WO2020177128A1 - Composé d'acide 2,6-diazaspiro[3,4]octane pyrimidine-hydroxamique et son utilisation - Google Patents

Composé d'acide 2,6-diazaspiro[3,4]octane pyrimidine-hydroxamique et son utilisation Download PDF

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WO2020177128A1
WO2020177128A1 PCT/CN2019/077356 CN2019077356W WO2020177128A1 WO 2020177128 A1 WO2020177128 A1 WO 2020177128A1 CN 2019077356 W CN2019077356 W CN 2019077356W WO 2020177128 A1 WO2020177128 A1 WO 2020177128A1
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compound
group
unsubstituted
substituted
diazaspiro
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Chinese (zh)
Inventor
李剑
江陆斌
王熳炯
李若曦
汤同柯
凌大正
黄正辉
朱进
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East China University of Science and Technology
Institut Pasteur of Shanghai of CAS
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East China University of Science and Technology
Institut Pasteur of Shanghai of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the fields of medicinal chemistry and pharmacotherapy. Specifically, the present invention provides a class of small molecule compounds with 2,6-diazaspiro[3.4]octane-like pyrimidine-hydroxamic acid structure and their pharmacy Acceptable salt, the compound has excellent malaria parasite killing activity in vivo and in vitro. Such compounds are expected to be developed into new anti-malaria drugs.
  • Malaria is one of the most prominent problems in public health in the world today, and it is the most widespread and harmful parasitic disease in the world. According to the World Health Organization (WHO) World Malaria Report in 2018, there were 219 million malaria cases worldwide in 2017, including 435,000 deaths; most of the malaria cases occurred in the WHO African region (200 million cases, 92%), among which children under 5 years old are the most vulnerable population. In addition to endangering human health and life safety, the malaria epidemic has severely weakened the health systems of many African countries, profoundly affected the socio-economic development of developing countries, and made poverty a vicious circle that cannot be escaped. Coupled with factors such as global warming, frequent international exchanges, and a slowdown in global funding for malaria control, global malaria control will face enormous challenges.
  • Malaria is caused by a parasite called Plasmodium, which is spread by the bite of an infected mosquito. This parasite reproduces in the human liver and then infects red blood cells. Symptoms of malaria include fever, headache, and vomiting, which usually appear 10-15 days after a mosquito bite. If left untreated, malaria may interrupt the blood supply to vital organs that sustain life, thereby quickly threatening life.
  • the purpose of the present invention is to provide a pharmaceutical compound that can effectively kill malaria parasites, especially drug-resistant malaria parasites.
  • the first aspect of the present invention provides a 2,6-diazaspiro[3.4]octane pyrimidine-hydroxamic acid compound represented by the following formula I, or a pharmaceutically acceptable salt or optical isoform thereof Structure,
  • R 1 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C15 monocyclic, bicyclic or tricyclic aryl, substituted Or unsubstituted 5-15 membered monocyclic, bicyclic or tricyclic heterocyclic group (including saturated, partially unsaturated or aromatic heterocyclic group); wherein, the heteroaryl group includes one or more selected from Group of heteroatoms as the ring skeleton: N, O or S;
  • R 2 is selected from the group consisting of NHOH, or OR 3 ;
  • R 3 is selected from the following group: hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-15 membered heterocyclic group;
  • R 2 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted Groups of the following groups:
  • X is selected from N, O, and S.
  • the aryl group is an aryl group containing 1 to 4 bicyclic rings.
  • the heterocyclic group is a heteroaryl group containing 1-4 bicyclic rings, wherein each bicyclic ring is independently a 5- to 6-membered aromatic ring or aromatic heterocyclic ring.
  • the C1-C6 alkyl group is methyl or ethyl.
  • the R 1 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C15 aryl , Substituted or unsubstituted 5-15 membered heteroaryl; wherein, the C3-C8 cycloalkyl group is selected from the following group: cyclopentyl, cyclohexyl;
  • the aryl group is selected from the following group: phenyl, naphthyl, phenanthryl;
  • the 5-15 membered heteroaryl group is selected from the following group:
  • the substituents are selected from the group consisting of halogen, OH, NH 2 , CN, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, C1-C6 alkoxy Group, C1-C6 alkylamino.
  • the R 1 is NHOH.
  • the compound of formula I can be selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a therapeutically effective amount of the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, Hydrate or solvate; and (b) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is used for:
  • the pharmaceutical composition is used to regulate the activity or expression of HDAC.
  • the third aspect of the present invention provides a use of the compound of formula I as described in the first aspect of the present invention for preparing a pharmaceutical composition for treating or preventing diseases or disorders caused by malaria parasites.
  • the disease or condition is malaria.
  • the Plasmodium is resistant or non-drug resistant.
  • the plasmodium is a plasmodium in a stage selected from the group consisting of hepatic stage, gametophyte stage, and intraerythrocytic stage.
  • the drug-resistant plasmodium is a plasmodium that has developed resistance to drugs selected from the group consisting of artemisinin, dihydroartemisinin, artemether, artesunate, and fluorene Alcohol, sulfadoxine, pyrimethamine, pyronaridine, atovaquinone, quinine, chloroquine, piperquine, mefloquine, amodiaquine, primaquine, and tafenoquine.
  • drugs selected from the group consisting of artemisinin, dihydroartemisinin, artemether, artesunate, and fluorene Alcohol, sulfadoxine, pyrimethamine, pyronaridine, atovaquinone, quinine, chloroquine, piperquine, mefloquine, amodiaquine, primaquine, and tafenoquine.
  • the fourth aspect of the present invention provides a use of the compound of formula I as described in the first aspect of the present invention for preparing a pharmaceutical composition for treating or preventing diseases or disorders related to the activity or expression of HDAC.
  • the disease or condition is a tumor.
  • the tumor is selected from the group consisting of lung cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, and lymphatic system tumors.
  • Figure 1 is a Western Blot experimental result diagram of the compound of the present invention.
  • Figure 2 is a broken line diagram of the protozoan rate in mice in the in vivo drug efficacy experiment in mice;
  • Figure 3 is a broken line graph of the survival ratio of mice in the results of in vivo drug efficacy experiments in mice.
  • the inventor prepared a compound with HDAC inhibitory activity, which can kill drug-resistant and non-drug-resistant plasmodium activity in various periods, and has low toxicity to human cells, so it can For the treatment of diseases caused by malaria parasites such as malaria. Based on the above findings, the inventor completed the present invention.
  • the present invention provides a compound having the structure of the following general formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • R 1 is selected from H, straight or branched chain alkyl or II:
  • Ring A in formula II is an aliphatic cycloalkyl group, a ring aryl group, and a heteroatom-containing ring aryl group.
  • the compound according to general formula I is characterized in that the A ring in II is a 3-8 membered alicyclic alkyl group.
  • the compound of general formula I is characterized in that the ring A in II is a ring aryl group with or without heteroatoms, wherein the number of heteroatoms is 0-4, and the type of heteroatoms is selected from one of nitrogen, oxygen, and sulfur. Two or three.
  • the compound in accordance with formula I is characterized in that the cyclic aryl group described by ring A is an aryl group containing 1 to 4 parallel rings, wherein the aromatic ring is composed of a 5- to 6-membered aromatic ring or aromatic heterocyclic ring, each The number of heteroatoms constituting an aromatic ring is 0-2, and the heteroatom types are selected from one or two of nitrogen, oxygen, and sulfur.
  • R 2 and R 3 are independently selected from H, halogen, OH, NH 2 , CN, linear or branched alkyl, cycloalkyl, aryl, alkoxy, alkyl Amino.
  • X is selected from N, O, S.
  • the compound according to the general formula I is characterized in that it is used to prepare a pharmaceutical composition or preparation for inhibiting the activity of histone deacetylase (HDAC), or for preparing a pharmaceutical composition or preparation for inhibiting Plasmodium or treating malaria.
  • HDAC histone deacetylase
  • the pharmaceutical composition contains 0.001 to 99% by weight, preferably 0.1 to 90% by weight, and more preferably 1 to 80% by weight of the compound of general formula I or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
  • the dosage form of the medicine or pharmaceutical composition is an oral dosage form or an injection. Oral dosage forms include tablets, capsules, films, granules, etc., and also include sustained-release or non-sustained-release dosage forms.
  • the pharmaceutical composition may also contain other pharmaceutical ingredients with anti-malarial activity, including but not limited to artemisinin, dihydroartemisinin, artemether, artesunate, benfluorenol, sulfadoxine, pyrimethamine, Pyrolidine, atovaquinone, quinine, chloroquine, piperaquine, mefloquine, amodiaquine, primaquine, talfinoquine, etc.
  • other pharmaceutical ingredients with anti-malarial activity including but not limited to artemisinin, dihydroartemisinin, artemether, artesunate, benfluorenol, sulfadoxine, pyrimethamine, Pyrolidine, atovaquinone, quinine, chloroquine, piperaquine, mefloquine, amodiaquine, primaquine, talfinoquine, etc.
  • the present invention also provides a preparation method of 2,6-diazaspiro[3.4]octane pyrimidine-hydroxamic acid and its intermediate compounds with the structure of general formula I.
  • the specific synthesis method is as follows:
  • step 2 1) Dissolve the compound obtained in step 1 and 2,6-di-tert-butylpyridine in dichloromethane, cool to 0 ⁇ 5°C in an ice water bath, slowly add trimethylsilyl trifluoromethanesulfonate dropwise, and the addition is complete Keep the ice water bath, stir for 15 min, remove the ice water bath, and stir at room temperature until the reaction is complete (TLC detection). Then cool the reaction liquid in an ice-water bath, slowly add anhydrous methanol (the addition amount is the same as trimethylsilyl trifluoromethanesulfonate) to the system under vigorous stirring. After the methanol is added, remove the ice-water bath and wait for the system to rise.
  • anhydrous methanol the addition amount is the same as trimethylsilyl trifluoromethanesulfonate
  • Step 3 The compound obtained in Step 2 was dissolved in 1,2-dichloroethane is added an aldehyde substituted with R 1, glacial acetic acid, triacetoxy sodium borohydride, stirred at room temperature overnight. After the reaction is completed, a saturated aqueous sodium bicarbonate solution is added, the liquid is separated by shaking, the organic phase is distilled under reduced pressure to remove the solvent, and the remaining mixture is separated and purified by silica gel column chromatography to obtain compound Id.
  • step 4 Dissolve the compound obtained in step 3 with a mixed solution of methanol and water, add solid potassium carbonate, and heat to react at 65-70°C for 5-6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was acidified with 2M hydrochloric acid to a pH of about 1, and water was distilled off under reduced pressure to obtain compound I-e mixed with inorganic salts and used directly in the next reaction.
  • step 5 Dissolve the mixture obtained in step 4 with N,N-dimethylformamide solution, add 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in sequence Amine hydrochloride, after stirring for 30 min at room temperature, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine and triethylamine were added in sequence, and stirred at room temperature for 48 hours.
  • step 6 Dissolve the compound obtained in step 5 with dichloromethane, add 4M hydrogen chloride-dioxane solution, and stir for 30 min at room temperature. Filtration with suction and washing the solid with a large amount of dichloromethane to obtain compound I.
  • the compound of the present invention Since the compound of the present invention has excellent HDAC activation activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and containing the compound of the present invention as the main active ingredient
  • the pharmaceutical composition can be used to treat, prevent and alleviate diseases caused by the activity or expression of HDAC.
  • the compounds of the present invention can be used to treat the following diseases: lung cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, lymphatic system tumors, and diseases caused by malaria parasites (such as malaria).
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 0.1-1000 mg of the compound of the present invention per agent, more preferably, 0.5-500 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting Agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting Agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • a particularly preferred mode of administration is oral.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and gly
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily dose administered is usually 0.2 to 1000 mg, preferably 0.5 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • Example 4 The solid obtained in Example 4 was dissolved in 10 mL of N,N-dimethylformamide solution, and 0.16g 1-hydroxybenzotriazole and 0.23g 1-(3-dimethylaminopropyl)-3-ethyl were added in sequence. After stirring for 30 min at room temperature, 0.35 g of O-(tetrahydro-2H-pyran-2-yl) hydroxylamine and 0.42 mL of triethylamine were added in sequence, and stirred at room temperature for 48 hours.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 2-furaldehyde, and the remaining raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-2d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 3-furaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-3d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 2-thiophenecarbaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-4d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 3-thiophenecarbaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-5d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 2-pyridinecarboxaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-6d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 3-pyridinecarboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-7d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 4-pyridinecarboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-8d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 1-naphthaldehyde, and the remaining raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-9d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 2-naphthaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-10d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with biphenyl-4-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-11d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with benzaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-12d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with cyclopentylcarbaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-13d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with cyclohexylcarbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-14d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 1-benzothiophene-2-carboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-15d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 3-carboxaldehyde benzothiophene, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-16d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with benzo[b]furan-2-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-17d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 4-indolecarbaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-18d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 1-methylindole-2-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-19d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 3-quinolinecarboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-20d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with quinoline-2-carboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-21d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with quinoline-6-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-22d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with quinoline-8-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-23d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 8-isoquinolinecarboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-24d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with isoquinoline-5-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-25d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 4-quinolinecarboxaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-26d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with isoquinoline-4-carbaldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-27d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with imidazo[1,2-a]pyridine-3-carbaldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I- 28d.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 1-methyl-2-formylbenzimidazole, and the remaining required raw materials, reagents and preparation methods were the same as in Example 3 to obtain I-29d.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde.
  • the remaining raw materials, reagents and preparation methods are the same In Example 3, I-30d was obtained.
  • Example 3 Replace the N-methylindole-3-carboxaldehyde in Example 3 with 1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid, and other required raw materials, reagents and preparation methods Same as Example 3 to obtain I-31d.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde, and the other required raw materials, reagents and preparation methods are the same In Example 3, I-32d was obtained.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 1-methyl-1H-indazole-3-carbaldehyde, and the other required raw materials, reagents and preparation methods are the same as those in Example 3 to obtain I-33d .
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 1-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde, and the other required raw materials, reagents and preparation methods are the same In Example 3, I-34d was obtained.
  • Example 3 The N-methylindole-3-carbaldehyde in Example 3 was replaced with 9-anthracene aldehyde, and the remaining raw materials, reagents and preparation methods were the same as those in Example 3 to obtain I-35d.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 6-methoxy-1-methyl-1H-indole-3-carbaldehyde, and the other required raw materials, reagents and preparation methods are the same as those in the example 3. Get I-36d.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 1,6-dimethyl-1H-indole-3-carbaldehyde, and the remaining raw materials, reagents and preparation methods are the same as those in Example 3. I-37d.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 6-cyano-1-methyl-1H-indole-3-carbaldehyde, and the other required raw materials, reagents and preparation methods are the same as in Example 3. , Get I-38d.
  • Example 3 Replace the N-methylindole-3-carbaldehyde in Example 3 with 6-bromo-1-methyl-1H-indole-3-carbaldehyde, and the remaining raw materials, reagents and preparation methods are the same as in Example 3. Get I-39d.
  • Example 4 Replace I-1d in Example 4 with I-2d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-2 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-3d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-3 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-4d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-4 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-5d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-5 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-6d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-6 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-7d, and the remaining raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-7 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-8d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-8 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-9d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-9 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-10d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-10 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-11d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-11 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-12d, and the remaining raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-12 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-13d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-13 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-14d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-14 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-15d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-15 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-16d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-16 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-17d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-17 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-18d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-18 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-19d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-19 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-20d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-20 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-21d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-21 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-22d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-22 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-23d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-23 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-24d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-24 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-25d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-25 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-26d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-26 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-27d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-27 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-28d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-28 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-29d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-29 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-30d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-30 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-31d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-31 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-32d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-32 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-33d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-33 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-34d, and the remaining raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-34 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-35d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-35 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-36d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-36 is obtained through a three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-37d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-37 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-38d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-38 is obtained through three-step reaction.
  • Example 4 Replace I-1d in Example 4 with I-39d, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 4-6, and I-39 is obtained through three-step reaction.
  • Plasmodium culture Use PRMI (containing NaHCO 3 , HEPES, Albumax I, Hypoxanthine, Genaotamicin) complete medium (complete medium) for plasmodium culture, in a 37°C incubator (5% CO 2 , 5% O 2 ) In the cultivation.
  • PRMI containing NaHCO 3 , HEPES, Albumax I, Hypoxanthine, Genaotamicin
  • 3D7 is a wild-type strain and has no obvious resistance to drugs; Dd2 is resistant to chloroquine, quinine, sulfadoxine, pyrimethamine, and amodiaquine.
  • Table 1 shows that the compounds have strong in vitro insecticidal activity, and the IC 50 values of some compounds against 3D7 and Dd2 are comparable to DHA.
  • Inhibition rate (%) [A(0)-A(dosing)]/[A(0)-A(blank)] ⁇ 100%
  • the experiment uses mouse liver microsomes (0.5mg/mL), purchased from Corning.
  • the positive control is ketanserin.
  • the test compound is first prepared into a 10 mM DMSO solution and diluted to 0.5 mM with acetonitrile; the above 0.5 mM solution is added to the buffer containing liver microsomes to make the compound concentration 1.5 ⁇ M; Take 30 ⁇ L of the 1.5 ⁇ M compound/liver microsome mixture and add 15 ⁇ L of 6 mM NADPH solution to make the final concentration of the compound 1.5 ⁇ M and the final concentration of NADPH 2 mM.
  • the compound/liver microsome test solution was placed on the test plate, incubated in a 37°C water bath, and quenched by adding 135 ⁇ L of acetonitrile at each time point (0, 5, 15, 30, 45 min). After all the samples are quenched, shake the samples with a shaker (IKA, MTS 2/4) for 10 minutes (600 rpm/min), and then centrifuge at 5594g for 15 minutes (Thermo Multifuge ⁇ 3R). Take the supernatant, dilute it with distilled water 1:1, and analyze by LC-MS. The peak area response ratio (PARR) of the compound at 5, 15, 30, and 45 min was compared with the PARR at time 0 to determine the percentage of test compound retained at each time point.
  • PARR peak area response ratio
  • GB4 is resistant to chloroquine; C2A is resistant to quinine; CP286 is resistant to sulfadoxine, pyrimethamine, and mefloquine; 6218 and 6320 have time-dependent resistance to artemisinin drugs, only in It will be displayed within 6h after the ring phase is synchronized.
  • Table 1 and Table 4 the 72h IC 50 values of the compounds are equivalent to DHA, indicating that the compounds have the potential to treat malaria that is resistant to current first- and second-line antimalarial drugs and cope with malaria resistance.
  • Plasmodium culture uses RPMI (containing NaHCO3, HEPES, Albumax I, Hypoxanthine Genaotamicin) complete medium (Complete Medium), cultivated in a 37°C incubator
  • the drug was dissolved in DMSO to prepare an initial concentration of 200*20*IC50.
  • SDS-PAGE gel electrophoresis Load 10 ⁇ L in each well of the precast gel, run at 80V for 30 minutes, adjust the voltage to 120V, and then run until the loading is close to the bottom edge of the separation gel.
  • Transfer membrane Cut out the PVDF membrane with corresponding coverage area, adopt wet transfer method, fast transfer membrane buffer, 400mA constant current transfer for 35 minutes, and take out the PVDF membrane after finishing.
  • Sealing Put the membrane in the sealing solution (add 5% skimmed milk powder in TBST), shake and seal for 2h on a shaker.
  • Incubate the primary antibody use histone histone H3 antibody and H3K9 acetylated antibody, dilute with 5% skimmed milk powder at a ratio of 1:2000, incubate the PVDF membrane on a shaker for 2 hours, discard the incubation solution, add TBST to wash the membrane three times, each time for 10 minutes.
  • Incubate the secondary antibody Dilute the secondary antibody at 1:5000, incubate the PVDF membrane on a shaker for 1 hour and discard the incubation solution.
  • Color development and exposure Temporarily prepare color development solution and spread it evenly on the PVDF film. The exposure time can be adjusted according to the brightness of the strip.
  • JL01 is the positive control compound. Comparing the acetylation bands of Plasmodium histone H3 after treatment with compound and DMSO for 4 hours, it can be seen that the compound up-regulated the level of acetylation, that is, inhibited deacetylation. The activity of the enzyme indirectly proves that the compound is a pan pfHDAC inhibitor.
  • Protozoa rate number of red blood cells infected by plasmodium/total number of red blood cells ⁇ 100%
  • the results are shown in Figures 2 and 3.
  • the protozoan rate curve ( Figure 2) shows that compared with the blank group, compound I-39 has better insecticidal activity at 60 mg/kg, and the protozoan rate of the surviving mice is 0 on the 30th day. The protozoan has been eliminated.
  • the protozoan rate curve and survival curve ( Figure 3) comprehensively show that I-39 has a good balance of efficacy and toxicity.
  • (1) hHDAC1-3,6 test method add 250nL DMSO or compound solution to the OptiPlate TM-384F black assay plate via Echo, and add 15 ⁇ L enzyme solution and 10 ⁇ L GL-8 substrate solution to the assay plate in turn. Incubate at 25°C for 60 minutes and read the value using the setting of Ex350-360/Em450-465 (sensitive 60). The inhibition rate was calculated, and the IC 50 value was calculated with GraphPad Prism.
  • (2) hHDAC8 test method add 250nL DMSO or compound solution to the OptiPlate TM-384F black assay plate via Echo, add 15 ⁇ L enzyme solution, 10 ⁇ L corresponding substrate solution, and react at 25°C for 4 hours. Add 10 ⁇ L stop solution to stop the reaction, and use the setting of Ex350-360/Em450-465 to read the value. The inhibition rate was calculated, and the IC 50 value was calculated with GraphPad Prism.
  • (3) hSirt2 test method add 800nL DMSO or compound solution to the OptiPlate TM-384F black assay plate via Echo, add 10 ⁇ L enzyme solution and 10 ⁇ L corresponding substrate solution in sequence, and react at 25°C for 4h. Add 20 ⁇ L stop solution to stop the reaction, and use the setting of Ex350-360/Em450-465 to read the value. The inhibition rate was calculated, and the IC 50 value was calculated with GraphPad Prism.
  • the 2,6-diazaspiro[3.4]octane pyrimidine-hydroxamic acid compound of the present invention has a relatively simple molecular structure and a simple preparation process. It is useful in HDAC enzyme inhibition experiments and experiments that are closely related to the survival and reproduction of plasmodium. Both internal and external insecticidal efficacy experiments have shown strong inhibitory activity, and the cytotoxicity is weak, and the selectivity index can reach thousands. Therefore, such compounds are not only expected to be developed into a new type of single-drug antimalarial drugs, but also can be developed into antimalarial drugs for combined administration with existing antimalarial drugs.

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Abstract

L'invention concerne un composé d'acide 2,6-diazaspiro [3,4]octane pyrimidine-hydroxamique et son utilisation. Plus précisément, la présente invention concerne un composé tel que représenté par la formule I, ou un sel pharmaceutiquement acceptable de celui-ci, ou un stéréoisomère de celui-ci, et son procédé de préparation, et son utilisation dans la préparation de médicaments antipaludiques inhibiteurs d'HDAC.
PCT/CN2019/077356 2019-03-07 2019-03-07 Composé d'acide 2,6-diazaspiro[3,4]octane pyrimidine-hydroxamique et son utilisation Ceased WO2020177128A1 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2014026467A1 (fr) * 2012-08-14 2014-02-20 山东轩竹医药科技有限公司 Composés de pyrimidine substitués bicycliques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014026467A1 (fr) * 2012-08-14 2014-02-20 山东轩竹医药科技有限公司 Composés de pyrimidine substitués bicycliques

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