CN115433119A - 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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- CN115433119A CN115433119A CN202110623646.5A CN202110623646A CN115433119A CN 115433119 A CN115433119 A CN 115433119A CN 202110623646 A CN202110623646 A CN 202110623646A CN 115433119 A CN115433119 A CN 115433119A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- LXBIFEVIBLOUGU-JGWLITMVSA-N duvoglustat Chemical class OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 20
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 14
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- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 7
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 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
- 238000010254 subcutaneous injection Methods 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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 Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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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
- C07D211/04—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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 thereofAnd applications. The 1-deoxynojirimycin derivative provided by the invention is a compound with a structure shown in a formula (I) and pharmaceutically acceptable salt thereof; wherein R is 1 Is C2-C20 alkyl; r is 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, hydroxyl, nitro and halogen; the compound has a carbon at position 5 with a spatial configuration of R or S. The C5-branched DNJ derivative provided by the invention has excellent glycosidase inhibitory 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 an iminosugar isolated from Morus alba in 1966, has a strong inhibitory effect on α -glucosidase, and also has inhibitory activity on other glycosidases such as β -glucosidase. DNJ and its derivatives have important pharmaceutical values, e.g., ability to treat diabetes, gaucher's disease, antiviral, anti-tumor, antioxidant and to lower postprandial blood glucose (compare, P. Et al, iminosugars: from synthesis to Therapeutic Application; wiley, 2007), and thus have received extensive attention in the field of new drug development.
Currently, about 300 DNJ derivatives are reported, of which two are marketed, both N-alkylated DNJ derivatives, miglitol (N-hydroxyethyl-DNJ) and meglumine (N-butyl-DNJ), respectively. This greatly facilitates the study 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 in various forms, for example, alkyl, unsaturated hydrocarbon, phenyl, glycosyl, fluoro, chloro, heterocyclic aryl, hydroxyl, amino, etc. The modification sites relate to various sites of DNJ: to N onThe modifications are mainly alkylation containing 1-20 carbons, some C atoms of the alkyl chain may be substituted with heteroatoms or functional groups, and other groups may also be linked at the end, such as amino acids, glycosyl groups and heterocyclic aryl groups etc ((wolfsgrouber, a. Et al, molecules 2020,25,4618, ghisaidoobe, a. Et al, ACS med. Chem. Lett.2011,2,119, ghisaidoobe, a.t. Et al, med. Chem.2014,57,9096 wennekes, t. Et al, j.org. Chem.2007,72,1088 hoogoendn, s et al, eur.j.org. Chem.2015,2015,4437; wang, L, et al, acta Chimica Slovenica 2020,67, 812) the modifications on O are mainly alkylation and glycosidation, isotopic substitution is mainly isotopically substituting hydrogen and carbon in the compound.the modifications on C are mainly concentrated at C1, including alkylation and glycosidation.the modifications on C2-C4 are mainly fluoro and chloro.at present, only a small number of compounds 5-C-methyl-DNJ have been reported for modification at C5, which compounds have only been tested for activity on alpha-glucose (IC) in humans 50 =1 μ M) activity evaluation; 5-C-benzyl-DNJ; 5-C-hydroxymethyl-DNJ; 5-C-hydroxy-DNJ; 5-C-cyano-DNJ. (Maughan, m.a.t. et al, angelw.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 not high enough inhibitory activity on glycosidase, large molecular polarity, good water solubility, poor fat solubility, unfavorable membrane penetration and poor drug-forming property.
In addition, the current synthesis methods of C5 branched compounds mainly include the following two methods: 1) Using tetrabenzyl-DNJ as a raw material, using 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 and low in yield, and particularly, the yield of addition reaction of imine and Grignard reagent is only 17%, so that the method is difficult to industrialize. 2) The compound is obtained by taking D-glucose as a raw material and an azido substituted sugar derivative as a key intermediate. Although the raw materials are relatively cheap and easy to obtain, the reaction conditions are mild, the reaction steps are more, the toxic azide reagent is used for many times, and the universality is low.
Method 1):
method 2):
therefore, there is a need for a highly active and pharmaceutically useful glycosidase inhibitor and a preparation method thereof, which has the advantages of readily available raw materials, simple steps and easy 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 inhibitory activity, and a preparation method and application thereof.
The inventors of the present invention have made intensive studies and found, through molecular docking mode studies, that when a derivative obtained by C5-branching DNJ (1-deoxynojirimycin) with different substituents binds to different enzymes, the bound active centers and the mode of action are greatly different, which results in a large difference in the inhibitory activity against the enzymes. For example, when DNJ is combined with N-terminal human maltase-glucoamylase (ntMGAM, PDB ID:3L 4W), hydrogen bonding occurs between the secondary amino group and the C-2, C-3, C-6 hydroxyl groups and amino acid residues Asp-443, arg-526, asp-542 and Asp-327; while 5-C-methyl-DNJ binds to ntMGAM, the conformation adopted 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, so that the influence of the groups adopted for C5 branching on the performance of the final branched compound is difficult to predict. The inventor of the invention finds out through research that: a series of DNJ (1-deoxynojirimycin), branched with long chain alkyl, all have a good affinity for different glycosidases.
Accordingly, to achieve the above object, the present invention provides in a first aspect a C5 branched 1-deoxynojirimycin derivative, which is a compound having the structure represented by formula (I):
wherein R is 1 Is C2-C20 alkyl;
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, hydroxyl, nitro and halogen;
the compound has a carbon at position 5 with a spatial configuration of R or S.
In a second aspect, the present invention provides a method of preparing a C5 branched 1-deoxynojirimycin derivative, comprising the steps of:
(1) Reacting a compound of formula (II) with a compound having R 1 Nucleophilic addition of an 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 carry out catalytic hydrogenation reaction to obtain a compound shown in the formula (I') or a salt thereof;
wherein in the formulae (II), (I ') and (I'), R is involved 1 、R 2 、R 3 、R 4 、R 5 Or R 6 Are as defined in the foregoing first aspect.
A third aspect of the present invention provides a glycosidase inhibitor comprising the C5-branched DNJ derivative described above in the first aspect as an active ingredient.
In a fourth aspect, the present invention provides a use of the glycosidase inhibitor of the third aspect for inhibiting glycosidase.
In a fifth aspect, the present invention provides a use of the glycosidase inhibitor of the third aspect for the preparation of a medicament selected from at least one of the following: 1) A medicament for the prophylaxis and/or treatment of diabetes; 2) A medicament for preventing and/or treating gaucher's disease; 3) Drugs for preventing and/or treating tumors; 4) An antiviral drug; 5) An antibacterial agent; 6) A medicament for the prevention and/or treatment of pompe disease.
The C5 branched DNJ derivative provided by the invention has excellent glycosidase inhibitory activity and high medicinal value.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In the present invention, the term "on carbon" is understood by those skilled in the art to mean that the carbon is a chiral carbon and may be in an R-or S-shaped conformation. The number at the carbon position on the piperidine ring in the following formula indicates the position number. For example, of the formula (I)
The piperidine having "5" in the compound shown herein means that the carbon at this position is the 5-th carbon, and "1" means that the carbon at this position is the 1-th carbon, and the other cases are similarly explained.
Specific examples of the "C2-C20 alkyl group" in the present invention 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 for a narrower range of carbon atoms may also be selected from this specific example based on the limitations in the number of carbon atoms.
In the present invention, specific examples of the alkoxy group having 1 to 6 carbon atoms may include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. Alkyl groups for a narrower range of carbon atoms may also be selected from this specific example based on the limitations in the number of carbon atoms.
In a first aspect, the present invention provides a C5 branched 1-deoxynojirimycin derivative, wherein the 1-deoxynojirimycin derivative is a compound having a structure represented by formula (I):
wherein R is 1 Is C2-C20 alkyl;
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, hydroxyl, nitro and halogen (which can be F, cl, br, I);
the spatial configuration of the 5-position carbon of the compound is R or S.
According to some embodiments of the invention, R 1 Is C2-C12 alkyl.
According to some embodiments of the invention, R 2 Is hydrogen.
According to some embodiments of the invention, R 3 -R 6 Can be H, benzyl or substituted benzyl independently, wherein, the substituent of the benzyl can be one selected from C1-C4 alkoxy, C1-C4 alkyl, hydroxyl, nitro and halogen.
According to some embodiments of the invention, R 3 -R 6 Are both 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 compound has the stereoconfiguration at the 5-carbon 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 of preparing a C5 branched 1-deoxynojirimycin derivative, comprising the steps of:
(1) Reacting a compound of formula (II) with a compound having R 1 Nucleophilic addition of an 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 carry out catalytic hydrogenation reaction to obtain a compound shown in the formula (I') or a salt thereof;
wherein in the formula (II), the formula (I ') and the formula (I')To R 1 、R 2 、R 3 、R 4 、R 5 Or R 6 Are as defined above in relation to the first aspect.
In the invention, in the step (1), the compound (nitrone) shown as the formula (II) is reacted with the compound with R 1 Nucleophilic addition of an organometallic reagent of the group, i.e. the group R is made 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) can be obtained commercially or can be prepared. The compound represented by formula (II) is not particularly limited, and can be produced by a method conventionally used in the art (for example, boisson, J.; thomaset, A.; racine, E.; cividino, P.; banchelin Saint-Lune, 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 the nucleophilic addition may comprise: 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 present 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 can be represented by the formula MgR 1 X represents, wherein X is halogen (F, cl, br, I). The organozinc reagent may be represented by the formula ZnR 1 X represents, wherein X is halogen (F, cl, br, I). The organolithium reagent may be represented by the formula LiR 1 And (4) showing. The organocopper reagent can be represented by the formula Cur 1 X represents, wherein X is halogen (F, cl, br, I). The above-mentioned radical R 1 The selection of (A) may be specifically selected depending on the compound represented by the formula (I') to be produced.
According to some embodiments of the inventionThe nucleophilic addition is carried out in the presence of a first solvent, which is an aprotic solvent and 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 the requirements of the present invention can be satisfied, and preferably, the amount of the first solvent is 2 to 200mL, more preferably 5 to 50mL, relative to 1g of the compound represented by formula (II).
In the present invention, in order to obtain a further improved effect, in the step (1), the compound (nitrone) represented by the formula (II) is reacted with a compound having R 1 The organometallic reagent of the group is added in the following manner: the organometallic reagent is added to a solution containing the compound represented by the formula (II) (preferably obtained by dissolving the compound represented by the formula (II) in a first solvent).
In the present invention, the post-treatment of affinity addition is not particularly limited as long as the requirements of the present invention can be satisfied. The post-treatment can be carried out, for example, as follows: with saturated NH 4 And (3) quenching the reacted system by using a Cl aqueous solution, extracting by using ethyl acetate, concentrating an organic phase, and separating and purifying the compound shown in the formula (I') by using column chromatography.
According to some embodiments of the invention, in step (2), the conditions of the catalytic hydrogenation reaction may include: the temperature is 0-50 ℃, preferably 10-30 ℃; 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 which is conventional in the art. According to the present invention, the catalytic hydrogenation reaction can remove a protecting group on a hydroxyl group in the presence of a deprotection reagent.
According to some embodiments of the invention, the deprotecting agent may be selected from at least one of raney nickel, pd/C (e.g. Pd/C with a Pd content of 10 mass%, expressed as 10 mass%), 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 present invention, when the deprotection reagent is selected from at least one of raney nickel, pd/C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide, and platinum black, the mass ratio of the compound represented by formula (I') to the deprotection reagent is 1: (0.1-5), preferably 1: (0.1-0.2).
In the present invention, when the deprotecting agent is selected from at least one of iodotrimethylsilane, boron trichloride, boron tribromide, aluminum trichloride, and zinc/ammonium chloride, the molar ratio of the compound represented by the formula (I') to the deprotecting agent 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 present 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 the requirements of the present invention can be satisfied, and preferably, the amount of the second solvent is 0.02 to 2mL, and preferably 0.04 to 1.5mL, relative to 1mg of the compound represented by 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 used is not particularly limited as long as the requirements of the present invention can be satisfied, and preferably, the amount of hydrochloric acid used may be 0.01 to 1mmol relative to 1mg of the compound represented by formula (I'). Wherein, when hydrochloric acid is present in the deprotection reaction, step (2) provides the hydrochloride of the compound of formula (I').
In the present invention, the post-treatment of step (2) is not particularly limited as long as the requirements of the present invention can be satisfied. The post-treatment can be carried out, 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 the 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 free base (the compound represented by the formula (I)) can be obtained by treating the salt with an acidic ion exchange resin. In order to extract the compound shown in the formula (I '), the step can also comprise filtering the product of the catalytic hydrogenation reaction by using kieselguhr, removing the solvent of the filtrate, adding ammonia water to neutralize the filtrate to be alkaline, 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) can be performed in a manner conventional in the art.
A third aspect of the present invention provides a glycosidase inhibitor comprising the C5-branched DNJ derivative or salt thereof described above in the first aspect as an active ingredient.
In a fourth aspect, the present invention provides a use of the glycosidase inhibitor of the third aspect for inhibiting glycosidase.
According to some embodiments of the invention, the glycosidase may be selected from the group consisting of alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-rhamnosidase, amyloglucosidase, and beta-glucuronidase.
In a fifth aspect, the present invention provides a use of the glycosidase inhibitor of the third aspect in the preparation of a medicament selected from at least one of the following: 1) A prophylactic and/or therapeutic agent for diabetes; 2) A medicament for preventing and/or treating gaucher's disease; 3) Drugs for preventing and/or treating tumors; 4) An antiviral drug; 5) An antibacterial agent; 6) A medicament for the prevention and/or treatment of pompe disease.
When necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, and optionally other additives, which are conventional in the pharmaceutical field. The medicine prepared by the compound with the structure shown in the formula (I) or the pharmaceutically acceptable hydrate or the pharmaceutical compound can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the field of pharmacy.
The drug may be administered using a variety of routes of administration, including, but not limited to, oral, inhalation, rectal, transdermal, transmucosal enteral, and subcutaneous, intramuscular, or intravenous injection. The compound with the structure shown in the invention or the pharmaceutically acceptable hydrate or the pharmaceutical compound thereof can be independently administered or administered together with other known drugs for treating diabetes, virus resistance, bacteria resistance and tumor resistance.
The present invention will be described in detail below by way of examples.
In the following preparations and examples, the raw materials used were all obtained commercially without specific description.
Preparation example 1
This preparation is illustrative of the synthesis of a compound of formula (II) (see Boisson, J.; thomaset, A.; racine, E.; cividino, P.; banchelin Saint-Luce, T.; poisson, J.F.; behr, J.B.; py, S.Org.Lett.2015,17, 3662), wherein R is 3 -R 6 Are all hydrogen.
(1) Acetyl chloride (27 mL) was added dropwise to 1500mL of methanol at-10 ℃ for half an hour. Then, the mixture was transferred to room temperature, and L-sorbose (90 g) was added thereto to conduct a reaction at room temperature overnight. After the raw materials disappear, sodium bicarbonate is added to neutralize to be alkaline, ethyl acetate is added to extract, organic phases are combined and concentrated to obtain a crude product IV, and the crude product IV is dissolved by 200mL of N, N-dimethylformamide and 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 bubble was generated. And one-step N, N-Dimethylformamide (DMF) solution of the crude product IV was added dropwise thereto, and after the addition was completed, the reaction was carried out for 1 hour. 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 starting material disappeared. And slowly dropwise adding saturated ammonium chloride aqueous solution into the mixture to quench, adding water, extracting with ethyl acetate, combining organic phases, and evaporating to dryness to obtain a crude product V which is directly used for 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 reaction was allowed to warm to 90 ℃ overnight. The 1, 4-dioxane was distilled off, water was added, extraction was performed with ethyl acetate, and the organic phases were combined. Adding sodium bicarbonate to adjust to alkalinity, extracting again, combining organic phases, and evaporating to dryness. And separating by column chromatography to obtain a product VI.
(4) 20g of product VI are dissolved in 200mL of dried Tetrahydrofuran (THF), and 12mL of dried pyridine are added. And argon is used for protection. 35.6g of Br were added 2 ·PPh 3 And heating to 70 ℃ for reaction. After the disappearance of the starting material, it was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and combined with the organic phase. Using petroleum ether and ethyl acetate as solvents, recrystallizing to obtain most of white solid which is triphenylphosphine oxide, and removing the solid. Evaporating the organic phase to dryness, and separating by column chromatography to obtain a product VII.
(5) 11g of product VII were dissolved in dry Tetrahydrofuran (THF), 13mL of triethylamine were added, and 5g of hydroxylamine hydrochloride were added and reacted at room temperature overnight. After the raw material disappears, adding water for quenching, evaporating to dryness, and separating by column chromatography to obtain nitrone II.
Example 1
This example illustrates the preparation of compounds of formulae (IA-1), (IA-2), (IB-1) and (IB-2)
(1) Nitrone of formula II (0.97g, 1.81mmol) obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (20 mL), ethylmagnesium chloride (5.55 mmol) was added dropwise to the above solution over 3 minutes in ice water bath (0-5 deg.C), 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, washed with saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh silica gel) to give the compound of formula (IA-1) in 59% yield and the compound of formula (IA-2) in 35% yield.
(2-1) the compound represented by the formula (IA-1) (287 mg) was dissolved in methanol (20 mL), 28.7mg of 10% Pd/C was added, hydrochloric acid (5mL, 1N) was added, argon substitution was carried out three times, hydrogen substitution was carried out three times, the reaction was carried out for 12 hours, filtration was carried out, the cake was discarded, and a filtrate was obtained, and the solvent was removed under reduced pressure of-0.1 MPa to obtain the hydrochloride of the compound represented by the formula (IB-1), with the yield of 98%.
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) the compound represented by the formula (IA-2) 115mg was dissolved in methanol (25 mL), 17.25mg of 10% Pd/C was added, hydrochloric acid (3 mL, 1N) was added, argon gas was substituted three times, hydrogen gas 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) with a yield of 92%.
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 illustrates the preparation of formulae (IA-3), (IA-4), (IB-3) and (IB-4)
(1) The nitrone of formula II (0.98g, 1.82mmol) obtained in preparation example 1 above was dissolved in dry diethyl ether (15 mL), propylmagnesium bromide (4.5 mmol) was added dropwise to the above solution in an ice-water bath (0-5 ℃ C.), the addition took 11 minutes, the reaction was continued for 40 minutes, the reaction was quenched with saturated ammonium chloride solution, ethyl acetate (3X 25 mL) was extracted, the organic phases were combined, washed with saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh on silica gel) to give a colorless syrup, the compound of formula (IA-3) in 25% yield, and the compound of formula (IA-4) in 56% yield.
(2-1) the compound represented by the formula (IA-3) 236mg was dissolved in methanol (25 mL), 70.8mg of 10% Pd/C was added, hydrochloric acid (7 mL, 1N) was added, argon gas was substituted three times, hydrogen gas was substituted three times, the reaction was carried out for 16 hours, the filtrate was filtered, the cake was discarded to obtain a filtrate, and the solvent was removed under reduced pressure of 0.15MPa to obtain the hydrochloride of the compound represented by the formula (IB-3) with a yield of 98%.
1 H NMR(500MHz CD 3 OD) δ 3.58 (1h, d, j = 12.3hz), 3.52-3.43 (1h, m), 3.40 (1h, d, j = 12.3hz), 3.30 (1h, t, j = 8.9hz), 3.22 (1h, d, j = 9.0hz), 3.00-2.91 (1h, m), 2.69 (1h, t, j = 11.9hz), 1.59 (1h, td, j =13.6hz, 4.3mhz), 1.43 (1h, td, j =13.5hz, 4.4hz), 1.28-1.06 (2h, m), 0.96 (3h, t, j = 7.2hz) (2-2) 36mg of the compound represented by formula (IA-4) was dissolved in methanol (30 mL), 3.96mg of hydrogen was added, 10mg of pd was added, 10.6 mg of the filtrate was removed, and the filtrate was filtered under reduced pressure to obtain a cake of the compound represented by-18 mg, 18MPa, C, and the filtrate was filtered under the conditions of replacement reaction.
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 illustrates the preparation of formulae (IA-5), (IA-6), (IB-5) and (IB-6)
(1) Nitrone represented by the formula II (0.2 g, 0.37mmol) obtained in the above preparation example 1 was dissolved in dry tetrahydrofuran (30 mL), n-butyl magnesium bromide (0.74 mmol) was added dropwise to the above solution in an ice water bath (0-5 ℃ C.), the dropwise addition took 10 minutes, the reaction was continued for 35 minutes, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh silica gel) to give the compound represented by the formula (IA-5) in 84% yield and the compound represented by the formula (IA-6) in 8% yield.
A compound of the formula (IA-5), 1 H NMR(500MHz,CDCl 3 ) Δ 7.35-7.23 (20H, m), 6.41 (1H, s, br), 4.92 (1H, d, J = 10.9Hz), 4.89 (1H, d, J = 11.2Hz), 4.72 (1H, d, J = 10.8Hz), 4.67 (2H, s), 4.60 (1H, d, J = 11.1Hz), 4.51 (2H, s), 4.19 (1H, d, J = 9.4Hz), 3.81 (1H, t, J = 8.9Hz), 3.76-3.68 (2H, m), 3.62 (1H, dd, J =10.4Hz, 5.4Hz), 3.53 (1H, 1d, J = 9.1H), 3.12 (1H, t, J = 10.1H), 2.1H, 21.1H, 3.1H, 1.88 Hz), 3.1H-3.1H, 3.1-3.6H, 1.88 Hz), 3.1H, 1-3.9.12 (1H, 1-3.34 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 (10mL 1N) was added, argon gas was substituted three times, hydrogen gas 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 a yield of 92%.
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 (13mL, 1N) was added, argon gas was substituted three times, hydrogen gas 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 0.05MPa to obtain the hydrochloride of the compound represented by the formula (IB-6) with 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 illustrates the preparation of formulae (IA-7), (IA-8), (IB-7) and (IB-8)
(1) The nitrone of formula II (1.03g, 1.92mmol) obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (20 mL), magnesium n-pentyl bromide (5.55 mmol) was added dropwise to the solution in an ice water bath (0-5 deg.C) over 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, washed with saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh silica gel) to give the compound of formula (IA-7) in 67% yield and the compound of formula (IA-8) in 9% yield.
The compound of the 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)；
a compound of the 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) 346mg of the compound represented by (IA-7) was dissolved in redistilled dichloromethane (DCM, 25 mL) and protected with argon. Stirring for 15 minutes at-78 deg.C, adding BCl dropwise 3 (1M in DCM, 10mL), after the addition, the temperature was raised to-40 ℃ for reaction, and after 4 hours, the raw material disappeared. Cooling to-78 deg.C, adding methanol, heating to room temperature, evaporating to dryness, extracting with deionized water and dichloromethane, mixing water phases, evaporating to dryness to obtain hydrochloride of compound represented by formula (IB-7) with yield of 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) under argon. Stirring for 15 minutes at-78 ℃, and dropwise adding BCl 3 (1M in DCM, 15mL), after the addition, the temperature was raised to-40 ℃ for reaction, and after 4 hours, the starting material disappeared. Cooling to-78 deg.C, adding methanol, heating to room temperature, evaporating to dryness, extracting with deionized water and dichloromethane, mixing water phases, and evaporating to dryness to obtain hydrochloride of compound represented by formula (IB-8) with yield of 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 illustrates the preparation of formula (IA-9), (IA-10), (IB-9) and (IB-10)
(1) The nitrone of formula II (1g, 1.85mmol) 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 in an ice water bath (0-5 deg.C) over 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, washed with saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh silica gel) to give the compound of formula (IA-9) in 67% yield and the compound of formula (IA-10) in 11% yield.
Of the 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)；
a compound of the 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) dissolving 320mg of the compound represented by the formula (IA-9) in methanol (15 mL), adding 41.6mg of 10% Pd/C, adding hydrochloric acid (9mL, 1N), replacing three times with argon, replacing three times with hydrogen, reacting for 18 hours, filtering, discarding the cake to obtain a filtrate, removing the solvent under reduced pressure of-0.18 MPa to obtain the hydrochloride of the compound represented by the formula (IB-9) in a yield of 100%.
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) dissolving 100mg of the compound represented by the formula (IA-10) in methanol (30 mL), adding 18mg of 10% Pd/C, adding hydrochloric acid (21mL, 1N), replacing with argon three times, replacing with hydrogen three times, reacting for 12 hours, filtering, discarding the cake to obtain a filtrate, removing the solvent under reduced pressure of-0.4 MPa to obtain the hydrochloride of the compound represented by the formula (IB-10), with a yield of 71%.
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 illustrates the preparation of formulae (IA-11), (IA-12), (IB-11) and (IB-12)
(1) The nitrone represented by the formula II (1g, 1.85mmol) obtained in the above preparation example 1 was dissolved in dry tetrahydrofuran (30 mL), n-heptylmagnesium bromide (7.4 mmol) was added dropwise to the above solution in an ice water bath (0-5 ℃ C.), the reaction was continued for 20 minutes, quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh silica gel) to give the compound represented by the formula (IA-11) in a yield of 46% and the compound represented by the formula (IA-12) in a yield of 13%.
Of the 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)；
the compound of the 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) the compound represented by the formula (IA-11) 542mg was dissolved in methanol (18 mL), 108mg of 10% Pd/C was added, hydrochloric acid (12mL, 1N) was added, argon gas was substituted three times, hydrogen gas was substituted three times, the reaction was carried out for 19 hours, the filtrate was filtered, the cake was discarded to obtain a filtrate, 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) with a yield of 99%.
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) dissolving 60mg of the compound represented by the formula (IA-12) in methanol (20 mL), adding 6mg of 10% Pd/C, adding hydrochloric acid (14mL, 1N), replacing with argon three times, replacing with hydrogen three times, reacting for 14 hours, filtering, discarding the cake to obtain a filtrate, removing the solvent 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 illustrates the preparation of formulae (IA-13), (IA-14), (IB-13) and (IB-14)
(1) Nitrone represented by the formula II (1.04g, 1.94mmol) obtained in the above preparation example 1 was dissolved in dry tetrahydrofuran (25 mL), n-octyl magnesium bromide (7.8 mmol) was added dropwise to the above solution in an ice-water bath (0-5 ℃ C.), the reaction was continued for 7 minutes, quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to obtain the compound represented by the formula (IA-13) in a yield of 69% and the compound represented by the formula (IA-14) in a yield of 12%.
Of the 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)；
of the 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) dissolve 660mg of the compound represented by the formula (IA-13) in methanol (27 mL), add 72.6mg of 10% Pd/C, add hydrochloric acid (13mL, 1N), replace three times with argon, replace three times with hydrogen, react for 20 hours, filter, discard the cake to obtain a filtrate, remove the solvent under reduced pressure of-0.19 MPa to obtain the hydrochloride of the compound represented by the formula (IB-13) in a yield of 99%.
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) dissolving 135mg of the compound represented by the formula (IA-14) in methanol (35 mL), adding 17.8mg of 10% Pd/C, adding hydrochloric acid (15mL, 1N), replacing three times with argon, replacing three times with hydrogen, reacting for 15 hours, filtering, discarding the cake to obtain a filtrate, removing the solvent under reduced pressure of-0.6 MPa to obtain the hydrochloride of the compound represented by the formula (IB-14) in a yield of 93%.
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 illustrates the preparation of formulae (IA-15), (IA-16), (IB-15) and (IB-16)
(1) Nitrone represented by the formula II (0.5 g, 0.93mmol) obtained in the above preparation example 1 was dissolved in dry tetrahydrofuran (30 mL), n-nonylmagnesium bromide (3.7 mmol) was added dropwise to the above solution in an ice-water bath (0-5 ℃ C.), the reaction was continued for 20 minutes, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to give the compound represented by the formula (IA-15) in 84% yield and the compound represented by the formula (IA-16) in 8% yield.
Formula (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)；
Formula (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 (14mL, 1N) was added, argon gas was substituted three times, hydrogen gas was substituted three times, the reaction was carried out for 18 hours, filtration was carried out, the cake was discarded to obtain a filtrate, and the solvent was removed under reduced pressure of-0.52 MPa to obtain the hydrochloride of the compound represented by the formula (IB-15) with a yield of 94%.
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) dissolving 31mg of the compound represented by the formula (IA-16) in methanol (18 mL), adding 4.7mg of (10% of Pd/C), adding hydrochloric acid (11mL, 1N), replacing three times with argon, replacing three times with hydrogen, reacting for 27 hours, filtering, discarding the cake to obtain a filtrate, removing the solvent under reduced pressure of-0.14 MPa to obtain the hydrochloride of the compound represented by the formula (IB-16) with a yield of 93%.
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 illustrates the preparation of formulae (IA-17), (IA-18), (IB-17) and (IB-18)
(1) Nitrone represented by the formula II (0.82g, 1.52mmol) obtained in the above preparation example 1 was dissolved in dried tetrahydrofuran (30 mL), n-decylsmagnesium bromide (6.08 mmol) was added dropwise to the above solution in an ice-water bath (0-5 ℃ C.), the dropwise addition took 13 minutes, the reaction was continued for 35 minutes, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh on silica gel) to give the compound represented by the formula (IA-17) in 73% yield and the compound represented by the formula (IA-18) in 19% yield.
Formula (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)；
Formula (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) the hydrochloride of the compound represented by the formula (IB-17) was obtained by dissolving 494mg of the compound represented by the formula (IA-17) in methanol (23 mL), adding 89mg of 10% Pd/C, adding hydrochloric acid (17mL, 1N), replacing three times with argon, replacing three times with hydrogen, reacting for 30 hours, filtering, discarding the cake to obtain a filtrate, and removing the solvent under reduced pressure of-0.17 MPa to obtain the hydrochloride of the compound represented by the formula (IB-17) with a yield of 61%.
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) dissolving 110mg of the compound represented by the formula (IA-18) in methanol (26 mL), adding 11mg of 10% Pd/C, adding hydrochloric acid (2mL, 1N), replacing with argon three times, replacing with hydrogen three times, reacting for 36 hours, filtering, discarding the cake to obtain a filtrate, removing the solvent under reduced pressure of 0.8MPa 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 illustrates the preparation of compounds of formulae (IA-19), (IA-20), (IB-19) and (IB-20)
(1) Nitrone represented by the formula II (1.98g, 3.67mmol) obtained in the above preparation example 1 was dissolved in dry tetrahydrofuran (30 mL), n-decylshium bromide (14.68 mmol) was added dropwise to the above solution in an ice water bath (0-5 ℃ C.) over a period of 7 minutes, the reaction was continued for 40 minutes, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (200-300 mesh on silica gel) to give the compound represented by the formula (IA-19) in a yield of 65% and the compound represented by the formula (IA-20) in a yield of 25%.
Formula (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)；
Formula (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 gas was substituted three times, hydrogen gas was substituted three times, 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) with a yield of 100%.
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) the hydrochloride of the compound represented by the formula (IB-20) was obtained by dissolving 227mg of the compound represented by the formula (IA-20) in methanol (24 mL), adding 36mg of 10% Pd/C, adding hydrochloric acid (5.5mL, 1N), substituting three times with argon, substituting three times with hydrogen, reacting for 40 hours, filtering, and removing the solvent under reduced pressure of-0.37 MPa, with a yield of 99%.
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 illustrates the preparation of formulae (IA-21), (IA-22), (IB-21) and (IB-22)
(1) The nitrone represented by the formula II (0.96g, 1.78mmol) obtained in preparation example 1 was dissolved in dry tetrahydrofuran (35 mL), n-decylsagnesium bromide (7.12 mmol) was added dropwise to the solution in an ice-water bath (0-5 ℃ C.), the dropwise addition took 6 minutes, the reaction was continued for 35 minutes, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to obtain the compound represented by (IA-21) in 73% yield and the compound represented by (IA-22) in 11% yield.
Of the 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)；
of the 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 (6.5mL, 1N) was added, argon substitution was carried out three times, hydrogen substitution was carried out three times, the reaction was carried out for 36 hours, filtration was carried out, the cake was discarded, 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) with a yield of 89%.
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) the compound represented by the formula (IA-22) 35mg was dissolved in methanol (35 mL), 6mg of 10% Pd/C was added, hydrochloric acid (4.5mL 1N) was added, argon gas was substituted three times, hydrogen gas was substituted three times, the reaction was carried out for 40 hours, filtration was carried out, the cake was discarded to obtain a filtrate, 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) with a yield of 99%.
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 formula (DIA-1), (DIA-2), (DIB-1) and (DIB-2)
(1) Nitrone represented by the formula II (1.01g, 1.88mmol) obtained in preparation example 1 above was dissolved in dry tetrahydrofuran (15 mL), methylmagnesium chloride (3.0M in THF,1.85mL, 5.55mmol) was added dropwise to the above solution in an ice-water bath (0-5 ℃ C.), the reaction was continued for 0.5 hour with 14 minutes of dropwise addition, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (3X 25 mL), the organic phases were combined, washed with a saturated sodium chloride solution (2X 25 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography (silica gel 200-300 mesh) to give a white solid represented by (DIA-1) in a yield of 31% and (DIA-2) in a yield of 35%.
The compound of 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)。
the compound of 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 represented by the formula (DIA-1) (116 mg) was dissolved in methanol (15 mL), 19mg of 10% Pd/C was added, hydrochloric acid (10mL 1N) was added, argon gas was substituted three times, hydrogen gas was substituted three times, the reaction was carried out for 48 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 a hydrochloride (82mg, 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 represented by the formula (IA-2) (320 mg) was dissolved in methanol (25 mL), 60mg of 10% Pd/C was added, hydrochloric acid (4.5 mL 1N) was added, argon gas was substituted three times, hydrogen gas was substituted three times, reaction was carried out for 48 hours, and filtration was carried out under reduced pressure of-9 MPa to remove the solvent to obtain a hydrochloride of the compound represented by the formula (DIB-2). (37.9mg, 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 example
The following test examples are intended to illustrate the inhibitory activity of the C5-branched DNJ derivatives of the present invention
(1) Test materials and sources
Test compounds: the C5-branched DNJ derivatives represented by the formulae (IB-1) to (IB-22) provided by the present invention and DNJ, compounds represented by the formulae (DIB-1) and (DIB-2) as control compounds.
Test materials: the 4-nitrophenol pyranoside substrates, disaccharides and glycosidases (alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-rhamnosidase, amyloglucosidase, beta-glucuronidase, etc.) used in the following tests were purchased from Sigma-Aldrich.
(2) Test method
The activity test was carried out on 4-nitrophenol pyranoside as a substrate at the optimum pH for the activity of each enzyme. The substrate, enzyme solution (0.1-0.5 mg/mL) and inhibitors (C5 branched DNJ derivative of the invention and control compounds) were incubated at 37 ℃ for 30 minutes, and then the reaction was initiated in an ultraviolet-visible spectrophotometer and tested for absorption of light at 400nM wavelength. Finally, data analysis was performed using the GraFit program (see leather barrow, r.j. GraFit 4.0, erithacus software, staines, uk, 1998).
(3) Evaluation results
The results of the inhibitory activity of the C5-branched DNJ derivative and the control compound provided by the present invention on glycosidase are shown in table 1.
In Table 1, IC 50 (. Mu.M) represents the concentration of inhibitor that inhibits 50% of the activity of the enzyme. The percentage indicates the inhibition at 1000. Mu.M. ND represents the activity of the untested compound on the enzyme. The glycosidases used below were purchased from Sigma-Aldrich.
TABLE 1
TABLE 1
TABLE 1
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (9)
1. A C5 branched 1-deoxynojirimycin derivative, wherein the 1-deoxynojirimycin derivative is a compound having a structure represented by formula (I):
wherein R is 1 Is C2-C20 alkyl;
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, hydroxyl, nitro and halogen;
the compound has a carbon at position 5 with a spatial configuration of R or S.
2. The derivative according to claim 1, wherein R 1 Is C2-C12 alkyl and/or R 2 Is hydrogen;
and/or, R 3 -R 6 Each independently is H, benzyl or substituted benzyl, wherein, the substituent of the benzyl is selected from one of C1-C4 alkoxy, C1-C4 alkyl, hydroxyl, nitro and halogen;
preferably, R 3 -R 6 Are both hydrogen or benzyl;
more preferably, R 3 -R 6 Are all hydrogen;
and/or the spatial configuration of the 5-position carbon of the compound is R.
3. The derivative according to claim 1 or 2, wherein the compound is selected from one of the compounds of the structure shown below:
4. a method of preparing a C5 branched 1-deoxynojirimycin derivative, comprising the steps of:
(1) Reacting a compound of formula (II) with a compound having R 1 Nucleophilic addition of an 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 carry out catalytic hydrogenation reaction to obtain a compound shown in the formula (I') or a salt thereof;
wherein in the formulae (II), (I ') and (I'), R is involved 1 、R 2 、R 3 、R 4 、R 5 Or R 6 Are as defined in any one of claims 1 to 3.
5. The method of claim 4, wherein in step (1), the conditions of the nucleophilic addition comprise: the temperature is-20 to 50 ℃, preferably-10 to 35 ℃; for a period of 0.5 to 5 hours, preferably 0.5 to 2 hours;
and/or the molar ratio of the compound represented by the formula (II) to the organometallic reagent is 1: (1.2-50), preferably 1: (1.2-10);
and/or, the organometallic reagent is 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;
and/or, the nucleophilic addition is carried out in the presence of a first solvent, the first solvent being an aprotic solvent selected from at least one of diethyl ether, tetrahydrofuran, dioxane and dichloromethane, preferably selected from tetrahydrofuran and/or dioxane;
preferably, the amount of the first solvent used is 2 to 200mL, more preferably 5 to 50mL, relative to 1g of the compound represented by formula (II).
6. The process according to claim 4 or 5, wherein in step (2), the conditions of the catalytic hydrogenation reaction comprise: the temperature is 0-50 ℃, preferably 10-30 ℃; the time is 6 to 100 hours, preferably 6 to 48 hours;
and/or, the deprotection reagent is selected from at least one of raney nickel, pd/C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide, platinum black, iodotrimethylsilane, boron trichloride, boron tribromide, aluminum trichloride and zinc/ammonium chloride, preferably at least one of raney nickel, pd/C, palladium black, palladium hydroxide, palladium acetate, boron trichloride and boron tribromide;
and/or, when the deprotection reagent is at least one of 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);
and/or, when the deprotecting agent is selected from at least one of iodotrimethylsilane, boron trichloride, boron tribromide, aluminum trichloride, and zinc/ammonium chloride, the molar ratio of the compound represented by formula (I') to the deprotecting agent is 1: (1-20), preferably 1: (5-10);
and/or the molar ratio of the compound shown in the formula (I') to the hydrogen source is 1: (5-100), preferably 1: (10-50);
and/or, the hydrogen source is selected from at least one of hydrogen gas, sodium borohydride and ammonium formate, preferably hydrogen gas;
and/or, 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;
preferably, the amount of the second solvent used is 0.02 to 2mL, preferably 0.04 to 1.5mL, relative to 1mg of the compound represented by formula (I').
7. A glycosidase inhibitor characterized by comprising the C5-branched DNJ derivative according to any one of claims 1 to 3 as an active ingredient.
8. Use of the glycosidase inhibitor of claim 7 for inhibiting glycosidase enzymes.
9. Use of the glycosidase inhibitor of claim 7 for the preparation of a medicament selected from at least one of the following: 1) A prophylactic and/or therapeutic agent for diabetes; 2) A medicament for preventing and/or treating gaucher's disease; 3) Drugs for preventing and/or treating tumors; 4) An antiviral drug; 5) An antibacterial agent; 6) A medicament for preventing and/or treating pompe disease.
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