Dihydroartemisinin derivatives and methods for their preparation

Abstract

The present application relates to a kind of dihydroartemisinin derivatives, its preparation method and its application. Specifically, the present application relates to a kind of dihydroartemisinin derivatives shown in general formula (I), its stereoisomer or pharmaceutically acceptable salt, its preparation method and the pharmaceutical composition containing them and the use in the preparation of drugs. The structure of general formula (I) compound is as shown below, and the definition of its group is consistent with the definition in the specification.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of dihydroartemisinin derivatives, its preparation method and its application. Specifically, the present application relates to a kind of dihydroartemisinin derivatives shown in general formula (I), its stereoisomer or pharmaceutically acceptable salt, its preparation method and the pharmaceutical composition containing them and the use in the preparation of drugs. BACKGROUND

[0002] Artemisia annua, alias grass, is a kind of annual or biennial herbaceous plant belonging to Compositae. Artemisinin is a kind of peroxide group-containing sesquiterpene lactone compound extracted from the leaves of Compositae plant Artemisia annua by Chinese pharmacists in the 1970s. Artemisinin drugs, as the first-line antimalarial drugs recommended by the World Health Organization, have the advantages of high efficiency, rapid effect, safety, small dose, convenient taking, simple preparation, etc. Artemisinin derivatives mainly include artesunate, dihydroartemisinin, artemether and arteether. As the first developed artemisinin derivative, dihydroartemisinin has the advantages of high efficiency, low toxicity and rapid onset, and has good bidirectional regulation in the field of antitumor immunity, which can not only reduce B cell hyperreactivity to reduce the deposition of immune complexes caused by autoimmune diseases, but also improve the immune function of T cells. However, due to the poor stability and low water solubility of dihydroartemisinin, oral bioavailability, it is easy to cause drug resistance problem. Therefore, it is of great significance to improve the water solubility and stability of dihydroartemisinin. SUMMARY

[0003] To solve the shortcomings and deficiencies in the prior art, the present application provides a new dihydroartemisinin derivative, which can improve its stability and water solubility, thereby improving the characteristics of drug absorption and metabolism distribution in vivo, improving drug oral bioavailability, reducing drug dosage and frequency, improving patient compliance, improving safety, and prolonging the action time.

[0004] Specifically, the present application relates to a kind of compound shown in general formula (I) and its stereoisomer or its pharmaceutically acceptable salt, wherein:

[0005]

[0006] R1 and R2 are each independently selected from

[0007] R a selected from hydrogen atom or C 1-6 alkyl;

[0008] R b and R b’ are each independently selected from hydrogen atom, C 1-6 alkyl or natural or pharmaceutically acceptable amino acid side chain;

[0009] Rc selected from C 1-6 alkyl or benzyl;

[0010] L is selected from

[0011] X1is selected from C 1-4 alkylene, said alkyl being optionally further substituted with 0 to 4 substituents selected from halogen or C 1-4 alkoxy;

[0012] X2is selected from a bond, -C(=O)O- or -OC(=O)-;

[0013] X3is selected from a bond or C 1-4 alkylene, said alkyl being optionally further substituted with 0 to 4 substituents selected from halogen or C 1-4 alkoxy;

[0014] X4is selected from a bond, -OC(=O)- or -C(=O)-.

[0015] In a preferred embodiment of the present application, a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0016] wherein:

[0017] R a is selected from a hydrogen atom;

[0018] R b and R b’ are each independently selected from a hydrogen atom or a methyl group;

[0019] R c is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group or a benzyl group;

[0020] L is selected from -CH2-OC(=O)- or -CH2-OC(=O)-C2H4-C(=O)-.

[0021] In a preferred embodiment of the present application, a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, includes but is not limited to one of the following structures:

[0022]

[0023] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0024] The present invention also provides the use of compounds of general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicines, including but not limited to the use for the treatment of malaria, inflammation, autoimmune diseases or tumors.

[0025] Detailed description

[0026] The elements carbon, hydrogen, oxygen, nitrogen, or halogen involved in the groups and compounds described in this invention include their isotopes. The elements carbon, hydrogen, oxygen, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include... 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of nitrogen include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0027] "Natural or medicinally acceptable amino acids": The basic backbone of a protein molecule is the amino acid sequence. There are 20 basic amino acids that make up proteins. These 20 basic amino acids are the basis for later protein modifications in organisms. In addition, based on these basic amino acids, derived amino acids such as hydroxyproline and hydroxylysine are biosynthesized. These biosynthesized amino acids are collectively called "natural amino acids." Amino acids synthesized artificially are called "non-natural amino acids." "Medicinally acceptable amino acids" refer to pharmaceutically acceptable natural or non-natural amino acids.

[0028] "Side chain of an amino acid" refers to the part covalently attached to the structure of a D or L-amino acid and can be represented as -CH(COOH)(NH2)-R. For example, in the case of alanine -CH(COOH)(NH2)(CH3), the side chain of amino acid (R) is -CH3.

[0029] In this invention, “=O” is a common usage in the art, referring to an oxygen atom connected by a double bond, such as the double oxygen atom connected to a carbon atom in a carbonyl group.

[0030] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include... 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0031] When "alkyl" is used as a group or part of a group, it refers to a straight-chain or branched aliphatic hydrocarbon group comprising 1 to 20 carbon atoms. Preferably, there are 1 to 10 alkyl groups, more preferably 1 to 6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy, or amino.

[0032] "alkylene" is a divalent alkyl group. Preferably, it is a C1-C10 alkylene group, more preferably a C1-C6 alkylene group, and particularly preferably a C1-C4 alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene. Alkylene groups can be substituted or unsubstituted.

[0033] "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused ring, bridged ring, and spirocyclic carbocyclic rings, but no aromatic ring system having a fully conjugated pi-electron system. Preferred are 3 to 12 membered cycloalkyl groups, more preferred are 3 to 8 membered cycloalkyl groups, and most preferred are 3 to 6 membered cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl and cyclohexenyl being preferred.

[0034] "Fused ring group" refers to a fully carbon polycyclic group of 5 to 18 members, the system containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings can contain one or more double bonds, but no aromatic ring system having a fully conjugated pi-electron system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to:

[0035]

[0036] "Bridged ring group" refers to a fully carbon polycyclic group of 5 to 18 members, the system containing two or more cyclic structures sharing two non-directly connected carbon atoms with each other, one or more rings can contain one or more double bonds, but no aromatic ring system having a fully conjugated pi-electron system, preferably 6 to 12 members, more preferably 7 to 10 members. Preferred are 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic bridged ring alkyl, preferably bicyclic, tricyclic or pyridone, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged ring alkyl" include, but are not limited to:

[0037]

[0038] "Spiro ring alkyl" refers to a polycyclic group of 5 to 18 members between single rings sharing one carbon atom (called spiro atom), which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferred are 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiro ring alkyl is divided into single spiro ring alkyl, double spiro ring alkyl or multi-spiro ring alkyl. Preferred is single spiro ring alkyl. Non-limiting examples of "spiro ring alkyl" include, but are not limited to:

[0039]

[0040] Cycloalkyl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy or amino.

[0041] "Alkoxy" means a group of the formula (alkyl-O-), wherein alkyl is as defined herein. C1-C6 alkoxy is preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like.

[0042] "Cycloalkyloxy" means a group of the formula (cycloalkyl-O-), wherein cycloalkyl is as defined herein. C3-C8 cycloalkyloxy is preferred. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0043] "Hydroxy" means -OH.

[0044] "Amino" means -NH2.

[0045] "Halogen" means fluorine, chlorine, bromine, and iodine.

[0046] "Benzyl" means -CH2-phenyl.

[0047] "DMAP" means 4-dimethylaminopyridine.

[0048] "BTC" means triphosgene.

[0049] "Et" means ethyl.

[0050] "Bn" means benzyl.

[0051] "DIPEA" means N,N-diisopropylethylamine.

[0052] "TMS" means trimethylsilyl.

[0053] "BOP" means benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate.

[0054] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, such that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0055] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and excipients.

[0056] "Carrier" means a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0057] "Excipient" refers to an inert substance added to a pharmaceutical composition to further the administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, including microcrystalline cellulose, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, lubricants, disintegrating agents, and the like.

[0058] "Prodrug" refers to a drug that can be converted to a more active pharmacological agent, such as an estrogen, under physiological conditions, or by solvolysis. Prodrugs of the present application are prepared by modifying functional groups in the estradiol in such a way that their functionality is temporarily destroyed by a process of removal that is reversible, either chemically or metabolically, to yield an estradiol. Biological activity

[0059] "Stereoisomers" refer to isomers that have the same molecular formula but different spatial arrangement of atoms. Stereoisomers include enantiomers (which are mirror images of one another) and diastereomers.

[0060] "Therapeutically effective amount" refers to an amount of a compound that, when administered to a subject for treatment of a disease, is sufficient to effect such treatment for the disease in question.

[0061] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic acid or base salt, including salts of inorganic acids and bases, salts of organic acids and bases. DETAILED DESCRIPTION

[0062] The following examples are provided to further illustrate the present application, but are not meant to limit the scope of the application.

[0063] Examples

[0064] The examples below provide representative compounds of Formula (I) and related structural identification data. It must be understood that the examples below are illustrative of the present application and are not meant to limit the present application.

[0065] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0066] 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm. Tetramethylsilane internal standard (0.00 ppm) was used and the solvent was dimethyl sulfoxide-d6 (DMSO-d6), chloroform-d (CDCI3), methanol-d (CD3OD) and the internal standard was tetramethylsilane (TMS). 1 ​NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. If coupling constants are given, the units are Hz.

[0067] Mass spectra were determined using LC / MS instrument, ionization mode can be ESI or APCI.

[0068] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, the specification of silica gel plates used in thin layer chromatography (TLC) was 0.15mm-0.2mm, the specification of silica gel plates used in thin layer chromatography separation and purification of products was 0.4mm-0.5mm.

[0069] Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0070] HPLC was determined using Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100x4.6mm).

[0071] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, the specification of silica gel plates used in thin layer chromatography (TLC) was 0.15mm-0.20mm, the specification of silica gel plates used in thin layer chromatography separation and purification of products was 0.4mm-0.5mm.

[0072] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius.

[0073] Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available starting materials and reagents are used without further purification, unless otherwise indicated, commercially available manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanyuan Chemical Technology (Shanghai) Co., Ltd., Sinopharm Chemical Co., Ltd., Bailingwei Technology Co., Ltd., etc.

[0074] The compounds were purified by silica gel column chromatography and thin layer chromatography, and the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: petroleum ether: dichloromethane system; wherein the volume ratio of the solvents is different according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added for adjustment, such as acetic acid or triethylamine, etc.

[0075] Unless otherwise specified in the examples, the reaction was carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0076] Unless otherwise specified, the reaction temperature in the examples is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.

[0077] Example 1

[0078] (2S,2'S)-2,2'-((((benzyloxy)methyl)phosphoryl)bis(nitrilodiacyl) dipropionate

[0079]

[0080] First step

[0081] 1a was prepared using a known method "Journal of Organic Chemistry, 2014, 79(6), 2666-2681".

[0082] Second step

[0083] 1b was prepared using a known method "Journal of Medicinal Chemistry, 2017, 60(20), 8580-8590".

[0084] Third step

[0085] 1c was prepared using a known method "Journal of Medicinal Chemistry, 2017, 60(20), 8580-8590".

[0086] Fourth step

[0087] (2S,2'S)-2,2'-((((benzyloxy)methyl)phosphoryl)bis(nitrilodiacyl) dipropionate

[0088]

[0089] Benzyl oxymethyl phosphoryl dichloride 1c (4.2 g, 0.018 mol) was dissolved in 200 mL of dichloromethane, under argon protection, and cooled to -60 °C. L-alanine isopropyl ester hydrochloride (6.5 g, 0.039 mol) was added. After the addition was completed, triethylamine (8.87 g, 0.088 mol) was added dropwise. After the dropwise addition was completed, the reaction was allowed to warm to room temperature for 3 hours. The reaction solution was washed with 1 M hydrochloric acid and saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1:10-1:1) to obtain the title product 1d (2.5 g of yellow oil), yield: 33.2%.

[0090] MS m / z (ESI): 429.5 [M+1]

[0091] Fifth step

[0092] (2S,2'S)-2,2'-(((hydroxymethyl)phosphoryl)bis(nitrilodiacyl)diisopropyl propanedioate

[0093]

[0094] (2S,2'S)-2,2'-(((hydroxymethyl)phosphoryl)bis(nitrilodiacyl)diisopropyl propanedioate 1d (2.5 g, 5.8 mmol) was dissolved in 50 mL of methanol, and hydrogenated for 3 days. Filtration and concentration gave the title product 1e (1.2 g of yellow oil), yield: 61.5%.

[0095] MS m / z (ESI): 339.3 [M+1]

[0096] Sixth step

[0097] 4-oxo-4-((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-oxo[1,2]dioxo[4,3-i]isochromene-10-yl)oxy)butanoic acid

[0098]

[0099] 1h was prepared by a known method "Patent CN104418864".

[0100] Seventh step

[0101] (((((S)-1-ethoxy-1-oxopropan-2-yl)amino)oxy)phosphoryl)methyl ((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo-adamantane-10-yl) butanedioate

[0102]

[0103] To a stirred solution of (2S,2'S)-2,2'-(((hydroxymethyl)phosphoryl)bis(nitrilodiacyl) diisopropyl propanedioate 1e (0.5 g, 1.48 mmol), 4-oxo-4-((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo-adamantane-10-yl)oxy)butanoic acid 1h (0.57 g, 1.48 mmol), N,N-diisopropylethylamine ethyl acetate (0.29 g, 2.22 mmol) and benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.8 g, 1.78 mmol) in 10 ml of tetrahydrofuran was added sequentially and stirred overnight. The reaction was diluted with 50 ml of ethyl acetate and washed sequentially with 1M hydrochloric acid, sodium carbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1:10-1:1) to give the title product 1 (0.55 g colorless oil) in 55.2% yield.

[0104] MS m / z (ESI): 727.3 [M+23]

[0105] 1 H NMR (400 MHz, DMSO-d6): δ 5.67 (d, 1H), 5.57 (s, 1H), 4.65-4.92 (m, 4H), 4.11-4.25 (m, 2H), 3.72-3.87 (m, 2H), 2.61-2.71 (m, 4H), 2.11-2.32 (m, 2H), 1.95-2.05 (m, 1H), 1.75-1.85 (m, 1H), 1.35-1.65 (m, 5H), 1.15-1.35 (m, 22H), 0.85 (d, 3H), 0.75 (d, 3H)

[0106] Example 2

[0107] (2S, 2'S)-Diisopropyl 2,2'-((((((((((((((((((3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR)- 3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10-yl)oxy)carbonyl)oxy)methyl)phosphono)bis(azanediyl)dicarbonic acid

[0108]

[0109] Dihydroartemisinin (0.2 g, 0.7 mmol) and DMAP (0.2 g, 1.62 mmol) were dissolved in 5 mL of tetrahydrofuran. Under argon protection, the solution was cooled to 0 °C. 1 mL of a solution of triphosgene (71 mg, 0.24 mmol) in dichloromethane was added dropwise. The solution was then allowed to warm to room temperature and react for 30 minutes. 5 mL of (2S, 2'S)-2,2'-(((hydroxymethyl)phosphono)bis(azanediyl) dipropionic acid diisopropyl ester 1e (0.36 g, 1.07 mmol) was added under ice bath. The solution was allowed to react overnight at room temperature. 50 mL of ethyl acetate was added. The solution was washed with 1 M hydrochloric acid and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1:10-1:1-ethyl acetate) to give the title product 2 (0.1 g colorless oil), yield: 21.9%.

[0110] 1 H NMR (400 MHz, CDC13): δ 5.53 (s, 1H), 4.96-5.06 (m, 3H), 4.82 (d, 1H), 3.95-4.12 (m, 3H), 3.61-3.68 (m, 1H), 3.28-3.38 (m, 2H), 2.62-2.72 (m, 1H), 2.35 (t, 1H), 1.95-2.05 (m, 1H), 1.61-1.91 (m, 4H), 1.15-1.47 (m, 34H), 0.89-0.97 (m, 6H)

[0111] Example 3

[0112] (2S, 2'S)-Diisopropyl 2,2'-((((((((((((((((((3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR)- 3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isoquinolin-10-yl)oxy)carbonyl)oxy)methyl)phosphono)bis(azanediyl)dicarbonic acid

[0113]

[0114] To a stirred solution of (2S,2'S)-diethyl 2,2'-((((((((((((((((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo[4,3-i]isoquinolin-10- yl)oxy)carbonyl)oxy)methyl)phosphoryl)bis(nitrilodiacyl)carbonate 3a (0.97 g, 3.12 mmol) (synthesis of 3a is same as synthesis of 1e in example 1, replace L-alanine isopropyl ester hydrochloride in the fourth step with L-alanine ethyl ester hydrochloride), 4-oxo-4-((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo[4,3-i]isoquinolin-10- yl)oxy)butanoic acid 1h (1.2 g, 3.12 mmol), DIPEA (0.6 g, 4.7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.66 g, 3.75 mmol) in 20 mL of tetrahydrofuran was stirred overnight. 50 mL of ethyl acetate was added, the reaction solution was washed with 1M hydrochloric acid, sodium carbonate solution and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1:10-1:1) to obtain the title product 3 (1.2 g of colorless oil), yield: 57.1%. MS m / z (ESI): 699.4 [M+23]

[0115] 1 H NMR (400 MHz, CDC13): δ 5.80 (d, 1H), 5.44 (s, 1H), 4.41 (d, 2H), 4.11-4.22 (m, 4H), 3.95-4.05 (m, 2H), 3.37-3.48 (m, 2H), 2.71-2.82 (m, 4H), 2.51-2.61 (m, 1H), 2.31-2.42 (m, 1H), 2.01-2.08 (m, 1H), 1.85-1.95 (m, 1H), 1.65-1.75 (d, 2H), 1.58-1.65 (m, 1H), 1.21-1.52 (m, 21H), 0.96 (d, 3H), 0.85 (d, 3H)

[0116] Example 4

[0117] (2S,2'S)-diethyl 2,2'-((((((((((((((((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo[4,3-i]isoquinolin-10- yl)oxy)carbonyl)oxy)methyl)phosphoryl)bis(nitrilodiacyl)carbonate

[0118]

[0119] Dihydroartemisinin (1 g, 3.52 mmol) and DMAP (1 g, 8.2 mmol) were dissolved in 20 mL of tetrahydrofuran. Under argon protection, the solution was cooled to 0 °C. 4 mL of a solution of triphosgene (71 mg, 0.24 mmol) in dichloromethane was added dropwise. The solution was then allowed to warm to room temperature and react for 30 minutes. 15 mL of (2S,2'S)-2,2'-(((hydroxymethyl)phosphoryl)bis(azanediyl) dipropionic acid diisopropyl ester 3a (1.3 g, 4.22 mmol) was added under ice bath. The solution was allowed to react at room temperature overnight. 50 mL of ethyl acetate was added. The solution was washed with 1 M hydrochloric acid and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1:10-1:1-ethyl acetate) to give the title product 4 (0.3 g colorless oil), yield: 14.2%.

[0120] 1 H NMR (400 MHz, CDC13): δ 5.53 (s, 1H), 4.82 (d, 1H), 4.11-4.21 (m, 4H), 3.97-4.11 (m, 3H), 3.65 (m, 1H), 3.25-3.43 (m, 2H), 2.62-2.72 (m, 1H), 2.35 (t, 1H), 1.95-2.05 (m, 1H), 1.61-1.91 (m, 4H), 1.35-1.48 (m, 12H), 1.21-1.31 (m, 6H), 0.85-0.97 (m, 7H)

[0121] Example 5

[0122] ( ( ( (S) -1-benzyloxy-1-oxopropan-2-yl) amino) phosphoryl) methyl ( (3R,5aS,6R,8aS,9R,10S,12R,12aR) -3,6,9-trimethyldecahydro-3H-3,12-epoxy [1,2] dioxo [1,2] adamentane-10-yl) butanedioate

[0123]

[0124] First step

[0125] Acetyloxymethyl phosphonic acid diethyl ester

[0126]

[0127] Hydroxymethyl phosphonic diethyl ester (30 g, 0.178 mol) and triethylamine (27 g, 0.268 mol) were dissolved in 300 mL of dichloromethane. Acetyl chloride (16.9 g, 0.214 mol) was added dropwise at 0 °C. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 M hydrochloric acid, 10% sodium carbonate solution and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title product 5a (35 g of colorless oil) in 93.3% yield.

[0128] Second step

[0129] Acetyloxymethyl phosphonic dichloride

[0130]

[0131] The synthesis was carried out according to the procedure described in Example 1 for the synthesis of 1c. The title product 5b (22 g of yellow oil) was obtained in 69.2% yield.

[0132] Third step

[0133] (2S,2'S)-2,2'-((acetyloxymethyl)phosphonic bis(azaldicarboxylate) dibenzyl ester

[0134]

[0135] The synthesis was carried out according to the procedure described in Example 1 for the synthesis of 1d. The title product 5c (16 g of oil) was obtained in 44.3% yield.

[0136] MS m / z (ESI): 499.4 [M+23]

[0137] Fourth step

[0138] (2S,2'S)-2,2'-((hydroxymethyl)phosphonic bis(azaldicarboxylate) dibenzyl ester

[0139]

[0140] 5c (15 g, 0.032 mol) was dissolved in 120 mL of benzyl alcohol and stirred. Triethylamine (16 g, 0.16 mol) was added. The reaction mixture was stirred at room temperature overnight. The benzyl alcohol was removed by distillation under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (V / V) = 1:10-1:1-ethyl acetate) to give the title product 5d (6 g of colorless oil) in 44.2% yield.

[0141] MS m / z (ESI): 424.4 [M+1]

[0142] Fifth step

[0143] ((S)-1-benzyloxy-1-oxopropan-2-yl)amino)phosphoryl)methyl ((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo[4,3-i]iso chromene-10-yl) butanedioate

[0144]

[0145] Synthetic procedure similar to the synthesis of 1 in example 1 (replace 1e with 5d). The title product 5 (0.3 g white solid) was obtained in 41.2% yield.

[0146] MS m / z (ESI): 823.5 [M+23]

[0147] 1 H NMR (400 MHz, CDC13): δ 7.32-7.37 (m, 10H), 5.78 (d, 1H), 5.43 (s, 1H), 5.09-5.45 (m, 4H), 4.39-4.45 (m, 2H), 4.01-4.15 (m, 2H), 3.35-3.55 (m, 2H), 2.52-2.79 (m, 5H), 2.31-2.41 (m, 1H), 2.01-2.08 (m, 1H), 1.85-1.95 (m, 1H), 1.55-1.75 (m, 3H), 1.21-1.51 (m, 13H), 0.96 (d, 3H), 0.85 (d, 3H)

[0148] Example 6

[0149] (2S,2'S)-dibenzyl 2,2'-(((((((((((((((((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxo[4,3-i]iso chromene-10-yl)oxy)carbonyl)oxy)methyl)phosphoryl)bis(nitrilodiacyl)carbonate

[0150]

[0151] Synthetic procedure similar to the synthesis of 2 in example 2 (replace 2a with 5d). The title product 6 (0.25 g colorless oil) was obtained in 6.36% yield.

[0152] 1H NMR (400 MHz, CDC13): δ 7.29-7.37 (m, 10H), 5.49 (s, 1H), 5.09-5.25 (m, 4H), 4.79 (d, 1H), 3.98-4.18 (m, 3H), 3.65 (m, 1H), 3.25-3.43 (m, 2H), 2.65 (m, 1H), 2.35 (t, 1H), 1.95-2.05 (m, 1H), 1.71-1.91 (m, 4H), 1.59-1.65 (m, 1H), 1.37-1.48 (m, 9H), 1.32 (d, 3H), 1.21-1.31 (m, 1H), 0.85-0.97 (m, 7H)

[0153] Test Example 1: Pharmacokinetics study in Sprague Dawley (SD) rats

[0154] Healthy adult SD rats, male, 180-220 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.; adaptive feeding for 3 days before starting the test. The test compound was dissolved in DMSO, then Solutol HS-15 and physiological saline were added in turn, and vortexed to mix evenly. The final solvent ratio of the drug solution was DMSO:Solutol HS-15:physiological saline = 5:5:90 (v / v / v). All test compounds were freshly prepared before use, and were clear and transparent solutions. Animals were randomly divided into groups according to body weight, 3 rats per group. The animals were fasted for not less than 8 hours before administration, and free water was provided. Food was given 4 hours after administration. The rats in each group were given test compound solution by intravenous injection (IV) or gavage (PO), respectively. Venous blood about 0.1 ml was collected at different time points before and after administration, and heparin was used for anticoagulation. After centrifugation at 12000 rpm for 10 minutes at 4°C, the plasma was collected and stored at -80°C for testing. The concentrations of the original drug (prodrug) and metabolite (original drug) in the plasma were determined by LC-MS / MS method. The main pharmacokinetic parameters were calculated based on the plasma concentration of the original drug, and the results are shown in Table 1:

[0155] Table 1 Pharmacokinetic test results of SD rats

[0156]

[0157] Conclusion: After gavage administration in rats, Example 1 is rapidly metabolized in the animal body, mainly in the form of dihydroartemisinin. According to the exposure level of dihydroartemisinin in the plasma, the absolute oral bioavailability is 10.9%, indicating that the prodrug design of Example 1 effectively improves the oral bioavailability of the original drug dihydroartemisinin.

[0158] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without the specific details that are set forth herein. Further, it should be noted that, in this application, "exemplary" or "for example" is used on a purely illustrative basis to aid the reader in understanding the application. Any process steps, or sequences of steps, or examples, or embodiments, or materials, or components, or compounds, or elements described herein are understood to be illustrative only and not limiting.

Claims

1. A compound of the general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein: ###0001### L is -CH2-OC(=0)-C2H4-C(=0)-. R1and R2are each independently selected from R a selected from a hydrogen atom; R b and R b’ are each independently selected from a hydrogen atom or a methyl group; R c is selected from methyl, ethyl, propyl, isopropyl or benzyl; The compound of formula (I) is any one of the following compounds: ###0002### 2. The compound according to claim 1, and stereoisomers thereof, or pharmaceutically acceptable salts thereof, characterized in that, 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-2, and its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

4. Use of a compound according to any one of claims 1-2, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 3, for the manufacture of a medicament for malaria. ​

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