WO2019020099A1 - 一种硼酸酯化合物、其合成方法及其用途 - Google Patents
一种硼酸酯化合物、其合成方法及其用途 Download PDFInfo
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- WO2019020099A1 WO2019020099A1 PCT/CN2018/097360 CN2018097360W WO2019020099A1 WO 2019020099 A1 WO2019020099 A1 WO 2019020099A1 CN 2018097360 W CN2018097360 W CN 2018097360W WO 2019020099 A1 WO2019020099 A1 WO 2019020099A1
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- Prior art keywords
- compound
- acid
- amino
- bromo
- methyl
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- -1 Borate compound Chemical class 0.000 title abstract description 33
- 238000001308 synthesis method Methods 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 229940079156 Proteasome inhibitor Drugs 0.000 claims abstract description 14
- 239000003207 proteasome inhibitor Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 86
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 38
- 206010028980 Neoplasm Diseases 0.000 claims description 37
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 14
- 229960004889 salicylic acid Drugs 0.000 claims description 14
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 13
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 13
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 12
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Chemical group OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 10
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical group O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 8
- 229960002510 mandelic acid Drugs 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012317 TBTU Substances 0.000 claims description 6
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 239000004310 lactic acid Chemical group 0.000 claims description 6
- 235000014655 lactic acid Nutrition 0.000 claims description 6
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 claims description 5
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- DIXMBHMNEHPFCX-MCMMXHMISA-N (2r)-2-[5-[6-amino-5-[(1r)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol Chemical compound O([C@H](C)C=1C(=CC=C(F)C=1)N1N=CC=N1)C(C(=NC=1)N)=CC=1C=1SC([C@](C)(O)CO)=NC=1C DIXMBHMNEHPFCX-MCMMXHMISA-N 0.000 claims description 4
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 claims description 4
- DMQYDVBIPXAAJA-VHXPQNKSSA-N (3z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1h-imidazol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1CN(CC)CCC1NC1=CC=C(NC(=O)\C2=C(/C=3NC=C(C)N=3)C=3C=C(F)C=CC=3)C2=C1 DMQYDVBIPXAAJA-VHXPQNKSSA-N 0.000 claims description 4
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 4
- LVHOHZHTZXRVRJ-CMDGGOBGSA-N (e)-3-(3-methoxyphenyl)-n-(3,4,5-trimethoxyphenyl)prop-2-enamide Chemical compound COC1=CC=CC(\C=C\C(=O)NC=2C=C(OC)C(OC)=C(OC)C=2)=C1 LVHOHZHTZXRVRJ-CMDGGOBGSA-N 0.000 claims description 4
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- 125000000524 functional group Chemical group 0.000 claims description 4
- 229960000448 lactic acid Drugs 0.000 claims description 4
- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 claims description 4
- PHHRKRGXWSEXFZ-UHFFFAOYSA-N n-(pyridin-3-ylmethyl)-3-[[2-[(2,3,4-trifluorophenoxy)methyl]-1,3-benzoxazol-4-yl]oxy]propan-1-amine Chemical compound FC1=C(F)C(F)=CC=C1OCC(OC1=CC=C2)=NC1=C2OCCCNCC1=CC=CN=C1 PHHRKRGXWSEXFZ-UHFFFAOYSA-N 0.000 claims description 4
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- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- IDOJPCDZTOWXOK-HZMBPMFUSA-N 2-bromo-5-chloro-N-[2-[[(1R)-3-methyl-1-[(4S)-4-methyl-5-oxo-1,3,2-dioxaborolan-2-yl]butyl]amino]-2-oxoethyl]benzamide Chemical compound BrC1=C(C(=O)NCC(=O)N[C@@H](CC(C)C)B2OC([C@@H](O2)C)=O)C=C(C=C1)Cl IDOJPCDZTOWXOK-HZMBPMFUSA-N 0.000 claims description 3
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- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the field of chemical medicines, and in particular to a borate ester compound suitable for use as a proteasome inhibitor. Another aspect of the invention relates to a method of synthesizing the compound and the use thereof for the preparation of a medicament for the treatment of cancer.
- Boric acid and borate compounds exhibit a variety of biological activities that are pharmaceutically suitable due to their unique structural characteristics.
- the proteasome is an important component of the ubiquitin-proteasome system, responsible for the regulation and degradation of proteins in most cells, and plays a central role in regulating cell cycle, cell proliferation and apoptosis.
- Boricezomib boratezomib (trade name: Is the first market-targeted proteasome inhibitor approved by the FDA in 2003.
- the new anti-tumor drug developed by Millennium Pharmaceuticals of the United States is a freeze-dried powder for injection for the treatment of recurrent and refractory multiple Myeloma. Bortezomib can selectively bind to threonine at the active site of the proteasome, degrade and alter the regulatory protein levels in the body, destroy cell stability, and cause tumor cell death.
- Ixazomib Citrate (MLN9708, trade name: ), a second-generation proteasome inhibitor developed by Millennium Pharmaceuticals based on bortezomib, was approved by the US FDA on November 20, 2015 for the treatment of multiple myeloma (MM). It preferentially binds to and inhibits the chymotrypsin-like proteolytic ( ⁇ 5) site of the 20S proteasome, and inhibits proliferation of the myeloma cells by blocking the protease.
- the borate ester compound MLN9708 is rapidly hydrolyzed in vivo to the active boric acid structure MLN2238 to exert pharmacological activity. Due to the conversion of unstable boronic acid groups into a stable borate structure, MLN9708 has the greatest advantage over MLN2238 and Bortezomib in changing the injectable dosage form into an oral capsule dosage form, which greatly improves patient compliance.
- the synthesis of MLN9708 is obtained by one-step reaction of MLN2238 with citric acid. Since the citric acid structure has the characteristics of both ⁇ -hydroxycarboxylic acid and ⁇ -hydroxycarboxylic acid, it has a plurality of sites which can react with boric acid, resulting in the presence of a six-membered cyclic borate structure and a five-membered cyclic boronic acid in MLN9708. There are two possibilities for the ester structure, which brings great difficulties to the purification and purification of MLN9708, and the production cost is greatly improved.
- Patent Document CN103435638A discloses a compound (8l) having the following structure in the examples.
- the present invention provides a boric acid ester compound of the formula I or a pharmaceutically acceptable salt thereof:
- X 1 and X 2 together form a cyclic moiety formed by removing a hydrogen atom from two functional groups of a borate esterifying agent, the cyclic moiety being a boron atom directly bonded to two oxygen atoms and covalent with other fragments optionally substituted rings;
- Ring A is selected from one of the following fragments:
- ring A when ring A is selected from The ⁇ -hydroxy acid and the ⁇ -hydroxy acid do not include citric acid, malic acid, and tartaric acid.
- the borating agent is R 3 —NH—R 4
- it may be imino dicarboxylic acid, iminodiacetic acid, iminodipropionic acid, N-carboxy-2-acetic acid amine or N-acetic acid-3. - Propionate and the like. Therefore, R 3 and R 4 may be the same or different.
- the X 1 and X 2 together form a cyclic moiety formed by removing a hydrogen atom from two functional groups of a borating acidulant, and is a 5-12 membered ring.
- it may be a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring.
- the borating agent is selected from one of salicylic acid, mandelic acid, lactic acid or iminodiacetic acid substituted or unsubstituted by a substituent; the substituent is selected from the group consisting of halogen, amino, C1 One or more of an alkyl group of -6, a C3-C8 cycloalkyl group, a C2-C6 carboxyalkyl group or a C1-6 hydroxyalkyl group;
- the phenyl group in the salicylic acid or mandelic acid substituted or unsubstituted as a substituent of the borate esterifying agent is hydrogenated or partially hydrogenated.
- the mandelic acid is preferably R-mandelic acid or S-mandelic acid, and may also be racemic DL-mandelic acid; the lactic acid is preferably L-lactic acid.
- the borating agent is a substituted or unsubstituted salicylic acid, mandelic acid or lactic acid, preferably salicylic acid or R-mandelic acid; the substituent is selected from the group consisting of halogen, amino, C1 One or more of an alkyl group of -6, a carboxyalkyl group of C2-C6 or a hydroxyalkyl group of C1-6.
- ring A is selected from
- the borating agent is a substituted or unsubstituted salicylic acid, R-mandelic acid or L-lactic acid;
- the substituent is selected from the group consisting of halogen, amino, C1-6 alkyl, C2 One or more of -C6 carboxyalkyl or C1-6 hydroxyalkyl;
- the phenyl group in the salicylic acid or R-mandelic acid substituted or unsubstituted as a substituent of the borate esterifying agent is hydrogenated or partially hydrogenated.
- the compound of the invention is selected from the group consisting of:
- Another aspect of the invention provides a process for the preparation of a compound of formula I, which process comprises the following synthetic steps:
- rings A, X 1 and X 2 are as described above;
- a compound of formula V is obtained by condensation with a chiral alpha-amino boronate compound (formula IV) to give a compound of formula III; preferably, in formula IV, R 1 and R 2 are independently selected from a hydrogen atom, substituted by a substituent or not Substituted C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C7-18 arylalkyl, substituted or unsubstituted C3-15 ring Alkyl, substituted or unsubstituted C4-10 cycloalkylalkyl, substituted or unsubstituted 5-15 membered heteroaryl or substituted or unsubstituted 6-21 membered heteroaryl Or a combination of a boron atom and an oxygen atom to which R 1 and R 2 are bonded to form a 5-10 membered carbocyclic ring which is substituted or unsubstituted with a substituent
- the condensation reaction carried out in the step a) is one of TBTU, EDCI/HOBT, DCC/HOBT, and the reaction solvent is one of dichloromethane, DMF, THF or a mixed solvent of the two;
- the base used in the saponification reaction carried out in a) is LiOH, NaOH or KOH, preferably NaOH, and the reaction solvent is a mixed solvent of ethanol and water;
- the condensation reaction used in the step b) is one of TBTU, EDCI/HOBT, DCC/HOBT, preferably EDCI/HOBT;
- the reaction solvent is one of dichloromethane, DMF, THF or both a mixed solvent, preferably dichloromethane; in the compound of formula IV, R 1 and R 2 are combined
- the reaction solvent in the step c) is preferably methanol / n-hexane, or methanol / n-heptane;
- the inorganic acid is selected from any one or a combination of hydrochloric acid, sulfuric acid, nitric acid, preferably hydrochloric acid;
- the reaction solvent is one of ethyl acetate, THF, acetone, dichloromethane, n-hexane, heptane or a mixed solvent of the two, preferably ethyl acetate or ethyl acetate mixed with n-hexane Solvent; reaction temperature is from 0 ° C to 100 ° C, preferably from 30 ° C to 75 ° C.
- condensation reaction carried out in said steps a) and b) is carried out in the presence of an organic base, preferably DIPEA;
- the reaction solvent is preferably a mixed solvent of methanol and n-hexane or a mixture of methanol and n-heptane.
- the cancer treating drug is a proteasome inhibitor drug.
- the proteasome inhibitor anticancer drug includes: a drug for preventing and/or treating plasmacytoma, such as multiple myeloma; and a drug for preventing and/or treating lymphoma, such as non-Hodgkin's lymphoma, a set A drug for cell lymphoma and/or follicular lymphoma; and a drug for preventing and treating breast cancer, colon cancer, lung cancer, kidney cancer, cervical cancer, nasopharyngeal cancer.
- the present invention still further provides a pharmaceutical composition or pharmaceutical preparation comprising the compound of the present invention.
- the compounds described herein can be administered in pure form, in combination with other active ingredients, or in combination with pharmaceutically acceptable non-toxic excipients or carriers.
- alkyl refers herein to a saturated aliphatic hydrocarbyl group having from 1 to 6 carbon atoms, and the term includes both straight-chain and branched hydrocarbyl groups.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
- cycloalkyl refers to a cyclic alkyl group having from 3 to 8 carbon atoms having a single or multiple ring (including fused, bridged, and spiro ring systems).
- Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- substituted refers to the degree to which a group is mono- or polysubstituted by a given substituent to such a mono- or poly-substitution (including multiple substitutions in the same moiety), each substituent being Located at any available position on the group and may be attached through any available atom on the substituent. "Any position that is available” means that it is chemically obtainable by methods known in the art or as taught herein, and does not create any position on the group of molecules that are excessively unstable. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different.
- the substituent refers to a group consisting of hydrogen, fluorine, chlorine, bromine, iodine, nitro, amino, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethyl.
- compound of the invention refers herein to a compound as claimed and all pure nitrogen oxides, sulfur oxides, solvates, and isotopically labeled compounds thereof, and any pharmaceutically acceptable compound thereof. Acceptable salt.
- the solvate of the compound of the present invention means a compound or a salt thereof, such as a hydrate, an ethanolate, a methanolate or the like, in combination with a stoichiometric and non-stoichiometric solvent.
- the compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.
- the borate ester compound of the present invention may further form a salt, for example, a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
- a salt for example, a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
- a salt for example, a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
- a salt for example, a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
- basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including chlorides, bromides and iodines of methyl, ethyl, propyl and butyl groups.
- a dialkyl sulfate including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long chain halides, including sulfhydryl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
- the invention also includes isotopically-labeled compounds of the invention, i.e., identical to those disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons.
- isotopes incorporating compounds of the invention include isotopes of hydrogen, carbon, oxygen, sulfur, fluorine, chlorine, iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, respectively. , 18 F, 36 Cl and 131 I, etc.
- pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal to which it is treated.
- the "pharmaceutical preparation” referred to in the present invention may be a pharmaceutical composition of the invention directly or in combination with other active ingredients, in combination with a pharmaceutically acceptable adjuvant or carrier.
- the formulations include: tablets, pills, capsules, granules and suspensions, and emulsions and the like.
- the pharmaceutically acceptable adjuvant or carrier comprises: a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose; a dispersing agent such as alginic acid, Primogel or corn starch; a lubricant such as stearic acid.
- glidants such as colloidal silica
- sweeteners such as sucrose or saccharin
- flavoring agents such as peppermint oil, methyl salicylate or orange flavor
- non-aqueous solvents such as dimethyl sulfoxide, alcohol, propylene glycol , polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate
- aqueous carriers such as mixtures of alcohols and water, buffered media and saline; and preservatives, antibacterials, antioxidants, chelating agents, dyes , pigments or spices.
- the condensing agent TBTU described in the present invention means O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate;
- the condensing agent EDCI/HOBT means 1-(3-two) Methylaminopropyl)-3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole;
- condensing agent DCC/HOBT refers to dicyclohexylcarbodiimide/1-hydroxybenzotriazole .
- the DIPEA described in the present invention is diisopropylethylamine.
- the solvent DMF described in the present invention is dimethylformamide, and the THF is tetrahydrofuran.
- the "/" used in the present invention between the two reagents means a mixture of the two reagents.
- the boric acid ester compound of the present invention has the advantages of high activity and high safety as compared with the conventional borate ester compound used as a proteasome inhibitor. Moreover, the borate ester compound of the present invention is easier to synthesize and purify, and the production cost can be effectively saved.
- the compounds of the invention have better stability.
- the compounds of the invention 8b, 8a and the like have better stability under high temperature and high humidity accelerated test conditions.
- Figure 1 shows the mean tumor volume as a function of administration time for the MM.1S human multiple myeloma SCID mouse xenograft model with various proteasome inhibitors administered.
- Figure 2 shows the mean tumor weight of various proteasome inhibitors against the MM.1S human multiple myeloma SCID mouse xenograft model.
- the chemical and biological agents used as raw materials in the specific embodiments of the present invention are all commercially available.
- the two phases were separated, and the methanol phase was washed twice with 100 mL ⁇ 2 n-hexane, then the methanol phase was concentrated at least, and 100 mL of dichloromethane was added and mixed.
- reaction raw material diethanolamine is not easily removed in the post-treatment, and is easily carried into the product 8d.
- compound 8d is hydrolyzed and easily hydrolyzed in the body to produce diethanolamine, which is a second-class carcinogen published by the World Health Organization (http://www.sda.gov.cn/WS01/CL1991/215896.html).
- the cells RPMI-8226 (human multiple myeloma cells) and MM.1S (human multiple myeloma cells) were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37 ° C under 5% CO 2 . To logarithmic growth period. The cells were seeded into 96-well culture plates at a number of 3 ⁇ 10 4 /well, respectively. After incubation for 24 hours at 37 ° C, 5% CO 2 , solvent control DMSO (dimethyl sulfoxide) or test compound dissolved in DMSO (test compound at a concentration of 0.3 ⁇ M, diluted each time) was added to the cells. 3 times, a total of 5 dilutions gave 6 concentration gradients).
- solvent control DMSO dimethyl sulfoxide
- test compound dissolved in DMSO test compound at a concentration of 0.3 ⁇ M, diluted each time
- Test compounds were incubated with cells for 48 hours at 37 ° C, 5% CO 2 .
- CCK-8 reagent was added to each well, and incubated at 37 ° C for 2 hours as required by the reagent instructions, and the optical density values of the respective wells were read using a spectrophotometer at a wavelength of 450 nm.
- the cell optical density value at which the drug acts at 0 is set to a Tz value, which represents the value of the cell at the time of drug addition.
- the cell optical density value of the solvent control DMSO for 48 hours was taken as the C value; the cell optical density value of the test compound for 48 hours was set to the Ti value.
- the GI50 value concentration of the test compound required for the cell growth inhibition rate of 50%
- the activity data is shown in Table 1 below.
- a SCID mouse xenograft model of the human multiple myeloma cell line MM.1S was used.
- the specific modeling steps were as follows: The frozen MM.1S cells were cultured in vitro after resuscitation, and the cells were collected in the logarithmic growth phase and diluted with PBS into a tumor cell suspension having a concentration of 5 ⁇ 10 7 /ml.
- the above prepared tumor cell suspension was injected into the underarm subcutaneous side of a 5 week old SCID mouse, and the body weight was 16-18 g, and the whole female was injected with 0.2 ml per inoculation site.
- the tumor is touched by the armpit, and the passage is carried out in vivo when the tumor volume is greater than 500 mm 3 or more.
- the body surface was disinfected, the skin was cut, and the skin was aseptically operated.
- the tumor tissue was peeled off from the ankle, the fibrous capsule was removed, the tumor was taken out, washed in physiological saline, and then cut and removed.
- the necrotic part of the center was selected as a tumor tissue with good growth, pale red and fish-like shape, cut into small pieces of 1 mm ⁇ 1 mm ⁇ 1 mm, and placed in physiological saline for use.
- the cut tumor block was placed in the 18-gauge needle needle, and the iodine cotton sterilized mouse was placed under the backrest side and locally inoculated.
- the transplanted tumor used in this trial was the fourth passage in vivo.
- the tumor volume of most in vivo passaged SCID mice was as long as 100 mm 3 or more, the tumor volume was measured and calculated, and randomized according to the tumor volume.
- the administration method is oral gavage administration, and the administration volume is 10 ml/kg.
- the model group was given an equal volume of vehicle for gavage. All were administered orally by intragastric administration twice a week for 5 times, that is, on the first, fifth, eighth, twelfth, and fifteenth days of the experiment, and the time course was 18 days.
- the doses of the different samples were all equimolar doses, and the specific dose was 0.0166 mmol/kg; the model group was given only normal saline.
- the drugs were: 8b, 8l, and Ixazomib Citrate (MLN9708), Ixazomib (MLN2238).
- T RTV treatment group RTV
- C RTV model control group RTV.
- the tumors were weighed and the animals in each group were sacrificed, and the tumors were dissected and weighed.
- Figure 1 shows the mean tumor volume as a function of dosing time for the MM.1S human multiple myeloma SCID mouse xenograft model with various proteasome inhibitors administered. It can be seen that the initial average tumor volume is about 500 mm 3 before administration.
- the mean relative tumor volume (RTV) and relative tumor proliferation rate T/C (%) of each group during the test are given in Tables 2 and 3, respectively.
- ⁇ Compared with the 8b group in the same period, p ⁇ 0.05, ⁇ : compared with the 8b group in the same period, p ⁇ 0.01
- Table 4 shows the mean tumor weight of each group after the 18th day of administration.
- Figure 2 gives a comparative bar graph of the mean tumor weight for each group.
- Proteasome inhibitor anti-MM.1S human multiple myeloma SCID mouse xenograft model mean tumor weight ( g)
- the compound 8b of the present invention significantly inhibited the tumor growth of the MM.1S human multiple myeloma SCID mouse xenograft, and its inhibitory effect on tumor growth was significantly stronger than that of the comparative compound 8l (p ⁇ 0.01), Ixazomib (MLN9708) (p ⁇ 0.01) and Ixazomib active form (MLN2238) (p ⁇ 0.01), the difference was significant.
- This test is a single administration toxicity test of SD rats by oral gavage.
- 252 SD rats were randomly divided into 21 groups according to body weight, 12 animals in each group, male and female, respectively, solvent control group, MLN2238 dose 1, 2, 3, 4, MLN9708 dose 1, 2, 3, 4 , 8l dose 1, 2, 3, 4, 8d dose 1, 2, 3, 4, 8b dose 1, 2, 3, 4, the same sample of the same sample of the same dose of the same molar dose, dose 1
- the doses of groups 2, 3, and 4 were 0.001108, 0.001662, 0.002216, and 0.00277 mmol/kg, respectively.
- Each group was intragastrically administered once, and the withdrawal was resumed for 14 days. The death of the rats was as shown in Table 5.
- hERG electrophysiological results can be used to assess potential QT interval risks in compounds. It is a relatively safe range when the drug hERG semi-inhibitory concentration exceeds about 30 times its peak concentration in blood (Redferneltal, Cardiovascular Research, 58, 32-45 (2003)).
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Abstract
一种适用作蛋白酶体抑制剂的硼酸酯化合物,以及所述硼酸酯化合物的制备方法及用途。
Description
本发明涉及化学药物领域,具体而言,涉及一种适用作蛋白酶体抑制剂的硼酸酯化合物。本发明另一方面涉及该化合物的合成方法及其制备癌症治疗药物的用途。
硼酸及硼酸酯类化合物由于其独特的结构特征,呈现出医药学上适用的多种生物活性。蛋白酶体是泛素-蛋白酶体系统的重要组成部分,负责大多数细胞内蛋白质的调节和降解,在调节细胞周期、细胞增殖和细胞凋亡方面起核心作用。硼酸类药物硼替佐米(Bortezomib,商品名:
)是2003年被FDA批准的第一个上市靶向蛋白酶体抑制剂,由美国Millennium制药公司研发的新型抗肿瘤药物,为注射用冻干粉针,用于治疗复发性和难治性多发性骨髓瘤。硼替佐米可以选择性的与蛋白酶体活性位点的苏氨酸结合,降解并改变机体内调节蛋白水平,破坏细胞稳定性,导致肿瘤细胞死亡。
Ixazomib Citrate(MLN9708,商品名:
),是Millennium制药公司基于硼替佐米基础上开发的第二代蛋白酶体抑制剂,于2015年11月20日由美国FDA批准上市,用于治疗多发性骨髓瘤(Multiple myeloma,MM)。其可优先结合及抑制20S蛋白酶体的糜蛋白酶样蛋白水解(β5)位点,通过阻断蛋白酶来抑制从发性骨髓瘤细胞增殖。硼酸酯化合物MLN9708作为一个前药,在体内迅速水解为活性硼酸结构MLN2238发挥药理活性。由于将不稳定的硼酸基团转化为性质稳定的硼酸酯结构,MLN9708与MLN2238及Bortezomib相比,其最大的优势是将注射剂型改为口服胶囊剂型,极大的改善了患者药物依从性。
根据当前已有的专利文献WO2009154737、CN102066386A、CN103435638A等报道,MLN9708的合成通过MLN2238与柠檬酸一步反应得到。由于柠檬酸结构兼具α-羟基羧酸和β-羟基羧酸的特点,因此其有多个可以与硼酸反应的位点,从而导致MLN9708存在六元环硼酸酯结构和五元环硼酸酯结构两种可能,这给MLN9708的精制纯化带来很大的困难,生产成本大幅度提升。
另外,专利文献CN103435638A在实施例中公开了一种如下结构的化合物(8l)。
现有技术中,仍然存在获得一种更易于精制纯化,同时具有更高的生物活性和安全性的新的硼酸酯化合物以将其用于治疗癌症的需要。
发明内容
为了解决上述技术问题,本发明提供了一种如式I所示的硼酸酯化合物或其药学上可接受的盐:
其中,X
1和X
2共同形成通过与硼酸酯化剂的两个官能团去除氢原子后所形成的环状部分,该环状部分是硼原子直接与两个氧原子连接并和其他片段共同组成的任选取代的环;所述硼酸酯化剂选自α-羟基酸、β-羟基酸、氨基酸或R
3-NH-R
4,所述R
3和R
4独立地选自-(CH
2)
nCOOH,n=0、1、2、3、4或5;
环A选自以下片段之一:
当所述硼酸酯化剂为R
3-NH-R
4时,可以是亚氨基二甲酸、亚氨基二乙酸、亚氨基二丙酸、N-羧基-2-乙酸胺或N-乙酸-3-丙酸胺等。因此,R
3和R
4可以相同也可以不同。
优选地,所述X
1和X
2共同形成通过与硼酸酯化剂的两个官能团去除氢原子后所形成的环状部分,为5-12元环。例如可为5元环、6元环、7元环、8元环、9元环、10元环、11元环、12元环。
优选地,所述硼酸酯化剂选自被取代基取代或未被取代的水杨酸、扁桃酸、乳酸或亚氨基二乙酸中的一种;所述取代基选自卤素、氨基、C1-6的烷基、C3-C8环烷基、C2-C6的羧烷基或C1-6的羟烷基中的一种或多种;
任选地,作为所述硼酸酯化剂的被取代基取代或未被取代的水杨酸或扁桃酸中的苯基被氢化或部分氢化。
所述扁桃酸优选为R-扁桃酸或S-扁桃酸,也可为消旋的DL-扁桃酸;所述乳酸优选为L-乳酸。
优选地,当环A为
时,所述硼酸酯化剂为被取代基取代或未被取代的水杨酸、扁桃酸或乳酸,优选为水杨酸或R-扁桃酸;所述取代基选自卤素、氨基、C1-6的烷基、C2-C6的羧烷基或C1-6的羟烷基中的一种或多种。
任选地,作为所述硼酸酯化剂的被取代基取代或未被取代的水杨酸或R-扁桃酸中的苯基被氢化或部分氢化。
优选地,本发明的化合物选自:
化合物8a:2-氯-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺
化合物8b:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
化合物8c:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
化合物8e:2-溴-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺
化合物8f:2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
化合物8g:2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
化合物8h:2-溴-5-氯-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺
化合物8i:2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
化合物8j:2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基] 丁基}氨基)-2-氧代乙基]苯甲酰胺
本发明另一方面提供了一种式I化合物的制备方法,所述方法包括如下合成步骤:
其中:环A、X
1和X
2的定义如上所述;
a)以式VII化合物(即卤素取代的苯甲酸)为起始原料,与甘氨酸乙酯盐酸盐(式VI)通过缩合、皂化反应得到式V化合物;
b)式V化合物通过与手性α-氨基硼酸酯化合物(式IV)缩合得到式III化合物;优选地,式IV中R
1和R
2独立地选自氢原子、被取代基取代或未取代的C1-6烷基、被取代基取代或未取代的C6-10芳基、被取代基取代或未取代的C7-18芳基烷基、被取代基取代或未取代的C3-15环烷基、被取代基取代或未取代的C4-10环烷基烷基、被取代基取代或未取代的5-15元杂芳基或被取代基取代或未取代的6-21元杂芳基烷基;或者R
1和R
2与它们所连接的硼原子和氧原子一起形成被取代基取代或未取代的5-10元含碳环,所述被取代基取代或未取代的5-10元含碳环除了硼原子和与其相连的两个氧原子外,还可具有0-2个选自氮、氧和硫的杂原子;其中,所述取代基选自卤素、氨基、C1-6的烷基、C2-C6的羧烷基或C1-6的羟烷基中的一种或多种;
c)式III化合物在无机酸条件下水解得到式II化合物;
d)式II化合物与硼酸酯化剂反应得到式I化合物。
在上述制备方法中,所述手性α-氨基硼酸酯化合物(式IV化合物)的制备方法是现有 技术已知的,例如记载在CN103204867B、CN1960996B中。
在上述制备方法中,优选地:
步骤a)中进行的缩合反应采用的缩合剂为TBTU、EDCI/HOBT、DCC/HOBT中的一种,反应溶剂为二氯甲烷、DMF、THF中的一种或其中二者的混合溶剂;步骤a)中进行的皂化反应所用的碱为LiOH、NaOH或KOH,优选NaOH,反应溶剂为乙醇与水的混合溶剂;
步骤b)中进行的缩合反应采用的缩合剂为TBTU、EDCI/HOBT、DCC/HOBT中的一种,优选EDCI/HOBT;反应溶剂为二氯甲烷、DMF、THF中的一种或其中二者的混合溶剂,优选二氯甲烷;式IV化合物中R
1和R
2共同构成
步骤c)中反应溶剂优选为甲醇/正己烷,或甲醇/正庚烷;所述无机酸选自盐酸、硫酸、硝酸中的任一种或一种以上的组合,优选盐酸;
步骤d)中,反应溶剂为乙酸乙酯、THF、丙酮、二氯甲烷、正己烷、庚烷中的一种或者其中二者的混合溶剂,优选乙酸乙酯或乙酸乙酯与正己烷的混合溶剂;反应温度为0℃-100℃,优选30℃-75℃。
优选地,在所述步骤a)和b)中进行的缩合反应在有机碱的存在下进行,所述有机碱优选DIPEA;
优选地,在所述步骤c)中,反应溶剂优选为甲醇和正己烷的混合溶剂或甲醇与正庚烷的混合物。
本发明进一步提供了上述化合物用于制备治疗癌症的药物的用途。优选地,所述治疗癌症的药物为蛋白酶体抑制剂类药物。所述蛋白酶体抑制剂类抗癌药,包括:预防和/或治疗浆细胞瘤的药物,如多发性骨髓瘤;以及预防和/或治疗淋巴瘤的药物,如非霍奇金淋巴瘤、套细胞淋巴瘤和/或滤泡性淋巴瘤的药物;以及预防和治疗乳腺癌、结肠癌、肺癌、肾癌、宫颈癌、鼻咽癌的药物。
此外,本发明还进一步提供了包含本发明化合物的药物组合物或药物制剂。例如,本发明所述的化合物可以纯的形式、与其他活性成分组合或与可药用非毒性赋形剂或载体组合施用。
以下对本发明的技术方案中使用的术语进行说明。
术语“烷基”在本文中是指具有1至6个碳原子的饱和脂肪族烃基基团,该术语包括直链和支链烃基。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、正己基等。
术语“环烷基”在本文中是指具有3至8个碳原子,具有单环或多环(包括稠环、桥环及螺环系统)的环状烷基。环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基 等。
术语“取代”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部分的多重取代)在化学上允许的程度,每个取代基可以位于该基团上任何可利用的位置,且可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到,并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时,每个取代基独立于任何其它取代基而定义,因此可以是相同或不同的。所述取代基是指由下列各基团组成的群组:氢、氟、氯、溴、碘、硝基、氨基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、烷基、酰基、烷氧基、环烷基、杂环烷基、羧烷基、羟烷基、芳基或杂芳基,其中所述各基团如本文中所定义。
术语“本发明的化合物”(除非另有具体指明)在本文中是指权利要求所保护的化合物及其所有纯的氮氧化物、硫氧化物、溶剂合物、及同位素标记的化合物和任何药学上可接受的盐。本发明的化合物的溶剂合物是指与化学计量和非化学计量的溶剂结合的化合物或其盐,如水合物、乙醇合物、甲醇合物等。化合物也可以一种或多种结晶状态存在,即作为共晶体、多晶型物,或其可以无定形固体存在。所有此种形式均被权利要求所涵盖。
本发明硼酸酯化合物可以进一步形成盐,例如从无机酸或有机酸衍生得到的“医药上可接受的盐”。这些包括但并不限于下列所述:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、延胡索酸盐、氢氯化物、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、盐酸盐、2-萘磺酸盐、草酸盐、果胶酯酸盐、硫酸盐、3-苯基丙酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和癸酸盐。另外,碱性含氮基团可以与以下试剂发生季铵化反应生成季铵盐:如低碳烷基卤化物,包括甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;如二烷基硫酸盐,包括二甲基、二乙基、二丁基和二戊基的硫酸盐;如长链卤化物,包括癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;如芳烷基卤化物,如苯甲基和苯乙基的溴化物等。
本发明还包括同位素标记的本发明化合物,即与上述所公开的结构相同,但该结构中一个或多个原子被与其具有相同质子数但不同中子数的原子所替代。结合本发明化合物的同位素实施例包括氢、碳、氧、硫、氟、氯、碘的同位素,分别如
2H、
3H、
13C、
14C、
15N、
18O、
17O、
35S、
18F、
36Cl和
131I等。
术语“药学上可接受”表示物质或组合物在化学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。
本发明所称的“药物制剂”,可以是发明所述药物组合物直接,或加上其他活性成分组 合一起,与可药用辅料或载体组合而成。所述制剂包括:片剂、药丸、胶囊、颗粒剂和悬浮液和乳状液剂等。所述可药用辅料或载体包括:粘合剂如微晶纤维素、黄蓍胶或明胶;赋形剂如淀粉或乳糖;分散剂如褐藻酸、Primogel或玉米淀粉;润滑剂如硬脂酸镁;助流剂如胶状二氧化硅;甜味剂如蔗糖或糖精;或调味剂如薄荷油、水杨酸甲酯或橙味剂;非水溶剂如二甲基亚砜、醇、丙二醇、聚乙二醇、植物油如橄榄油和可注射的有机酯如油酸乙酯;水性载体如醇和水的混合物,缓冲的介质和盐水;以及防腐剂、抗菌剂、抗氧化剂、螯合剂、染料、色素或香料等。
本发明中所述的缩合剂TBTU指O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯;缩合剂EDCI/HOBT指1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐/1-羟基苯并三氮唑;缩合剂DCC/HOBT指二环己基碳二亚胺/1-羟基苯并三氮唑。
本发明中所述的DIPEA为二异丙基乙基胺。
本发明中所述的溶剂DMF为二甲基甲酰胺,THF为四氢呋喃。
本发明中在两种试剂中间使用的“/”,意为前后两种试剂的混合物。
本发明具有以下有益的技术效果:本发明的硼酸酯化合物与现有的用作蛋白酶体抑制剂的硼酸酯化合物相比,具有活性强、安全性高的优点。并且,本发明的硼酸酯化合物更易于合成和纯化,可有效节约生产成本。
此外,本发明化合物具有更好的稳定性。例如较现有技术化合物8l、MLN9708和MLN2238等,本发明8b、8a等化合物在高温、高湿加速试验条件下的稳定性更好。
图1示出了在给药各种蛋白酶体抑制剂的情况下,MM.1S人多发性骨髓瘤SCID鼠移植瘤模型平均肿瘤体积随给药时间的变化。
图2示出了各种蛋白酶体抑制剂抗MM.1S人多发性骨髓瘤SCID鼠移植瘤模型平均肿瘤重量情况。
下面再以实施例的方式对本发明进一步说明,给出本发明的实施细节,但需要指出的是下面描述的实施例是实例性的,仅用于解释本发明,而不能理解为对本发明的限制。对于本领域技术人员根据现有技术对其进行修改或替代仍属于本发明的保护范围内。
本发明具体实施方式中作为原料使用的化学及生物试剂均是可常规商购的。
制备实施例1:化合物3:[(2-氯-5-溴苯甲酰基)氨基]乙酸乙酯的合成
在1.0L圆底烧瓶中,依次称入23.5g 2-氯-5-溴苯甲酸(化合物1,100mmol),14.0g甘氨酸乙酯盐酸盐(化合物2,100mmol),35.32g TBTU(110mmol),倒入250mL二氯甲烷,冰浴条件下滴加38.3mL DIPEA(220mmol)与50mL二氯甲烷的混合液,30min左右滴加完毕。随后反应混合液逐渐恢复至室温反应4h,TLC检测反应情况至2-氯-5-溴苯甲酸完全消失。反应结束后,反应混合液依次用300mL水、200mL 3%K
2CO
3溶液、200mL 2%H
3PO
4溶液、200mL水、150mL饱和食盐水洗涤,100g无水硫酸钠干燥1h后真空浓缩至干,可得白色固体产物[(2-氯-5-溴苯甲酰基)氨基]乙酸乙酯(化合物3),粗品不经纯化直接投入下一步反应。
制备实施例2:化合物4:[(2-氯-5-溴苯甲酰基)氨基]乙酸的合成
在1.0L圆底烧瓶中,称入40.0g上步所得的[(2-氯-5-溴苯甲酰基)氨基]乙酸乙酯(化合物3)粗品,倒入160mL乙醇,室温条件下滴加100mL 2N NaOH溶液(2当量),TLC检测反应情况至2-氯-5-溴苯甲酰基氨基乙酸乙酯完全消失,反应2h后将反应液浓缩至剩余三分之一体积,随后用1N HCl溶液调节pH至弱酸性(pH=5左右),体系中即有大量白色固体析出,抽滤反应液,滤饼用200mL×3水洗涤三次,真空干燥后可得白色固体产物[(2-氯-5-溴苯甲酰基)氨基]乙酸(化合物4)共23.0g,两步总收率为80%。
1H NMR(400MHz,DMSO)δ=8.61(t,J=5.6Hz,1H),7.65(m,2H),7.47(d,J=8.4Hz,1H),5.24(s,3H).
13C NMR(101MHz,DMSO)δ=171.79,165.21,138.70,134.05,132.25,132.08,129.97,120.16,42.63;熔点162-164℃;ESI-MS(m/z):[C
9H
7BrClNO
3-H]的计算值291.92,实测值291.77。
制备实施例3:化合物6:[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸新戊二醇酯的合成
在1.0L圆底烧瓶中,依次称入21.2g[(2-氯-5-溴苯甲酰基)氨基]乙酸(化合物4,72.5mmol),21.6g(R)-1-氨基-3-甲基丁烷-1-硼酸新戊二醇酯盐酸盐(化合物5,79.8mmol;化合物5可参照中国专利CN103204867B实施例方法制备),16.7g EDCI(87.0mmol)及11.8g HOBT(87.0mmol)倒入250mL二氯甲烷,冰浴条件下滴加38.3mL DIPEA(220mmol)与50mL二氯甲烷的混合液,30min左右滴加完毕。随后反应混合液逐渐恢复至室温反应4h,TLC检测反应情况至2-氯-5-溴苯甲酸完全消失。反应结束后,反应混合液依次用300mL水、200mL 3%K
2CO
3溶液、200mL 2%H
3PO
4溶液、200mL水、150mL饱和食盐水洗涤,100g无水硫酸钠干燥1h后真空浓缩至干,可得白色固体产物[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨 基)-3-甲基丁基]硼酸新戊二醇酯(化合物6)共29.5g,收率86%,粗品不经纯化直接投入下一步反应。
制备实施例4:化合物7:[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸的合成
在1.0L圆底烧瓶中,称入上步所得的化合物[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸新戊二醇酯5.3g((化合物6,11.1mmol),倒入100mL甲醇与正己烷为1:1的混合液,随后加入3.6g异丁基硼酸(33.3mmol),搅拌5min后加入1N HCl溶液15mL(1.2当量),反应混合液剧烈搅拌4h后。分离两相,甲醇相用100mL×2正己烷洗涤两次,随后将甲醇相浓缩至少量,加入100mL二氯甲烷,混合液搅拌条件下用2N NaOH溶液中和至碱性(pH=11左右),萃取分液,水相再用100mL×2二氯甲烷洗涤两次。随后再向水相中加入150mL二氯甲烷,并用1N HCl溶液中和至弱酸性(pH=5左右),萃取分液,水相用100mL×2二氯甲烷,合并二氯甲烷相,150mL饱和食盐水洗涤一次后,无水硫酸钠干燥浓缩至干,于28℃真空干燥箱烘干,可得白色固体产物[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7)共3.1g,收率68%。
1H NMR(400MHz,DMSO)δ=9.03-8.93(m,1H),8.75(m,1H),7.83-7.76((d,J=4.8,1H),7.67(m,1H),7.49(dd,J=8.8,4.8Hz,1H),4.05(d,J=6.4Hz,2H),2.71-2.64(m,1H),1.63(m,1H),1.45-1.22(m,2H),0.85(dd,J=6.4,2.0Hz,6H).
13C NMR(101MHz,DMSO)δ=171.85,168.16,165.65,138.07,134.19,132.22,130.08,120.18,55.37,25.66,23.43,23.35,22.57;熔点118-120℃。
制备实施例5:化合物8a:2-氯-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺的合成
在100mL圆底烧瓶中,称入0.35g水杨酸(2.5mmol),加入10mL乙酸乙酯,加热至70℃使水杨酸完全溶解,随后加入1.01g原料[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7,2.5mmol),反应混合液搅拌5min后体系中即有大量白色固体析出,继续搅拌半小时后恢复至室温,抽滤反应液,滤饼用乙酸乙酯洗涤,真空干燥后可得白色固体产物2-氯-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺(化合物8a)共1.08g,收率85%。
1H NMR(400MHz,DMSO) δ=10.93(s,1H),9.16(t,J=5.6Hz,1H),7.78(dd,J=8.0,1.6Hz,1H),7.74-7.61(m,2H),7.48(m,2H),7.01-6.86(m,2H),4.28(d,J=5.6Hz,2H),2.96-2.76(m,1H),1.69(m,1H),1.55-1.33(m,2H),0.91(t,J=6.4Hz,6H).
13C NMR(101MHz,DMSO)δ=176.30,166.11,163.00,159.01,137.61,135.55,134.42,132.24,132.09,130.10,129.72,120.27,120.14,118.62,116.34,38.87,38.56,26.02,23.44,22.57;熔点252-254℃;ESI-MS(m/z):[C
21H
21BBrClN
2O
5-H]的计算值507.03,实测值506.84;[C
21H
21BBrClN
2O
5+H
+]的计算值509.05,实测值508.86;[C
21H
21BBrClN
2O
5+Na
+]的计算值531.03,实测值530.85。
制备实施例6:化合物8b:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
在100mL圆底烧瓶中,称入0.38g R-扁桃酸(2.5mmol),加入10mL乙酸乙酯,加热至70℃使R-扁桃酸完全溶解,随后加入1.01g原料[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7,2.5mmol),反应混合液搅拌5min后体系中即有大量白色固体析出,继续搅拌半小时后恢复至室温,并加入10mL正己烷搅拌半小时,随后抽滤反应液,滤饼用乙酸乙酯和正己烷混合液洗涤,真空干燥后可得白色固体产物2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(化合物8b)共1.12g,收率86%。
1H NMR(400MHz,DMSO)δ=10.91(s,1H),9.24(s,1H),7.81(d,J=16.4Hz,1H),7.72(d,J=8.8Hz,1H),7.56-7.26(m,6H),5.30-5.11(m,1H),4.37(d,J=4.6Hz,2H),2.84(m,1H),1.69(m,1H),1.40(m,2H),0.94(d,J=6.4Hz,6H).
13C NMR(101MHz,DMSO)δ=176.83,176.57,166.03,139.82,137.47,134.58,132.40,132.22,130.22,128.52,127.96,126.56,120.24,76.70,60.24,39.31,38.74,26.23,23.42,22.49,21.23;熔点170-173℃;ESI-MS(m/z):[C
22H
23BBrClN
2O
5-H]的计算值521.05,实测值520.75;[C
22H
23BBrClN
2O
5+Na
+]的计算值545.04,实测值544.76。
制备实施例7:化合物8c:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
在100mL圆底烧瓶中,称入0.20g L-乳酸(2.0mmol),加入8mL乙酸乙酯,加热至70℃使L-乳酸完全溶解,随后加入0.81g原料[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨 基)-3-甲基丁基]硼酸(化合物7,2.0mmol),反应混合液搅拌30min后体系为澄清状,随后加入12mL正己烷,继续在70℃搅拌半小时后恢复至室温,体系中逐渐有白色固体析出,随后快速抽滤反应液,滤饼用乙酸乙酯和正己烷混合液洗涤,真空干燥后可得白色固体产物2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(化合物8c)共0.75g,收率80%。
1H NMR(400MHz,DMSO)δ=10.73(s,1H),9.17(t,J=5.6Hz,1H),7.89-7.77(m,1H),7.75-7.64(m,1H),7.56-7.45(m,1H),4.30(d,J=5.2Hz,2H),2.76-2.61(t,J=7.2Hz,1H),1.64(d,J=5.7Hz,1H),1.45-1.12(m,5H),0.94-0.80(m,6H).
13C NMR(101MHz,DMSO)δ=179.52,176.28,166.04,137.53,134.48,132.29,130.14,120.18,70.23,39.28,38.69,25.97,23.38,22.55,14.43;熔点135-138℃;ESI-MS(m/z):[C
17H
21BBrClN
2O
5-H]的计算值459.03,实测值458.76;[C
17H
21BBrClN
2O
5+Na
+]的计算值483.03,实测值482.76。
制备实施例8:化合物8e:2-溴-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺的合成
参照制备实施例1-5的反应过程,只是替换2-氯-5-溴苯甲酸为2-溴-5-溴苯甲酸,其余步骤参照进行,从而得到化合物2-溴-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺化合物8e。
制备实施例9:化合物8f:2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
参照制备实施例1-4和制备实施例6的反应过程,只是替换2-氯-5-溴苯甲酸为2-溴-5-溴苯甲酸,其余步骤参照进行,从而得到2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8f。
制备实施例10:化合物8g:2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
参照制备实施例1-4和制备实施例7的反应过程,只是替换2-氯-5-溴苯甲酸为2-溴-5-溴苯甲酸,其余步骤参照进行,从而得到化合物2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8g。
制备实施例11:化合物8h:2-溴-5-氯-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺的合成
参照制备实施例1-5的反应过程,只是替换2-氯-5-溴苯甲酸为2-溴-5-氯苯甲酸,其余步骤参照进行,从而得到化合物2-溴-5-氯-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺化合物8h。
制备实施例12:化合物8i:2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
参照制备实施例1-4和制备实施例6的反应过程,只是替换2-氯-5-溴苯甲酸为2-溴-5-氯苯甲酸,其余步骤参照进行,从而得到2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8i。
制备实施例13:化合物8j:2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
参照制备实施例1-4和制备实施例7的反应过程,只是替换2-氯-5-溴苯甲酸为2-溴-5-氯苯甲酸,其余步骤参照进行,从而得到化合物2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8j。
制备实施例14:化合物8m:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(5S)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
在100mL圆底烧瓶中,称入0.31g S-扁桃酸(2.0mmol),加入10mL乙酸乙酯,加热至70℃使S-扁桃酸完全溶解,随后加入0.81g原料[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7,2.0mmol),反应混合液搅拌5min后体系中即有大量白色固体析出,继续搅拌半小时后恢复至室温,并加入10mL正己烷搅拌半小时,随后抽滤反应液,滤饼用乙酸乙酯和正己烷混合液洗涤,真空干燥后可得白色固体产物2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(5S)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(化合物8m)共0.73g,收率70%。
1H NMR(400MHz,DMSO)δ=10.92(s,1H),9.25(s,1H),7.84(d,J=24.0Hz,1H),7.72(d,J=8.0,1H),7.52(d,J=8.0Hz,2H),7.46-7.23(m,4H),5.20(d,J=40.0Hz,1H),4.38(d,J=2.8Hz,2H),2.87(m,1H),1.92-1.54(m,1H),1.41(m,2H),0.92(d,J=6.4Hz,6H).
制备实施例15:化合物8n:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
在100mL圆底烧瓶中,称入0.31g DL-扁桃酸(2.0mmol),加入10mL乙酸乙酯,加热至70℃使DL-扁桃酸完全溶解,随后加入0.81g原料[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7,2.0mmol),反应混合液搅拌5min后体系中即有大量白色固体析出,继续搅拌半小时后恢复至室温,并加入10mL正己烷搅拌半小时,随后抽滤反应液,滤饼用乙酸乙酯和正己烷混合液洗涤,真空干燥后可得白色固体产物2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(化合物8n)共0.75g,收率72%。
1H NMR(400MHz,DMSO)δ=10.92(s,1H),9.25(s,1H),7.92-7.76(m,1H),7.72(d,J=8.0Hz,1H),7.52(d,J=8.0Hz,2H),7.47-7.25(m,4H),5.19(m,1H),4.37(d,J=4.0Hz,2H),3.00-2.73(m,1H),1.70(m,1H),1.57-1.26(m,2H),0.92(d,J=6.4Hz,6H)
制备对比例1:化合物8d:2-氯-5-溴-N-(2-{[(1R)-1,3,5,2-二氧氮杂硼戊环-2-基)-3-甲基丁基]氨基}-2-氧代乙基)苯甲酰胺的合成
室温条件下,在100mL圆底烧瓶中,称入1.01g原料[(1R)-1-({[(2-氯-5-溴-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7,2.5mmol),加入10mL乙酸乙酯使之溶解,随后加入0.27g二乙醇胺(2.5mmol),反应混合液搅拌5min后体系中即有大量白色固体析出,继续搅拌半小时后,抽滤反应液,滤饼用乙酸乙酯洗涤,真空干燥后可得白色固体产物2-氯-5-溴-N-(2-{[(1R)-1,3,5,2-二氧氮杂硼戊环-2-基)-3-甲基丁基]氨基}-2-氧代乙基)苯甲酰胺(化合物8d)共1.08g,收率88%。
1H NMR(400MHz,DMSO)δ=8.85(t,J=6.0Hz,1H),7.73-7.60(m,2H),7.50(d,J=8.4Hz,1H),7.00(d,J=8.4Hz,1H),6.59(s,1H),3.90-3.63(m,5H),3.63-3.54(m,1H),3.15(m,1H),3.05-2.90(m,2H),2.84-2.66(m,2H),1.68-1.50(m,1H),1.40-1.27(m,1H),1.20(m,1H),0.88-0.75(dd,J=6.4Hz,J=10.8Hz,6H).
13C NMR(101MHz,DMSO)δ=168.21,165.63,138.58,134.15,132.23,131.95,129.91,120.24,62.94,51.39,50.96,43.31,25.00,24.44,22.14;熔点217-218℃。
其中,反应原料二乙醇胺在后处理中不易除尽,易残留带入产物8d中。同时化合物8d会水解,易在体内水解产生二乙醇胺,而二乙醇胺是世界卫生组织公布的二类致癌物(http://www.sda.gov.cn/WS01/CL1991/215896.html)。
制备对比例2:化合物8k:2-溴-5-氯-N-(2-{[(1R)-1,3,5,2-二氧氮杂硼戊环-2-基)-3-甲基丁基]氨基}-2-氧代乙基)苯甲酰胺的合成
室温条件下,在100mL圆底烧瓶中,称入1.22g原料[(1R)-1-({[(2-溴-5-氯-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7-1,3.0mmol),加入20mL乙酸乙酯使之溶解,随后加入0.315g二乙醇胺(3.0mmol),反应混合液搅拌5min后体系中即有大量白色固体析出,继续搅拌半小时后,抽滤反应液,滤饼用乙酸乙酯洗涤,真空干燥后可得白色固体产物2-溴-5-氯-N-(2-{[(1R)-1,3,5,2-二氧氮杂硼戊环-2-基)-3-甲基丁基]氨基}-2-氧代乙基)苯甲酰胺(化合物8k)共1.20g,收率84%。
1H NMR(400MHz,DMSO)δ=8.85(t,J=6.0Hz,1H),7.71(d,J=8.4Hz,1H),7.60-7.40(m,2H),7.03(d,J=8.4Hz,1H),6.60(s,1H),3.89-3.64(m,5H),3.63-3.53(m,1H),3.16(m,1H),3.09-2.92(m,2H),2.86-2.65(m,2H),1.70-1.53(m,1H),1.43-1.28(m,1H),1.20(m,1H),0.82(dd,J=11.2,6.8Hz,6H).
制备对比例3:化合物8l:2-氯-5-氯-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺的合成
在100mL圆底烧瓶中,称入0.46g R-扁桃酸(3.0mmol),加入10mL乙酸乙酯,加热至70℃使R-扁桃酸完全溶解,随后加入1.08g原料[(1R)-1-({[(2-氯-5-氯-苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(化合物7-2,3.0mmol),反应混合液搅拌10min后体系中即有大量白色固体析出,继续搅拌半小时后恢复至室温,并加入10mL正己烷搅拌半小时,随后抽滤反应液,滤饼用乙酸乙酯和正己烷混合液洗涤,真空干燥后可得白色固体产物2-氯-5-氯-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(化合物8l)共0.81g,收率57%。
1H NMR(400MHz,DMSO)δ=10.90(s,1H),9.24(s,1H),7.79-7.56(m,3H),7.54-7.21(m,5H),5.19(s,1H),4.36(d,J=5.2Hz,2H),2.82(m,1H),1.68(m,1H),1.39(m,2H),0.93(d,J=6.8Hz,6H).
实验例1:体外活性测试
将细胞RPMI-8226(人多发性骨髓瘤细胞)和MM.1S(人多发性骨髓瘤细胞)在37℃、5%CO
2条件下,在含10%胎牛血清的RPMI 1640培养基中培养至对数生长期。分别将细胞以3×10
4/每孔的数量接种至96孔培养板中。在37℃、5%CO
2条件下培养24小时后,向细胞中加入溶剂对照DMSO(二甲基亚砜)或溶解于DMSO的试验化合物(试验化合物以0.3μM为起始浓度,每次稀释3倍,共稀释5次得到6个浓度梯度)。在37℃、5%CO
2条件下将试验化合物同细胞孵育48小时。向各孔中添加CCK-8试剂,并按照试剂说明书要求在37℃孵育2小时,使用分光光度计在450nm波长下读取各孔的光密度值。
将药物作用0时的细胞光密度值设为Tz值,代表药物加入时细胞的值。溶剂对照DMSO作用48小时的细胞光密度值设为C值;试验化合物作用48小时的细胞光密度值设为Ti值。根据美国NIH–NCI(美国国立卫生研究院-国立癌症研究所)提出的方法计算细胞对药物的响应:当Ti≥Tz时,为[(Ti-Tz)/(C-Tz)]x 100;当Ti<Tz时,为[(Ti-Tz)/Tz]x 100。根据上述计算,应用XLfit软件中的4 Parameter Logistic Model计算GI50值(细胞生长抑制率为50%时所需的试验化合物的浓度)。活性数据如下表1所示。
表1.体外活性试验结果
实验例2:药效学试验
本试验采用人源性多发性骨髓瘤细胞系MM.1S的SCID小鼠移植瘤模型。具体造模步骤如下:冻存的MM.1S细胞经复苏后按常规进行体外培养,在对数生长期时收集细胞,用PBS稀释成浓度为5×10
7/ml的肿瘤细胞悬液。将上述制备好肿瘤细胞悬液,注射于5周龄SCID小鼠的腋下靠背侧皮下,体重16-18g,全雌性,每个接种部位注射0.2ml。注射接种后约1-2周,腋下触及肿瘤,待肿瘤体积大于500mm
3以上时进行体内传代。采用拉颈法处死小鼠后,体表消毒,剪开皮肤,无菌操作,从腋部皮下剥取肿瘤组织,剔除纤维包膜,取 出肿瘤,在生理盐水中洗涤干净,然后切开,去处中心坏死部分选取生长良好、呈淡红色、鱼肉状的瘤组织,切成1mm×1mm×1mm小块,置于生理盐水中备用。将切好的瘤块置于18号套管针针口内,碘棉消毒小鼠腋下靠背侧,局部接种。本次试验所用移植瘤为体内传代的第4代。待大部分体内传代SCID小鼠的肿瘤体积长至100mm
3以上时,测量并计算肿瘤体积,按照肿瘤体积大小进行随机分组。
给药方式为口服灌胃给药,给药体积10ml/kg。模型组给予等体积溶媒灌胃。均口服灌胃给药,每周2次,共给药5次,即在实验第1、5、8、12、15天给药,,时程为18天。
不同受试样的给药剂量均为等摩尔剂量,具体剂量为0.0166mmol/kg;模型组仅给予生理盐水。药物为:8b、8l,以及Ixazomib Citrate(MLN9708)、Ixazomib(MLN2238)。
在给药后第5、8、12、15、18天用游标卡尺测量各小鼠肿瘤的短径(a)及长径(b),按(a
2×b)/2公式计算肿瘤体积。根据测量计算的肿瘤体积计算出相对肿瘤体积(RTV),RTV=V
t/V
0。其中V
0为随机分组(即d
0)时的肿瘤体积,V
t为每一次测量(即d
n)时的肿瘤体积。按下列公式计算抗肿瘤活性评价指标相对肿瘤增殖率:相对肿瘤增殖率T/C(%):
(注:T
RTV:治疗组RTV;C
RTV:模型对照组RTV。疗效的评价标准T/C%≤40%,并经统计学处理P<0.05为有效)。
第18天时称重测量肿瘤后处死各组动物,剖取肿瘤并称重。
图1给出了在给药各种蛋白酶体抑制剂的情况下,MM.1S人多发性骨髓瘤SCID鼠移植瘤模型平均肿瘤体积随给药时间的变化。可见,在给药前,初始的平均肿瘤体积在500mm
3左右。表2和3中分别给出了各组在试验过程中的平均相对肿瘤体积(RTV)以及相对肿瘤增殖率T/C(%)。
注:
▲:与同期模型组比较p<0.05,
▲▲:与同期模型组比较p<0.01
★:与同期8b组比较p<0.05,
★★:与同期8b组比较p<0.01
表3.蛋白酶体抑制剂抗MM.1S人多发性骨髓瘤SCID鼠移植瘤模型相对肿瘤增殖率T/C(%)(T/C(%)=RVT
T/RVT
C,RVT
T为给药组平均肿瘤相对体积,RVT
C Vd为同时期模型对照组平均肿瘤相对体积)
注:
★:与同期8b组比较p<0.05,
★★:与同期8b组比较p<0.01
表4示出了在给药第18天后各组的平均肿瘤重量。图2给出了各组的平均肿瘤重量的对比柱形图。
组别 | 瘤重(g) |
模型 | 3.675±1.786 ★★ |
8b | 0.028±0.025 |
Ixazomib(MLN9708) | 0.284±0.312 ★ |
Ixazomib(MLN2238) | 0.374±0.291 ★★ |
8l | 0.560±0.566 ★ |
注:
★:与8b组比较p<0.05,
★★:与8b组比较p<0.01
结果可见,本发明的化合物8b显著抑制MM.1S人多发性骨髓瘤SCID鼠移植瘤的肿瘤生长,其抑制肿瘤生长的作用显著强于对比化合物8l(p<0.01)、Ixazomib(MLN9708)(p<0.01)和Ixazomib活性形式(MLN2238)(p<0.01),差异具有显著性。
实验例3:安全性试验
本试验为SD大鼠经口灌胃给药的单次给药毒性试验。将252只SD大鼠按体重随机分组为21组,每组12动物,雌雄各半,分别为溶剂对照组、MLN2238剂量1、2、3、4组、MLN9708剂量1、2、3、4组、8l剂量1、2、3、4组、8d剂量1、2、3、4组、8b剂量1、2、3、4组,不同受试样的相同序号剂量组为同摩尔剂量,剂量1、2、3、4组的剂量分别为0.001108、0.001662、0.002216、0.00277mmol/kg。各组灌胃给药1次,停药恢复观察14天,大鼠死亡 情况如表5。
表5.SD大鼠经口灌胃给予蛋白酶体抑制剂单次给药毒性试验分组及大鼠存活情况
结果可见在雌性大鼠中,8b的最大耐受量为0.002216mmol/kg,而Ixazomib(MLN2238)、Ixazomib(MLN9708)、8l和8k的最大耐受量为0.001108mmol/kg,显著低于8b,差异具有统计学意义(p<0.01)。
实验例4 心脏hERG钾通道抑制试验
利用膜片钳技术检测被测样品(化合物8a,8b)对hERG钾通道的阻断作用浓度效应关系,从而评价样品对心脏hERG钾通道抑制作用的风险。以通用标准来判断被试化合物对hERG的抑制效应(Roche O.等人.ChemBioChem.2002,3:455-459.):
极强抑制:IC50<0.1μM;强抑制:0.1μM≤IC50≤1μM;中度抑制:1μM≤IC50≤10μM;弱抑制或无抑制:IC50>10μM。
一般的,膜片钳研究是预测化合物引起QT间期延长风险的灵敏指标;hERG电生理的结果可用于评价化合物潜在的延长QT间期风险。当药物hERG半抑制浓度超过其在血液中的浓度峰值的30倍左右时,是一个相对安全的范围(Redferneltal,Cardiovascular Research,58,32-45(2003))。
实验结果如下表6所示。
表6.测试化合物对hERG电流的抑制比例及IC50结果:
根据以上标准,实验结果表明化合物8a,8b对hERG钾通道无抑制作用,即表明化合物8a、8b无心脏毒性。
Claims (11)
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述X 1和X 2共同形成通过与硼酸酯化剂的两个官能团去除氢原子后所形成的环状部分,为5-12元环。
- 根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于:所述硼酸酯化剂选自被取代基取代或未被取代的水杨酸、扁桃酸、乳酸或亚氨基二乙酸中的一种;所述取代基选自卤素、氨基、C1-6的烷基、C3-C8环烷基、C2-C6的羧烷基或C1-6的羟烷基中的一种或多种;任选地,作为所述硼酸酯化剂的被取代基取代或未被取代的水杨酸或扁桃酸中的苯基被氢化或部分氢化;其中,所述扁桃酸优选为R-扁桃酸或S-扁桃酸,所述乳酸优选为L-乳酸。
- 根据权利要求5所述的化合物或其药学上可接受的盐,其特征在于,所述化合物选自:化合物8a:2-氯-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺化合物8b:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8c:2-氯-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8e:2-溴-5-溴-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基] 氨基}-2-氧代乙基)苯甲酰胺化合物8f:2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8g:2-溴-5-溴-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8h:2-溴-5-氯-N-(2-{[(1R)-3-甲基-1-(4-氧代-4H-1,3,2-苯并二氧硼戊环-2-基)丁基]氨基}-2-氧代乙基)苯甲酰胺化合物8i:2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(5R)-4-氧代-5-苯基-1,3,2-二氧硼戊烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺化合物8j:2-溴-5-氯-N-[2-({(1R)-3-甲基-1-[(4S)-4-甲基-5-氧代-1,3,2-二氧硼戊环-2-基] 丁基}氨基)-2-氧代乙基]苯甲酰胺
- 根据权利要求8所述的制备方法,其特征在于:步骤a)中进行的缩合反应采用的缩合剂为TBTU、EDCI/HOBT、DCC/HOBT中的一种,反应溶剂为二氯甲烷、DMF、THF中的一种或其中二者的混合溶剂;步骤a)中进行的皂化反应所用的碱为LiOH、NaOH或KOH,优选NaOH,反应溶剂为乙醇与水的混合溶剂;步骤b)中进行的缩合反应采用的缩合剂为TBTU、EDCI/HOBT、DCC/HOBT中的一种,优选EDCI/HOBT;反应溶剂为二氯甲烷、DMF、THF中的一种或其中二者的混合溶剂,优选二氯甲烷;式IV化合物中R 1和R 2共同构成步骤c)中在作为反应溶剂的甲醇/正己烷或甲醇/正庚烷中采用无机酸使式III化合物水解生成式II化合物;所述无机酸选自盐酸、硫酸、硝酸中的任一种或多种的组合,优选盐酸;步骤d)中,反应溶剂为乙酸乙酯、THF、丙酮、二氯甲烷、正己烷、庚烷中的一种或者其中二者的混合溶剂,优选乙酸乙酯或乙酸乙酯与正己烷的混合溶剂;反应温度为0℃-100℃,优选30℃-75℃。
- 根据权利要求8所述的制备方法,其特征在于,在步骤a)和b)中进行的缩合反应在有机碱的存在下进行,所述有机碱优选DIPEA。
- 根据权利要求1-7中任意一项所述化合物用于制备治疗癌症的药物的用途,所述治疗癌症的药物优选为蛋白酶体抑制剂类药物。
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