WO2017000869A1 - 噻嗪酰胺衍生物及其用途 - Google Patents

噻嗪酰胺衍生物及其用途 Download PDF

Info

Publication number
WO2017000869A1
WO2017000869A1 PCT/CN2016/087433 CN2016087433W WO2017000869A1 WO 2017000869 A1 WO2017000869 A1 WO 2017000869A1 CN 2016087433 W CN2016087433 W CN 2016087433W WO 2017000869 A1 WO2017000869 A1 WO 2017000869A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
disease
alkyl
methyl
Prior art date
Application number
PCT/CN2016/087433
Other languages
English (en)
French (fr)
Inventor
李松
肖军海
吕博群
王洪强
钟武
王莉莉
郑志兵
谢云德
周辛波
李行舟
王晓奎
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国人民解放军军事医学科学院毒物药物研究所 filed Critical 中国人民解放军军事医学科学院毒物药物研究所
Priority to JP2017567680A priority Critical patent/JP6849615B2/ja
Priority to EP16817233.6A priority patent/EP3327010B1/en
Priority to US15/739,872 priority patent/US10335417B2/en
Publication of WO2017000869A1 publication Critical patent/WO2017000869A1/zh

Links

Classifications

    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings

Definitions

  • the present invention relates to the field of medical technology, and in particular, the present invention relates to a thiazolamide derivative compound, a pharmaceutically acceptable salt thereof or a solvate thereof, and a medicament containing the compound, a pharmaceutically acceptable salt thereof or a solvate thereof
  • the above acceptable salts or solvates thereof are useful for the prevention and/or treatment of neurodegenerative diseases and neuropathy caused by physical damage or related diseases.
  • Neurodegenerative diseases are a group of diseases caused by progressive pathological changes in the nervous system, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and muscular atrophy. Lateral cord hardening (ALS) and the like. Due to the complex causes of these diseases, the pathogenesis is not very clear, and no effective treatment has been found yet.
  • ALS Lateral cord hardening
  • FKBPs FK506 binding protein
  • FK506 immunosuppressive agent
  • FK506 TAK506 binding protein
  • Steiner J.P. et al. found in 1992 that the concentration of FKBPs in the brain and periphery is much greater than that in immune tissues, which suggests that there may be some relationship between FKBPs and the nervous system. Dawson et al. showed that FK506 blocks the excitatory toxicity of glutamate-activated NMD receptors (N-methyl-D-aspartic acid receptors).
  • FKBPs inhibit the phosphorylation of nitric oxide synthase (NOS) after inhibiting calcineurin, inhibiting the catalytic activity of NOS and avoiding the damage of neurons by NO.
  • NOS nitric oxide synthase
  • GAP43 growth associated protein-43
  • the nerve regeneration of facial and sciatic nerve injury is accompanied by significant GAP43 mRNA levels. Increase while at the same time The mRNA level of FKBPs also increased accordingly.
  • Chinese invention patent ZL01142744.2 (replacement of six-membered nitrogen heterocyclic compounds and their use as neuromodulators) discloses a novel structure of FKBP ligands with nerve regeneration, of which compound 4 is the optimal compound.
  • compound 4 is the optimal compound.
  • the Chinese invention patent CN102675244 discloses an optimized compound, but it has room for further improvement in nerve growth growth activity and in vivo efficacy.
  • thiazine refers to a six-membered ring structure containing four ring carbon atoms, one ring nitrogen atom and one ring sulfur atom, including but not limited to 1,3-thiazine, 1,4 - thiazide, dihydro-1,3-thiazine, dihydro-1,4-thiazine, tetrahydro-1,3-thiazine, tetrahydro-1,4-thiazine, and the like.
  • thiazinamide refers to a thiazide structure substituted with an amide group.
  • C 1-4 alkyl group as used in the present invention means a straight or branched alkyl group having 1 to 4 carbon atoms, including but not limited to a C 1-2 alkyl group, a C 1-3 alkyl group, C 2-4 alkyl, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl and the like.
  • C 1-4 alkoxy group as used in the present invention means a group in which a C 1-4 alkyl group is bonded to another structure through an oxygen atom, including but not limited to a C 1-2 alkoxy group, C 1-3.
  • Alkoxy, C 2-4 alkoxy for example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, isobutoxy Base.
  • a "solvate" of a compound of the invention refers to a substance formed by association of a compound of the invention with a solvent molecule.
  • the solvent may be an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, etc.), water, or the like.
  • the compound of formula (I) of the present invention can form an ethanolate with ethanol and form a hydrate with water.
  • neurodegenerative disease refers to a disease caused by progressive pathological changes of the nervous system, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Multiple sclerosis of the cerebral spinal cord.
  • the "neuropathy caused by related diseases” as used in the present invention includes but is not limited to acquired Neuropathy caused by immunodeficiency, neuropathy caused by diabetes, and neuropathy caused by stroke.
  • an effective amount is meant an amount sufficient to achieve, or at least partially achieve, the desired effect.
  • an effective amount for preventing a disease for example, a neurodegenerative disease, a neuropathy caused by physical damage, or a neuropathy caused by a related disease
  • a disease for example, a neurodegenerative disease, a nerve caused by physical damage
  • the amount of occurrence of a lesion or a neuropathy caused by a related disease; an effective amount for treating a disease means an amount sufficient to cure or at least partially arrest the disease and its complications of a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art.
  • the amount effective for therapeutic use will depend on the severity of the condition to be treated, the overall condition of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously. and many more.
  • the inventors obtained a thiazine amide derivative through intensive research and creative labor.
  • the present inventors have found that by appropriately selecting the R1, R2 and/or R3 groups in the thiazinamide derivative represented by the formula (I), the obtained compound can be made in a neurotrophic activity against a mouse brain.
  • the in vivo efficacy of stroke and/or the ability to pass through the blood-brain barrier is improved relative to existing thiazinamide derivatives.
  • the present invention provides a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof,
  • R1 is selected from C 1-4 alkyl
  • R 2 and R 3 are each independently selected from a C 1-4 alkyl group, and optionally, the C 1-4 alkyl group is substituted with a phenyl group;
  • the phenyl group is substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, hydroxy, amino and carboxy;
  • R2 is in the R configuration.
  • R2 is in the S configuration.
  • R1 is selected from C2-3 alkyl, such as ethyl, n-propyl, isopropyl.
  • R 2 and R 3 are each independently selected from C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, Isobutyl.
  • R2 is selected from C3-4 alkyl, such as n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl.
  • R2 is isobutyl
  • R3 is selected from C3-4 alkyl, such as n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl.
  • R3 is selected from C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl.
  • R2 is in the R configuration.
  • R2 is in the S configuration.
  • R2 is selected from C1-4 alkyl (eg, C1-2 alkyl), and said C1-4 alkyl (eg, C1-2 alkyl) is substituted with phenyl,
  • the phenyl group is substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, hydroxy, amino and carboxy.
  • R2 is phenethyl
  • R1 is methyl
  • R3 is methyl, ethyl, isopropyl, tert-butyl or benzyl.
  • R3 is methyl, ethyl, isopropyl or tert-butyl.
  • R3 is methyl
  • R3 is ethyl
  • R3 is isopropyl
  • R3 is a tert-butyl group.
  • R3 is benzyl
  • R1 is methyl;
  • R2 is benzyl or phenethyl; and
  • R3 is methyl, ethyl, isopropyl, tert-butyl or benzyl.
  • R1 is methyl;
  • R2 is benzyl or phenethyl; and
  • R3 is methyl, ethyl, isopropyl or t-butyl.
  • R2 is in the R configuration.
  • R2 is in the S configuration.
  • R1 is methyl
  • R2 is benzyl
  • R2 is phenethyl
  • R3 is isopropyl
  • R3 is a tert-butyl group.
  • R1 is methyl;
  • R2 is benzyl or phenethyl; and
  • R3 is ethyl, isopropyl or t-butyl.
  • R1 is methyl; R2 is benzyl or phenethyl; and R3 is ethyl.
  • R1 is methyl; R2 is benzyl or phenethyl; and R3 is isopropyl.
  • R1 is methyl; R2 is benzyl or phenethyl; and R3 is tert-butyl.
  • R1 is methyl; R2 is benzyl; and R3 is ethyl, isopropyl or t-butyl.
  • R1 is methyl; R2 is phenethyl; and R3 is ethyl, isopropyl or t-butyl.
  • R2 is in the S configuration.
  • R1 is methyl
  • R2 is selected from C2-4 alkyl, such as ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl.
  • R2 is selected from C3-4 alkyl, such as n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl.
  • R2 is isopropyl
  • R2 is a sec-butyl group.
  • R3 is methyl, ethyl, tert-butyl or benzyl.
  • R3 is methyl, ethyl or tert-butyl.
  • R3 is methyl
  • R3 is a tert-butyl group.
  • R3 is benzyl
  • R1 is methyl
  • R2 is selected from C2-4 alkyl
  • R3 is methyl, ethyl, tert-butyl or benzyl.
  • R1 is methyl
  • R2 is selected from C3-4 alkyl
  • R3 is methyl, ethyl, tert-butyl or benzyl.
  • R1 is methyl
  • R2 is isopropyl or sec-butyl
  • R3 is methyl, ethyl, tert-butyl or benzyl.
  • R2 is in the R configuration.
  • R2 is in the S configuration.
  • R1 is methyl
  • R2 is isopropyl
  • R3 is methyl, ethyl or tert-butyl.
  • R1 is methyl
  • R2 is sec-butyl
  • R3 is methyl, ethyl or tert-butyl.
  • R1 is methyl
  • R2 is isopropyl or sec-butyl
  • R3 is methyl
  • R1 is methyl
  • R2 is isopropyl or sec-butyl
  • R3 is ethyl
  • R1 is methyl
  • R2 is isopropyl or sec-butyl
  • R3 is tert-butyl
  • R2 is in the R configuration.
  • R2 is in the S configuration.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined above, a pharmaceutically acceptable salt thereof or a solvate thereof; preferably, the composition further comprises one or A wide variety of pharmaceutically acceptable carriers and/or excipients.
  • the carrier and/or excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate.
  • a partial glyceride mixture of saturated plant fatty acids, water, salt or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyethylene Pyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, polyethylene-polyoxypropylene block polymer and lanolin.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • the pharmaceutical composition may also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal or pulmonary administration.
  • the pharmaceutical composition can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule, etc.; or an oral liquid preparation such as an oral solution or an oral suspension. , syrup, and the like.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • the pharmaceutical composition can be formulated into an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • the pharmaceutical composition can be formulated as a suppository or the like.
  • the pharmaceutical composition can be formulated as an inhalant or a spray.
  • the present invention provides the use of any of the compounds as defined above, a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the manufacture of a medicament for preventing and/or treating a nerve in a subject Degenerative diseases, neuropathy caused by physical damage, or neuropathy caused by related diseases;
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis of the brain;
  • the physical damage is selected from the group consisting of thermal damage, cold damage, mechanical damage and electrical damage;
  • the related disease is selected from the group consisting of acquired immunodeficiency, diabetes, and stroke;
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate; wherein, particularly preferred The subjects are human.
  • the present invention provides a method of preventing and/or treating a neurodegenerative disease in a subject, a neuropathy caused by physical damage, or a neuropathy caused by a related disease, which includes receiving the need
  • the test subject is administered a therapeutically and/or prophylactically effective amount of any of the compounds as defined above, a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition as defined above.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis of the brain;
  • the physical damage is selected from the group consisting of thermal damage, cold damage, mechanical damage and electrical damage;
  • the related disease is selected from the group consisting of acquired immunodeficiency, diabetes, and stroke;
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate;
  • a mammal such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate;
  • the particularly preferred subjects are humans.
  • the present invention provides a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, as defined above, for use in the prevention and/or treatment of a neurodegenerative disease, physical damage caused by a subject Neuropathy or neuropathy caused by related diseases;
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis of the brain;
  • the physical damage is selected from the group consisting of thermal damage, cold damage, mechanical damage and electrical damage;
  • the related disease is selected from the group consisting of acquired immunodeficiency, diabetes, and stroke;
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate; wherein, particularly preferred The subjects are human.
  • the present invention also provides a process for the preparation of a compound of the formula (I) as shown in the following scheme:
  • R1, R2, and R3 are as defined above.
  • L-cysteine is dissolved in a polar solvent (for example, water), the pH is adjusted to 7, and ethylene oxide is added dropwise at 0 to 10 ° C to obtain a compound 1.
  • a polar solvent for example, water
  • the compound of the present invention as shown in the general formula (I) has one or more of the following advantageous effects as compared with the prior art:
  • the blood-brain barrier passage ability of the compound of the present invention is superior to that of the existing thiazinamide derivative.
  • Reagents Reaction materials not given the synthesis process are commercially available, and the reaction solvents are all standardized.
  • the melting point of the compound was determined by a RY-1 type melting point apparatus; 1 H NMR was measured by an ARX-400 NMR meter; and the mass spectrum was measured by a VG-Zab Spec MS instrument.
  • the starting material 2 was D-leucine isopropyl ester hydrochloride to obtain (3R)-4-[(4-methylphenylsulfonyl)]-1,4-thiazide-3.
  • the product was white crystals (yield: 91.5%).
  • Specific optical rotation [ ⁇ ] D 24.5 -103.7 °.
  • the starting material 2 was L-isoleucine ethyl ester hydrochloride (1.45 g) to obtain (2S,3R)-ethyl-3-methyl-2((R)-4-toluene. Sulfonylthiazol-3-carbamoyl) valerate, product as a white solid (yield 65%).
  • the starting material 2 was 1.44 g (7 mmol) of L-valine phenylmethyl ester as a white solid product (1.64 g, yield 67%).
  • the starting material 2 was 1.55 g (7 mmol) of tert-butyl L-phenylalanine.
  • the product was obtained as a white solid (1.72 g, yield 68%).
  • the neurotrophic activity of the compounds of the invention can be demonstrated in a multi-in vitro biological model, such as a serum-free culture model of chicken embryo dorsal root ganglia in vitro.
  • Table 1 shows the scores of the growth of chick embryo dorsal root ganglion at different doses, which is the average score of 5 ganglia.
  • the neurotrophic activity of the compound of the present invention is superior to that of Compound 5, and is superior to or comparable to that of Compound 6, for example, the neurotrophic activity of Compound 20 at a dose of 1 pM and 100 pM Compared to compound 6, it was increased by 25% and 30%, respectively.
  • R1 has a significant effect on the neurotrophic activity of the compound.
  • R2 and R3 of compound 6 and compound 28 are respectively the same, R1 of compound 28 is an ethyl group, and R1 of compound 6 is a methyl group.
  • the neurotrophic activity of Compound 28 was increased by 19% and 16%, respectively, over the neurotrophic activity of Compound 6 at doses of 1 pM and 100 pM, respectively. It can be seen that as the number of R1 carbon atoms increases, the neurotrophic activity of the thiazolamide derivative is improved.
  • R2 also has a significant effect on the neurotrophic activity of the compound.
  • compounds 24, 25, and 26 are the same as R1 and R3 of compound 6, respectively, R2 of compound 24 is a benzyl group, R2 of compounds 25 and 26 is a phenethyl group, and R2 of compound 6 is an isobutyl group.
  • the neurotrophic activities of compounds 24, 25, and 26 were increased by 4.8-12.5% and 5.1-9.8%, respectively, compared to compound 6. This indicates that as the volume and/or hydrophobicity of R2 increases, the neurotrophic activity of the thiazolamide derivative increases.
  • CMC-Na sodium carboxymethyl cellulose
  • mice Twenty-eight mice that had been acclimated to the laboratory environment for one week were divided into groups according to their body weight, and 0.7% CMC-Na or each compound was intragastrically administered once a day for 3 days.
  • the specific groups are as follows:
  • Cerebral ischemia model group 12 rats were intragastrically administered with 0.7% CMC-Na solution;
  • the drug-administered group 12 rats were intragastrically administered at a dose of 0.2 ml/10 g, respectively, and the dose of each compound was 30 mg/kg.
  • mice 2.3.1 bilateral common carotid artery ligation in mice: 1 hour after the last administration, the eyelids of the mice were bled and blood pressure (about 30% of the total blood volume of the mice), and then the upper back position was fixed on the surgical plate. The neck is open at the center, the common carotid artery is bluntly removed, and 2 lines on each side are ligated separately. When the third line is ligated, the time is started. Then, the common carotid artery is cut in the middle of the two lines, and the incision is made. The surgical group only stripped the common carotid artery without ligation.
  • the mouse brain was taken, weighed, and 15% brain homogenate was prepared with NS.
  • 1.2 ml was taken in a 37 ° C water bath for 1 h (every 10 min shock), and then added with 20% trichloroacetic acid 0.6 ml, mixed and placed for 10 min. After centrifugation at 2000 rpm for 10 min, 1.2 ml of the supernatant was taken, 0.6 ml of 0.67% TBA was added, and the mixture was cooled in a boiling water bath for 10 min, and the OD value at a wavelength of 532 nm was measured.
  • the compound of the present invention is superior to Compound 5 and/or Compound 6 in protecting against incomplete global cerebral ischemia in mice.
  • the neurological deficit scores of the mice in the groups 8, 15, 23, and 28 were reduced by about 15%, 8%, 13%, and 10%, respectively, compared with the compound 6 group; the mice of the compound groups 9, 13, 18, and 22;
  • the neurological defect score was reduced by about 35%, 32%, 27%, and 15%, respectively, compared to the compound 5 group. Therefore, the in vivo efficacy of the compound of the present invention against stroke in mice has been significantly improved as compared with the existing compounds.
  • MDCK-MDR1 cells are monolayer cells with high expression of P-gp transporter after transfection of MDR1 gene in MDCK (canine kidney epithelial cells). Due to the compactness of monolayer cells and high expression of drug efflux proteins, MDCK-MDR1 cells are highly expressed. Similar to the structure of the blood-brain barrier (BBB), it is currently used as one of the models for evaluating BBB permeability.
  • the present invention uses MDCK-MDR1 cells to study the membrane permeability of the compound of the present invention, and initially evaluates its ability to permeate BBB.
  • Culture medium preparation Dulbecco's modified eagle medium (DMEM) with 10% fetal bovine serum (FBS), 1% glutamine, 100 U ⁇ mL-1 penicillin and streptomycin double-resistance solution, 1% non-essential amino acid, genetic mold (G418) 1.2 mg ⁇ L-1.
  • HBSS Hank's balanced salt solution
  • HEPES tetrahydroxyethyl piperazine ethanesulfonic acid
  • the frozen MDCK-MDR1 cells were thawed in a 37 ° C water bath.
  • the resuscitation cells were added to DMEM medium containing 10% FBS, and cultured in an incubator at 37 ° C, 5% CO 2 , and a relative humidity of 90%, and the medium was changed every other day.
  • the digest was mixed with 0.25% trypsin-EDTA (0.2%), digested at 37 ° C, subcultured at a certain ratio, and the cell number used for the experiment was 40-60 generations.
  • the cells reached 80% confluence, and after the digestion, the cells were suspended in complete medium, and inoculated onto Millicell plates at 1 ⁇ 10 6 ⁇ mL -1 .
  • the culture medium was changed once every 2 days, and the liquid was changed every 1 day after 1 week. After 5 days of incubation, the resistance value reached Pingtai (>200 ⁇ cm 2 ), which can be used for transport experiments.
  • the electrode was immersed in DMEM culture solution for 24 hours, taken out and immersed in 70% alcohol for 15 minutes, then placed at room temperature and allowed to dry naturally, and then placed in sterile DMEM medium for 15 min.
  • the two ends of the electrode were sequentially inserted into the upper and lower cells of each well of a 24-well Millicell culture plate to measure the resistance value. Each hole was measured three times at any point, the resistance value was recorded, and the resistance value of the blank hole was measured, and the transmembrane resistance was calculated according to the following formula. Value (TEER).
  • R t is the measured resistance value
  • R 0 is the blank hole resistance value
  • S is the effective membrane area
  • Rhodamine 123 (Rho-123) was used as a positive control compound, and the compound was diluted to 5 ⁇ mol ⁇ L -1 with HBSS. The medium in each well was discarded before the experiment, and washed twice with HBSS at 37 ° C, then Incubate in a 37 ° C incubator, add Rho-123 in the upper pool, add HBSS in the lower pool, incubate in a constant temperature shaker, collect the solution in the lower pool at each time point (0 min, 30 min, 90 min, 120 min), store at -20 °C . The amount of Rho-123 permeation in the lower cell was measured by a fluorescence spectrophotometer. The emission wavelength was set to 430 nm, and the excitation wavelength was set to 530 nm. The P app value of Rho-123 in this experiment is consistent with the literature reports.
  • mice inoculated with cells at 37°CHBSS for a suitable time before the test, slightly Flush the Millicell to remove adherence to the cell surface.
  • Permeability from cavity surface to basal plane 0.35 mL of drug-containing HBSS was added to the top side (AP), and 1.2 mL of blank HBSS was added to the bottom side (BL).
  • the cells were shaken at 50 ° ⁇ min -1 at 37 ° C, and 50 ⁇ L were sampled at 0, 30, 90, and 120 min, respectively, and the same volume of blank HBSS was added. Repeat 3 wells for each concentration.
  • the sample taken is precisely added to the internal standard solution 50 ⁇ L, ethyl acetate 350 ⁇ L, shake and mix, centrifuge 12000rmp, 5min. 300 ⁇ L of the supernatant was taken, evaporated, reconstituted with 50 ⁇ L of acetonitrile, and 10 ⁇ L of the solution was injected for measurement.
  • Permeability from the basal plane to the luminal surface the drug is added to the bottom side (BL), and the top side (AP) is added to the blank HBSS.
  • the following steps are the same as the permeability test of the cavity surface to the basal plane.
  • the apparent permeability coefficient (P app ) of the drug reflects the ability of the drug to pass through the monolayer and the rate and extent of drug absorption. It can be calculated by:
  • Q is the amount of drug permeated during the t period
  • A is the cell surface area, which is the area of the support membrane (0.6 cm 2 ) in this model
  • C 0 is the initial concentration.
  • the unit of P app is expressed in centimeters per second (cm ⁇ s -1 ).
  • Detection was performed using LC/MS, and each sample concentration was quantified using its standard curve (50 nM - 10000 nM).
  • the compounds of the present invention have better blood-brain barrier passage ability than Compound 5 and are superior to Compound 6 or similar to Compound 6.
  • the P app values of the compounds 7, 23, and 28 were increased by 7% or more as compared with the compound 6. The results indicate that the compounds of the present invention have excellent blood-brain barrier-passing ability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

本发明属于医药技术领域，特别地，本发明涉及噻嗪酰胺衍生物化合物、其药物上可接受的盐或其溶剂化物，含有所述化合物、其药物上可接受的盐或其溶剂化物的药物组合物，制备所述化合物、其药物上可接受的盐或其溶剂化物的方法，以及所述化合物、其药物上可接受的盐或其溶剂化物的用途，例如，本发明的化合物、其药物上可接受的盐或其溶剂化物可用于预防和/或治疗神经退行性疾病和由物理损伤或相关疾病引起的神经病变疾病。

Description

噻嗪酰胺衍生物及其用途 技术领域
本发明属于医药技术领域，特别地，本发明涉及噻嗪酰胺衍生物化合物、其药物上可接受的盐或其溶剂化物，含有所述化合物、其药物上可接受的盐或其溶剂化物的药物组合物，制备所述化合物、其药物上可接受的盐或其溶剂化物的方法，以及所述化合物、其药物上可接受的盐或其溶剂化物的用途，例如，本发明的化合物、其药物上可接受的盐或其溶剂化物可用于预防和/或治疗神经退行性疾病和由物理损伤或相关疾病引起的神经病变。
背景技术
神经退行性疾病是一类由神经系统进行性病变所引起的疾病，包括阿尔茨海默氏病(Alzheimer’s disease)、帕金森氏病(Parkinson’s disease)、亨廷顿氏病(Huntington’s disease)、肌萎缩性侧索硬化(ALS)等。由于这类疾病的发生原因复杂,致病机制不很明确,目前尚没有找到有效的治疗药物。
FK506结合蛋白(FKBPs)由于其能与免疫抑制剂FK506(tacrolimus)结合而得名，是FK506产生免疫抑制作用的重要介质，其生理功能仍未完全阐明。Steiner J.P.等人于1992年发现FKBPs在脑和外周的浓度远大于其在免疫组织中的浓度，这就让人猜想FKBPs与神经系统可能存在某种关系。Dawson等人的研究结果表明，FK506能够阻断谷氨酸激活NMDA受体(N-methyl-D-aspartic acid receptor)引起的神经兴奋性毒性。据推测，这可能是由于FKBPs抑制了钙依赖磷酸酶(Calcineurin)后，增加了一氧化氮合成酶(NOS)的磷酸化水平，抑制了NOS的催化活性，避免了神经元受到NO的损伤。此外，研究发现，与神经元的增长密切相关的蛋白——GAP43(growth associated protein-43)同时也是钙依赖磷酸酶的底物，面神经和坐骨神经损伤的神经再生总伴有明显的GAP43的mRNA水平增加，而同时， FKBPs的mRNA水平也相应提高。这些研究结果都表明，FKBPs与神经生长可能存在一定的关系。上述结果最终促使人们从FKBPs的配体中找到了可促神经生长的有机小分子化合物，而FKBPs也因此被称为神经亲免素。
在这种思想的指导下，1994年，Lyons等人研究发现，免疫抑制剂FK506在体外有显著的促神经生长活性，开创了有机小分子神经生长促进剂研究的先河。虽然FKBP家族配体促神经生长和保护的机理目前尚未完全清楚，但越来越多的研究表明，FKBPs参与介导了这一过程。使用体外试验(例如鸡胚背根神经生长试验、PC12细胞分化试验以及神经细胞株氧化损伤试验等)和多种动物模型(例如大鼠外周围坐骨神经损伤模型、糖尿病鼠外周神经变性病模型、帕金森氏症动物模型和早老性痴呆症动物模型等)进行评价，结果表明，一些基于FKBPs结构设计和合成的化合物具有显著的促神经生长和保护功能,这些化合物中的典型代表是Guilford Pharmaceuticals Inc.的GPI1485。该公司将GPI1485作为治疗帕金森氏症及脑卒中的防治药，已完成了II期临床研究，III期临床也正在进行之中。与此同时，大量的高活性化合物也正不断涌现，使FKBPs成为神经退行性疾病防治药物的重要靶标。
中国发明专利ZL01142744.2(取代六元氮杂环类化合物及其作为神经调节剂的用途)披露了一类全新结构的具有促神经再生的FKBP配体，其中化合物4是最优化合物。但研究发现其血脑屏障通过能力较差，且由于熔点较低，常温下呈油状，不适合用于制备神经退行性疾病防治药物的用途。中国发明专利CN102675244公开了其优化的化合物，但其促神经纤维生长活性和体内药效有进一步提高的空间。
发明内容
在本申请的说明书和权利要求书中，化合物都是依据化学结构式而命名的，如果表示同一化合物时化合物的命名与化学结构式不符，以化学结构式或化学反应式为准。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具 有本领域技术人员所通常理解的含义。并且，本文中所涉及的实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
如本文中使用的，术语“噻嗪”是指含有四个环碳原子、一个环氮原子和一个环硫原子的六元环状结构，包括但不限于1,3-噻嗪、1,4-噻嗪、二氢-1,3-噻嗪、二氢-1,4-噻嗪、四氢-1,3-噻嗪、四氢-1,4-噻嗪等。术语“噻嗪酰胺”是指被酰胺基团所取代的噻嗪结构。
本发明所述的“C1-4烷基”是指直链或支链的含有1-4个碳原子的烷基，包括但不限于C1-2烷基、C1-3烷基、C2-4烷基，例如：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基等。
本发明所述的“C1-4烷氧基”是指C1-4烷基通过氧原子与其他结构相连接的基团，包括但不限于C1-2烷氧基、C1-3烷氧基、C2-4烷氧基，例如：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、异丁氧基等。
本发明所述的“药学上可接受的盐”包括但不限于无机酸盐例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐，和有机酸盐，例如乙酸盐、丙酸盐、丁酸盐、草酸盐、三甲乙酸盐、乙二酸盐、藻酸盐、柠檬酸盐、苦味酸盐、葡糖酸盐、酒石酸盐、马来酸盐、甲磺酸盐、琥珀酸盐、双羟萘酸盐等。
本发明化合物的“溶剂化物”是指本发明化合物与溶剂分子缔合形成的物质。所述溶剂可以是有机溶剂(例如甲醇、乙醇、丙醇、乙腈等)、水等。例如本发明式(I)化合物可以与乙醇形成乙醇化物，与水形成水合物。
本发明所述的“神经退行性疾病”是指由神经系统进行性病变所引起的疾病，包括但不限于阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化。
本发明所述的“物理损伤”包括但不限于热损伤、冷损伤、机械损伤和电损伤。
本发明所述的“由相关疾病引起的神经病变”包括但不限于获得性 免疫缺陷引起的神经病变、糖尿病引起的神经病变和中风引起的神经病变。
本发明所述的“有效量”是指足以获得或至少部分获得期望的效果的量。例如，预防疾病(例如神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变)有效量是指，足以预防、阻止或延迟疾病(例如神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变)的发生的量；治疗疾病有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄、体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
本发明所述的“约”应该被本领域技术人员理解，并将随其所用之处的上下文而有一定程度的变化。如果根据术语应用的上下文，对于本领域技术人员而言，其使用不是清楚的，那么“约”的意思是不超过所述特定数值或范围的正负10％。
本发明人通过深入的研究和创造性的劳动，得到了一种噻嗪酰胺衍生物。本发明人发现，通过对如式(I)所示的噻嗪酰胺衍生物中的R1、R2和/或R3基团进行合适的选择，可以使得到的化合物在神经营养活性、对小鼠脑卒中的体内药效和/或血脑屏障通过能力等方面相对于现有噻嗪酰胺衍生物得到提高。由此提供了下述发明：
在一个方面，本发明提供了如通式(I)所示的化合物、其药物上可接受的盐或其溶剂化物，
Figure PCTCN2016087433-appb-000001
其中，
R1选自C1-4烷基；
R2、R3分别独立地选自C1-4烷基，任选地，所述C1-4烷基被苯基取代；
任选地，所述苯基被选自C1-4烷基、C1-4烷氧基、羟基、氨基和羧基的取代基取代；
在一个优选的实施方案中，R2为R构型。
在一个优选的实施方案中，R2为S构型。
在一个优选的实施方案中，R1选自C2-3烷基，例如乙基、正丙基、异丙基。
在一个更为优选的实施方案中，R1为乙基。
在一个优选的实施方案中，R2、R3分别独立地选自C1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基。
在一个优选的实施方案中，R2选自C3-4烷基，例如正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基。
在一个优选的实施方案中，R2为异丁基。
在一个优选的实施方案中，R3选自C3-4烷基，例如正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基。
在一个优选的实施方案中，R3选自C1-3烷基，例如甲基、乙基、正丙基、异丙基。
在一个优选的实施方案中，R3为异丙基。
在一个优选的实施方案中，R2为R构型。
在一个优选的实施方案中，R2为S构型。
在一个优选的实施方案中，R2选自C1-4烷基(例如C1-2烷基)，并且所述C1-4烷基(例如C1-2烷基)被苯基取代，任选地，所述苯基被选自C1-4烷基、C1-4烷氧基、羟基、氨基和羧基的取代基取代。
在一个优选的实施方案中，R2为苯甲基。
在一个优选的实施方案中，R2为苯乙基。
在一个优选的实施方案中，R1为甲基。
在一个优选的实施方案中，R3为甲基、乙基、异丙基、叔丁基或苯甲基。
在一个优选的实施方案中，R3为甲基、乙基、异丙基或叔丁基。
在一个优选的实施方案中，R3为甲基。
在一个优选的实施方案中，R3为乙基。
在一个优选的实施方案中，R3为异丙基。
在一个优选的实施方案中，R3为叔丁基。
在一个优选的实施方案中，R3为苯甲基。
在一个更为优选的实施方案中，R1为甲基；R2为苯甲基或苯乙基；R3为甲基、乙基、异丙基、叔丁基或苯甲基。
在一个更为优选的实施方案中，R1为甲基；R2为苯甲基或苯乙基；R3为甲基、乙基、异丙基或叔丁基。
在一个优选的实施方案中，R2为R构型。
在一个优选的实施方案中，R2为S构型。
在一个优选的实施方案中，R1为甲基。
在一个优选的实施方案中，R2为苯甲基。
在一个优选的实施方案中，R2为苯乙基。
在一个优选的实施方案中，R3为乙基。
在一个优选的实施方案中，R3为异丙基。
在一个优选的实施方案中，R3为叔丁基。
在一个更为优选的实施方案中，R1为甲基；R2为苯甲基或苯乙基；R3为乙基、异丙基或叔丁基。
在一个优选的实施方案中，R1为甲基；R2为苯甲基或苯乙基；R3为乙基。
在一个优选的实施方案中，R1为甲基；R2为苯甲基或苯乙基；R3为异丙基。
在一个优选的实施方案中，R1为甲基；R2为苯甲基或苯乙基；R3为叔丁基。
在一个优选的实施方案中，R1为甲基；R2为苯甲基；R3为乙基、异丙基或叔丁基。
在一个优选的实施方案中，R1为甲基；R2为苯乙基；R3为乙基、异丙基或叔丁基。
在一个优选的实施方案中，R2为R构型。
在一个优选的实施方案中，R2为S构型。
在一个优选的实施方案中，R1为甲基。
在一个优选的实施方案中，R2选自C2-4烷基，例如乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基。
在一个优选的实施方案中，R2选自C3-4烷基，例如正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基。
在一个优选的实施方案中，R2为异丙基。
在一个优选的实施方案中，R2为仲丁基。
在一个优选的实施方案中，R3为甲基、乙基、叔丁基或苯甲基。
在一个优选的实施方案中，R3为甲基、乙基或叔丁基。
在一个优选的实施方案中，R3为甲基。
在一个优选的实施方案中，R3为乙基。
在一个优选的实施方案中，R3为叔丁基。
在一个优选的实施方案中，R3为苯甲基。
在一个更为优选的实施方案中，R1为甲基，R2选自C2-4烷基；R3为甲基、乙基、叔丁基或苯甲基。
在一个更为优选的实施方案中，R1为甲基，R2选自C3-4烷基；R3为甲基、乙基、叔丁基或苯甲基。
在一个更为优选的实施方案中，R1为甲基，R2为异丙基或仲丁基；R3为甲基、乙基、叔丁基或苯甲基。
在一个优选的实施方案中，R2为R构型。
在一个优选的实施方案中，R2为S构型。
在一个优选的实施方案中，R1为甲基，R2为异丙基，R3为甲基、乙基或叔丁基。
在一个优选的实施方案中，R1为甲基，R2为仲丁基，R3为甲基、乙基或叔丁基。
在一个优选的实施方案中，R1为甲基，R2为异丙基或仲丁基，R3为甲基。
在一个优选的实施方案中，R1为甲基，R2为异丙基或仲丁基，R3为乙基。
在一个优选的实施方案中，R1为甲基，R2为异丙基或仲丁基，R3为叔丁基。
在一个优选的实施方案中，R2为R构型。
在一个优选的实施方案中，R2为S构型。
本发明的部分化合物如下表所示。
本发明的部分化合物
Figure PCTCN2016087433-appb-000002
Figure PCTCN2016087433-appb-000003
Figure PCTCN2016087433-appb-000004
Figure PCTCN2016087433-appb-000005
在另一方面，本发明提供了一种药物组合物，其含有如上述定义的任一种化合物、其药物上可接受的盐或其溶剂化物；优选地，所述组合物还含有一种或多种药学上可接受的载体和/或赋形剂。所述载体和/或赋形剂包括但不限于:离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血清蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，聚乙烯-聚氧丙烯嵌段聚合物和羊毛脂。
所述药物组合物可以制成药学上可接受的任一剂型。所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时， 所述药物组合物可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。
在另一方面，本发明提供了如上定义的任一种化合物、其药物上可接受的盐或其溶剂化物用于制备药物的用途，所述药物用于预防和/或治疗受试者的神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变；
优选地，所述神经退行性疾病选自阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化；
优选地，所述物理损伤选自热损伤、冷损伤、机械损伤和电损伤；
优选地，所述相关疾病选自获得性免疫缺陷、糖尿病和中风；
优选地，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
在另一方面，本发明提供了一种预防和/或治疗受试者的神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的如上定义的任一种化合物、其药物上可接受的盐或其溶剂化物，或如上定义的药物组合物。
优选地，所述神经退行性疾病选自阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化；
优选地，所述物理损伤选自热损伤、冷损伤、机械损伤和电损伤；
优选地，所述相关疾病选自获得性免疫缺陷、糖尿病和中风；
优选地，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其 中，特别优选的受试者为人。
在另一方面，本发明提供了如上定义的任一种化合物、其药物上可接受的盐或其溶剂化物，其用于预防和/或治疗受试者的神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变；
优选地，所述神经退行性疾病选自阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化；
优选地，所述物理损伤选自热损伤、冷损伤、机械损伤和电损伤；
优选地，所述相关疾病选自获得性免疫缺陷、糖尿病和中风；
优选地，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
本发明还提供了如通式(I)所示的化合物的制备方法，如下述工艺路线所示：
Figure PCTCN2016087433-appb-000006
其中，R1、R2、R3的定义如前文所述。
所述制备方法中，各缩写所代表的物质如下：DCC：二环己基碳二亚胺；DMAP：4-二甲氨基吡啶；DCM：二氯甲烷；THF：四氢呋喃。
所述制备方法的示例性步骤如下：
(1)将L-半胱氨酸溶于极性溶剂(例如水)中，调节pH值至7，在0-10℃下滴入环氧乙烷，反应得到化合物1。
(2)将化合物1溶于浓盐酸，在90-95℃下反应得到化合物2。
(3)将化合物2溶于水中，滴加碱性溶液(例如碳酸氢钠水溶液)。经萃取、干燥和浓缩，得到有机相。加入极性溶剂(例如甲醇)，室温下反应，得到化合物3。
(4)将化合物3溶于极性溶剂(例如THF)中，加入碱性溶液(例如碳酸氢钠水溶液)和原料1，室温下反应，得到化合物4；所述原料1优选如上述路线中所示的R1取代的苯磺酰氯。
(5)将化合物4和原料2在失水剂(例如DCC)、催化剂(例如DMAP)和碱(例如三乙胺)存在的条件下反应，得到目标产物；所述原料2优选如上述路线中所示的含有R2、R3基团的氨基酸酯或其盐，例如其盐酸盐。
发明的有益效果
与现有技术相比，本发明的如通式(I)所示的化合物具有以下有益效果中的一个或多个：
(1)本发明化合物的神经营养活性与现有的噻嗪酰胺衍生物相比得到提高；
(2)本发明化合物对小鼠脑卒中的体内药效优于现有的噻嗪酰胺衍生物；
(3)本发明化合物的血脑屏障通过能力优于现有的噻嗪酰胺衍生物。
本发明化合物可用于预防和/或治疗神经退行性疾病，例如阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化，以及由物理损伤或相关疾病，例如获得性免疫缺陷、糖尿病和中风等引起的神经病变。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限 定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
试剂：未给出合成过程的反应原料均为市售，反应用溶剂都经标准化预处理。
仪器：化合物熔点由RY-1型熔点仪测定；1H NMR由ARX-400 NMR仪测定；质谱由VG-ZabSpec MS仪测定。
实施例1 2-羟乙基半胱氨酸(化合物1)的合成
在2000ml的圆底烧瓶中加入109g(0.9mol)L-半胱氨酸，用1000ml蒸馏水溶解，冰浴冷却至10℃，加入24ml 1M的NaOH水溶液，中和至pH约为7。在10℃下移取提前冷却的环氧乙烷100ml，加毕，10℃下恒温反应1小时，之后，室温反应1.5小时。
用乙醚萃取(400ml×4)以除去未反应的环氧乙烷。在低于60℃的条件下，蒸馏除去体系中的水层，得黄色固体，用混合溶剂(水:乙醇＝85ml:350ml)重结晶，过滤，用95wt％的乙醇充分洗涤，得到产物，为白色鳞片状固体(约100g，产率67.5％)。
m.p.195-196℃.1H-NMR(400MHz,D2O)δ:3.96131(dd,1H,J1＝4.272Hz,J2＝7.816Hz),3.80680-3.77293(m,2H),3.17887(dd,1H,J1＝4.268Hz,J2＝14.814Hz),3.08224(dd,1H,J1＝7.480Hz,J2＝14.814Hz),2.80103(t,2H,J＝6.036Hz).
实施例2 2-氯乙基半胱氨酸盐酸盐(化合物2)的合成
在1000ml圆底烧瓶中加入44g 2-羟乙基半胱氨酸，溶于600ml浓盐酸中，加热至90-95℃，搅拌下反应7小时。反应完毕，在冰箱中冷藏静置过夜，体系中析出大量针状固体。抽滤去除溶剂，所得固体自然干燥，得到产物，为灰白色固体(约40g，产率>70％)。
m.p.185-186℃.1H-NMR(400MHz,D2O)δ:4.30477-4.26952(m,1H),3.81913-3.78409(m,2H),3.25903(dd,1H,J1＝4.444Hz, J2＝14.984Hz),3.18877(dd,1H,J1＝7.352Hz,J2＝15.072Hz),3.04410-3.00625(m,2H).
实施例3 L-1,4-噻嗪-3-羧酸盐酸盐(化合物3)的合成
取20g 2-氯乙基半胱氨酸盐酸盐，溶于水中，冰浴下滴加含7.2gNaHCO3的水溶液。加毕，充分搅拌溶液以中和，用乙酸乙酯萃取3次，合并有机相，Na2SO4干燥。减压蒸除溶剂，加入400ml无水甲醇，室温下搅拌反应5天。减压蒸除溶剂，用混合溶剂(甲醇-乙醚)重结晶，得到近白色固体(约6g)。比旋光度[α]D 24.5＝-27.1°(H2O)。
m.p.>230℃.1H-NMR(400MHz,CDCl3)δ:3.67672-3.64308(m,1H),3.55044-3.50108(m,1H),3.16622-3.08322(m,1H),2.92045-2.90326(m,1H),2.83678-2.75406(m,2H),2.61390-2.59272(m,1H).MS(FAB)m/z:148.
实施例4 L-4-对甲苯磺酰-1,4-噻嗪-3-羧酸(化合物4)的合成
将2.3g(15.7mmol)L-1,4-噻嗪-3-羧酸盐酸盐溶于17mlTHF中，加入77ml 10wt％NaHCO3水溶液，滴加溶有2.90g(15.2mmol)对甲苯磺酰氯的17ml的THF溶液，室温下搅拌19-24小时。反应完毕后加入盐酸调节pH值至1-2，用乙酸乙酯萃取(10ml×3)。取上层溶液，用无水硫酸镁干燥，抽滤，旋蒸除去溶剂，得到棕色油状物。用乙酸乙酯和环己烷的混合溶剂重结晶，得到白色晶体(4.3g，产率93.5％)。m.p.66℃(分解)。比旋光度[α]D 24.5＝-81.6°(H2O)。
1H-NMR(400MHz,CDCl3)δ:7.68268-7.66234(d,2H),7.30642-7.26434(m,2H),5.12406-5.10728(m,1H),4.03322-3.99196(m,1H),3.46642-3.40848(m,1H),3.02301-2.99292(m,2H),2.76875-2.73724(m,1H),2.42688(s,3H),2.38062(s,1H).MS(FAB)m/z:301.2.
实施例5 (3R)-4-[(4-甲基苯磺酰基)]-1,4-噻嗪-3-羧酸-L-亮氨酸乙酯(化合物5,ZL01142744.2)的合成
将4.2g(0.14mol)L-4-对甲苯磺酰-1,4-噻嗪-3-羧酸、3.0g(0.017mmol)L-亮氨酸乙酯盐酸盐(原料2)、3.2g(0.014mol)DCC和1.7g(0.014mol)DMAP溶于200ml的二氯甲烷中，加入6ml(0.042mol)的三乙胺，室温反应24小时。过滤除去固体，蒸馏除去溶剂，以适量的乙酸乙酯溶解残留物。过滤除去不溶物，加入乙酸乙酯稀释，溶液依次以10％NaHCO3溶液、饱和NaCl溶液洗涤，无水Na2SO4干燥。除去干燥剂，蒸去部分乙酸乙酯，闪色谱柱分离(洗脱剂为DCM:CH3Cl＝1:1)，得油状物4.0g。比旋光度[α]D 24.5＝-110.1°(c2.00,DCM)。
1H-NMR(400M Hz,CDCl3)δ:7.77237-7.74077(m,2H),7.36382(d,2H,J＝7.988Hz),6.74090(d,1H,J＝9.244Hz),4.80098-4.77466(m,1H),4.68244-4.58898(m,1H),4.28174-4.15708(m,3H),3.53789-3.28674(m,1H),3.13092(d,1H,J＝13.676),2.56954-2.42247(m,5H),2.24620-2.20545(m,1H),1.66352-1.53450(m,3H),1.30702-1.26745(m,3H),0.96159-0.91891(m,6H).MS(EI)m/z:443.4,397.2,369.2,263.1,256.1,155.0,139.2,101.1.
实施例6 (3R)-4-[(4-甲基苯磺酰基)]-1,4-噻嗪-3-羧酸-D-亮氨酸异丙酯(化合物6，CN102675244)的合成
按实施例5的步骤，原料2为D-亮氨酸异丙酯盐酸盐，制得(3R)-4-[(4-甲基苯磺酰基)]-1,4-噻嗪-3-羧酸-D-亮氨酸异丙酯，产物为白色晶体(产率91.5％)。比旋光度[α]D 24.5＝-103.7°。
m.p.81-83℃.1H-NMR(400MHz,CDCl3)δ:7.76237-7.74077(d,2HJ＝8.208Hz),7.37382-7.26511(d,2H,J＝8.208Hz),6.75090(d,1H,J＝8.944Hz),5.40112(m,1H),4.79298-4.25166(m,3H),3.54989-3.53674(t,1H,J＝12.31110),3.15292-3.11800(d,1H,J＝13.676HZ),2.56054-2.46247(m,4H),2.23220-2.20345(m,1H),1.62552-1.43450(m,4H),1.26202-1.24745(m,6H),0.94659-0.93191(m,6H).MS(EI)m/z:457.3,397.2,369.2,256.2,154.7,101.1.
实施例7 (2S,3R)-乙基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)戊酸酯(化合物7)的合成
按实施例5的步骤，原料2为L-异亮氨酸乙酯盐酸酸盐(1.45g)，得(2S,3R)-乙基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)戊酸酯，产物为白色固体(产率65％)。
m.p.88-90℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.42Hz),7.37(2H,d,J＝8.41Hz),7.01(1H,d,J＝8.64Hz),4.79(1H,t,J＝2.82Hz),4.58(1H,m),4.20(3H,m),3.66(1H,t,J＝2.43Hz),3.34(1H,d,J＝13.71Hz),3.13(1H,d,J＝11.86Hz),2.56-0.93(14H,m).MS-EI(m/z):443.1669[M+H]+.
实施例8 (2S,3R)-甲基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)戊酸酯(化合物8)的合成
按实施例5的步骤，原料2为1.02g(7mmol)L-异亮氨酸甲酯，得到白色固体产物(1.52g，产率71％)。
m.p.92-94℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.42Hz),7.37(2H,d,J＝8.41Hz),7.01(1H,d,J＝8.64Hz),4.81(1H,t,J＝3.14Hz),4.58(1H,m),4.20(1H,m),3.75(3H,m),3.33(1H,t,J＝2.60Hz),3.11(1H,d,J＝11.82Hz),2.57-0.93(15H,m).MS-EI(m/z):429.1512[M+H]+.
实施例9 (2S,3R)-叔丁基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)戊酸酯(化合物9)的合成
按实施例5的步骤，原料2为1.31g(7mmol)L-异亮氨酸叔丁酯，得到白色固体产物(1.53g，产率65％)。
m.p.80-82℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.41Hz),7.37(2H,d,J＝8.40Hz),7.01(1H,d,J＝8.67Hz),4.78(1H,t,J＝3.40Hz),4.47(1H,m),4.25(1H,t,J＝5.20Hz),3.44(1H,t,J＝12.43Hz),3.13(1H,d,J＝13.72Hz),2.60-0.93(24H,m).MS-EI(m/z):471.1982[M+H]+.
实施例10 (S)-甲基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物10)的合成
按实施例5的步骤，原料2为0.91g(7mmol)L-缬氨酸甲酯，得到白色固体产物(1.26g，产率61％)。
m.p.93-95℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.43Hz),7.37(2H,d,J＝8.43Hz),7.01(1H,d,J＝8.62Hz),4.81(1H,t,J＝3.40Hz),4.58(1H,m),4.20(1H,m),3.75(3H,m),3.33(1H,t,J＝2.60Hz),3.11(1H,d,J＝11.82Hz),2.60-0.92(13H,m).MS-EI(m/z):415.1356[M+H]+.
实施例11 (S)-苯甲基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物11)的合成
按实施例5的步骤，原料2为1.44g(7mmol)L-缬氨酸苯甲酯，得到白色固体产物(1.64g，产率67％)。
m.p.85-87℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.41Hz),7.37(2H,d,J＝8.43Hz),7.34(4H,m),7.01(1H,d,J＝8.62Hz),5.20(2H,dd),4.82(1H,t,J＝3.40Hz),4.56(1H,d,J＝12.31Hz),4.19(1H,m),3.34(1H,d,J＝12.63Hz),3.14(1H,d,J＝13.76Hz),2.56-0.80(13H,m).MS-EI(m/z):491.1669[M+H]+.
实施例12 (S)-叔丁基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物12)的合成
按实施例5的步骤，原料2为1.20g(7mmol)L-缬氨酸叔丁酯，得到白色固体产物(1.65g，产率71％)。
m.p.90-92℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.42Hz),7.37(2H,d,J＝8.41Hz),7.01(1H,d,J＝8.65Hz),4.78(1H,t,J＝3.40Hz),4.44(1H,m),4.25(1H,t,J＝5.20Hz),3.36(1H,m),3.17(1H,d,J＝13.34Hz),2.59-0.89(22H,m).MS-EI(m/z):457.1825[M+H]+.
实施例13 (S)-乙基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁 酸酯(化合物13)的合成
按实施例5的步骤，原料2为1.01g(7mmol)L-缬氨酸乙酯，得到白色固体产物(1.46g，产率68％)。
m.p.87-89℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.42Hz),7.37(2H,d,J＝8.44Hz),7.01(1H,d,J＝8.64Hz),4.80(1H,t,J＝3.40Hz),4.54(1H,m),4.21(3H,m),3.48(1H,t,J＝12.31Hz),3.13(1H,d,J＝12.52Hz),2.59-0.88(16H,m).MS-EI(m/z):429.1512[M+H]+.
实施例14 (R)-甲基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物14)的合成
按实施例5的步骤，原料2为0.91g(7mmol)D-缬氨酸甲酯，得到白色固体产物(1.43g，产率69％)。
m.p.90-92℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.42Hz),7.37(2H,d,J＝8.41Hz),7.01(1H,d,J＝8.65Hz),4.80(1H,t,J＝3.40Hz),4.59(1H,m),4.24(1H,d,J＝12.52Hz),3.75(3H,m),3.44(1H,t,J＝12.33Hz),3.15(1H,d,J＝13.75Hz),2.59-0.84(13H,m).MS-EI(m/z):415.1356[M+H]+.
实施例15 (R)-叔丁基-3-甲基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物15)的合成
按实施例5的步骤，原料2为1.21g(7mmol)D-缬氨酸叔丁酯，得到白色固体产物(1.51g，产率66％)。
m.p.88-90℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.12Hz),7.36(2H,d,J＝8.41Hz),6.91(1H,d,J＝8.35Hz),4.80(1H,t,J＝3.40Hz),4.48(1H,m),4.23(1H,d,J＝12.32Hz),3.50(1H,t,J＝11.95Hz),3.13(1H,d,J＝13.74Hz),2.59-0.83(22H,m).MS-EI(m/z):457.1825[M+H]+.
实施例16 (S)-甲基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物16)的合成
按实施例5的步骤，原料2为1.25g(7mmol)L-苯丙氨酸甲酯，得到白色固体产物(1.55g，产率67％)。
m.p.85-98℃.1H-NMR(400MHz,CDCl3)δ:7.69(2H,d,J＝8.42Hz),7.30(5H,m),7.15(2H,d,J＝8.41Hz),6.86(1H,d,J＝8.62Hz),4.80(1H,t,J＝3.40Hz),4.10(1H,m),3.75(3H,m),3.29(1H,t),3.07(2H,d),2.65-0.88(8H,m).MS-EI(m/z):463.1356[M+H]+.
实施例17 (S)-乙基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物17)的合成
按实施例5的步骤，原料2为1.35g(7mmol)L-苯丙氨酸乙酯，得到白色固体产物(1.65g，产率69％)。
m.p.91-93℃.1H-NMR(400MHz,CDCl3)δ:7.69(2H,d,J＝8.42Hz),7.30(5H,m),7.16(2H,d,J＝8.41Hz),6.88(1H,d,J＝8.63Hz),4.77(2H,m),4.22(2H,m),3.89(1H,m),3.29(1H,m),3.08(2H,m),2.69-0.91(10H,m).MS-EI(m/z):477.1512[M+H]+.
实施例18 (S)-苯甲基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物18)的合成
按实施例5的步骤，原料2为1.79g(7mmol)L-苯丙氨酸苯甲酯，得到白色固体产物(1.70g，产率63％)。
m.p.88-90℃.1H-NMR(400MHz,CDCl3)δ:7.67(2H,d,J＝8.32Hz),7.41(5H,m),7.30(3H,m),7.19(2H,d,J＝8.42Hz),7.06(2H,m),6.87(1H,d,J＝8.01Hz),5.21(2H,dd,J＝3.60Hz),4.84(1H,m),4.72(1H,t,J＝3.10Hz),3.92(1H,m),3.31(1H,d,J＝12.15Hz),3.04(2H,d,J＝11.66Hz),2.75-0.94(7H,m).MS-EI(m/z):539.1669[M+H]+.
实施例19 (S)-叔丁基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物19)的合成
按实施例5的步骤，原料2为1.55g(7mmol)L-苯丙氨酸叔丁酯， 得到白色固体产物(1.72g，产率68％)。
m.p.92-94℃.1H-NMR(400MHz,CDCl3)δ:7.72(2H,d,J＝8.32Hz),7.32(2H,d,J＝8.13Hz),7.22(5H,m),6.88(1H,d,J＝8.10Hz),4.68(1H,t,J＝6.40Hz),3.96(1H,m),3.26(1H,m),3.08(2H,d,J＝12.30Hz),2.78(1H,d,J＝19.34Hz),2.57-0.94(16H,m).MS-EI(m/z):505.1825[M+H]+.
实施例20 (R)-叔丁基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物20)的合成
按实施例5的步骤，原料2为1.55g(7mmol)D-苯丙氨酸叔丁酯，得到白色固体产物(1.59g，产率63％)。
m.p.88-92℃.1H-NMR(400MHz,CDCl3)δ:7.70(2H,d,J＝8.21Hz),7.33(5H,m),7.25(2H,d,J＝8.13Hz),6.97(1H,d,J＝8.15Hz),4.79(1H,t,J＝6.40Hz),4.11(1H,m),3.38(1H,t,J＝12.30Hz),3.10(2H,m),3.07(1H,d,J＝19.36Hz),2.57-0.94(16H,m).MS-EI(m/z):505.1825[M+H]+.
实施例21 (R)-乙基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物21)的合成
按实施例5的步骤，原料2为1.35g(7mmol)D-苯丙氨酸乙酯，得到白色固体产物(1.65g，产率69％)。
m.p.86-89℃.1H-NMR(400MHz,CDCl3)δ:7.69(2H,d,J＝8.43Hz),7.33(5H,m),7.27(2H,d,J＝8.42Hz),7.13(1H,d,J＝8.31Hz),4.94(1H,m),4.80(1H,m),4.12(2H,m),3.73(2H,d,J＝12.33Hz),3.21(1H,t,J＝11.96Hz),3.10(3H,m),2.56-0.94(8H,m).MS-EI(m/z):463.1356[M+H]+.
实施例22 (S)-乙基-4-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物22)的合成
按实施例5的步骤，原料2为1.45g(7mmol)L-高苯丙氨酸乙酯，得到白色固体产物(1.64g，产率67％)。
m.p.87-89℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.44Hz),7.33(5H,m),7.25(2H,d,J＝8.12Hz),7.16(1H,d,J＝8.31Hz),4.85(1H,m)，4.62(1H,m),4.19(2H,d,J＝19.33Hz),4.02(1H,m),3.43(1H,d),3.11(1H,m),2.55-0.94(13H,m).MS-EI(m/z):491.1669[M+H]+.
实施例23 (S)-异丙基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物23)的合成
按实施例5的步骤，原料2为1.45g(7mmol)L-苯丙氨酸异丙酯，得到白色固体产物(1.65g，产率67％)。
m.p.85-87℃.1H-NMR(400MHz,CDCl3)δ:7.69(2H,d,J＝8.46Hz),7.31(5H,m),7.17(2H,d,J＝8.46Hz),6.90(1H,d,J＝8.34Hz),5.01(1H,t,J＝6.40Hz),4.74(1H,m),4.12(1H,m),4.08(1H,m)，3.28(1H,t,J＝12.3Hz),3.08(2H,d,J＝19.33Hz),2.50-0.94(13H,m).MS-EI(m/z):491.1669[M+H]+.
实施例24 (R)-异丙基-3-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丙酸酯(化合物24)的合成
按实施例5的步骤，原料2为1.45g(7mmol)D-苯丙氨酸异丙酯，得到白色固体产物(1.60g，产率65％)。
m.p.86-89℃.1H-NMR(400MHz,CDCl3)δ:7.70(2H,d,J＝8.42Hz),7.32(5H,m),7.18(2H,d,J＝8.41Hz),6.92(1H,d,J＝8.33Hz),5.01(1H,t,J＝6.40Hz),4.82(1H,m),4.11(2H,m),3.35(1H,t,J＝12.43Hz),3.09(2H,d,J＝12.12Hz),2.50-0.92(13H,m).MS-EI(m/z):491.1669[M+H]+.
实施例25 (S)-异丙基-4-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物25)的合成
按实施例5的步骤，原料2为1.55g(7mmol)L-高苯丙氨酸异丙酯，得到白色固体产物(1.67g，产率66％)。
m.p.87-89℃.1H-NMR(400MHz,CDCl3)δ:7.75(2H,d,J＝8.31Hz), 7.36(2H,d,J＝8.33Hz),7.28(5H,m),7.16(1H,d,J＝8.12Hz)，5.09(1H,t,J＝3.14Hz),4.82(1H,m),4.58(1H,m),4.12(2H,m),3.32(1H,t,J＝12.6Hz),3.13(1H,d,J＝11.86Hz),2.65-0.93(15H,m).MS-EI(m/z):505.1825[M+H]+.
实施例26 (R)-异丙基-4-苯基-2((R)-4-甲苯磺酰基噻嗪-3-氨甲酰基)丁酸酯(化合物26)的合成
按实施例5的步骤，原料2为1.55g(7mmol)D-高苯丙氨酸异丙酯，得到白色固体产物(1.62g，产率64％)。
m.p.88-90℃.1H-NMR(400MHz,CDCl3)δ:7.76(2H,d,J＝8.33Hz),7.36(2H,d,J＝8.33Hz),7.26(5H,m),7.14(1H,d,J＝8.12Hz)，5.06(1H,t,J＝3.14Hz),4.84(1H,m),4.53(1H,m),4.08(2H,m),3.31(1H,t,J＝12.6Hz),3.11(1H,d,J＝11.84Hz),2.65-0.93(15H,m).MS-EI(m/z):505.1825[M+H]+.
实施例27 L-4-对乙苯磺酰-1,4-噻嗪-3-羧酸(化合物27)的合成
按实施例4的步骤，将对甲苯磺酰氯换为对3.0g对乙基苯磺酰氯，得4.3g油状物，产率92.5％，比旋光度[α]D 24.5＝-80.2°(H2O)。
1H-NMR(400MHz,CDCl3)δ:7.68354-7.66122(d,2H),7.30423-7.26221(m,2H),5.12202-5.10518(m,1H),4.03122-3.99012(m,1H),3.46436-3.40624(m,1H),3.02103-2.99122(m,2H),2.76654-2.73502(m,1H),2.42466-2.37862(m,4H),1.86453-1.82354(t,3H).MS(FAB)m/z:315.4.
实施例28 (3R)-4-[(4-乙基苯磺酰基)]-1,4-噻嗪-3-羧酸-L-亮氨酸异丙酯(化合物28)的合成
按实施例5的步骤，D-亮氨酸异丙酯盐酸酸盐与2.45g L-4-对乙苯磺酰-1,4-噻嗪-3-羧酸反应，得到2.08g无色油状物。
1H-NMR(400M Hz，CDCl3)δ:7.7681-7.7474(d,2H),7.3793-7.3589 (m,2H),6.7543-6.7326(d,1H),5.0288-4.9980(m,2H),4.7738(m,1H),4.6267-4.6042(m,1H),4.2673-4.2301(m,1H),3.5295-3.5176(m,1H),3.1029(m,1H),2.7532-2.7023(m,2H),2.5487-2.5144(m,2H),2.2188-2.1888(m,1H),1.5826-1.4237(m,1H),1.4047-1.3605(m,1H),1.2821-1.2246(m,8H),0.9178-0.9024(m,6H).MS(FAB)m/z:470.4.
实施例29 化合物神经营养活性评价
本发明化合物的神经营养活性可在多体外生物模型上体现,如鸡胚背根神经节体外无血清培养模型。
实验方法：取孵育8d的鸡胚,无菌环境中,在解剖镜下暴露其脊柱及两侧神经节。用尖镊逐个摘取背根神经节,接种于铺有鼠尾胶原的培养瓶中,每瓶接种5-6个,每剂量2瓶。置于37℃,5％CO2培养箱内贴壁培养1h后,加入含神经生长因子(NGF)(0.15ng/mL)的无血清培养基DMEM及本发明化合物。对照组只加培养基和相同剂量的NGF。培养箱中培养48h后,倒置相差显微镜下观察背根神经节周围突起生长情况,依突起的长短及疏密打分。
评价标准：0:不长突起；1:长稀少突起；2:突起较长或较密；3:突起长且密。
表1所示为各化合物在不同剂量下促鸡胚背根神经节突起生长的分值情况，该分值为5个神经节的平均分值。
表1 本发明化合物促鸡胚背根活性评价结果
Figure PCTCN2016087433-appb-000007
Figure PCTCN2016087433-appb-000008
Figure PCTCN2016087433-appb-000009
从上述结果可以看出，本发明化合物的神经营养活性均优于化合物5，并且优于化合物6或与化合物6的活性相当，例如：在1pM和100pM的剂量下，化合物20的神经营养活性与化合物6相比，分别提高了25％和30％。
从化合物结构上看，R1对化合物的神经营养活性的影响显著。例如，化合物6和化合物28的R2和R3分别相同，化合物28的R1为乙基，化合物6的R1为甲基。在1pM和100pM的剂量下，化合物28的神经营养活性比化合物6的神经营养活性分别提高了19％和16％。由此可以看出，随着R1碳原子数的增加，噻嗪酰胺衍生物的神经营养活性得到提高。
另一方面，R2对化合物的神经营养活性也有显著影响。例如，化合物24、25、26与化合物6的R1和R3分别相同，化合物24的R2为苯甲基，化合物25和26的R2为苯乙基，化合物6的R2为异丁基。在1pM和100pM的剂量下，化合物24、25、26与化合物6相比，神经营养活性分别提高了4.8-12.5％和5.1-9.8％。这表明，随着R2的体积和/或疏水性的增加，噻嗪酰胺衍生物的神经营养活性也随之增加
实施例30 化合物对脑卒中的体内药效学评价
1.实验方案
本实施例以昆明种小鼠为实验对象，采用灌胃(i.g.)给药方式，应用小鼠双侧颈总动脉结扎合并低血压(bilateral carotid artery occlusion with low blood pressure,BCAO-LBP)模型，通过测定小鼠神经功能学评分及脑内丙二醛(MDA)含量，考察化合物预防给药对小鼠不完全性全脑缺血的保护作用。
2.实验方法
2.1药物配制
2.1.1 0.7％羧甲基纤维素钠(CMC-Na)溶液的配制：临用前一天称取0.7g CMC-Na干粉，加入到100ml蒸馏水中，边适度加热边搅拌，待CMC-Na全部溶解后，放置过夜，使其充分混匀，密封装。
2.1.2灌胃给药途径药物的配制：化合物用0.7％CMC-Na溶液配制成1.5mg/ml溶液。
2.2分组与给药
取已适应实验室环境一周的小鼠28只，按体重均衡分组，分别灌胃给予0.7％CMC-Na或各化合物，1次/d，连续3d。具体组别如下：
假手术组：4只，灌胃给予0.7％CMC-Na溶液；
脑缺血模型组：12只，灌胃给予0.7％CMC-Na溶液；
给药组：12只，分别按0.2ml/10g剂量灌胃给药，则各化合物的剂量为30mg/kg。
2.3小鼠不完全性全脑缺血及大脑MDA含量的测定
2.3.1小鼠双侧颈总动脉结扎：末次给药1h后，将小鼠眼眶放血降压(约为小鼠总血量的30％)后，然后将其仰背位固定于手术板上，颈部正中开口，钝性剥离颈总动脉，每侧备线2根，分别结扎，当第三根线结扎完时开始计时，然后在两根线中间将颈总动脉剪断，缝合切口，假手术组只剥离颈总动脉不结扎。手术结束后迅速松开小鼠，观察并记录6h内小鼠的行为状态(盲法按下表打分)和死亡时间，小鼠死亡后迅速取脑，去除小脑，用硫代巴比妥酸法(TBA)法测其大脑全脑的MDA含量，6h还没死亡的小鼠处死取脑。
2.3.2神经功能评分：评分标准见表2
表2 神经行为评价表
Figure PCTCN2016087433-appb-000010
2.3.3小鼠脑MDA含量测定：
取小鼠大脑，称重，用N.S制成15％脑匀浆，取1.2ml于37℃水浴1h(每10min震荡一次)后取出，加20％三氯乙酸0.6ml，混匀，放置10min，2000rpm离心10min，取上清液1.2ml，加0.67％TBA0.6ml，沸水浴10min，取出冷却，测量532nm波长处的OD值。
3.统计分析
实验数据以
Figure PCTCN2016087433-appb-000011
表示，应用SPSS13.0统计学软件，通过单因素方差分析Homogeneity of variance test判断方差是否齐性，方差齐性采 用LSD检验，方差非齐性采用Dunnett’s T3检验，比较各组间显著性差异，P<0.05有统计学意义。结果如表3所示。
表3 化合物在BCAO-LBP小鼠上MDA含量及神经行为得分评价结果
Figure PCTCN2016087433-appb-000012
Figure PCTCN2016087433-appb-000013
*p<0.05，与假手术组相比,**p<0.01，与假手术组相比；#p<0.05，与脑缺血模型组相比,##p<0.01与脑缺血模型组相比,###p<0.001与脑缺血模型组相比
上述结果表明：本发明的化合物对小鼠不完全性全脑缺血的保护作用优于化合物5和/或化合物6。其中，化合物8、15、23、28组的小鼠神经缺陷分值比化合物6组分别降低了约15％、8％、13％、10％；化合物9、13、18、22组的小鼠神经缺陷分值比化合物5组分别降低了约35％、32％、27％、15％。因此，与现有化合物相比，本发明的化合物对小鼠脑卒中的体内药效有了明显提高。
通过分析化合物的结构可以发现，R1和/或R2的改变会对化合物的上述药效产生影响。分别对比化合物28和化合物6，以及化合物23和化合物6，可以发现：R1碳原子数的增加，或R2的体积和/或疏水性的增加，对提高脑卒中的体内药效是有利的。
实施例31 化合物血脑屏障通过评价
1.实验方案
MDCK-MDR1细胞是在MDCK(犬肾上皮细胞)中转染了MDR1基因后，高表达P-gp转运体的单层细胞，由于其单层细胞的致密性以及高表达药物外排蛋白，因此与血脑屏障(BBB)结构有相似性，目前可用作评价BBB通透性的模型之一。本发明应用MDCK-MDR1细胞研究本发明化合物的透膜性，初步评价其透BBB的能力。
2.实验方法
2.1溶液配制
培养液配制：Dulbecco's modified eagle medium(DMEM)用时加入10％胎牛血清(FBS)，1％谷氨酰胺，100U·mL-1青霉素和链霉素双抗液，1％非必需氨基酸，遗传霉素(G418)1.2mg·L-1。
消化液配制：称取胰蛋白酶1g，乙二胺四乙酸(EDTA)80mg，加400mL磷酸盐缓冲液(PBS)，0.22μm滤膜过滤除菌，-20℃冻存备用。
谷氨酰氨储备液配制：谷氨酰氨2.92g，加100mL PBS，0.22μm滤膜过滤除菌，1mL分装，-20℃冻存备用。
青链霉素储备液的配制：青霉素80万U，加入20mL生理盐水，链霉素100万U，加入25mL生理盐水。将两者1：1混匀，0.22μm过滤除菌，1mL分装，-20℃冻存备用。
Hank’s平衡盐溶液(HBSS)配制：NaCl 8.0g，KCl 0.4g，Na2HPO4·H2O 0.0475g，KH2PO4 0.06g，四羟乙基哌嗪乙磺酸(HEPES)6g，加入超纯水中使其溶解，调pH值至7.2－7.4，加水至1L，0.22μm滤膜过滤除菌，-20℃保存备用。
2.2细胞培养
取冻存的MDCK-MDR1细胞，于37℃水浴中快速解冻。复苏后的细胞加入含10％FBS的DMEM培养基中，在37℃，5％CO2，相对湿度90％的培养箱中培养，隔天更换培养基。生长1－2天细胞融合后，用0.25％胰蛋白酶-EDTA(0.2％)混合消化液，于37℃条件下消化，按一定比例传代培养，实验用的细胞代数为40－60代。
细胞达到80％融合，消化后用完全培养基将细胞悬浮，按1×106个·mL-1接种到Millicell板上。以后每2天换培养液1次，1周后每1天换液。培育5天，电阻值达到坪台(＞200Ω·cm2)，即可以用于转运实验。
2.3MDCK-MDR1单层细胞的质控：
2.3.1跨膜上皮细胞电阻(TEER)的测量
先将电极浸入DMEM培养液中平衡24h，取出并浸入70％酒精中消毒15min后，室温放置并使电极自然干燥，再放入无菌的DMEM培养液中平衡15min。实验时将电极两端依次插入24孔Millicell培养板各孔的上下池中检测电阻值，每孔在任意点测三次，记录电阻值，同时测定空白孔的电阻值，根据以下公式计算跨膜电阻值(TEER)。
TEER＝(Rt-R0)×S
其中，Rt为实测电阻值；R0为空白孔电阻值；S为有效膜面积。
2.3.2阳性化合物质控：
以罗丹明123(Rho-123)作为阳性质控化合物，将该化合物用HBSS稀释到5μmol·L-1，实验前先吸弃各孔中的培养基，用37℃的HBSS洗涤两次，然后在37℃培养箱孵育，于上池加入Rho-123，下池中加入HBSS，在恒温摇床中孵育，各时间点(0min，30min，90min,120min)收集下池的溶液，-20℃储存备测。用荧光分光光度计检测下池中Rho-123透过的量。其中发射波长设为430nm，激发波长设为530nm。本实验中Rho-123的Papp值与文献报道相符。
2.4药物转运实验
试验前以37℃HBSS浸泡接种有细胞的Millicell合适时间，轻微 冲洗Millicell，除去细胞表面的附着物。
腔面到基底面的通透性：在顶侧(AP)加入含药的HBSS 0.35mL，底侧(BL)加入空白HBSS 1.2mL。置37℃，以50r·min-1振摇，并分别于0、30、90、120min于下层采样50μL，并补充同体积空白HBSS。每个浓度重复3个孔，取出的样品精密加入内标溶液50μL，乙酸乙酯350μL，震荡混匀，离心12000rmp，5min。取上清300μL，挥干，用50μL乙腈复溶，取10μL溶液进样测定。
基底面到腔面的通透性：将药物加入底侧(BL)，顶侧(AP)加入空白的HBSS，以下步骤同腔面到基底面的通透性试验操作。
药物的表观通透系数(Papp)的大小反映了药物透过单层细胞的能力以及药物吸收的速度、程度。它可由下式计算：
Figure PCTCN2016087433-appb-000014
其中，Q为药物在t时间段内透过的量，A为细胞表面积，在本模型中即为支持膜的面积(0.6cm2)，C0为初始浓度。Papp的单位用厘米/秒(cm·s-1)表示。
2.5样品检测
应用LC/MS进行检测，每个样品浓度应用其标准曲线(50nM-10000nM)进行定量。
3.实验结果
各化合物的表观通透系数测量结果见表4。
表4 化合物的表观通透系数
Figure PCTCN2016087433-appb-000015
Figure PCTCN2016087433-appb-000016
从表4可以看出，本发明化合物的血脑屏障通过能力均优于化合物5，并优于化合物6或与化合物6相近。其中，化合物7、23、28的Papp值与化合物6相比，提高了7％以上。结果表明，本发明化合物具有优良的血脑屏障通过能力。
尽管本发明的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公开的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (13)

  1. 如通式(I)所示的化合物、其药物上可接受的盐或其溶剂化物，
    Figure PCTCN2016087433-appb-100001
    其中，R1选自C1-4烷基；
    R2、R3分别独立地选自C1-4烷基，任选地，所述C1-4烷基被苯基取代；
    任选地，所述苯基被选自C1-4烷基、C1-4烷氧基、羟基、氨基和羧基的取代基取代；
    优选地，R2为R构型；
    优选地，R2为S构型。
  2. 权利要求1的化合物、其药物上可接受的盐或其溶剂化物，
    其中，R1选自C2-3烷基，例如乙基；
    优选地，R2、R3分别独立地选自C1-4烷基；
    优选地，R2选自C3-4烷基，例如异丁基；
    优选地，R3选自C3-4烷基，例如异丙基。
  3. 权利要求1的化合物、其药物上可接受的盐或其溶剂化物，
    其中，R2选自C1-4烷基(例如C1-2烷基)，并且所述C1-4烷基(例如C1-2烷基)被苯基取代，任选地，所述苯基被选自C1-4烷基、C1-4烷氧基、羟基、氨基和羧基的取代基取代；
    优选地，R2为苯甲基或苯乙基；
    优选地，R1为甲基；
    优选地，R3为甲基、乙基、异丙基、叔丁基或苯甲基；
    优选地，R3为甲基、乙基、异丙基或叔丁基。
  4. 权利要求3的化合物，其中，R1为甲基；
    R2为苯甲基或苯乙基；
    R3为乙基、异丙基或叔丁基。
  5. 权利要求1的化合物、其药物上可接受的盐或其溶剂化物，
    其中，R1为甲基；
    R2选自C2-4烷基(例如C3-4烷基)；
    优选地，R2为异丙基或仲丁基；
    优选地，R3为甲基、乙基、叔丁基或苯甲基；
    优选地，R3为甲基、乙基或叔丁基。
  6. 权利要求5的化合物，
    其中，R1为甲基；
    R2为异丙基或仲丁基；
    R3为甲基、乙基或叔丁基。
  7. 权利要求1-6任一项的化合物、其药物上可接受的盐或其溶剂化物，所述化合物选自：
    Figure PCTCN2016087433-appb-100002
    Figure PCTCN2016087433-appb-100003
  8. 权利要求1-7任一项的化合物，其中，R2为R构型。
  9. 权利要求1-7任一项的化合物，其中，R2为S构型。
  10. 一种药物组合物，其含有权利要求1-9任一项所述的化合物、其药物上可接受的盐或其溶剂化物；
    优选地，所述药物组合物还含有一种或多种药学上可接受的载体和/或赋形剂。
  11. 权利要求1-9任一项所述的化合物、其药物上可接受的盐或其溶剂化物用于制备药物的用途，所述药物用于预防和/或治疗受试者的神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变；
    优选地，所述神经退行性疾病选自阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化；
    优选地，所述物理损伤选自热损伤、冷损伤、机械损伤和电损伤；
    优选地，所述相关疾病选自获得性免疫缺陷、糖尿病和中风；
    优选地，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
  12. 一种预防和/或治疗受试者的神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的权利要求1-9任一项所述的化合物、其药物上可接受的盐或其溶剂化物，或权利要求10的药物组合物；
    优选地，所述神经退行性疾病选自阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化；
    优选地，所述物理损伤选自热损伤、冷损伤、机械损伤和电损伤；
    优选地，所述相关疾病选自获得性免疫缺陷、糖尿病和中风；
    优选地，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
  13. 权利要求1-9任一项所述的化合物、其药物上可接受的盐或其溶剂化物，其用于预防和/或治疗受试者的神经退行性疾病、物理损伤引起的神经病变或由相关疾病引起的神经病变；
    优选地，所述神经退行性疾病选自阿尔兹海默病、帕金森氏症、亨廷顿氏病、肌萎缩性侧索硬化和脑脊髓多发性硬化；
    优选地，所述物理损伤选自热损伤、冷损伤、机械损伤和电损伤；
    优选地，所述相关疾病选自获得性免疫缺陷、糖尿病和中风；
    优选地，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
PCT/CN2016/087433 2015-06-30 2016-06-28 噻嗪酰胺衍生物及其用途 WO2017000869A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2017567680A JP6849615B2 (ja) 2015-06-30 2016-06-28 チアジドアミド誘導体とその利用
EP16817233.6A EP3327010B1 (en) 2015-06-30 2016-06-28 Thiazideamide derivative and use thereof
US15/739,872 US10335417B2 (en) 2015-06-30 2016-06-28 Thiazideamide derivative and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510373078.2A CN106316982B (zh) 2015-06-30 2015-06-30 噻嗪酰胺衍生物及其用途
CN201510373078.2 2015-06-30

Publications (1)

Publication Number Publication Date
WO2017000869A1 true WO2017000869A1 (zh) 2017-01-05

Family

ID=57607779

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/087433 WO2017000869A1 (zh) 2015-06-30 2016-06-28 噻嗪酰胺衍生物及其用途

Country Status (5)

Country Link
US (1) US10335417B2 (zh)
EP (1) EP3327010B1 (zh)
JP (1) JP6849615B2 (zh)
CN (1) CN106316982B (zh)
WO (1) WO2017000869A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023178378A1 (en) * 2022-03-21 2023-09-28 DMTC Limited Mip inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1422852A (zh) * 2001-12-06 2003-06-11 中国人民解放军军事医学科学院毒物药物研究所 取代六元氮杂环类化合物及其作为神经调节剂的用途
WO2014029102A1 (zh) * 2012-08-24 2014-02-27 中国人民解放军军事医学科学院毒物药物研究所 噻嗪酰胺衍生物及其药物组合物和用途

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6291453B1 (en) 1997-07-31 2001-09-18 Athena Neurosciences, Inc. 4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6939855B2 (en) * 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
CN1942161B (zh) * 2003-01-24 2012-05-30 伊兰药品公司 通过施用髓鞘再生药物用于脱髓鞘疾病和麻痹的组合物和治疗
EP3527228A1 (en) * 2003-01-24 2019-08-21 Biogen MA Inc. Composition for a treatment of demyelinating diseases and paralysis by administration of remyelinating agents
CN1683340A (zh) * 2004-04-13 2005-10-19 中国人民解放军军事医学科学院毒物药物研究所 2－氮－双环[2.2.1]庚－5－烯－3－羧酸衍生物及其用于制备神经调节剂的用途
CN102675244B (zh) * 2011-03-16 2016-03-30 中国人民解放军军事医学科学院毒物药物研究所 噻嗪酰胺衍生物及其在制备神经退行性疾病防治药物的用途
US9359312B2 (en) 2011-12-23 2016-06-07 Basf Se Process for manufacturing benzoxazinones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1422852A (zh) * 2001-12-06 2003-06-11 中国人民解放军军事医学科学院毒物药物研究所 取代六元氮杂环类化合物及其作为神经调节剂的用途
WO2014029102A1 (zh) * 2012-08-24 2014-02-27 中国人民解放军军事医学科学院毒物药物研究所 噻嗪酰胺衍生物及其药物组合物和用途

Also Published As

Publication number Publication date
US10335417B2 (en) 2019-07-02
US20180185376A1 (en) 2018-07-05
CN106316982B (zh) 2020-08-14
EP3327010B1 (en) 2019-12-25
JP6849615B2 (ja) 2021-03-24
JP2018524340A (ja) 2018-08-30
EP3327010A4 (en) 2019-01-09
CN106316982A (zh) 2017-01-11
EP3327010A1 (en) 2018-05-30

Similar Documents

Publication Publication Date Title
US10351514B2 (en) Benzimidazole inhibitors of the sodium channel
JP6775560B2 (ja) Ｊａｋ阻害剤としてのビピラゾール誘導体
CN103415521B (zh) 用作β分泌酶（BACE）抑制剂的3,4-二氢-吡咯并[1,2-a]吡嗪-1-基胺衍生物
CA3041811A1 (en) Compounds, compositions, and methods for modulating cftr
RU2382029C2 (ru) Новые производные циклогексана
KR20080089494A (ko) 화합물
EA032526B1 (ru) Применение ингибитора кинуренин-3-монооксигеназы для лечения заболеваний и состояний, опосредованных активностью кинуренин-3-монооксигеназы
JP2017538676A (ja) ミトコンドリア透過性遷移孔（ｍｔＰＴＰ）の小分子阻害剤
CN117050013A (zh) 6-氨基异喹啉的单(酸)盐及其用途
JP2022530967A (ja) 多形化合物およびその使用
KR20210102887A (ko) 말초 세로토닌과 관련된 질병 또는 장애를 치료하기 위한 트립토판 하이드록실라제 1 (tph1)의 결정질 스피로사이클릭 화합물 억제제
US20230303497A1 (en) Benzylamine or benzyl alcohol derivative and uses thereof
JP2015522531A (ja) 神経筋疾患及び神経変性疾患の治療のための組成物及び方法
CN105705484B (zh) 作为甲酰肽受体调节剂的苯基氨基甲酸酯衍生物
EP2403839A2 (en) Neurotrophin mimetics and uses thereof
KR101055236B1 (ko) 알파-케토아미드 유도체, 및 이의 제조 방법 및 용도
WO2017000869A1 (zh) 噻嗪酰胺衍生物及其用途
WO2017190708A1 (zh) 吡唑‐三嗪类衍生物、其制备方法、药物组合物和用途
TW201922690A (zh) 環－amp反應元素結合蛋白的抑制劑
WO2018068357A1 (zh) 一类新型sirt2蛋白抑制剂及其在制药中的用途
TW201811769A (zh) 哌嗪（ｐｉｐｅｒａｚｉｎｅ）衍生物
JP2003503476A (ja) 環化アミド誘導体
JP6078153B2 (ja) チアンジンアミド誘導体、並びにその医薬組成物及び使用
WO2023077977A1 (zh) 秋水仙碱衍生物的制备方法及其用途
WO2017076358A1 (zh) 咪唑基联苯基化合物盐的新晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16817233

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017567680

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE