WO2010012222A1 - Acide peptidyl-borique et ses dérivés esters, synthèse et utilisation correspondantes - Google Patents

Acide peptidyl-borique et ses dérivés esters, synthèse et utilisation correspondantes Download PDF

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WO2010012222A1
WO2010012222A1 PCT/CN2009/072967 CN2009072967W WO2010012222A1 WO 2010012222 A1 WO2010012222 A1 WO 2010012222A1 CN 2009072967 W CN2009072967 W CN 2009072967W WO 2010012222 A1 WO2010012222 A1 WO 2010012222A1
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acid
compound
reaction
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Chinese (zh)
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朱永强
赵欣
朱新荣
胡杨
吴刚
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江苏先声药物研究有限公司
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    • 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 System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid 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 invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a novel peptide boric acid and an ester compound thereof and the application thereof in pharmacodynamics. Background technique
  • the number of benign tumor patients in China is about 1.2 million, and the total number of cancer patients is about 2.685 million.
  • the annual mortality rate of cancer patients in China is about 119.54 deaths per 100,000 people in the country. That is to say, the number of cancer deaths in the country is about 1.54 million per year, and the urban death rate is slightly higher than that in rural areas. mortality rate.
  • cancer treatment has made great progress, it has not yet been able to fundamentally treat cancer.
  • the anti-cancer drugs currently on the market have certain curative effects, they are mostly cytotoxic drugs with serious side effects. Therefore, how to develop targeted new anticancer drugs from effective tumor targets has become a top priority.
  • the degradation pathway of ubiquitin-proteasome plays a very important role in the regulation of many physiological processes and the development of many important human diseases. For example, if this process excessively degrades the tumor suppressor P 53 and the cyclin-dependent kinase inhibitor ⁇ 27 ⁇ 1 , it causes tumorigenesis and leads to uncontrolled proliferation of human cancer cells. At the same time, this process has also played a key role in immune surveillance, muscle atrophy, regulation of metabolic processes, acquisition of long-term memory, and regulation of circadian rhythms. Recently, this process has also been found in neurodegenerative diseases, Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), and Parkinson' disease (PD). Huntington's disease (HD), cortical striatum-Creutzfeld-Jacob disease (CJD), and the onset of diabetes have a large impact.
  • ALS Amyotrophic Lateral Sclerosis
  • AD Alzheimer's disease
  • PD Parkinson' disease
  • CDJD cortical
  • proteasome plays a very important catalytic role.
  • Proteasome is ATP dependent
  • the protease hydrolysis complex is the main enzyme system for decomposing endogenous proteins in eukaryotic cells and belongs to the family of threonine proteases.
  • the largest proteasome component is the largest and most complex protein ever discovered, accounting for approximately 1-2% of all gene products.
  • the proteasome density gradient centrifugal sedimentation coefficient is 26S, so it is also called 26S proteasome. It consists of catalytic particles (CP) and regulatory particles (RP).
  • the sedimentation coefficient of CP is 20S, so it is also called 20S proteasome, molecular weight 700 ⁇ 750kD, CP consists of multiple catalytic subunits with molecular weight of 20 ⁇ 30kD; RP has triploid ATPase subunit (RP triple ATPase, Rpt) and non-ATPase subunit (RP non- ATPase) , RPn), molecular weight between 30 ⁇ 110kD.
  • the 26S proteasome is a cylindrical symmetrical structure with two "caps"-like 19S proteasomes at the ends and two "bucket”-like 20S proteasomes in the middle. Although this proteasome is generally referred to as the 26S proteasome and was originally considered to have a molecular weight of 1000 kD or 1500 kD, more precise measurements in recent years have shown a sedimentation coefficient of 30 s and a molecular weight of 2000 kD. Baumeister et al. used digital mirror analysis coupled with electron microscopy to show that the complexes extracted from amphibians, mammals, higher plants and yeast have a fairly consistent structure.
  • X-rays showed that the 20S proteasome of the archaeal heat source T. acidophilur was cylindrical, with a length of 148 people, a maximum diameter of 113 A, and a minimum diameter of 75 A. It consisted of four rings with a total of 28 subunits. According to the (0C1-0C7, ⁇ 1- ⁇ 7) ⁇ method, they are stacked in an orderly manner and are expressed as 7 symmetry. The center is the channel that runs through the entire particle. There are three large cavities inside the particle, and the larger cavity in the middle is the place where the protein is hydrolyzed.
  • the entrance to the chamber is located in the center of each ring, which is narrow enough to control the entry of proteins on the one hand and the partially hydrolyzed substrate from the active site on the other hand.
  • X-ray confirmed that the 20S proteasome and yeast of mammalian cattle have the same sequence of subunits, and the primary structural characteristics are similar to those of yeast, which is highly conserved.
  • the high-grade structure of the 20S proteasome of cattle is different from that of yeast.
  • subunits such as oc2, ⁇ 1, ⁇ 5, ⁇ 6 and ⁇ 7 are different.
  • the ⁇ 7 subunit has the activity of a terminal nucleophilic hydrolase, and the cleft of this active site is smaller than that of the ⁇ 1, ⁇ 2 and ⁇ 5 subunits.
  • the eukaryotic 20S proteasome contains six active sites, three on each beta loop, located on the ⁇ 1, ⁇ 2 and ⁇ 5 subunits, respectively.
  • the 20S proteasome has been found to have three distinct enzymatic activities: 1.
  • chymotrypsin-like (CT-L) activity hydrolyzing peptide bonds after large hydrophobic amino acid residues, the active site is mainly located on the ⁇ 5 subunit 2
  • trypsin-like (TL) activity hydrolyze peptide bonds after basic amino acid residues, the active site is mainly located in the ⁇ 2 subunit; 3 polypeptide-glutamyl-peptide hydrolase activity (postglutamyl-hydrolase) , PGPH), hydrolyzes the peptide bond after the acidic amino acid residue, and the active site is mainly located in the ⁇ subunit.
  • TL trypsin-like
  • PGPH polypeptide-glutamyl-peptide hydrolase activity
  • Caspase-like activity (Caspase is an intracellular lysine-degrading enzyme that acts on the cell's metabolic apoptotic pathway and acts only on aspartate residues). It should be noted that these names only express their similarities with traditional proteolytic enzymes and are not to be construed as the same catalytic or physiological function.
  • the proteasome shows two other activities: one is to preferentially hydrolyze the peptide bond activity (BrAAP activity) after the amino acid residue with the branched side chain; the other is small
  • studies using methods such as X-ray diffraction, kinetics, and site-directed mutagenesis have shown that new sites with these two activities do not exist.
  • the decomposition of branched chain amino acids such as leucine, isoleucine and valine
  • the chymotrypsin-like site is slightly weak. Therefore, the names of the proteasome active sites do not reflect all of their properties.
  • Covalent bond inhibitors include peptide aldehydes, ⁇ -ketoamides, peptide boronic acids and esters thereof, peptide vinyl sulfones, natural products TMC-95-AD, ⁇ -lactone compounds, epoxy ketone compounds, and the like;
  • Non-covalent bond inhibitors include tea polyphenols and 2-substituted aminobenzyl statines.
  • PS-341 dipeptide boronic acid Bortezomib
  • the drug is a new anti-tumor drug developed by Millennium Pharmaceuticals.
  • An object of the present invention is to provide a novel boric acid and borate compound having a novel structure and having a function of inhibiting proteasome.
  • a 20S proteasome inhibitor they can block tumor cell proliferation and induce tumor cell apoptosis, which can be used for the treatment and prevention of various diseases such as malignant tumors in humans and animals.
  • Another object of the present invention is to provide a process for producing the above-described peptide boronic acid and an ester compound thereof.
  • Still another object of the present invention is to provide an application of the above-described peptide boronic acid and an ester compound thereof for the preparation of an antitumor drug.
  • the object of the present invention can be specifically achieved by the following measures:
  • Each is independently substituted or unsubstituted decyl, benzyl, naphthylmethyl or fluorenylmethyl, most preferably substituted or unsubstituted decyl, benzyl, 1-naphthyl
  • the group, 2-naphthylmethyl or fluorenylmethyl, R 2 is most preferably a substituted or unsubstituted fluorenyl or benzyl group of Cl 10 .
  • R 2 or R 2 does not mean narrowly the sulfhydryl group of Cl 10 , but extends to all such groups, ie substituted or unsubstituted C 3 -6 cyclodecyl or hetero a fluorenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted naphthylmethyl group, a substituted or unsubstituted fluorenylmethyl group, etc., wherein the substituent is a fluorenyl group, a cyano group, a hydroxy group of Cl 1-4 A mercapto group, an amino group or a halogen, preferably a fluorenyl group or a halogen of Cl 4 .
  • 3 ⁇ 4 or ⁇ 2 are each independently hydroxy, Cl ⁇ 10 the embankment group, Cl ⁇ 10 the embankment or aryloxy group, or B, 3 ⁇ 4, and ⁇ 2 - is formed from N, S or a heterocyclic group containing 0 3 ⁇ 4 or ⁇ 2 is preferably independently a hydroxyl group, a decyl group of Cl ⁇ 10, a decyloxy group or an aryloxy group of Cl ⁇ 10, or B, 3 ⁇ 4 and ⁇ 2 together to form a boric acid-a-decanediol ester.
  • 3 ⁇ 4 or Z 2 is most preferably independently a hydroxyl group, or B, 3 ⁇ 4 and ⁇ 2 together form a boronic acid-a-decanediol ester.
  • Pg is a substituted or unsubstituted bicyclic acyl or tricyclic acyl group containing at least one unsaturated ring, preferably a substituted or unsubstituted tetrahydronaphthoyl group, wherein the substituent is a fluorenyl group of Cl 4 , a decyloxy group of Cl ⁇ 4, a halogen or a halogenated fluorenyl group of Cl ⁇ 4. Further, Pg is preferably:
  • R 3 or R 4 are each independently hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
  • mercapto is used to mean a saturated hydrocarbon group
  • fluorenyl group of Cl ⁇ 10 means a saturated hydrocarbon group having 1 to 10 carbon atoms
  • fluorenyl group of Cl ⁇ 4 means a saturated hydrocarbon group having 1 to 10 carbon atoms.
  • cycloalkyl refers to a non-aromatic carbocyclic group, including a cyclized fluorenyl group.
  • Cyclodecyl groups may include bicyclic or polycyclic systems System. Examples of the cyclodecyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclodecyl group of C3 to 6 means a cyclodecyl group having 1 to 10 carbon atoms.
  • benzyl refers to benzyl, and substituted benzyl means that at least one hydrogen atom on the phenyl ring of the benzyl group is substituted by a non-hydrogen moiety, and the substituent of the benzyl group may be halogen, -CN, -OH, - SH, -NH 2 , a linear or branched fluorenyl group of 1 to 6 carbons, a substituted linear or branched fluorenyl group of 1 to 6 carbons.
  • heterocyclic fluorenyl refers to a non-aromatic heterocarbocyclyl group including a cyclized fluorenyl group in which one or more ring-forming carbon atoms are replaced by a hetero atom such as a 0, N or S atom.
  • the heterocyclic fluorenyl group preferably has 3, 4, 5, 6 or 7 ring-forming atoms.
  • Metal group means an -O-fluorenyl group having a carbon number of usually 1 to 10.
  • Examples of the decyloxy group include methoxyethoxy group, propoxy group (e.g., n -propoxy group and isopropoxy group), t-butoxy group and the like.
  • Aryl means an aromatic carbocyclic group including monocyclic or polycyclic aromatic hydrocarbons such as phenyl, naphthyl, anthracenyl, phenanthryl and the like.
  • aryloxy group means a -0-aryl group, and the concept of the aryl group is as described above, and the most preferable example of the aryloxy group is a phenoxy group.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention can be used to prepare antitumor drugs, and the overall preparation route is as follows:
  • the preparation method of the compound (II) includes the following steps:
  • a compound of the formula (II-3) can be produced by the following two routes: a. A compound of the formula (II-2) is condensed with Pg in the presence of a peptide condensing agent to form a formula (II-3). a compound; b, Pg reacts with SOCl 2 to form an acid chloride, and then reacts with a compound of the formula (II-2) to form a compound of the formula (II-3).
  • a compound of the formula (II-3) is subjected to saponification under basic conditions to form a sodium salt thereof, and then a compound (11) is produced under acidic conditions.
  • the peptide condensing agent commonly used in the above reaction is hydrazine, fluorene-dicyclohexyl-carbodiimide (abbreviated as DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. (abbreviated as EDGHC1), 1-hydroxybenzotriazole (abbreviated as HOBt) or isobutyl chloroformate.
  • the preparation method of the compound (III) includes the following steps (taking B, 3 ⁇ 4 and Z 2 together to form boric acid - 0C-nonanediol ester as an example):
  • a compound represented by the formula (III-8) is subjected to removal of a protective group bis(trimethylsilyl) under acidic conditions to give an amino group-exposed borate compound represented by the formula (III).
  • R1 is as defined above
  • R 5 is a linear, branched or substituted anthracene of 1 to 4 carbon atoms
  • X represents a halogen such as F, Cl, Br, I
  • M represents an alkali metal such as Li, Na, K, etc.
  • compounds (II) and (III) are reacted in the presence of a certain condensing agent to form (1).
  • the condensing agent used is TBTU (0-benzotriazole-oxime, oxime, ⁇ ', ⁇ ,-tetramethyluronium tetrafluoroborate), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (abbreviated as EDOHCl), 1-hydroxybenzotriazole (abbreviated as HOBt) or isobutyl chloroformate.
  • the ester group can be removed to form boric acid by the following reaction: pg,
  • ester groups There are two methods for removing ester groups: First, under the action of sodium periodate, the diol is broken to form the sodium salt of boric acid, and the pH of the system is adjusted to be acidic to obtain boric acid. Second, the boric acid ester and space Boric acid with a higher steric hindrance (such as isobutylboronic acid, phenylboronic acid) is transesterified to obtain the desired product boric acid, and the product is obtained by some separation means.
  • a higher steric hindrance such as isobutylboronic acid, phenylboronic acid
  • the inventors of the present invention have confirmed by experiments that the compounds of the present invention have good proteasome-inhibiting activity and anti-tumor activity, and all of the compounds exhibit better proteasome inhibitory activity and antitumor activity at a nanomolar level, and have broad Value.
  • the preparation method of the compound designed by the invention has high yield and simple process, and is suitable for industrial production. ⁇
  • the amino acid methyl ester oxime-2 prepared in the amino protecting agent Pg and 1 was dissolved in THF, and N-methylmorpholine and a suitable peptide condensation reaction reagent (DCC + HOBt) were added at 0 °C. Slowly warm to room temperature and continue to react for a certain period of time until TLC shows the reaction is complete. The insoluble solid was removed by filtration, the filtrate was evaporated to dryness, and an appropriate amount of ethyl acetate was added to dissolve the obtained viscous liquid, and the organic phase was washed with alkali (5% sodium hydrogencarbonate), pickled (10% citric acid), and alkali-washed ( Wash with 5% sodium bicarbonate) and saturated brine.
  • alkali 5% sodium hydrogencarbonate
  • pickled 10% citric acid
  • alkali-washed Wash with 5% sodium bicarbonate
  • the desiccant was dried (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated to dryness under reduced pressure to give the crude product of amino-protected amino acid methyl ester. The crude product was used in the next step without saponification.
  • the amino protecting agent Pg was dissolved in SOC1 2 at 0 ° C, and a catalytic amount of dry DMF was added thereto, and the mixture was reacted at room temperature for 20 minutes, and heated to 50 ° C for a certain period of time to evaporate unreacted SOCl 2 .
  • the acid chloride of the protective agent Pg is obtained. Dissolve in an appropriate amount of dry toluene, dry and set aside.
  • the amino acid methyl ester II-2 was dissolved in an organic solvent (toluene), an excess of N-methylmorpholine was added, and a toluene solution of the Pg acid chloride prepared above was added dropwise at 0 °C.
  • the reaction was carried out at 0 ° C for a certain period of time, and then slowly raised to room temperature for a certain period of time until TLC showed completion of the reaction.
  • the solvent was distilled off under reduced pressure, and the obtained solid was dissolved with an organic solvent (ethyl acetate), respectively, and washed with alkali (5% sodium hydrogen carbonate), acid (10% citric acid), and alkali (5% sodium hydrogencarbonate) Wash with saturated saline.
  • the desiccant was dried (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a crude product of amino-protected amino acid methyl ester. The crude product was used directly in the next step of saponification without purification.
  • the crude product of the above prepared II-3 was dissolved in an organic solvent (acetone), and an aqueous solution of an inorganic base (2N NaOH) was added at 0 ° C to maintain the pH of the system between 11 and 13, until TLC showed The reaction is complete.
  • the organic solvent was distilled off under reduced pressure, and the aqueous phase was extracted twice with an organic solvent (ethyl acetate), and aqueous aqueous solution (5N HCl) was added dropwise at 0 ° C until the pH of the system was between 1 and 3.
  • the organic layer was extracted with an organic solvent (ethyl acetate) and the organic phase was dried (dry sodium sulfate and anhydrous magnesium sulfate).
  • the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the product II.
  • III-3 ln . 5 III-6a
  • III-2a ⁇ 3 ⁇ 2 ⁇ 20 is dissolved in water, and III-la, tert-butanol, a small amount of pyridine and a catalytic amount of osmium tetroxide are added to the reaction system. The mixture was heated to reflux for 24 hours at a certain temperature (10 CTC), and the reaction was completed by TLC. Naturally, it was cooled to room temperature, and an appropriate amount of reducing agent (NaHS0 3 ) and solid salt were added. The liquid layer was separated, and the aqueous layer was extracted with an organic solvent (diethyl ether), and the organic phase was combined, and the organic phase was dried (dry sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a viscous liquid. The product III-2a was isolated by column chromatography.
  • Magnesium chips, an anhydrous organic solvent (anhydrous THF or anhydrous ether) and a small iodine tablet were placed in a strictly dried reaction flask.
  • a mixed solution of a halogenated hydrocarbon R 2 X and an anhydrous organic solvent (anhydrous THF or anhydrous diethyl ether) was added dropwise to the reaction mixture at room temperature.
  • the reaction system was heated to a slightly boiling state with a water bath. After most of the magnesium reaction was completed, the refluxing system was heated for 30 minutes to completely react the remaining magnesium. The reaction system was slowly cooled and set aside.
  • III-6a is dissolved in an anhydrous organic solvent (anhydrous THF or diethyl ether), and the reaction system is cooled to a temperature of 78 °C.
  • anhydrous organic solvent anhydrous THF or diethyl ether
  • the reaction system was naturally warmed to room temperature, and stirring was continued for 18 h at room temperature. The solid was removed by filtration, and concentrated to give the compound III-7a.
  • ⁇ 3 ⁇ 2 ⁇ 20 is dissolved in water, and III-lb, tert-butanol, a small amount of pyridine, and a catalytic amount of osmium tetroxide are added to the reaction system.
  • the mixture was heated under reflux at a certain temperature (10 CTC) for 48 hours, and the reaction was completed by TLC. Naturally, it was cooled to room temperature, and an appropriate amount of reducing agent (NaHS0 3 ) and solid salt were added.
  • the organic solvent was distilled off under reduced pressure, and the organic solvent (diethyl ether and ethyl acetate) was added to the mixture of the mixture of the liquid and the solid, and the aqueous layer was extracted with an organic solvent (diethyl ether and ethyl acetate). It is dried with a drying agent (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a viscous liquid.
  • the product III-2b was obtained by distillation under reduced pressure at a high vacuum.
  • Magnesium chips, an anhydrous organic solvent (anhydrous THF or anhydrous ether) and a small iodine tablet were placed in a strictly dried reaction flask.
  • a mixed solution of a halogenated hydrocarbon R 2 X and an anhydrous organic solvent (anhydrous THF or anhydrous diethyl ether) was added dropwise to the reaction mixture at room temperature.
  • the reaction system was heated with a water bath. The solution was brought to a slightly boiling state. After most of the magnesium reaction was completed, the system was heated to reflux for 30 minutes to completely react the remaining magnesium. The reaction system was slowly cooled and set aside.
  • III-6b is dissolved in an anhydrous organic solvent (anhydrous THF or diethyl ether), and the reaction system is cooled to a temperature of 78 °C.
  • anhydrous organic solvent anhydrous THF or diethyl ether
  • the reaction system was naturally warmed to room temperature, and stirring was continued for 24 h at room temperature. The solid was removed by filtration, and concentrated to give the compound III-7b.
  • Dissolve II and III in an organic solvent such as THF, CH 2 C1 2
  • an organic solvent such as THF, CH 2 C1 2
  • N-methylmorpholine and a condensing agent TBTU or EDGHC1 + HOBt or isobutyl chloroformate
  • the organic phase is dried with a drying agent (anhydrous sodium sulfate and anhydrous magnesium sulfate).
  • a drying agent anhydrous sodium sulfate and anhydrous magnesium sulfate.
  • the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a glassy solid compound boronic acid I.
  • the boronic acid ester I prepared in 1 is dissolved in an organic solvent such as diethyl ether and CH 2 C 1 2 , and water and phenylboronic acid are added. After stirring the reaction for 4 hours at room temperature, TLC showed the reaction was completed. The organic phase was extracted 3 times with water, the aqueous phases were combined and evaporated to dryness. The resulting viscous solid was washed with a small amount of diethyl ether to give a solid compound of boronic acid IV.
  • an organic solvent such as diethyl ether and CH 2 C 1 2
  • the boric acid ester I prepared in 1 was dissolved in an organic solvent (acetone or methanol), and then an aqueous solution of ammonium acetate and NaI0 4 were added . After stirring at room temperature for 24 hours, TLC showed the reaction was completed.
  • the organic solvent is distilled off under reduced pressure, the aqueous phase is adjusted to pH 3 with a mineral acid (hydrochloric acid), extracted with an organic solvent (ethyl acetate or CH 2 C1 2 ), and the organic phase is combined, and the organic phase is dried with a drying agent (anhydrous sulfuric acid) Sodium and anhydrous magnesium sulfate).
  • the desiccant was filtered off, and the solvent was evaporated to dryness under reduced pressure to give the crude compound boric acid IV.
  • the preparation of the compounds of the invention is described below by the synthesis of specific compounds:
  • the 1-na structure is;
  • the 3-Indol structure is The stereo configuration may be a racemate (m) of G), (r) or both;
  • Type can be (s), (r) or both races; ⁇ -naTH knot
  • the hydrochloride of the other amino acid methyl ester used in the present invention can be produced by the above procedure, the compound lb: synthesized by the method of synthesizing the compound la using L-leucine; and the compound lc: by the method of synthesizing the compound la using ⁇ -( Synthesis of ⁇ -1-naphthyl)alanine; Compound Id: synthesized by the method of synthesizing compound la using L-(P-2-naphthyl)alanine; Compound le: L-oxime according to the method of synthesizing compound la Acid synthesis; Compound If: synthesized by the method of synthesizing compound la using L-tryptophan; Compound lg : synthesized by the method of synthesizing compound la using L-isoleucine.
  • the specific compounds synthesized and their properties are shown in the following table.
  • Method b acid chloride method To 0 (1), S0C1 2 (3.8 ml, 52 mmol) was added to 1-(S)-1,2,3,4-tetrahydronaphthoic acid (0.92 g, 5.2 mmol), followed by a catalytic amount of dry DMF. . The mixture was slowly warmed to room temperature, reacted for 20 minutes, and further heated to 50 ° C for 1 hour to stop the reaction. Unreacted S0C1 2 was distilled off. 1-(S)-1,2,3,4-tetrahydronaphthoyl chloride was obtained. This was dissolved in 10 ml of dry toluene and was used.
  • the compound la (1.12 g, 5.2 mmol) was dissolved in 20 mL of THF, and N-methylmorpholine (NMM) (0.7 mL, 6.2 mmol) was added, and the 1-(S) prepared above was added dropwise at 0 °C. a toluene solution of -1,2,3,4-tetrahydronaphthoyl chloride. The reaction was carried out at 0 ° C for 2 hours, and then slowly raised to room temperature for 1 hour, and TLC showed the reaction was completed.
  • NMM N-methylmorpholine
  • the solvent was evaporated under reduced pressure, and the obtained solid was dissolved in 30 ml of ethyl acetate, and washed with 5% sodium hydrogen carbonate (30mL), 10% citric acid (30mL), 5% sodium hydrogencarbonate (30mL) and saturated brine (2 X 20mL).
  • the organic phase was dried over anhydrous Na 2 SO 4 .
  • the desiccating agent was filtered off, and the solvent was evaporated to dryness to dryness to give a white solid.
  • the product was used in the next step without saponification.
  • Example (3) Other amino protected amino acids used in the present invention can be prepared by the methods described in Example (3).
  • Trimethyl borate (7.5 mL, 66 mmol) was added to a solution of the above-prepared compound III-3a at 110 ° C, and stirring was continued for 1 hour, and then 12 mL of 5N HCl solution was added, and the temperature was naturally raised to room temperature.
  • the reaction mixture was transferred to a sep. funnel, and the organic layer was evaporated. The solvent was evaporated to give a white solid, 9.3 g, yield 99.4%. The product was used in the next step without purification.
  • a crushed magnesium strip (1.45 g, 60 mmol)
  • 70 mL of anhydrous tetrahydrofuran was added, and a small amount of iodine was added thereto.
  • 30 ml of a solution of tert-butyl bromide (8.22 g, 60 mmol) in tetrahydrofuran was added dropwise at room temperature. After heating, the mixture was slightly boiled until the magnesium strip was dissolved, and the solution was cooled to a tetrahydrofuran solution of a t-butyl format reagent. Dry and set aside.
  • Dichloromethylborate -0C-decanediol ester III-6a ( 15.78 g, 60 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran. Pass dry nitrogen, and cool to a temperature of 78 ° C, then slowly add the above prepared t-butyl format reagent four After the dropwise addition, the dried ZnCl 2 powder (4.09 g, 30 mmol was naturally warmed to room temperature, and the mixture was stirred at room temperature. After TLC detection, the reaction was completed after 18 h. The solid was removed by filtration, and concentrated by column chromatography.
  • Dichloromethylene borate-OC-decanediol ester III-6a ( 1.58 g, 6 mmol) was dissolved in 20 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to a temperature of 78 ° C, and then a diethyl ether solution of the prepared n-butyl format reagent was slowly added dropwise. After the dropwise addition was completed, dried ZnCl 2 powder (0.41 g, 3 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 18 hours.
  • Dichloromethylene borate-0C-decanediol ester III-6a ( 1.31 g, 5 mmol) was dissolved in 20 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to a temperature of 78 ° C, and then a solution of the prepared benzyl chloride format reagent in diethyl ether was slowly added dropwise. After the dropwise addition was completed, dried ZnCl 2 powder (0.41 g, 3 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 24 hours.
  • Dichloromethylene borate-0C-decanediol ester III-6a (4.52 g, 20 mmol) was dissolved in 30 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to 78 ° C, and then a solution of the prepared methylbenzyl chloride format reagent in diethyl ether was slowly added dropwise. After the dropwise addition was completed, dried ZnCl 2 powder (0.55 g, 4 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 24 hours.
  • Dichloromethylene borate-OC-decanediol ester III-6a (2.66 g, 10 mmol) was dissolved in 20 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to a temperature of 78 ° C, and then a solution of the prepared fluorobenzyl bromide format reagent in diethyl ether was slowly added dropwise. After the dropwise addition was completed, dry ZnCl 2 powder (0.27 g, 2 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 24 hours.
  • the filtrate was cooled to a temperature of 78 ° C, and 34.5 mL of a diethyl ether solution of a concentration of 1.3 M hydrogen chloride was added, and then naturally warmed to room temperature, and a large amount of milky white solid appeared. Freezing allows the solid to completely precipitate. Filtration and diethyl ether washing afforded 3.86 g of a white solid.
  • LiN(SiMe 3 ) 2 (10 mL, 10 mmol) was added to a 100 mL single-mouth bottle, nitrogen gas was passed through, and the temperature was lowered to 78 ° C, and then 1-phenyl-2-chloro-ethylboronic acid was slowly added by a syringe. 10 mL of a solution of 0C-nonanediol ester III-9a ( 3.19 g, 10 mmol) in THF was added, and after the dropwise addition, the mixture was allowed to warm to room temperature and then stirred at room temperature. After TLC detection, the reaction was completed after 24 hours.
  • Dichloromethylborate -0C-decanediol ester III-6b ( 1.18 g, 4.49 mmol) was dissolved in 12 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to 78 ° C. Then, a solution of the prepared tert-butyl format reagent in diethyl ether (6 mL, 4.50 mmol) was slowly added dropwise. After the dropwise addition, dry ZnCl 2 powder (0.44 g) was added. , 3.25mmol). Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 18 hours.
  • LiN(SiMe 3 ) 2 (5 mL, 5 mmol) was added to a 100 mL single-mouth bottle, nitrogen gas was passed through, and the temperature was lowered to 78 ° C, and then slowly added with a syringe containing 2-methyl-4-chloro-butylboronic acid - 10 mL of a solution of 0C-nonanediol ester III-7b ( 1.42 g, 5 mmol) in THF was added, and after the dropwise addition, the mixture was allowed to warm to room temperature and then stirred at room temperature. After TLC detection, the reaction was completed after 20 hours.
  • the solvent was distilled off under reduced pressure, dissolved in 20 mL of hexanes and filtered to remove insolubles.
  • the filtrate was cooled to a temperature of 78 ° C, and 12 mL of a solution of 1.3 M hydrogen chloride in diethyl ether was added, and then naturally warmed to room temperature, and a large amount of milky white solid appeared.
  • the solid was completely precipitated by freezing, filtered, and the product was washed with diethyl ether to give 1.12 g of a white solid.
  • N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylalanine (s-3aA) (0.12 g, 0.37 mmol) in Example 1 under nitrogen atmosphere Dissolved in 10 ml of dry THF, the system was cooled to -5 °C, HOBt (0.06 g, 0.44 mmol) was added, and after reacting for 20 minutes, the system was cooled to -15 ° C, and EDC.HCl (0.37 mmol) was added.
  • the method of synthesizing other similar compounds of the present invention can employ the above method.
  • Nl-(-l,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid-oc-decanediol ester (0.1 g, 0.175 mmol) with 5 mL of acetone Dissolve, add NH 4 OAC solution (0.1 N, 4 mL), and finally add NaIO 4 (0.11 g, 0.525 mmol), and stir the reaction at room temperature. TLC detection showed that the reaction was complete after 10 h. Add NaOH to the reaction solution. Solution (2N, 3mL), CH 2 C1 2 extraction. The pH of the solution was adjusted to about 3 with concentrated hydrochloric acid.
  • the method utilizes the fluorescent substrate polypeptide Suc-Leu-Leu-Val-Tyr-AMC (abbreviated as Suc-LLVY-AMC, Sue represents succinyl group, AMC represents 7-amide-4-methylcoumarin) under the action of proteasome Hydrolysis will occur, releasing the principle of fluorescent AMC (Ex: 380nm, Em: 460nm).
  • Suc-LLVY-AMC the fluorescent substrate polypeptide Suc-Leu-Leu-Val-Tyr-AMC
  • Sue represents succinyl group
  • AMC represents 7-amide-4-methylcoumarin
  • the proteasome used in this experiment was the human erythrocyte 20S proteasome, and the enzyme, fluorescent substrate and test buffer were purchased from Biomol.
  • the experimental system is 100 ul, which contains the proteasome 90 ⁇ l (0.2 g), the substrate 10 ⁇ l, the final concentration is 50 ⁇ , the drug (inhibitor) 0.1 ⁇ 1, and the final concentration is 10-? ⁇ ! ⁇ 11 ⁇ ! ,
  • the actual configuration concentration is 10 - 4 ⁇ ⁇ 10 - 8 ⁇ .
  • the specific experimental process is as follows:
  • the drug was accurately weighed and dissolved in DMSO to 10 - 2 Torr. Pipette 90 lDMSO ⁇ was added to give 10- 3 M, and then added 90 lDMSO suction ⁇ 10- 4 M obtained from 10- 3 M concentration of the drug in the same manner to obtain 10- 5 M, 10- 6 M, 10 - 7 M, 10- 8 M concentration of the drug.
  • the 20S proteasome (1 ⁇ ⁇ / ⁇ 1) was diluted to a concentration of 0.0022 ⁇ ⁇ / ⁇ 1 in a buffer solution, 90 ⁇ 1 was added to each well of a 96-well fluorescent plate, and then ⁇ . ⁇ sample was added to each well.
  • the listed drug Wanxi was used as a positive control drug, and 0.1 l DMSO was added to the blank control group and the background control group, and the reaction was carried out at 37 ° C for 20 min.
  • a ⁇ fluorescent substrate was added to each well, and the reaction was carried out at 37 ° C for 1 hour in the dark, and the fluorescence value was measured by a 380 nm / 460 nm fluorescent microplate reader (Tecan, Infinite M200).
  • the therapeutic dose of the compound of the present invention may vary depending, for example, on the particular use of the treatment, the mode of administration of the compound, the health of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition will vary depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
  • the compounds of the invention may be provided for parenteral administration in an aqueous physiological buffer containing from about 0.1 to about 10% w/v of the compound. Some typical dosage ranges range from about 1 ⁇ g/kg to about lg/kg body weight per day.
  • the dosage ranges from about 0.01 mg/kg body weight to about 100 mg/kg body weight per day.
  • the dose is highly likely to depend on such variables as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and the route of administration. Effective doses can be derived from dose response curves from in vitro or animal model test systems.

Abstract

La présente invention concerne une sorte d'acide borique et ses composés esters tels que représentés dans la formule (I). Dans cette formule, R1 et R2 sont C1-10 alkyle, C3-6 ou hétéroalkyle, benzyle, ménaphtyle ou indyl-méthyle, le substituant de R1 et R2 étant C1-4 alkyle, cyano, hydroxyle, sulfhydryle, amino ou halogène. Z1 ou Z2 sont indépendamment hydroxyle, C1-10 alkyle, C1-10 alcoxy ou aryloxy, ou bien B, Z1 et Z2 peuvent former un hétérocycle incluant N, S ou O. Pg est acyle bicyclique ou tricyclique éventuellement substitué incluant au moins un cycle non saturé, le substituant considéré étant C1-4 alkyle, C1-4 alcoxy, halogène ou C1-4 haloalkyle. La présente invention concerne également le procédé d'élaboration de tels composés et leurs utilisations comme anticancéreux.
PCT/CN2009/072967 2008-07-30 2009-07-29 Acide peptidyl-borique et ses dérivés esters, synthèse et utilisation correspondantes WO2010012222A1 (fr)

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US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
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