]

[0222] Step 1: Dehydration cyclization reaction: Add 30 g of ε-benzyloxycarbonyl-L-lysine, 50 g of m-cresol, and 5 g of phosphorus pentoxide into a conical flask, heat to 200°C, distill off the water during the reaction, and then cool the reactants in a mixed solution of water and sodium hydroxide (10:1) to form a precipitate. Separate the precipitate and rinse it with 30 ml of ethanol, then filter it to obtain 20.6 g of the crude product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine. The obtained crude product was heated in 100 ml of glacial acetic acid solution (100°C), and then 30 ml of purified water was added for cooling. The crystals were then rinsed with 50 ml of glacial acetic acid solution to obtain 11.2 g of a refined product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine.

[0223] Step 2: Hydrogenation reaction: 11.2 g of the product from the previous step was dissolved in 50 ml of glacial acetic acid solution, and a catalyst (10% palladium / carbon) was added to carry out a hydrogenation reaction in a reactor filled with hydrogen. The obtained mixed solution was cooled and filtered. The filtrate was then distilled to remove the glacial acetic acid component, and the acetate of (2S,5S)-2,5-bis(4-aminobutyl)-3,6-diketopiperazine was obtained.

[0224] MS: 257 (M+H).

[0225] Step 3: Condensation reaction: The product of the previous step is dissolved in DMF, and an equivalent amount of monomethyl isophthalate, two equivalents of triethylamine and an equivalent amount of HATU are added to carry out a condensation reaction at room temperature. After the liquid phase detection shows that the raw material disappears, 100 ml of water is added, and then the obtained solid substance is separated to obtain 5.8 g of a solid crude product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl)benzoyl]aminobutyl}-3,6-diketopiperazine. The obtained solid crude product is added with 20 ml of glacial acetic acid, and then 20 ml of water is added to cool. After that, the crystals are washed with 10 ml of glacial acetic acid solution to obtain 3.8 g of a refined product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0226] MS: 582 (M+H).

[0227] Step 4: Saponification reaction: Add the product obtained in the previous step (theoretically 6.5 mmol) to a mixed solution of 20 ml methanol and 2 g sodium hydroxide (theoretically 50 mmol, 7.7 eq) and heat to 70°C, then filter and add glacial acetic acid to cool to room temperature. After separating the solid material and washing with 20 ml water, 2.5 g of crude product of (2S,5S)-2,5-bis{4-[N-(3'-carboxyl)benzoyl]aminobutyl}-3,6-diketopiperazine was obtained.

[0228] Step 5: Recrystallization: Add 10 ml of trifluoroacetic acid to the crude product obtained in the previous step and heat to 90°C. Filter the mixture, cool the filtrate, add 10 ml of glacial acetic acid, and further cool. Separate the solid material and rinse it with 10 ml of methanol, then rinse it with 10 ml of purified water, and dry it to obtain 1.8 g of a refined product of (2S,5S)-2,5-bis{4-[N-(3'-carboxyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0229] MS: 575 (M+Na).

[0230] 1 H NMR ((400MHz, CDCl 3)δ1.331~1.356(m,4H),1.480~1.509(m,4H),1.651~1.700(m,4H),3.210~3.249(m,4H),3.781~3.809 (m,2H),7.531~7.570(m,2H),8.021~8.044(m,4H),8.101(s,2H),8.389~8.403(m,2H),8.626(m,2H).

[0231] Embodiment 2:

[0232] Step 1: Dehydration cyclization reaction: 36 g of ε-benzyloxycarbonyl-L-lysine, 59 g of m-cresol, and 6 g of phosphorus pentoxide were added to a conical flask and heated to 200°C. Water was distilled off during the reaction, and then the reactants were cooled in a mixed solution of water and sodium hydroxide (10:1) to form a precipitate. The precipitate was separated and washed with 36 ml of ethanol, and then filtered to obtain 24.8 g of the crude product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine. The obtained crude product was heated (100°C) in 120 ml of glacial acetic acid solution, and then 36 ml of purified water was added for cooling. The crystals were then rinsed with 60 ml of glacial acetic acid solution to obtain 13.5 g of a refined product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine.

[0233] Step 2: Hydrogenation reaction: 13.5 g of the product from the previous step was dissolved in 60 ml of glacial acetic acid solution, and a catalyst (10% palladium / carbon) was added to carry out a hydrogenation reaction in a reactor filled with hydrogen. The obtained mixed solution was cooled and filtered. The filtrate was then distilled to remove the glacial acetic acid component, and the acetate of (2S,5S)-2,5-bis(4-aminobutyl)-3,6-diketopiperazine was obtained.

[0234] MS: 257 (M+H).

[0235] Step 3:

[0236]

[0237] Condensation reaction: The product of the previous step was dissolved in DMF, and an equivalent amount of monomethyl terephthalate, two equivalents of triethylamine and an equivalent amount of HATU were added to carry out the condensation reaction at room temperature. After the liquid phase detection showed that the raw material disappeared, 119 ml of water was added, and then the obtained solid substance was separated to obtain 6.9 g of a solid crude product of (2S,5S)-2,5-bis{4-[N-(4'-methoxycarbonyl)benzoyl]aminobutyl}-3,6-diketopiperazine. The obtained solid crude product was added with 24 ml of glacial acetic acid, and then 24 ml of water was added to cool. After that, the crystals were washed with 12 ml of glacial acetic acid solution to obtain 4.1 g of a refined product of (2S,5S)-2,5-bis{4-[N-(4'-methoxycarbonyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0238] MS: 582 (M+H).

[0239] Step 4: Saponification reaction: Add 22 ml of methanol and 2.2 g of sodium hydroxide to the product obtained in the previous step, heat to 70°C, filter, add glacial acetic acid and cool to room temperature. Separate the solid matter and rinse with 22 ml of water to obtain 2.7 g of crude product of (2S,5S)-2,5-bis{4-[N-(4'-carboxyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0240] Step 5: Recrystallization: Add 11 ml of trifluoroacetic acid to the crude product obtained in the previous step and heat to 90°C. Filter the mixture, cool the filtrate, add 11 ml of glacial acetic acid, and further cool. Separate the solid material and rinse it with 11 ml of methanol, then rinse it with 11 ml of purified water, and dry it to obtain 1.9 g of a refined product of (2S,5S)-2,5-bis{4-[N-(4'-carboxyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0241]

[0242] MS: 575 (M+Na).

[0243] 1 H NMR ((400MHz, CDCl 3 )δ1.342~1.357(m,4H),1.476~1.511(m,4H),1.721~1.730(m,4H),3.211~3.238(m,4H),3.801 ~3.812(m,2H),8.032~8.055(m,4H),8.175~8.199(m,4H),8.372~8.404(m,2H),8.640(m,2H).

[0244] Embodiment 3:

[0245] Step 1: Dehydration cyclization reaction: Add 25 g of ε-benzyloxycarbonyl-L-lysine, 42 g of m-cresol, and 4.2 g of phosphorus pentoxide into a conical flask, heat to 200°C, distill off the water during the reaction, and then cool the reactants in a mixed solution of water and sodium hydroxide (10:1) to form a precipitate. Separate the precipitate and rinse it with 25 ml of ethanol, then filter it to obtain 17.2 g of the crude product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine. The obtained crude product was heated (100°C) in 83 ml of glacial acetic acid solution, and then 25 ml of pure water was added to cool it. The crystals were then rinsed with 42 ml of glacial acetic acid solution to obtain 9.3 g of a refined product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine.

[0246] Step 2: Hydrogenation reaction: 9.3 g of the product from the previous step was dissolved in 41 ml of glacial acetic acid solution, and a catalyst (10% palladium / carbon) was added to carry out a hydrogenation reaction in a reactor filled with hydrogen. The obtained mixed solution was cooled and filtered. The filtrate was then distilled to remove the glacial acetic acid component, and the acetate of (2S,5S)-2,5-bis(4-aminobutyl)-3,6-diketopiperazine was obtained.

[0247] Step 3:

[0248]

[0249] Condensation reaction: The product of the previous step was dissolved in DMF, and an equivalent amount of monomethyl phthalate, two equivalents of triethylamine and an equivalent amount of HATU were added to carry out the condensation reaction at room temperature. After the liquid phase detection showed that the raw material disappeared, 83 ml of water was added, and then the obtained solid substance was separated to obtain 4.8 g of a solid crude product of (2S,5S)-2,5-bis{4-[N-(2'-methoxycarbonyl)benzoyl]aminobutyl}-3,6-diketopiperazine. 17 ml of glacial acetic acid was added to the obtained solid crude product, and then 17 ml of water was added to cool it. After that, the crystals were washed with 8 ml of glacial acetic acid solution to obtain 3.1 g of a refined product of (2S,5S)-2,5-bis{4-[N-(2'-methoxycarbonyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0250] MS: 582 (M+H).

[0251] Step 4: Saponification reaction: Add 16 ml of methanol and 1.6 g of sodium hydroxide to the product obtained in the previous step, heat to 70°C, filter, add glacial acetic acid and cool to room temperature. Separate the solid matter and rinse with 16 ml of water to obtain 2.0 g of crude product of (2S,5S)-2,5-bis{4-[N-(2'-carboxyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0252] Step 5: Recrystallization: Add 8 ml of trifluoroacetic acid to the crude product obtained in the previous step and heat to 90°C. Filter the mixture, cool the filtrate, add 8 ml of glacial acetic acid, and further cool. Separate the solid material and rinse it with 8 ml of methanol, then rinse it with 8 ml of purified water, and dry it to obtain 1.4 g of a refined product of (2S,5S)-2,5-bis{4-[N-(2'-carboxyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0253]

[0254] MS: 575 (M+Na)

[0255] 1 H NMR ((400MHz, CDCl 3 )δ1.333~1.350(m,4H),1.484~1.501(m,4H),1.709~1.731(m,4H),3.221~3.236(m,4H),3.810-~3 .836(m,2H),8.006~8.073(m,6H),8.183~8.205(m,2H),8.373~8.400(m,2H),8.617~8.628(m,2H).

[0256] Embodiment 4:

[0257] Step 1: Dehydration cyclization reaction: 150 g of ε-benzyloxycarbonyl-L-lysine, 250 g of m-cresol, and 25 g of phosphorus pentoxide were added to a conical flask and heated to 200°C. Water was distilled off during the reaction, and then the reactants were cooled in a mixed solution of water and sodium hydroxide (10:1) to form a precipitate. The precipitate was separated and washed with 150 ml of ethanol, and filtered to obtain 103 g of the crude product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine. The obtained crude product was heated (100°C) in 500 ml of glacial acetic acid solution, and then 150 ml of purified water was added for cooling. Then, the crystals were rinsed with 250 ml of glacial acetic acid solution to obtain 56 g of a refined product of the intermediate (2S,5S)-2,5-bis[4-(N-benzyloxycarbonyl)aminobutyl]-3,6-diketopiperazine.

[0258] Step 2: Hydrogenation reaction: The product of the previous step is dissolved in 250 ml of glacial acetic acid solution, a catalyst (10% palladium / carbon) is added, and a hydrogenation reaction is carried out in a reactor filled with hydrogen. The obtained mixed solution is cooled and filtered. The filtrate is then distilled to remove the glacial acetic acid component, and the acetate of (2S,5S)-2,5-bis(4-aminobutyl)-3,6-diketopiperazine is obtained.

[0259] Step 3:

[0260]

[0261] Condensation reaction: Dissolve part of the product in DMF, add an equivalent of 3-methoxycarbonyl-5-methylbenzoic acid, two equivalents of triethylamine and an equivalent of HATU, and carry out the condensation reaction at room temperature. After the liquid phase detection shows that the raw material disappears, add 119 ml of water, and then separate the obtained solid substance to obtain 6.9 g of the solid crude product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-methyl)benzoyl]aminobutyl}-3,6-diketopiperazine. Add 24 ml of glacial acetic acid to the obtained solid crude product, and then add 24 ml of water to cool. After that, rinse the crystals with 12 ml of glacial acetic acid solution to obtain 4.1 g of the refined product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-methyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0262] MS: 609 (M+H).

[0263] Step 4: Saponification reaction: Add 22 ml of methanol and 2.2 g of sodium hydroxide to the product obtained in the previous step, heat to 70°C, filter, add glacial acetic acid and cool to room temperature. Separate the solid matter and rinse with 22 ml of water to obtain 2.7 g of crude product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-methyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0264] Step 5: Recrystallization: Add 10 ml of trifluoroacetic acid to the crude product obtained in the previous step and heat to 90°C. Filter the mixture, cool the filtrate, add 11 ml of glacial acetic acid, and further cool. Separate the solid material and rinse it with 11 ml of methanol, then rinse it with 11 ml of purified water, and dry it to obtain 1.9 g of a refined product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-methyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0265]

[0266] MS: 603 (M+Na).

[0267] 1 H NMR ((400MHz, CDCl 3 )δ1.333~1.351(m,4H),1.478~1.502(m,4H),1.650~1.702(m,4H),2.417(s,6H),3.215~3.245(m, 4H), 3.787~3.803(m,2H), 8.001~8.039(m,4H), 8.112(s,2H), 8.502~8.517(m,2H), 8.644(m,2H).

[0268] Embodiment 5:

[0269] Condensation reaction:

[0270]

[0271] Dissolve 10 g of the product in Example 4 in DMF, add an equivalent of 3-methoxycarbonyl-5-phenylbenzoic acid, two equivalents of triethylamine and an equivalent of HATU, and carry out a condensation reaction at room temperature. After the liquid phase detection shows that the raw material disappears, add 100 ml of water, and then separate the obtained solid substance to obtain 7.2 g of a solid crude product of (2S, 5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-phenyl)benzoyl]aminobutyl}-3,6-diketopiperazine. Add 28 ml of glacial acetic acid to the obtained solid crude product, and then add 28 ml of water to cool. After that, rinse the crystals with 15 ml of glacial acetic acid solution to obtain 3.5 g of a refined product of (2S, 5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-phenyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0272] MS: 734 (M+H).

[0273] Step 4: Saponification reaction: Add 25 ml of methanol and 2.0 g of sodium hydroxide to the product obtained in the previous step, heat to 70°C, filter, add glacial acetic acid and cool to room temperature. Separate the solid matter and rinse with 25 ml of water to obtain 3.5 g of crude product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-phenyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0274] Step 5: Recrystallization: Add 12 ml of trifluoroacetic acid to the crude product obtained in the previous step and heat to 90°C. Filter the mixture, cool the filtrate, add 12 ml of glacial acetic acid, and further cool. Separate the solid material and rinse it with 12 ml of methanol, then rinse it with 12 ml of purified water, and dry it to obtain 1.5 g of a refined product of (2S,5S)-2,5-bis{4-[N-(3'-methoxycarbonyl-5'-phenyl)benzoyl]aminobutyl}-3,6-diketopiperazine.

[0275]

[0276] MS: 705 (M+H)

[0277] 1 H NMR ((400MHz, CDCl 3 )δ1.329~1.348(m,4H),1.482~1.500(m,4H),1.673~1.699(m,4H),3.222~3.268(m,4H),3.793~3.816(m,2H),7.564 ~7.601(m,6H),8.000~8.023(m,4H),8.211(s,2H),8.413~8.447(m,2H),8.643~8.660(m,2H),8.904~8.965(m,4H).

[0278] Embodiment 6:

[0279] According to the method described in Example 1, 1.7 g of (2S,5S)-2,5-bis{4-[N-(3'-carboxylic acid-5'-cyclopentyl)benzoyl]aminobutyl}-3,6-diketopiperazine was prepared.

[0280]

[0281] MS: 711(M+Na)

[0282] 1 H NMR ((400MHz, CDCl 3)δ1.320~1.348(m,4H),1.491~1.522(m,4H),1.647~1.704(m,16H),2. 035~2.060(m,4H),2.626~2.663(m,4H),3.237~3.288(m,4H),3.821~3 .844(m,2H),7.564~7.611(m,6H),8.050(s,2H),8.204~8.232(m,2H), 8.325(s,2H),8.437(s,2H),8.655~8.687(m,2H),8.904~8.925(m,4H).

[0283] Embodiment 7:

[0284] According to the method described in Example 1, 2.1 g of (2S,5S)-2,5-bis{4-[N-(3'-carboxylic acid-5'-piperidinyl)benzoyl]aminobutyl}-3,6-diketopiperazine was prepared.

[0285]

[0286] MS: 719 (M+H)

[0287] 1 H NMR ((400MHz, CDCl 3 )δ1.343~1.370(m,4H),1.485~1.526(m,10H),1.660~1.689(m,4H),3.237~3.299(m,8H),3 .801~3.820(m,2H),7.530(s,2H),7.562(s,2H),7.783(s,2H),8.115(s,2H),8.632(m,2H).

[0288] Embodiment 8:

[0289] According to the method described in Example 1, 3.2 g of (2S,5S)-2,5-bis{4-{N-[3'-carboxylic acid-5'-(1H-tetrazolyl)]benzoyl}aminobutyl}-3,6-diketopiperazine was prepared.

[0290]

[0291] MS: 689 (M+H)

[0292] 1 H NMR ((400MHz, CDCl 3)δ1.302~1.324(m,4H),1.466~1.499(m,4H),1.692~1.717(m,4H),3.176~3.203(m,4H),3. 785~3.802(m,2H),7.994(s,2H),8.193(m,2H),8.678(m,2H),8.784(s,2H),9.089(s,2H).

[0293] Embodiment 9:

[0294] According to the method described in Example 1, 1.4 g of (2S,5S)-2,5-bis{4-{N-[3'-carboxylic acid-5'-fluoro-benzoyl}aminobutyl}-3,6-diketopiperazine was prepared.

[0295]

[0296] MS: 589 (M+H)

[0297] 1 H NMR ((400MHz, CDCl 3 )δ1.332~1.354(m,4H),1.476~1.491(m,4H),1.667~1.701(m,4H),3.199~3.225 (m,4H),3.774~3.803(m,2H),7.921~7.960(m,6H),8.298(m,2H),8.632(m,2H).

[0298] Embodiment 10:

[0299] According to the method described in Example 1, 2.2 g of (2S,5S)-2,5-bis{4-{N-[3'-carboxylic acid-5'-hydroxybenzoyl}aminobutyl}-3,6-diketopiperazine was prepared.

[0300]

[0301] MS: 585 (M+H)

[0302] 1 H NMR ((400MHz, CDCl 3 )δ1.333~1.360(m,4H),1.482~1.501(m,4H),1.653~1.692(m,4H),3.208~3.239(m,4H) ,3.881~3.900(m,2H),7.584~7.617(m,6H),8.235~8.259(m,2H),8.631~8.666(m,2H).

[0303] Embodiment 11:

[0304] According to the method described in Example 1, 1.5 g of (2S,5S)-2,5-bis{4-{N-[3'-carboxylic acid-5'-methoxybenzoyl}aminobutyl}-3,6-diketopiperazine was prepared.

[0305]

[0306] MS: 613 (M+H)

[0307] 1 H NMR ((400MHz, CDCl 3 )δ1.329~1.355(m,4H),1.490~1.514(m,4H),1.654~1.688(m,4H),3.207~3.243(m,4H),3.795(s,6H),3. 887~3.906(m,2H),7.216(s,2H),7.759(s,2H),7.899(s,2H),8.231~8.249(m,2H),8.621~8.646(m,2H).

[0308] Embodiment 12:

[0309] According to the method described in Example 1, 2.8 g of (2S,5S)-2,5-bis{4-{N-[3'-carboxylic acid-5'-dimethylaminobenzoyl}aminobutyl}-3,6-diketopiperazine was prepared.

[0310]

[0311] MS: 639 (M+H)

[0312] 1 H NMR ((400MHz, CDCl 3 )δ1.322~1.347(m,4H),1.501~1.536(m,4H),1.673~1.706(m,4H),3.183~3.211(m,4H),3.392(s,12H),3 .769~3.811(m,2H),7.567(s,2H),7.703(m,2H),7.937(m,2H),8.230~8.260(m,2H),8.701~8.730(m,2H).

[0313] Embodiment 13:

[0314] According to the method described in Example 1, 3.8 g of (2S,5S)-2,5-bis{4-{N-[3'-carboxylic acid-5'-dimethylaminobenzoyl}aminobutyl}-3,6-diketopiperazine was prepared.

[0315]

[0316] MS: 689 (M+H)

[0317] Embodiment 14:

[0318] Using ε-benzyloxycarbonyl-D-lysine as a starting material, 2.6 g of (2R,5R)-2,5-bis{4-[N-(3'-carboxylic acid)benzoyl]aminobutyl}-3,6-diketopiperazine was prepared according to the method described in Example 1.

[0319]

[0320] MS: 553 (M+H)

[0321] Example 15: Using ε-benzyloxycarbonyl-DL-lysine as the starting material, 3.5 g of (2S,5R)-2,5-bis{4-[N-(3'-carboxylic acid)benzoyl]aminobutyl}-3,6-diketopiperazine was prepared according to the method described in Example 1.

[0322]

[0323] MS: 553 (M+H).

[0324] Example 16 Evaluation of drug loading

[0325] Experimental purpose: Using dolutegravir (hereinafter referred to as Dol) as a model drug, a preliminary study on the drug loading capacity of FDKP and its derivatives was conducted.

[0326] Experimental method: accurately weigh 100 mg of FDKP or its derivative, add 15 mL of 1% ammonia water (v / v) to dissolve, and filter to remove insoluble substances; accurately weigh 70 mg of dolutegravir, add 1 mL of aqueous solution to dissolve, and add dropwise to the FDKP solution under magnetic stirring, and continue to adjust the pH to 5.0 with 10% glacial acetic acid aqueous solution (v / v), precipitate solid, filter, wash and dry to obtain Dol-FDKP-Der.

[0327] The solution obtained in the previous step is dissolved in an ammonium acetate solution, the pH is adjusted to completely dissolve, and the insoluble matter is removed by filtering the membrane. Then, the content of dolutegravir is detected by HPLC through area comparison.

[0328] The HPLC test method is as follows:

[0329] Chromatographic column: Ultimate XB-C18 (4.6×150mm, 3μm)

[0330] Flow rate: 1.0ml / min

[0331] Wavelength: 230nm Column temperature: 25℃

[0332] Mobile phase A: 0.1% phosphoric acid

[0333] Mobile phase B: acetonitrile

[0334] Time (min) Mobile phase A (%) Mobile phase B (%) 0.00 60 40 12.00 10 90 17.00 10 90 17.01 60 40 25.00 60 40

[0335] Experimental results: drug loading data results

[0336]

[0337]

[0338] As can be seen from the above, the representative compounds of the present invention all achieved a drug loading of more than 20%, showing good drug loading performance; and most of the compounds, such as compounds 1-4, 7-9, 11-12, 14-15, were better than the drug loading effect of FDKP; among them, the compounds of Examples 1, 7, 8, and 12 were significantly better than FDKP.

[0339] Example 17 Cytotoxicity

[0340] 1. Purpose of the experiment

[0341] The toxicity of FDKP and its derivatives on mouse fibroblasts (NIH / 3T3) was tested.

[0342] 2. Test materials:

[0343] Reagents: FDKP and its derivatives, MTT, DMSO, DEME medium, gibico serum, etc.

[0344] Equipment: 96-well plates, EP tubes, centrifuge tubes, etc.

[0345] 3. Experimental steps

[0346] 1. Preparation of FDKP and derivative solutions

[0347] Accurately weigh 15 mg of FDKP or its derivative and dissolve it in 3 ml of 5% basal culture medium to prepare an initial solution of 5 mg / ml, and continue to dilute it with 5% basal culture medium to 2.5 mg / ml, 1.25 mg / ml, 0.625 mg / ml, 0.313 mg / ml, 0.156 mg / ml, 0.078 mg / ml, and 0.039 mg / ml.

[0348] 2. MTT solution preparation

[0349] Weigh 10 mg of MTT and dissolve it in 2 ml of PBS solution to obtain an MTT solution with a concentration of 5 mg / ml.

[0350] 3. Specific test steps

[0351] 3T3 cells were diluted to an appropriate concentration, seeded in a 96-well plate at a density of 5000 cells per well (N=6), and cultured at 37°C and 5% CO2 for 12 hours.

[0352] Subsequently, the culture medium was removed, and 100 μl of culture medium containing different concentrations of FDKP or derivatives was added to each well, and the cells were cultured for 24 hours.

[0353] Remove the culture medium from each well, add 100ul of fresh culture medium and 10ul of MTT solution, and incubate at 37°C with 5% CO 2 The culture was continued for 4 hours.

[0354] Then, the solution in the wells was removed, and 150ul of DMSO was added, and the crystals were fully dissolved by shaking at room temperature. The OD value of each group was recorded at 490nm using an ELISA reader.

[0355] Cell viability was calculated according to the following formula:

[0356] Cell viability percentage (%) = [(OD experimental group - OD blank group) / (OD control group - OD blank group)] * 100%.

[0357] Cytotoxicity assay results

[0358]

[0359] As can be seen from the above, the representative compounds of the present invention all show low cytotoxicity, and except for compounds 7 and 11, they can achieve effects basically equivalent to FDKP; among them, Examples 1-3, 5-6, 8-11, and 13-15 are all greater than 70% at each concentration, and compounds 5, 11, and 14-15 are better than FDKP.

Claims

1. A diketopiperazine compound as shown in formula I or a pharmaceutically acceptable salt thereof, in, n1 and n2 are independently 0, 1, 2, 3 or 4; R a and R a 'Independently selected from halogen and -LR 1 ; -L- is selected from the group consisting of a linking bond, -O-, -S- and -N(R 2 ); R 2 Selected from H, C 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 The alkyl group; R 1 is selected from H, or the following groups optionally substituted by substituents: C 1 -C 8 Alkyl, C 2 -C 8 Heteroalkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl and 5-10 membered heteroaryl; the C 2 -C 8 In the heteroalkyl group, the heteroatom or heteroatom group is selected from one or more of N, O and S, the number of the heteroatom or heteroatom group is 1-3, and the group is connected to -L- through a carbon atom; the heteroatom in the 3-7 membered heterocycloalkyl group is selected from one or more of N, O and S, the number of the heteroatom is 1-3; the heteroatom in the 5-10 membered heteroaryl group is selected from one or more of N, O and S, the number of the heteroatom is 1-4; when there are multiple substituents, they are the same or different; The substituents are independently selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 Alkyl-O-; The carbon atom with "*" indicates that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.

2. The diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, It is characterized in that R a and R a The halogen in ' is independently fluorine or chlorine; or, R 2 C 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl group 1 -C 6 Alkyl and C substituted by one or more halogen 1 -C 6 The C in the alkyl 1 -C 6 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, R 2 is C substituted by one or more halogens 1 -C 6 When the alkyl group is alkyl, the halogen is fluorine or chlorine; or, R 1 is C optionally substituted by a substituent 1 -C 8 When the alkyl group 1 -C 8 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, R 1 is C optionally substituted by a substituent 6 -C 10 When the C 6 -C 10 Aryl is phenyl or naphthyl; or, R 1 is C optionally substituted by a substituent 3 -C 12 When cycloalkyl, the C 3 -C 12 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; or, R 1 When it is a 3-7 membered heterocycloalkyl group optionally substituted by a substituent, the 3-7 membered heterocycloalkyl group is morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl, 1,4-dioxanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridine, diazepanyl or pyrazolidinyl; or, R 1 When it is a 5-10 membered heteroaryl group which is optionally substituted by a substituent, the 5-10 membered heteroaryl group is furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl or triazinyl; Or, R 1 When the substituents described in 1 are independently halogen, the halogen is fluorine or chlorine; or, R 1 The substituents are independently C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl-O- 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, and C substituted by one or more halogen 1 -C 6 The C in the alkyl-O- 1 -C 6 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, R 1 The substituents are independently C substituted by one or more halogens. 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl-O- is alkyl-O-, the number of the halogen is 1-3; or, R 1 The substituents are independently C substituted by one or more halogens. 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl-O- is alkyl-O-, the halogen is fluorine or chlorine; Or, n1 and n2 are independently 0 or 1; Or, -L- is selected from a linking bond, -O- or -N(R 2 )-; or, R 2 H or C 1 -C 6 The alkyl group; or, R 1 is selected from H, or the following groups optionally substituted by substituents: C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; or, R 1 The substituent described in is halogen; or, -LR 1 Selected from hydroxyl, C 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C 1 -C 8 Alkyl-N(C 1 -C 6 alkyl)-, C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; or, R a and R a 'same or different; or, for or, for or, The configuration is Alternatively, the pharmaceutically acceptable salt is a monovalent alkali metal salt and / or a divalent alkaline earth metal salt.

3. The diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 2, It is characterized in that R 2 C 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl group 1 -C 6 Alkyl and C substituted by one or more halogen 1 -C 6 The C in the alkyl 1 -C 6 The alkyl groups are independently methyl; or, R 1 is C optionally substituted by a substituent 1 -C 8 When the alkyl group 1 -C 8 The alkyl groups are independently methyl; or, R 1 is C optionally substituted by a substituent 6 -C 10 When the C 6 -C 10 Aryl is phenyl; or, R 1 is C optionally substituted by a substituent 3 -C 12 When cycloalkyl, the C 3 -C 12 Cycloalkyl is cyclopentyl; or, R 1 When it is a 3-7 membered heterocycloalkyl group optionally substituted by a substituent, the 3-7 membered heterocycloalkyl group is or, R 1 When it is a 5-10 membered heteroaryl group which is optionally substituted by a substituent, the 5-10 membered heteroaryl group is or, R 1 The substituents are independently C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, or C substituted by one or more halogen 1 -C 6 When the alkyl-O- 1 -C 6 Alkyl, C 1 -C 6 Alkyl-O-, C substituted by one or more halogen 1 -C 6 Alkyl, and C substituted by one or more halogen 1 -C 6 The C in the alkyl-O- 1 -C 6 The alkyl groups are independently methyl; or, R 2 C 1 -C 6 The alkyl group; or, R 1 Selected from H, C substituted by halogen 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; or, R a and R a 'same; or, for or, The configuration is Or, the monovalent alkali metal is Na + , K + and Li + One or more of .

4. The diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 2, It is characterized in that When the pharmaceutically acceptable salt is a divalent alkaline earth metal salt, the divalent alkaline earth metal is Mg 2+ and / or Ca 2+ .

5. The diketopiperazine compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that R a and R a ' is independently selected from H, fluorine, hydroxy, methyl, methoxy, trifluoromethyl, Cyclopentyl, phenyl or or, for or, for Or, n1 and n2 are independently 0 or 1; or, same.

6. The diketopiperazine compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that The diketopiperazine compound as shown in Formula I is any of the following schemes: Solution 1: for n1 and n2 are independently 0 or 1; R a and R a 'Selected from halogen and -LR 1 ; -L- is selected from a linking bond, -O-, -S- or -N(R 2 )-; R 2 H or C 1 -C 6 The alkyl group; R 1 is selected from H, or the following groups optionally substituted by a substituent: C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; same; Solution 2 for n1 and n2 are independently 0 or 1; R a and R a 'Independently selected from halogen and -LR 1 ; -LR 1 Selected from hydroxyl, C 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C 1 -C 8 Alkyl-N(C 1 -C 6 alkyl)-, C 1 -C 8 Alkyl, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl, 3-7 membered heterocycloalkyl, and 5-10 membered heteroaryl; same; Solution 3 for n1 and n2 are independently 0 or 1; R a and R a 'Independently selected from halogen and -LR 1 ; -LR 1 Selected from H, OH, C 1 -C 8 Alkyl, C substituted by one or more halogen 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C 6 -C 10 Aryl, C 3 -C 12 Cycloalkyl and 5-10 membered heteroaryl; same; Solution 4: for n1 and n2 are independently 0 or 1; R a and R a 'Independently selected from halogen and -LR 1 ; -LR 1 Selected from C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 1 -C 8 Alkyl-O- and C substituted by one or more halogen 1 -C 8 The alkyl group; Same; Solution 5: for n1 and n2 are independently 0 or 1; R a and R a 'Independently selected from halogen and -LR 1 ; -LR 1 Selected from H, OH, C 1 -C 8 Alkyl, C 1 -C 8 Alkyl-O-, C substituted by one or more halogen 1 -C 8 Alkyl, -N(R 2 )-C 1 -C 8 Alkyl, C 3 -C 12 Cycloalkyl, C 2 -C 8 heteroalkyl and 5-10 membered heteroaryl; R 2 Select from H or C 1 -C 6 The alkyl group; same; Solution 6: for n1 and n2 are independently 0 or 1; R a and R a 'Independently selected from halogen and -LR 1 ; -LR 1 Selected from H, C 1 -C 8 Alkyl, C 2 -C 8 heteroalkyl, 5-10 membered heteroaryl, C 1 -C 8 The alkyl-O- and -N(R 2 )-C 1 -C 8 Alkyl; R 2 Selected from H and C 1 -C 6 The alkyl group; same; Solution 7 for n1 and n2 are independently 0 or 1; R a and R a 'Independently selected from halogen and -LR 1 ; -LR 1 Selected from H, C 1 -C 8 Alkyl-O- and 5-10 membered heteroaryl; same.

7. The diketopiperazine compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that The diketopiperazine compound as shown in formula I is selected from any of the following structures:

8. A pharmaceutical composition, It is characterized in that It comprises a diketopiperazine compound as shown in formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, and one or more active pharmaceutical ingredients.

9. The pharmaceutical composition according to claim 8, It is characterized in that The pharmaceutical composition is a microsphere drug delivery system; Or, the weight percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 10% to 90%; Or, the active ingredient of the drug is a poorly soluble drug; Alternatively, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 8, It is characterized in that The active pharmaceutical ingredient is a cationic drug, anionic drug or polypeptide with an API molecular weight of 500-140000Da.

11. The pharmaceutical composition according to claim 8, It is characterized in that The active ingredient of the medicine is a hydrophilic / lipidic drug with an API molecular weight of 500-140000Da.

12. The pharmaceutical composition according to claim 8, It is characterized in that The active ingredient of the medicine is a protein with an API molecular weight of 500-140000Da.

13. The pharmaceutical composition according to claim 8, It is characterized in that The active ingredient of the medicine is a small molecule drug with an API molecular weight of 500-140000Da.

14. The pharmaceutical composition according to any one of claims 8 to 13, It is characterized in that The diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7 is a self-assembled microsphere; Or, the weight percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 20% to 80%; Or, the active ingredient of the drug is a poorly soluble drug, and the poorly soluble drug is selected from insulin, dolutegravir and sildenafil; Alternatively, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, and the pharmaceutical excipient is a lyophilized excipient.

15. The pharmaceutical composition according to claim 14, It is characterized in that The freeze-drying excipient is at least one of lactose, mannose, sucrose, trehalose, fructose, glucose, sodium alginate and gelatin.

16. Use of a diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 as a preparation excipient.

17. Use of the diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 16 as a preparation excipient; the diketopiperazine compound of formula I or a pharmaceutically acceptable salt thereof forms drug-loaded microspheres.

18. A method for preparing the pharmaceutical composition according to any one of claims 8 to 15, It is characterized in that The method comprises the following steps: adding a solution containing the active pharmaceutical ingredient into an alkaline solution containing the diketopiperazine compound shown in formula I or a pharmaceutically acceptable salt thereof, and adjusting the pH to precipitate a solid to obtain the pharmaceutical composition.

19. A method for preparing the pharmaceutical composition according to claim 18, It is characterized in that The mass ratio of the active pharmaceutical ingredient to the diketopiperazine compound or its pharmaceutically acceptable salt as shown in Formula I is 7:

10.

20. A method for preparing the pharmaceutical composition according to claim 18, It is characterized in that The alkaline solution is obtained by adding 1% v / v ammonia water.

21. A method for preparing the pharmaceutical composition according to claim 18, It is characterized in that The pH is 5.

0.

22. A method for preparing the pharmaceutical composition according to claim 18, It is characterized in that The pH is adjusted by adding a 10% v / v glacial acetic acid aqueous solution.

23. A method for preparing the pharmaceutical composition according to claim 18, It is characterized in that The obtained pharmaceutical composition is filtered, washed and then dried.

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