CN115433119B - C5 branched 1-deoxynojirimycin derivative and preparation method and application thereof - Google Patents
C5 branched 1-deoxynojirimycin derivative and preparation method and application thereof Download PDFInfo
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- CN115433119B CN115433119B CN202110623646.5A CN202110623646A CN115433119B CN 115433119 B CN115433119 B CN 115433119B CN 202110623646 A CN202110623646 A CN 202110623646A CN 115433119 B CN115433119 B CN 115433119B
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Chemical group 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/98—Nitrogen atom
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Abstract
The invention relates to the technical field of glycosidase inhibitors, and discloses a C5 branched 1-deoxynojirimycin derivative, and a preparation method and application thereof. The 1-deoxynojirimycin derivative provided by the invention is a compound with a structure shown in a formula (I) and pharmaceutically acceptable salts thereof; wherein R is 1 Alkyl of C2-C20; r is R 2 Is hydrogen or hydroxy; r is R 3 ‑R 6 Each independently is H, benzyl or substituted benzyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxy, nitro and halogen; the three-dimensional configuration of the carbon at the 5-position of the compound is R or S. The C5 branched DNJ derivative provided by the invention has excellent glycosidase inhibition activity and high medicinal value.
Description
Technical Field
The invention relates to the technical field of glycosidase inhibitors, in particular to a C5 branched 1-deoxynojirimycin derivative, and a preparation method and application thereof.
Background
DNJ (1-deoxynojirimycin) is iminosugar separated from mulberry in 1966, has strong inhibition effect on alpha-glucosidase and also has inhibition activity on other glycosidases such as beta-glucosidase. DNJ and its derivatives have important medicinal values, for example, can treat diabetes, gaoshan's disease, antiviral, antitumor, antioxidant and reduce postprandial blood sugar (Compain, P. Et al, iminosugars: from synthesis to Therapeutic Application; wiley, 2007), and thus are receiving a great deal of attention in the field of new drug development.
Currently, about 300 DNJ derivatives are reported, of which two are on the market, both N-alkylated DNJ derivatives, miglitol (N-hydroxyethyl-DNJ) and miglitol (N-butyl-DNJ), respectively. This greatly facilitates the investigation of DNJ derivatives. Modifications to DNJ can be broadly divided into four categories: 1) N-substitution; 2) C-substitution; 3) O-substitution 4) isotopic substitution. The substituent is various in kind, for example, alkyl group, unsaturated hydrocarbon group, phenyl group, sugar group, fluoro group, chloro group, heterocyclic aryl group, hydroxyl group, amino group and the like. The modification sites involved various sites of DNJ: the modification on N is mainly alkylation containing 1-20 carbons, some C atoms of the alkyl chain may be replaced by hetero atoms or functional groups, or other groups may be linked at the end, such as amino acids, glycosyl groups and heterocyclic aryl groups, etc. (Wolfsgruber, A. Et al, molecular 2020,25,4618; ghisapidoobe, A. Et al, ACS Med. Chem. Lett.2011,2,119)The method comprises the steps of carrying out a first treatment on the surface of the Ghisaidoobe, a.t. et al, med.chem.2014,57,9096; wennekes, T.et al, J.org.chem.2007,72,1088; hoogendorn, S et al, eur.j. Org. Chem.2015,2015,4437; wang, l. Et al, acta Chimica Slovenica 2020,67,812) modifications to O are mainly alkylation and glycosylation. Isotopic substitution is mainly the isotopic substitution of hydrogen and carbon in the compound. Modifications to C are primarily focused on the C1 position, including alkylation and glycosylation. Modifications to C2-C4 are mainly fluoro and chloro. Currently, modifications to the C5 position only report a small number of compounds: 5-C-methyl-DNJ, which compounds were tested only for activity on human alpha-glucose (IC 50 =1 μm) activity evaluation; 5-C-benzyl-DNJ; 5-C-hydroxymethyl-DNJ; 5-C-hydroxy-DNJ; 5-C-cyano-DNJ. (Maughan, M.A.T. et al Angew.Chem., int.Ed.2003,42,3788;Pawar,N.J. Et al J.Org.Chem.2012,77,7873;Wuensche,C et al J.org.Mass Spectrom.1984,19,176). The compounds have the defects of insufficient inhibitory activity on glycosidase, large molecular polarity, good water solubility, poor fat solubility, adverse membrane permeation and poor patentability.
In addition, the current synthesis methods of C5 branched compounds mainly comprise the following two methods: 1) The preparation method comprises the steps of taking tetrabenzyl-DNJ as a raw material, taking an N-chloro DNJ derivative as a key intermediate, obtaining a compound precursor through Grignard addition, and finally obtaining a compound through catalytic hydrogenation; although the procedure is relatively short, the raw material tetrabenzyl DNJ is expensive, the yield is low, and particularly, the yield is only 17% in the addition reaction of imine and Grignard reagent, so that the industrialization is difficult. 2) D-glucose is used as a raw material, and an azido-substituted sugar derivative is used as a key intermediate to obtain a compound. Although the raw materials are relatively cheap and easy to obtain, the conditions are mild, the reaction steps are more, and the universality is low due to the fact that highly toxic azide reagents are used repeatedly.
Method 1):
method 2):
therefore, there is a need for a glycosidase inhibitor with high activity, good pharmaceutical properties, and a preparation method which has the advantages of readily available raw materials, simple steps and suitability for industrialization.
Disclosure of Invention
The invention aims to overcome the technical problems in the prior art and provide a C5 branched 1-deoxynojirimycin derivative with excellent glycosidase inhibition activity, and a preparation method and application thereof.
Through intensive studies, the inventor of the present invention found that when a derivative obtained by C5 branching of DNJ (1-deoxynojirimycin) with different substituents is combined with different enzymes, the combined active center and action mode are greatly different, which results in great difference in enzyme inhibition activity. For example, when DNJ is bound to N-terminal human maltase-glucoamylase (ntMGAM, PDB ID:3L 4W), hydrogen bonding exists between its secondary amino group and the C-2, C-3, C-6 hydroxyl groups with amino acid residues Asp-443, arg-526, asp-542 and Asp-327; while 5-C-methyl-DNJ binds to ntMGAM, the conformation taken by the molecule is similar, but the amino acid residues involved in the binding are not exactly the same, his-600, asp-542, asp-327, asp-443 and Trp-406, and therefore the effect of the groups employed for C5 branching on the properties of the final branched compounds is difficult to predict. The inventors of the present invention have found that: a series of DNJ (1-deoxynojirimycin) branched by long chain hydrocarbon has better affinity for different glycosidases.
Accordingly, in order to achieve the above object, a first aspect of the present invention provides a C5 branched 1-deoxynojirimycin derivative, which is a compound having a structure represented by formula (I):
wherein R is 1 Alkyl of C2-C20;
R 2 is hydrogen or hydroxy;
R 3 -R 6 each independently is H, benzyl or substituted benzyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxy, nitro and halogen;
the three-dimensional configuration of the carbon at the 5-position of the compound is R or S.
In a second aspect, the present invention provides a method for preparing a C5 branched 1-deoxynojirimycin derivative, the method comprising the steps of:
(1) Combining a compound of formula (II) with a compound having the formula R 1 Nucleophilic addition of the organometallic reagent of the group to give a compound of formula (I');
(2) Optionally, contacting the compound shown in the formula (I ') with a deprotection reagent and a hydrogen source to perform catalytic hydrogenation reaction to obtain a compound shown in the formula (I') or a salt thereof;
wherein R is of the formula (II), formula (I ') and formula (I'), are mentioned 1 、R 2 、R 3 、R 4 、R 5 Or R is 6 Is the same as the definition of the first aspect.
In a third aspect, the present invention provides a glycosidase inhibitor comprising the C5 branched DNJ derivative according to the first aspect as an active ingredient.
In a fourth aspect, the present invention provides the use of a glycosidase inhibitor according to the third aspect above for the inhibition of glycosidases.
In a fifth aspect, the present invention provides a use of a glycosidase inhibitor according to the third aspect, for the manufacture of a medicament selected from at least one of the following: 1) A medicament for preventing and/or treating diabetes; 2) A medicament for preventing and/or treating Gaucher's disease; 3) A medicament for preventing and/or treating tumors; 4) Antiviral drugs; 5) An antibacterial agent; 6) A medicament for preventing and/or treating pompe disease.
The C5 branched DNJ derivative provided by the invention has excellent glycosidase inhibition activity and high medicinal value.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
In the present invention, "x" on a carbon is understood by those skilled in the art to mean that the carbon is chiral and may be in either R-or S-form conformation. The numbers at the carbon sites on the piperidine ring in the following formulas indicate the numbers of the positions where they are located. For example, formula (I)The "5" on piperidine in the illustrated compounds indicates the carbon at position 5, while the "1" indicates the carbon at position 1, and the other cases are similarly explained.
In the present invention, specific examples of the "C2-C20 alkyl group" may be ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl and the like. Alkyl groups having a narrower range of carbon atoms may also be selected from this specific example according to the definition of the number of carbon atoms.
In the present invention, specific examples of the C1-C6 alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. Alkyl groups having a narrower range of carbon atoms may also be selected from this specific example according to the definition of the number of carbon atoms.
The first aspect of the present invention provides a C5 branched 1-deoxynojirimycin derivative, wherein the 1-deoxynojirimycin derivative is a compound with a structure shown in a formula (I) and pharmaceutically acceptable salts thereof:
wherein R is 1 Alkyl of C2-C20;
R 2 is hydrogen or hydroxy;
R 3 -R 6 each independently is H, benzyl or substituted benzyl, wherein the substituent of the benzyl is selected from one of C1-C6 alkoxy, C1-C6 alkyl, hydroxy, nitro and halogen (which may be F, cl, br, I);
the three-dimensional configuration of the carbon at the 5-position of the compound is R or S.
According to some embodiments of the invention, R 1 Is a C2-C12 alkyl group.
According to some embodiments of the invention, R 2 Is hydrogen.
According to some embodiments of the invention, R 3 -R 6 May each independently be H, benzyl or substituted benzyl, wherein the substituent of benzyl may be selected from one of C1-C4 alkoxy, C1-C4 alkyl, hydroxy, nitro and halogen.
According to some embodiments of the invention, R 3 -R 6 Are hydrogen or benzyl.
According to some embodiments of the invention, R 3 -R 6 Are all hydrogen.
According to some embodiments of the invention, the carbon at the 5-position of the compound has a steric configuration of R or S.
According to some embodiments of the invention, the compound may be selected from one of the compounds of the structure shown below:
in a second aspect, the present invention provides a method for preparing a C5 branched 1-deoxynojirimycin derivative, the method comprising the steps of:
(1) Combining a compound of formula (II) with a compound having the formula R 1 Nucleophilic addition of the organometallic reagent of the group to give a compound of formula (I');
(2) Optionally, contacting the compound shown in the formula (I ') with a deprotection reagent and a hydrogen source to perform catalytic hydrogenation reaction to obtain a compound shown in the formula (I') or a salt thereof;
wherein R is of the formula (II), formula (I ') and formula (I'), are mentioned 1 、R 2 、R 3 、R 4 、R 5 Or R is 6 Is the same as the definition of the first aspect.
In the present invention, in the step (1), the compound represented by the formula (II) (nitrone) is reacted with a compound having R 1 Nucleophilic addition of the organometallic reagent of the group to give the group R 1 Is connected to the compound nitrone shown in the formula (II) to obtain the compound shown in the formula (I').
In the present invention, the compound represented by the formula (II) may be obtained commercially or may be prepared. The preparation of the compound represented by the formula (II) is not particularly limited, and may be carried out in a manner conventionally known in the art (for example, refer to Boisson, J.; thomaset, A.; racine, E.; cividin, P.; banchelin Sainte-Luce, T.; poisson, J.F.; behr, J.B.; py, S.org. Lett.2015,17,3662.).
According to some embodiments of the invention, in step (1), the conditions of nucleophilic addition may include: the temperature is-20 to 50 ℃, preferably-10 to 35 ℃; the time is 0.5 to 5 hours, preferably 0.5 to 2 hours.
According to some embodiments of the invention, the molar ratio of the compound of formula (II) to the organometallic reagent may be 1: (1.2-50), preferably 1: (1.2-10).
According to some embodiments of the invention, the organometallic reagent may be selected from at least one of an organomagnesium reagent, an organozinc reagent, an organolithium reagent and an organocopper reagent, preferably from an organomagnesium reagent and/or an organozinc reagent.
In the present invention, the organomagnesium reagent may be represented by the formula MgR 1 X represents, wherein X is halogen (F, cl, br, I). The organozinc reagent can be prepared from ZnR 1 X represents, wherein X is halogen (F, cl, br, I). The organolithium reagent can be prepared from LiR 1 And (3) representing. The organic copper reagent can be represented by formula CuR 1 X represents, wherein X is halogen (F, cl, br, I). The above radicals R 1 The choice of (c) may be specifically selected according to the compound represented by the formula (I') to be produced.
According to some embodiments of the invention, the nucleophilic addition is performed in the presence of a first solvent, which is an aprotic solvent, which may be selected from diethyl ether (Et 2 O), tetrahydrofuran (THF), dioxane and Dichloromethane (DCM), preferably selected from tetrahydrofuran and/or dioxane.
In the present invention, the amount of the first solvent is not particularly limited as long as it can satisfy the requirements of the present invention, and preferably the amount of the first solvent is 2 to 200mL, more preferably 5 to 50mL, with respect to 1g of the compound represented by the formula (II).
In the present invention, in order to obtain a better effect, in the step (1), the compound (nitrone) represented by the formula (II) and the compound having R 1 The group organometallic reagent is fed in the following manner: the organometallic reagent is added to a solution containing the compound of formula (II), preferably obtained by dissolving the compound of formula (II) in a first solvent.
In the present invention, the post-treatment of the affinity addition is not particularly limited as long as the requirements of the present invention can be satisfied. The post-treatment may be performed, for example, as follows: using saturated NH 4 The reaction system was quenched with aqueous Cl, extracted with ethyl acetate, and the organic phase was concentrated and the compound of formula (I') was purified by column chromatography.
According to some embodiments of the invention, in step (2), the conditions of the catalytic hydrogenation reaction may include: the temperature is 0-50deg.C, preferably 10-30deg.C; the time is 6 to 100 hours, preferably 6 to 48 hours.
In the present invention, the catalyst used in the catalytic hydrogenation reaction is a deprotection reagent conventional in the art. The invention can remove the protecting group on the hydroxyl through the catalytic hydrogenation reaction in the presence of the deprotection reagent.
According to some embodiments of the invention, the deprotection reagent may be selected from at least one of Raney nickel, pd/C (e.g. Pd/C with a Pd content of 10 mass%, denoted as 10% Pd/C), palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide, platinum black, trimethyliodosilane, boron trichloride, boron tribromide, aluminum trichloride and zinc/ammonium chloride, preferably at least one selected from Raney nickel, pd/C, palladium black, palladium hydroxide, palladium acetate, boron trichloride and boron tribromide.
In the invention, when the deprotection reagent is at least one selected from Raney nickel, pd/C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide and platinum black, the mass ratio of the compound shown in the formula (I') to the deprotection reagent is 1: (0.1-5), preferably 1: (0.1-0.2).
In the present invention, when the deprotecting reagent is at least one selected from the group consisting of trimethyliodosilane, boron trichloride, boron tribromide, aluminum trichloride, and zinc/ammonium chloride, the molar ratio of the compound represented by formula (I') to the deprotecting reagent is 1: (1-20), preferably 1: (5-10).
According to some embodiments of the invention, the molar ratio of the compound of formula (I') to the hydrogen source is 1: (5-100), preferably 1: (10-50).
According to some embodiments of the invention, the hydrogen source may be selected from at least one of hydrogen gas, sodium borohydride and ammonium formate, preferably hydrogen gas.
According to some embodiments of the invention, the catalytic hydrogenation reaction is carried out in the presence of a second solvent selected from at least one of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, acetic acid, water, dioxane, methanol, ethanol, acetonitrile, formamide and N, N-dimethylformamide.
In the present invention, the amount of the second solvent is not particularly limited as long as it can satisfy the requirements of the present invention, and preferably, the amount of the second solvent is 0.02 to 2mL, preferably 0.04 to 1.5mL, relative to 1mg of the compound represented by the formula (I').
In the present invention, the deprotection reaction may be carried out in the presence of hydrochloric acid, wherein the amount of hydrochloric acid is not particularly limited as long as the requirement of the present invention can be satisfied, and preferably, the amount of hydrochloric acid may be 0.01 to 1mmol relative to 1mg of the compound represented by formula (I'). Wherein, when hydrochloric acid exists in the deprotection reaction, the step (2) is carried out to obtain the hydrochloride of the compound shown as the formula (I').
In the present invention, the post-treatment in step (2) is not particularly limited as long as the requirements of the present invention can be satisfied. The post-treatment may be performed, for example, as follows: filtering the system after the reaction in the step (2) to obtain a filter cake and a filtrate, and removing the solvent of the filtrate under reduced pressure (-10 MPa to-0.01 MPa, preferably-1 MPa to-0.01 MPa) to obtain the compound shown in the formula (I') or a salt thereof.
In the present invention, the product obtained after deprotection is a salt (preferably hydrochloride) of the compound represented by the formula (I "), and the compound represented by the formula (I") can be obtained by treating with an acidic ion exchange resin. In order to extract the compound shown in the formula (I '), the step can further comprise filtering the product of the catalytic hydrogenation reaction by using diatomite, removing the solvent of the filtrate, adding ammonia water to neutralize to alkalinity, and separating and purifying the residue by using an acidic ion exchange resin column to obtain the compound shown in the formula (I').
In the present invention, the methods described in step (1) and step (2) may be carried out in a manner conventional in the art.
In a third aspect, the present invention provides a glycosidase inhibitor comprising the C5 branched DNJ derivative or a salt thereof according to the first aspect as an active ingredient.
In a fourth aspect, the present invention provides the use of a glycosidase inhibitor according to the third aspect above for the inhibition of glycosidases.
According to some embodiments of the invention, the glycosidase may be selected from at least one glycosidase consisting of alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-murine Li Tangmei, amyloglucosidase, and beta-glucosidase.
In a fifth aspect, the present invention provides a use of a glycosidase inhibitor according to the third aspect, for the manufacture of a medicament selected from at least one of the following: 1) A medicament for preventing and/or treating diabetes; 2) A medicament for preventing and/or treating Gaucher's disease; 3) A medicament for preventing and/or treating tumors; 4) Antiviral drugs; 5) An antibacterial agent; 6) A medicament for preventing and/or treating pompe disease.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. Such carriers include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and optionally other additives conventional in the pharmaceutical arts. The medicine prepared by the compound with the structure shown in the formula (I) or the pharmaceutically acceptable hydrate or the medicine compound thereof can be prepared into various forms such as injection, tablet, powder, granule, capsule, oral liquid, ointment, cream and the like. The medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
The drug may be administered by a variety of routes of administration including, but not limited to, oral, inhalation, rectal, transdermal, transmucosal enteral administration, and subcutaneous, intramuscular, or intravenous administration. The compounds of the structures of the present invention, or pharmaceutically acceptable hydrates or pharmaceutical complexes thereof, may be administered alone or in combination with other known therapeutic agents for diabetes, antiviral, antibacterial and antitumor agents.
The present invention will be described in detail by examples.
In the following preparation examples and examples, the starting materials used were all obtained commercially without particular explanation.
Preparation example 1
This preparation is used to illustrate the synthesis of the compound of formula (II) (see Boisson, J.; thomaset, A.; racine, E.; cividin, P.; banchelin Sainte-Luce, T.; poisson, J.F.; behr, J.B.; py, S.org. Lett.2015,17,3662), wherein R 3 -R 6 Are all hydrogen.
(1) Acetyl chloride (27 mL) was added dropwise to 1500mL of methanol at-10deg.C, and the reaction was continued for half an hour. Transfer to room temperature, add L-sorbose (90 g) thereto and react overnight at room temperature. After the raw materials disappear, sodium bicarbonate is added to neutralize to be alkaline, ethyl acetate is used for extraction, the organic phases are combined, the crude product IV is obtained through concentration, 200mL of N, N-dimethylformamide is used for dissolution, and the crude product IV is directly used for the next reaction.
(2) 60% NaH (120 g) was suspended in a mixed solvent of 200mL DMF and 700mL THF, and stirred for 10 minutes until no bubbles were generated. And a solution of one-step crude product IV in N, N-Dimethylformamide (DMF) was added dropwise thereto, and the reaction was carried out for 1 hour after the addition. A catalytic amount of tetrabutylammonium iodide (1.85 g) was then added thereto, followed by dropwise addition of benzyl bromide (261 mL). After the addition, the reaction was carried out for 10 minutes, and the raw materials disappeared. Then slowly dripping saturated ammonium chloride aqueous solution into the mixture for quenching, adding water, extracting by ethyl acetate, combining organic phases, evaporating to dryness to obtain a crude product V, and directly using the crude product V in the next reaction.
(3) The crude product V was dissolved in 500mL of 1, 4-dioxane, 110mL of 1N hydrochloric acid was added, and the temperature was raised to 90℃and reacted overnight. Evaporating 1, 4-dioxane, adding water, extracting with ethyl acetate, and mixing organic phases. Adding sodium bicarbonate to adjust to alkalinity, extracting again, combining organic phases, and evaporating to dryness. Separating by column chromatography to obtain the product VI.
(4) 20g of product VI are dissolved in 200mL of dry Tetrahydrofuran (THF) and 12mL of dry pyridine are added. And (3) protecting the steel plate by argon. 35.6g Br was added 2 ·PPh 3 Heating to 70 ℃ for reaction. After disappearance of the starting material, quench with saturated aqueous sodium thiosulfate, extract with ethyl acetate, dry the organic phase over anhydrous magnesium sulfate, filter and combine the organic phases. Petroleum ether and ethyl acetate are used as solvents, most white solid is triphenylphosphine oxide obtained by recrystallization, and the solid is removed. The organic phase is evaporated to dryness and separated by column chromatography to obtain a product VII.
(5) 11g of product VII are dissolved in dry Tetrahydrofuran (THF), 13mL of triethylamine and then 5g of hydroxylamine hydrochloride are added and reacted overnight at room temperature. After the raw materials disappear, adding water for quenching, evaporating to dryness, and separating by column chromatography to obtain nitrone II.
Example 1
This example is intended to illustrate the preparation of formulas (IA-1), (IA-2), (IB-1) and (IB-2)
(1) Nitrone (0.97 g,1.81 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (20 mL), ethyl magnesium chloride (5.55 mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.) for 3 minutes, the reaction was continued for 35 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-1), yield 59%, and the compound of formula (IA-2) in 35%.
(2-1) Compound (287 mg) represented by the formula (IA-1) was dissolved in methanol (20 mL), 28.7mg of 10% Pd/C was added, hydrochloric acid (5 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, reacted for 12 hours, filtered, the cake was discarded to obtain a filtrate, and the solvent was removed under reduced pressure of-0.1 MPa to obtain hydrochloride of the compound represented by the formula (IB-1) in 98% yield.
1 H NMR(500MHz,CD 3 OD)δ3.63(1H,d,J＝12.3Hz),3.56–3.41(2H,m),3.35(1H,t,J＝8.8Hz),3.26(1H,d,J＝8.9Hz),3.02–2.88(1H,m),2.74(1H,t,J＝11.8Hz),1.82–1.65(1H,m),1.64–1.49(1H,m),0.77(3H,t,J＝7.5Hz)
Free base (compound of formula IB-1) can be obtained via acidic ion exchange resin:
1 H NMR(400MHz CD 3 OD)δ3.74(1H，d,J＝11.4Hz),3.64(1H,d,J＝11.4Hz),3.52-3.42(1H,m),3.42-3.32(1H,m),3.29(1H,d,J＝9.1Hz),2.83(1H,dd,J＝12.4Hz,5.3Hz),2.61(1H,t,J＝9.1Hz),1.80-1.64(1H,m),1.64-1.50(1H,m),3.29(3H,t,J＝9.1Hz)。
(2-2) 115mg of the compound represented by the formula (IA-2) was dissolved in methanol (25 mL), 17.25mg of 10% Pd/C was added, hydrochloric acid (3 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 12 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.5 MPa to obtain the hydrochloride of the compound represented by the formula (IB-2) in 92% yield.
1 H NMR(500MHz CD 3 OD)δ3.93(1H,d,J＝11.7Hz),3.78–3.60(4H,m),3.32–3.24(1H,m),2.94(1H,t,J＝11.5Hz),1.96–1.85(1H,m),1.84–1.74(1H,m),1.00(3H,t,J＝7.2Hz)
Example 2
This example is intended to illustrate the preparation of formulas (IA-3), (IA-4), (IB-3) and (IB-4)
(1) Nitrone (0.98 g,1.82 mmol) of formula II obtained in preparation example 1 above was dissolved in dry diethyl ether (15 mL), propyl magnesium bromide (4.5 mmol) was added dropwise to the above solution under ice water bath (0-5 ℃ C.) for 11 minutes, the reaction was continued for 40 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to give colorless syrup, the compound of formula (IA-3), yield 25%, and the compound of formula (IA-4) in 56%.
(2-1) 236mg of the compound represented by the formula (IA-3) was dissolved in methanol (25 mL), 70.8mg of 10% Pd/C was added, hydrochloric acid (7 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 16 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.15 MPa to obtain the hydrochloride of the compound represented by the formula (IB-3) in 98% yield.
1 H NMR(500MHz CD 3 OD) delta 3.58 (1 h, d, j=12.3 Hz), 3.52-3.43 (1 h, m), 3.40 (1 h, d, j=12.3 Hz), 3.30 (1 h, t, j=8.9 Hz), 3.22 (1 h, d, j=9.0 Hz), 3.00-2.91 (1 h, m), 2.69 (1 h, t, j=11.9 Hz), 1.59 (1 h, td, j=13.6 Hz,4.3 mhz), 1.43 (1 h, td, j=13.5 Hz,4.4 Hz), 1.28-1.06 (2 h, m), 0.96 (3 h, t, j=7.2 Hz) (2-2) 36mg of the compound represented by formula (IA-4) was dissolved in methanol (30 mL), 3.96mg of 10% pd/C was added, hydrochloric acid (6 mL,1 n) was replaced three times, three times with argon, three times replaced with a filter cake represented by formula (IB was removed, the filtrate was removed under conditions of 0.92% reduced pressure, the filter cake was removed.
1 H NMR(500MHz CD 3 OD)δ3.94(1H,d,J＝11.8Hz),3.76–3.69(1H,m),3.68–3.64(2H,m),3.61(1H,d,J＝8.2Hz),3.25(1H,dd,J＝12.8Hz,4.8Hz),2.94(1H,dd,J＝12.7Hz,9.6Hz),1.84–1.76(1H,m),1.70–1.64(1H,m),1.54–1.44(1H,m),1.42–1.33(1H,m),0.97(3H,t,J＝7.2Hz)
Example 3
This example is intended to illustrate the preparation of formulas (IA-5), (IA-6), (IB-5) and (IB-6)
(1) Nitrone (0.2 g,0.37 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (30 mL), n-butylmagnesium bromide (0.74 mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.), the reaction was continued for 10 minutes at the time of the addition, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to obtain the compound of formula (IA-5), yield 84%, and the compound of formula (IA-6), yield 8%.
Formula (IA-5), 1 H NMR(500MHz,CDCl 3 ) Delta 7.35-7.23 (20H, m), 6.41 (1H, s, br), 4.92 (1H, d, J=10.9 Hz), 4.89 (1H, d, J=11.2 Hz), 4.72 (1H, d, J=10.8 Hz), 4.67 (2H, s), 4.60 (1H, d, J=11.1 Hz), 4.51 (2H, s), 4.19 (1H, d, J=9.4 Hz), 3.81 (1H, t, J=8.9 Hz), 3.76-3.68 (2H, m), 3.62 (1H, dd, J=10.4 Hz,5.4 Hz), 3.53 (1H, d, J=9.1 Hz), 3.12 (1H, t, J=10.5 Hz), 2.21-2.08 (1H, m), 1.66-1.52 (2H, t, J=8.9 Hz), 3.76-3.68 (2H, m), 3.62 (1H, dd, J=10.4 Hz), 3.8.4 Hz), 3.21-2.53 (1H, 3H, 3.4 Hz), 1 H NMR(500MHz,CDCl 3 )δ7.32–7.17(20H,m),5.41(1H,s,br),4.91(1H,d,J＝10.9Hz),4.87(1H,d,J＝11.3Hz),4.84–4.76(1H,m),4.71(1H,d,J＝11.7Hz),4.68–4.62(1H,m),4.51(1H,d,J＝11.4Hz),4.50(1H,d,J＝12.1Hz),4.44(1H,d,J＝12.0Hz),4.00–3.89(2H,m),3.84–3.72(2H,m),3.63(1H,d,J＝9.5Hz),3.41(1H,dd,J＝12.5Hz,5.5Hz),2.95(1H,t,J＝11.7Hz,),1.70–1.60(3H,m),1.46–1.31(1H,m),1.30–1.18(2H,m),0.88(3H,t,J＝7.2Hz)。
(2-1) 50mg of the compound represented by the formula (IA-5) was dissolved in methanol (20 mL), 6.5mg of 10% Pd/C was added, hydrochloric acid (10 mL of 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 17 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.3 MPa to obtain the hydrochloride of the compound represented by the formula (IB-5) in 92% yield.
1 H NMR(500MHz CD 3 OD)δ3.95(1H,d,J＝12.1Hz),3.82–3.71(2H,m),3.65(1H,t,J＝8.5Hz),3.55(1H,d,J＝8.6Hz),3.25(1H,dd,J＝12.4Hz,4.2Hz),3.03(1H,t,J＝11.5Hz),2.07–1.97(1H,m),1.88–1.76(1H,m),1.59–1.33(4H,m),0.99(3H,t,J＝6.9Hz)。
(2-2) 18mg of the compound represented by the formula (IA-6) was dissolved in methanol (20 mL), 2.16mg of 10% Pd/C was added, hydrochloric acid (13 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 12 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.05 MPa to obtain the hydrochloride of the compound represented by the formula (IB-6) in a yield of 95%.
1 H NMR(500MHz CD 3 OD)δ3.96(1H,d,J＝11.6Hz),3.78–3.59(4H,m),3.28–3.20(1H,m),2.94(1H,t,J＝10.9Hz),1.91–1.78(1H,m),1.78–1.66(1H,m),1.50–1.28(4H,m),0.96(3H,t,J＝6.6Hz)。
Example 4
This example is intended to illustrate the preparation of formulas (IA-7), (IA-8), (IB-7) and (IB-8)
(1) Nitrone (1.03 g,1.92 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (20 mL), n-pentylmagnesium bromide (5.55 mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.) for 15 minutes, the reaction was continued for 25 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-7), yield 67%, and the compound of formula (IA-8), yield 9%.
Formula (IA-7), 1 H NMR(500MHz,CDCl 3 )δ7.32–7.23(20H,m,PhCH 2 O),6.38(1H,s,br,NOH),4.91(2H,t,J＝11.0Hz),4.73(1H,d,J＝10.9Hz),4.67(2H,ABq,J＝11.7Hz),4.60(1H,d,J＝11.1Hz),4.49(2H,s),4.18(1H,d,J＝9.6Hz),3.83(1H,t,J＝8.9Hz),3.72(2H,m),3.62(1H,dd,J＝10.5Hz,5.4Hz),3.54(1H,d,J＝9.1Hz),3.14(1H,t,J＝10.5Hz),2.15–2.12(1H,m),1.62–1.58(2H,m),1.32–1.28(4H,m),1.17–1.15(1H,m),0.86(3H,t,J＝7.0Hz)；
formula (IA-8), 1 H NMR(500MHz,CDCl 3 )δ7.32–7.17(20H,m,PhCH 2 O),5.42(1H,s,br,NOH),4.91(1H,d,J＝10.9Hz),4.87(1H,d,J＝11.3Hz),4.79(1H,d,J＝10.9Hz),4.71(1H,d,J＝11.4Hz),4.65(1H,d,J＝11.4Hz),4.51–4.48(2H,m),4.44(1H,d,J＝11.9Hz),3.95-3.90(2H,m),3.82–3.74(2H,m),3.63(1H,d,J＝9.5Hz),3.41(1H,dd,J＝12.5Hz,5.5Hz),2.95(1H,t,J＝11.0Hz),1.67–1.59(2H,m),1.42–1.36(2H,m),1.31–1.25(2H,m),1.22–1.17(2H,m),0.87(3H,t,J＝7.2Hz)。
(2-1) Compound 346mg of (IA-7) was dissolved in redistilled dichloromethane (DCM, 25 mL) and protected with argon. Stirring at-78deg.C for 15 min, and dripping BCl 3 (1M in DCM,10 mL) and after the addition, the temperature was raised to-40℃and the starting material disappeared after 4 hours. Cooling to-78deg.C, adding methanol, heating to room temperature, evaporating to dryness, adding deionized water and dichloromethane, extracting, mixing water phases, evaporating to dryness to obtain hydrochloride of compound shown in formula (IB-7), and yield 80%.
1 H NMR(500MHz CD 3 OD)δ3.98(1H,d,J＝12.3Hz),3.88–3.82(1H,m),3.79(1H,d,J＝12.3Hz),3.71(1H,t,J＝8.9Hz),3.61(1H,d,J＝8.9Hz),3.35–3.28(1H,m),3.08(1H,t,J＝11.8Hz),2.02(1H,td,J＝13.5Hz,4.1Hz),1.84(1H,td,J＝13.5Hz,4.2Hz),1.66–1.46(2H,m),1.44–1.31(4H,m),0.95(3H,t,J＝7.1Hz)。
(2-2) 74mg of (IA-8) was dissolved in redistilled dichloromethane (DCM, 30 mL) and protected with argon. Stirring at-78deg.C for 15 min, and dripping BCl 3 (1M in DCM,15 mL) and after the addition, the temperature was raised to-40℃and the starting material disappeared after 4 hours. Cooling to-78deg.C, adding methanol, heating to room temperature, evaporating to dryness, adding deionized water and dichloromethane, extracting, mixing water phases, evaporating to dryness to obtain hydrochloride of compound shown in formula (IB-8), and yield 78%.
1 H NMR(500MHz CD 3 OD)δ3.95(1H,d,J＝11.7Hz),3.76–3.72(1H,m),3.70–3.62(3H,m),3.32–3.26(1H,m),2.93(1H,dd,J＝12.5Hz,9.9Hz),1.88–1.79(1H,m),1.74–1.65(1H,m),1.52–1.43(1H,m),1.40–1.28(5H,m),0.92(3H,t,J＝6.9Hz)。
Example 5
This example is intended to illustrate the preparation of formulas (IA-9), (IA-10), (IB-9) and (IB-10)
(1) Nitrone (1 g,1.85 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (25 mL), n-hexylmagnesium bromide (7.4 mmol) was added dropwise to the above solution under an ice-water bath (0-5 ℃ C.) for 6 minutes, the reaction was continued for 40 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-9), yield 67%, and the compound of formula (IA-10) in 11%.
Formula (IA-9), 1 H NMR(400MHz,CDCl 3 )δ7.25-7.15(20H,m,PhCH 2 O),6.31(1H,s,br NOH),4.83(2H,t,J＝10.4Hz),4.64(1H,d,J＝10.8Hz),4.58(2H,s),4.51(1H,d,J＝11.1Hz),4.42(2H,s),4.10(1H,d,J＝9.9Hz),3.74(1H,t,J＝8.9Hz),3.63(2H,d,J＝10.2Hz),3.54(1H,dd,J＝10.5Hz,5.4Hz),3.46(1H,d,J＝9.1Hz),3.05(1H,t,J＝10.4Hz),2.07–1.97(1H,m),1.56–1.46(2H,m),1.18–1.09(7H,m),0.77(3H,t,J＝6.7Hz)；
formula (IA-10), 1 H NMR(500MHz,CDCl 3 )δ7.21–7.08(20H,m,PhCH 2 O),6.14(1H,s,br,NOH),4.82(1H,d,J＝10.9Hz),4.78(1H,d,J＝11.3Hz),4.70(1H,d,J＝10.9Hz),4.62(1H,d,J＝11.3Hz),4.56(1H,d,J＝11.3Hz),4.42(1H,d,J＝11.3Hz),4.41(1H,d,J＝11.9Hz),4.33(1H,d,J＝11.9Hz),3.90–3.79(2H,m),3.72(1H,t,J＝9.3Hz),3.68(1H,d,J＝9.5Hz),3.53(1H,d,J＝9.4Hz),3.32(1H,dd,J＝12.3Hz,5.5Hz),2.90(1H,t,J＝11.5Hz),1.62–1.57(2H,m),1.33–1.30(2H,m),1.18–1.14(6H,m),0.79(3H,t,J＝6.8Hz)。
(2-1) 320mg of the compound represented by the formula (IA-9) was dissolved in methanol (15 mL), 41.6mg of 10% Pd/C was added, hydrochloric acid (9 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 18 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.18 MPa to obtain the hydrochloride of the compound represented by the formula (IB-9) in 100% yield.
1 H NMR(400MHz,CD 3 OD)δ3.99(1H,d,J＝12.2Hz),3.91–3.76(2H,m),3.71(1H,t,J＝8.8Hz),3.61(1H,d,J＝8.8Hz),3.36–3.27(1H,m),3.09(1H,t,J＝11.7Hz),2.10–1.96(1H,m),1.91–1.78(1H,m),1.68–1.44(2H,m),1.43–1.32(6H,m),0.98–0.88(3H,m)。
(2-2) 100mg of the compound represented by the formula (IA-10) was dissolved in methanol (30 mL), 18mg of 10% Pd/C was added, hydrochloric acid (21 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 12 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.4 MPa to obtain the hydrochloride of the compound represented by the formula (IB-10) in 71% yield.
1 H NMR(500MHz,CD 3 OD)δ3.94(1H,d,J＝11.6Hz),3.77–3.71(1H,m),3.70–3.62(3H,m),3.32–3.26(1H,m),2.93(1H,t,J＝10.5Hz),1.87–1.78(1H,m),1.69(1H,t,J＝12.4Hz),1.50–1.44(1H,m),1.38–1.30(7H,m),0.93–0.88(3H,m)。
Example 6
This example is intended to illustrate the preparation of formulas (IA-11), (IA-12), (IB-11) and (IB-12)
(1) Nitrone (1 g,1.85 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (30 mL), n-heptyl magnesium bromide (7.4 mmol) was added dropwise to the above solution under ice water bath (0-5 ℃ C.) for 20 minutes, the reaction was continued for 35 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-11), yield 46%, and the compound of formula (IA-12) in 13%.
Formula (IA-11), 1 H NMR(400MHz,CDCl 3 )δ7.22–7.13(20H,m,PhCH 2 O),6.31(1H,NOH),4.84(1H,d,J＝10.8Hz),4.82(1H,d,J＝10.8Hz),4.63(1H,d,J＝10.9Hz),4.56(2H,s),4.50(1H,d,J＝10.8Hz),4.39(2H,s),4.06(1H,d,J＝9.8Hz),3.78–3.74(1H,m),3.69–3.60(2H,m),3.51(1H,dd,J＝10.5Hz,5.4Hz),3.45(1H,d,J＝9.1Hz),3.06(1H,t,J＝10.5Hz),2.03–1.94(1H,m),1.54–1.45(2H,m),1.17–1.09(9H,m),0.76(3H,t,J＝6.6Hz)；
formula (IA-12), 1 H NMR(400MHz,CDCl 3 )δ7.22–7.10(20H,m,PhCH 2 O),5.42(1H,s,br,NOH),4.83(1H,d,J＝13.7Hz),4.80(1H,d,J＝11.5Hz),4.71(1H,d,J＝10.8Hz),4.64(1H,d,J＝11.3Hz),4.58(1H,d,J＝11.3Hz),4.44–4.35(3H,m),3.93–3.81(2H,m),3.71(2H,m),3.56(1H,d,J＝9.4Hz),3.34(1H,dd,J＝12.4Hz,5.3Hz),2.88(1H,t,J＝11.5Hz),1.58(1H,t,J＝7.9Hz),1.32–1.18(11H,m),0.81(3H,t,J＝6.5Hz)。
(2-1) 542mg of the Compound represented by the formula (IA-11) was dissolved in methanol (18 mL), 108mg of 10% Pd/C was added, hydrochloric acid (12 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 19 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.17 MPa to obtain the hydrochloride of the Compound represented by the formula (IB-11) in 99% yield.
1 H NMR(500MHz CD 3 OD)δ3.18(1H,d,J＝11.8Hz),3.14–3.04(1H,m),3.00(1H,d,J＝11.9Hz),2.94(1H,t,J＝8.2Hz),2.83(1H,d,J＝8.4Hz),2.56–2.48(1H,m),2.36–2.24(1H,m),1.26–1.14(1H,m),1.10–0.96(1H,m),0.85–0.62(2H,m),0.62–0.42(8H,m),0.16–0.04(3H,s)。
(2-2) 60mg of the compound represented by the formula (IA-12) was dissolved in methanol (20 mL), 6mg of 10% Pd/C was added, hydrochloric acid (14 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 14 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.3 MPa to obtain the hydrochloride of the compound represented by the formula (IB-12) in a yield of 51%.
1 H NMR(500MHz CD 3 OD)δ3.95(1H,d,J＝11.6Hz),3.76–3.70(1H,m),3.69–3.60(3H,m),3.30–3.26(1H,m),2.93(1H,t,J＝11.1Hz),1.87–1.79(1H,m),1.69(1H,t,J＝12.2Hz),1.51–1.41(1H,m),1.39–1.26(9H,m),0.89(3H,t,J＝6.7Hz)。
Example 7
This example is intended to illustrate the preparation of formulas (IA-13), (IA-14), (IB-13) and (IB-14)
(1) Nitrone (1.04 g,1.94 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (25 mL), n-octylmagnesium bromide (7.8 mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.) for 7 minutes, the reaction was continued for 30 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-13), yield 69%, and the compound of formula (IA-14) in 12% yield.
Formula (IA-13), 1 H NMR(500MHz,CDCl 3 )δ7.36–7.23(20H,m,PhCH 2 O),6.40(1H,s,br,NOH),4.91(2H,t,J＝12.0Hz),4.72(1H,d,J＝10.8Hz),4.67(2H,ABq,J＝11.6Hz),4.59(1H,d,J＝11.1Hz),4.51(2H,s),4.19(1H,d,J＝9.5Hz),3.83–3.79(1H,m),3.77–3.68(2H,m),3.62(1H,dd,J＝10.5Hz,5.4Hz),3.53(1H,d,J＝9.1Hz),3.12(1H,t,J＝10.5Hz),2.16–2.12(1H,m),1.62–1.54(2H,m),1.28–1.24(11H,m),0.86(3H,t,J＝7.0Hz)；
formula (IA-14), 1 H NMR(500MHz,CDCl 3 )δ7.20–7.07(20H,m,PhCH 2 O),6.18(1H,NOH),4.81(1H,d,J＝10.9Hz),4.77(1H,d,J＝11.3Hz),4.70(1H,d,J＝10.9Hz),4.61(1H,d,J＝11.3Hz),4.55(1H,d,J＝11.3Hz),4.40(2H,d,J＝12.1Hz),4.32(1H,d,J＝11.9Hz),3.88–3.78(2H,m),3.71(1H,d,J＝9.3Hz),3.68(1H,d,J＝9.4Hz),3.53(1H,d,J＝9.4Hz),3.33(1H,dd,J＝12.2Hz,5.5Hz),2.91(1H,t,J＝11.5Hz),1.58(2H,t,J＝8.5Hz),1.34–1.12(12H,m),0.80(3H,t,J＝6.9Hz)。
(2-1) 660mg of the compound represented by the formula (IA-13) was dissolved in methanol (27 mL), 72.6mg of 10% Pd/C was added, hydrochloric acid (13 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 20 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.19 MPa to obtain the hydrochloride of the compound represented by the formula (IB-13) in 99% yield.
1 H NMR(400MHz CD 3 OD)δ3.92(1H,d,J＝12.2Hz),3.88–3.78(1H,m),3.76–3.63(2H,m),3.56(1H,d,J＝8.7Hz),3.29–3.20(1H,m),3.03(1H,t,J＝11.4Hz),1.96–1.91(1H,m),1.82–1.70(1H,m),1.58–1.37(2H,m),1.32–1.16(10H,m),0.86–0.78(3H,m)。
(2-2) 135mg of the Compound represented by the formula (IA-14) was dissolved in methanol (35 mL), 17.8mg of 10% Pd/C was added, hydrochloric acid (15 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 15 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.6 MPa to obtain the hydrochloride of the Compound represented by the formula (IB-14) in 93% yield.
1 H NMR(400MHz CD 3 OD)δ3.93(1H,d,J＝11.8Hz),3.80–3.75(1H,m),3.72–3.64(3H,m),3.34–3.28(1H,m),2.98–2.88(1H,m),1.88–1.77(1H,m),1.75–1.64(1H,m),1.52–1.20(12H,m),0.87(3H,t,J＝6.5Hz)。
Example 8
This example is intended to illustrate the preparation of formulas (IA-15), (IA-16), (IB-15) and (IB-16)
(1) Nitrone (0.5 g,0.93 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (30 mL), n-nonylmagnesium bromide (3.7 mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.), the reaction was continued for 20 minutes at the time of the addition, quenched with saturated ammonium chloride solution for 30 minutes, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-15), yield 84%, and the compound of formula (IA-16), yield 8%.
(IA-15) 1 H NMR(500MHz,CDCl 3 )δ7.36–7.23(20H,m),6.40(1H,s,br),4.93(1H,d,J＝11.0Hz),4.91(1H,d,J＝12.4Hz),4.72(1H,d,J＝10.8Hz),4.67(2H,ABq,J＝11.7Hz),4.59(1H,d,J＝11.1Hz),4.51(2H,s),4.19(1H,d,J＝9.5Hz),3.81(1H,t,J＝8.9Hz),3.77–3.68(2H,m),3.62(1H,dd,J＝10.4Hz,5.4Hz),3.53(1H,d,J＝9.1Hz),3.12(1H,J＝10.5Hz),2.18–2.08(1H,m),1.69–1.50(3H,m),1.30–1.16(12H,m),0.86(3H,t,J＝6.9Hz)；
(IA-16) 1 H NMR(500MHz,CDCl 3 )δ7.38–7.14(20H,m),5.89(1H,s,br),4.90(1H,d,J＝10.9Hz),4.86(1H,d,J＝11.3Hz),4.78(1H,d,J＝10.9Hz),4.70(1H,d,J＝11.3Hz),4.64(1H,d,J＝11.2Hz),4.51(1H,d,J＝11.3Hz),4.50(1H,d,J＝11.9Hz),4.42(1H,d,J＝11.9Hz),3.99–3.85(2H,m),3.82–3.72(2H,m),3.62(1H,d,J＝9.4Hz),3.40(1H,dd,J＝12.4Hz,5.5Hz),2.97(1H,t,J＝11.6Hz),1.72–1.60(2H,m),1.46–1.15(14H,m),0.88(3H,t,J＝6.9Hz)。
(2-1) 40mg of the compound represented by the formula (IA-15) was dissolved in methanol (32 mL), 8mg of 10% Pd/C was added, hydrochloric acid (14 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 18 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.52 MPa to obtain the hydrochloride of the compound represented by (IB-15) in 94% yield.
1 H NMR(500MHz CD 3 OD)δ3.94(1H,d,J＝11.9Hz),3.75(2H,d,J＝11.6Hz),3.64(1H,t,J＝8.0Hz),3.54(1H,d,J＝8.3Hz),3.24(1H,d,J＝8.9Hz),3.02(1H,t,J＝11.0Hz),1.99(1H,t,J＝11.4Hz),1.80(1H,t,J＝11.6Hz),1.64–1.42(2H,m),1.42–1.10(12H,m),0.89(3H,d,J＝6.2Hz)。
(2-2) 31mg of the compound represented by the formula (IA-16) was dissolved in methanol (18 mL), 4.7mg (10% Pd/C) was added, hydrochloric acid (11 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 27 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.14 MPa to obtain the hydrochloride of the compound represented by the formula (IB-16) in 93% yield.
1 H NMR(500MHz CD 3 OD)δ3.95(1H,d,J＝11.5Hz),3.78–3.60(4H,m),3.27(1H,d,J＝9.2Hz),2.94(1H,t,J＝10.6Hz),1.88–1.78(1H,m),1.70(1H,t,J＝12.8Hz),1.52–1.22(14H,m),0.90(3H,t,J＝6.2Hz)。
Example 9
This example is intended to illustrate the preparation of formulas (IA-17), (IA-18), (IB-17) and (IB-18)
(1) Nitrone (0.82 g,1.52 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (30 mL), n-decyl magnesium bromide (6.08 mmol) was added dropwise to the above solution under ice water bath (0-5 ℃ C.), the reaction was continued for 13 minutes at the time of addition, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-17), yield 73%, and the compound of formula (IA-18) yield 19%.
(IA-17) 1 H NMR(400MHz,CDCl 3 )δ7.33–7.22(20H,m,PhCH 2 O),6.38(1H,s,br,NOH),4.94(1H,d,J＝10.7Hz),4.91(1H,d,J＝10.8Hz),4.72(1H,d,J＝10.8Hz),4.67(2H,s),4.59(1H,d,J＝11.1Hz),4.50(2H,s),4.19(1H,d,J＝9.8Hz),3.81(1H,t,J＝8.8Hz),3.78–3.68(2H,m),3.62(1H,dd,J＝10.4Hz,5.3Hz),3.53(1H,d,J＝9.0Hz),3.12(1H,t,J＝10.4Hz),2.20–2.08(1H,m),1.64–1.52(2H,m),1.28–1.22(15H,m),0.87(3H,t,J＝6.6Hz)；
(IA-18) 1 H NMR(400MHz,CDCl 3 )δ7.21–7.08(20H,m,PhCH 2 O),6.12(1H,br,NOH),4.82(1H,d,J＝10.9Hz),4.78(1H,d,J＝11.4Hz),4.70(1H,d,J＝10.8Hz),4.62(1H,d,J＝12.5),4.57–4.54(1H,m),4.43(1H,d,J＝11.2Hz),4.41(1H,d,J＝11.8Hz),4.33(1H,d,J＝11.8Hz),3.90–3.80(2H,m),3.72(1H,d,J＝9.2Hz),3.68(1H,d,J＝9.4Hz),3.54(1H,d,J＝9.4Hz),3.32(1H,dd,J＝12.2Hz,5.4Hz),2.90(1H,t,J＝11.5Hz),1.64–1.54(1H,m),1.40–1.27(2H,m),1.21–1.14(15H,m),0.80(3H,t,J＝6.5Hz)。
(2-1) 494mg of the compound represented by the formula (IA-17) was dissolved in methanol (23 mL), 89mg of 10% Pd/C was added, hydrochloric acid (17 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 30 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.17 MPa to obtain the hydrochloride of the compound represented by the formula (IB-17) in 61% yield.
1 H NMR(500MHz CD 3 OD)δ3.99(1H,d,J＝12.1Hz),3.88–3.78(2H,m),3.71(1H,t,J＝8.5Hz),3.61(1H,d,J＝8.6Hz),3.40–3.28(1H,m),3.09(1H,t,J＝11.4Hz),2.04(1H,t,J＝11.9Hz),1.85(1H,t,J＝11.9Hz),1.65–1.50(2H,m),1.40–1.31(14H,m),0.93(3H,t,J＝6.4Hz)。
(2-2) 110mg of the Compound represented by the formula (IA-18) was dissolved in methanol (26 mL), 11mg of 10% Pd/C was added, hydrochloric acid (2 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 36 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.8 MPa to obtain the hydrochloride of the Compound represented by the formula (IB-18) in a yield of 9%.
1 H NMR(500MHz CD 3 OD)δ3.95(1H,d,J＝11.7Hz),3.75–3.69(1H,m),3.68–3.59(3H,m),3.24(1H,dd,J＝12.7Hz,4.5Hz),2.96–2.88(1H,m),1.88–1.78(1H,m),1.72–1.64(1H,m),1.51–1.40(2H,m),1.32–1.24(14H,m),0.89(3H,t,J＝6.8Hz)。
Example 10
This example is intended to illustrate the preparation of formulas (IA-19), (IA-20), (IB-19) and (IB-20)
(1) Nitrone (1.98 g,3.67 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (30 mL), n-decyl magnesium bromide (14.68 mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.) for 7 minutes, the reaction was continued for 40 minutes, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, the saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound of formula (IA-19), yield 65%, and the compound of formula (IA-20) in 25%.
(IA-19) 1 H NMR(400MHz,CDCl 3 )δ7.32–7.23(20H,m,PhCH 2 O),6.36(1H,s,br,NOH),4.94(1H,d,J＝10.6Hz),4.91(1H,d,J＝10.2Hz),4.72(1H,d,J＝10.8Hz),4.66(2H,s),4.60(1H,d,J＝11.1Hz),4.50(2H,s),4.18(1H,d,J＝9.9Hz),3.82(1H,t,J＝8.8Hz),3.75–3.68(2H,m),3.62(1H,dd,J＝10.4Hz,5.3Hz),3.54(1H,d,J＝9.0Hz),3.13(1H,t,J＝10.4Hz),2.18–2.06(1H,m),1.65–1.49(2H,m),1.34–1.12(17H,m),0.87(3H,t,J＝6.5Hz)；
(IA-20) 1 H NMR(500MHz,CDCl 3 )δ7.33–7.17(20H,m,PhCH 2 O),5.56(1H,s,br,NOH),4.90(1H,d,J＝10.9Hz),4.87(1H,d,J＝11.3Hz),4.78(1H,d,J＝10.9Hz),4.71(1H,d,J＝11.4Hz),4.65(1H,d,J＝11.4Hz),4.51(1H,d,J＝11.4Hz),4.50(1H,d,J＝12.0Hz),4.44(1H,d,J＝11.9Hz),3.99–3.89(2H,m),3.80(1H,d,J＝9.3Hz),3.75(1H,d,J＝9.4Hz),3.63(1H,d,J＝9.4Hz),3.41(1H,dd,J＝12.5Hz,5.6Hz),2.95(1H,t,J＝11.7Hz),1.68–1.62(2H,m),1.45–1.16(18H,m),0.88(3H,t,J＝7.0Hz)。
(2-1) 220mg of the Compound represented by the formula (IA-19) was dissolved in methanol (20 mL), 26mg of 10% Pd/C was added, hydrochloric acid (5.5 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 36 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.44 MPa to obtain the hydrochloride of the Compound represented by the formula (IB-19) in 100% yield.
1 H NMR(500MHz CD 3 OD)δ3.99(1H,d,J＝12.2Hz),3.88–3.78(2H,m),3.71(1H,t,J＝8.7Hz),3.61(1H,d,J＝8.8Hz),3.31(1H,dd,J＝12.5Hz,4.6Hz),3.09(1H,t,J＝11.7Hz),2.08–2.00(1H,m),1.90–1.80(1H,m),1.67–1.46(2H,m),1.43–1.26(16H,m),0.93(3H,t,J＝6.8Hz)。
(2-2) A compound represented by the formula (IA-20) was dissolved in methanol (24 mL), 36mg of 10% Pd/C was added, hydrochloric acid (5.5 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 40 hours, filtration was carried out, and the solvent was removed under reduced pressure of-0.37 MPa to obtain a hydrochloride of the compound represented by the formula (IB-20) in 99% yield.
1 H NMR(500MHz CD 3 OD)δ3.95(1H,d,J＝11.7Hz),3.75–3.68(1H,m),3.68–3.66(1H,m),3.64(1H,d,J＝2.6Hz),3.61(1H,d,J＝8.1Hz),3.28–3.22(1H,m),2.93(1H,dd,J＝12.8Hz,9.4Hz),1.87–1.78(1H,m),1.72–1.64(1H,m),1.50–1.40(1H,m),1.38–1.22(17H,m),0.89(3H,t,J＝6.9Hz)。
Example 11
This example is intended to illustrate the preparation of formulas (IA-21), (IA-22), (IB-21) and (IB-22)
(1) Nitrone (0.96 g,1.78 mmol) of formula II obtained in preparation example 1 was dissolved in dry tetrahydrofuran (35 mL), n-decyl magnesium bromide (7.12 mmol) was added dropwise to the above solution under ice water bath (0-5 ℃ C.), the reaction was continued for 6 minutes at the time of addition, quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, saturated sodium chloride solution (2X 25 mL) was washed, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum concentration, and the crude product was isolated by column chromatography (silica gel 200-300 mesh) to give the compound represented by (IA-21), the yield 73% and the compound represented by (IA-22), the yield 11%.
Formula (IA-21), 1 H NMR(500MHz,CDCl 3 )δ7.32–7.23(20H,m,PhCH 2 O),6.37(1H,s,br,NOH),4.93(1H,d,J＝11.2Hz),4.91(1H,d,J＝11.8Hz),4.73(1H,d,J＝10.8Hz),4.66(2H,s),4.60(1H,d,J＝11.1Hz),4.49(2H,s),4.18(1H,d,J＝9.2Hz),3.86–3.80(1H,m),3.76–3.68(2H,m),3.64–3.59(1H,m),3.54(1H,d,J＝8.9Hz),3.14(1H,t,J＝10.5Hz),2.18–2.08(1H,m),1.65–1.50(2H,m),1.34–1.12(19H,m),0.91–0.83(3H,m)；
formula (IA-22), 1 H NMR(500MHz,CDCl 3 )δ7.24–7.09(20H,m,PhCH 2 O),5.83(1H,s,br,NOH),4.82(1H,d,J＝10.9Hz),4.78(1H,d,J＝11.3Hz),4.71(1H,d,J＝10.9Hz),4.62(1H,d,J＝11.3Hz),4.56(1H,d,J＝11.4Hz),4.41(2H,d,J＝11.5Hz),4.34(1H,d,J＝11.9Hz),3.90–3.80(2H,m),3.72(1H,d,J＝9.3Hz),3.68(1H,d,J＝9.5Hz),3.54(1H,d,J＝9.4Hz),3.33(1H,dd,J＝12.4Hz,5.5Hz),2.89(1H,t,J＝11.6Hz),1.58(2H,t,J＝8.5Hz),1.36–1.14(20H,m),0.80(3H,t,J＝6.9Hz)。
(2-1) 264mg of the compound represented by the formula (IA-21) was dissolved in methanol (25 mL), 34mg of 10% Pd/C was added, hydrochloric acid (6.5 mL, 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 36 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.78 MPa to obtain the hydrochloride of the compound represented by the formula (IB-21) in 89% yield.
1 H NMR(500MHz CD 3 OD)δ3.98(1H,d,J＝12.2Hz),3.86–3.77(2H,m),3.69(1H,t,J＝8.8Hz),3.59(1H,d,J＝8.9Hz),3.35–3.28(1H,m),3.07(1H,dd,J＝12.3Hz,11.3Hz),2.06–1.98(1H,m),1.88–1.80(1H,m),1.64–1.47(2H,m),1.41–1.26(18H,m),0.92(3H,t,J＝6.9Hz)。
(2-2) 35mg of the compound represented by the formula (IA-22) was dissolved in methanol (35 mL), 6mg of 10% Pd/C was added, hydrochloric acid (4.5 mL of 1N) was added, argon was substituted three times, hydrogen was substituted three times, the reaction was carried out for 40 hours, filtration was carried out, the cake was discarded, and the filtrate was obtained, and the solvent was removed under reduced pressure of-0.85 MPa to obtain the hydrochloride of the compound represented by the formula (IB-22) in 99% yield.
1 H NMR(500MHz CD 3 OD)δ 3.95(1H,d,J＝11.8Hz),3.76–3.69(1H,m),3.69–3.60(3H,m),3.28–3.24(1H,m),2.94(1H,dd,J＝12.6Hz,9.7Hz),1.88–1.78(1H,m),1.73–1.64(1H,m),1.52–1.40(1H,m),1.40–1.22(19H,m),0.88(3H,t,J＝6.8Hz)。
Comparative example 1
This comparative example is used to illustrate the preparation of formulas (DIA-1), (DIA-2), (DIB-1) and (DIB-2)
(1) Nitrone (1.01 g,1.88 mmol) of formula II obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (15 mL), methyl magnesium chloride (3.0M in THF,1.85mL,5.55mmol) was added dropwise to the above solution under an ice water bath (0-5 ℃ C.) for 14 minutes, the reaction was continued for 0.5 hours, the saturated ammonium chloride solution was quenched, ethyl acetate (3X 25 mL) was extracted, the organic phase was combined, the saturated sodium chloride solution (2X 25 mL) was washed, anhydrous magnesium sulfate was dried, the solvent was removed by concentration under reduced pressure, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to give a compound represented by (DIA-1), yield 31%, and a compound represented by (DIA-2) as a white solid, yield 35%.
Formula (DIA-1), 1 H NMR(400MHz CDCl 3 )7.20-7.05(20H,m,phCH 2 O),5.86(1H,s,NOH),4.84-4.31(8H,m,PhCH 2 O),3.64-3.58(3H,m),3.45(1H,d,J＝9.2Hz),3.35-3.32(2H,m),2.87(1H,t,J＝10.8Hz),0.93(3H,s)。
formula (DIA-2), 1 H NMR(500MHz CDCl 3 )7.33-7.23(20H,m,phCH 2 O),6.48(1H,s,NOH),4.92-4.51(8H,m,PhCH 2 O),3.84-3.80(3H,m),3.71(1H,s),3.48(2H,d,J＝7.2Hz),3.13(1H,t,J＝11.1Hz),1.41(3H,s)。
(2-1) the compound (116 mg) represented by the formula (DIA-1) was dissolved in methanol (15 mL), 19mg of 10% Pd/C was added, hydrochloric acid (10 mL of 1N) was added, argon was substituted three times, hydrogen was substituted three times, reacted for 48 hours, filtered, and the cake was discarded to obtain a filtrate, and the solvent was removed under reduced pressure of-0.8 MPa to obtain a hydrochloride (82 mg, 99%) of the compound represented by the formula (DIB-1).
1 H NMR(500MHz CD 3 OD)δ 3.85(1H,d,J＝11.7Hz),3.78-3.76(1H,m),3.63-3.58(3H,m),3.33-3.29(1H,m),3.02(1H,t,J＝12.0Hz),1.31(3H,s)。
(2-2) the compound (320 mg) represented by the formula (IA-2) was dissolved in methanol (25 mL), 60mg of 10% Pd/C was added, hydrochloric acid (4.5 mL of 1N) was added, argon was substituted three times, hydrogen was substituted three times, and the reaction was carried out for 48 hours, filtration, and the solvent was removed under reduced pressure of-9 MPa to obtain the hydrochloride of the compound represented by the formula (DIB-2). (37.9 mg, 85%).
1 H NMR(500MHz CD 3 OD)δ 3.96(1H,d,J＝12.1Hz),3.86-3.83(1H,m),3.72-3.66(2H,m),3.56(1H,d,J＝9.0Hz),3.35-3.29(1H,m),3.06(1H,t,J＝11.6Hz),1.54(3H,s)。
Test case
The following test examples are presented to demonstrate the inhibitory activity of the C5 branched DNJ derivatives of the present invention
(1) Test materials and sources
Test compound: the invention provides C5 branched DNJ derivatives shown in formulas (IB-1) - (IB-22), DNJ as a control compound, and compounds shown in formulas (DIB-1) and (DIB-2).
Test materials: the 4-nitrophenopyranoside matrices, disaccharides and glycosidases (alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-murine Li Tangmei, amyloglucosidase, beta-glucosidase, etc.) used in the following tests were purchased from Sigma-Aldrich.
(2) Test method
Activity assay the assay was performed at the pH optimum for activity of each enzyme using 4-nitrophenopyranoside as matrix. The substrate, enzyme solution (0.1-0.5 mg/mL) and inhibitor (C5 branched DNJ derivative of the invention and control compound) were incubated at 37℃for 30 minutes, and then the reaction was initiated in an ultraviolet-visible spectrophotometer and tested for absorption of 400nM wavelength light. Finally, data analysis was performed using GraFit program (see Leatherbarrow, R.J. Grafit 4.0; erithascus software: staines, UK, 1998).
(3) Evaluation results
The results of the inhibitory activity of the C5 branched DNJ derivative provided by the present invention and the control compound on glycosidase are shown in table 1.
In Table 1, IC 50 (mu M) represents inhibitionInhibitor concentration of 50% enzyme activity. The percentages represent the inhibition at 1000. Mu.M. ND represents the activity of the untested compound on the enzyme. Glycosidases used below were purchased from Sigma-Aldrich.
TABLE 1
Table 1, below
/>
Table 1, below
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (3)
1. A C5 branched 1-deoxynojirimycin derivative, wherein the 1-deoxynojirimycin derivative is a compound having the structure:
(IB-9)，/>(IB-14)，
(IB-18)，
(IB-21)。
2. a glycosidase inhibitor comprising the C5 branched 1-deoxynojirimycin derivative according to claim 1 as an active ingredient.
3. Use of the glycosidase inhibitor of claim 2 for the manufacture of a medicament for the prevention and/or treatment of glycosidase-related diabetes.
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| CN106748970A (en) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | The deoxidization nojirimycin derivative of N aryl 1 and its application in treatment diabetes medicament is prepared |
| CN106966943A (en) * | 2017-03-24 | 2017-07-21 | 中国科学院化学研究所 | Polyhydroxy pyrrole class compound of C4 cladodification and its preparation method and application |
| CN110128315A (en) * | 2019-04-02 | 2019-08-16 | 中国科学院化学研究所 | Compound and the preparation method and application thereof, glycosidase inhibitor |
| CN115551504A (en) * | 2020-04-23 | 2022-12-30 | 格勒诺布尔-阿尔卑斯大学 | Novel pharmacological chaperone compounds of human acid alpha-glucosidase and their therapeutic use |
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| CN106748970A (en) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | The deoxidization nojirimycin derivative of N aryl 1 and its application in treatment diabetes medicament is prepared |
| CN106966943A (en) * | 2017-03-24 | 2017-07-21 | 中国科学院化学研究所 | Polyhydroxy pyrrole class compound of C4 cladodification and its preparation method and application |
| CN110128315A (en) * | 2019-04-02 | 2019-08-16 | 中国科学院化学研究所 | Compound and the preparation method and application thereof, glycosidase inhibitor |
| CN115551504A (en) * | 2020-04-23 | 2022-12-30 | 格勒诺布尔-阿尔卑斯大学 | Novel pharmacological chaperone compounds of human acid alpha-glucosidase and their therapeutic use |
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| Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase inhibition;Hui Zhao et al.;《Chinese Chemical Letters》;第24卷;第1059-1063页 * |
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